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HYBRID IMAGING IN CONVENTIONAL NUCLEAR

A TECHNOLOGIST’S GUIDE

Produced with the kind support of Table of contents

Foreword 4 Andrea Santos

Introduction 6 Marius Mada, MarieClaire Attard and Agata Pietrzak

Chapter 1 Physics and reconstruction methods for SPECT/CT 9 Anne Larsson Strömvall

Chapter 2 QC of Hybrid Systems 31 Sebastijan Rep

Chapter 3 Quantitative SPECT 45 John Dickson

Chapter 4 Bone 65 Vladimir Vukomanovic, Vesna Ignjatovic, Milos Stevic, Nenad Mijatovic and Marija Z. Jeremic

Chapter 5 Lung Imaging 81 Bozena Birkenfeld, Jacek Iwanowski and Monika Gawron

Chapter 6 Clinical use of SPECT/CT: imaging of neuroendocrine tumours and sentinel node imaging 95 Luka Lezaic

Chapter 7 Myocardial Perfusion Imaging 105 MarieClaire Attard and Hein Verberne

Chapter 8 Accomplishing Good Diagnostic Examinations 117 from the Paediatric Population Pietro Zucchetta

Chapter 9 / Studies 129 Andor W. J. M. Glaudemans

Chapter 10 Parathyroid and Imaging 143 Martin Gotthardt

Chapter 11 The Contribution of Hybrid Imaging to therapy 163 Jan Taprogge, Paul Gape, Carla Abreu and Glenn Flux

EANM TECHNOLOGIST’S GUIDE 3 HYBRID IMAGING IN CONVENTIONAL FOREWORD FOREWORD

Foreword Since the introduction of hybrid imaging, nuclear medicine has experienced a great development within its practices and conventional nuclear medicine has benefited greatly from the application of hybrid imaging.

The definition of hybrid being the that bridge the gap between all the of molecular therapy and outline hybrid support. Last but not least, I thank the product of combining two or more background science and engineering imaging’s contribution to this field. EANM Board and Executive Office for their different things, it is evident that the and the patient. These professionals are It is with immense gratitude that I tireless efforts which have made this series purpose of any such combination is to equipped with the skills necessary to highlight the great contribution made of publications possible. extract the best qualities from them both use the imaging technology, for which by all the authors who gave their Hybrid Imaging in Conventional Nuclear and minimise their respective limitations. they require a combination of theoretical knowledge to this project. Here, special Medicine was only possible thanks to the It is thus vitally important that both and practical competencies. With this in acknowledgment is due to the Physics, contribution of everyone mentioned technologies are profoundly understood, mind, this book starts by outlining the Paediatric and Cardiovascular Committees before. Thank you all very much! not only in their individual characteristics basic concepts of physics, reconstruction of the EANM, who have supported us but also in their combined use. The de- methods and quality control procedures throughout as well as furnishing their own sired synergies can only be realised if the that allow image formation. This is followed contribution. Andrea Santos hybrid application makes optimum use of by a discussion of clinical applications A special word of appreciation goes Chair, EANM Technologist Committee the respective technologies. of hybrid conventional imaging, with a to the EANM-TC editorial group, who Nuclear medicine technologists interact practical focus to facilitate implementation have dedicated their time to putting this directly with the patient in the imaging and develop good practice. The later publication together, and also to Angela context, and are thus the professionals chapters of the book address the topic Parker, for her editing, reviewing and

4 EANM TECHNOLOGIST’S GUIDE EANM TECHNOLOGIST’S GUIDE 5 HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE INTRODUCTION INTRODUCTION

Introduction After nearly two decades since its first edition, the Technologist’s Guide is an established tradition and a valuable product of the nuclear medicine technologists’ community. We are all facing unprecedented challenges, both in our profession and in our homes. Seeing this Guide published in these circumstances is a tribute to our great colleagues, friends and our sponsor, who have dedicated time and other resources to ensure the tradition is kept alive.

Every year the Tech Guide, as we all know The Tech Guide is a partnership between the contribution of hybrid imaging to for all your passion and dedication to it, aims to bring together experts from the EANM committees, between physicians, . patient care. We wanted to showcase field and present concise opinion and scientists and technologists, and this As ever, the Tech Guide has a practical the impact of our profession within the guidance on a specific topic to support year’s edition is no different. We partnered content, with a focus on hands-on advice nuclear medicine community, as well as the workforce of technologists working with the Physics Committee to cover the for technologists, showing the artefacts the high standard of quality delivered by in nuclear medicine. This year the topic is technical aspects of the imaging modality, and pitfalls when imaging and the role technologists across Europe. hybrid imaging in conventional nuclear as well as with the Paediatric Committee for of the technologist in achieving high We trust that you will find the Tech medicine. When choosing the theme their chapter. We wanted to acknowledge standards of quality. The Technologists’ Guide enjoyable reading, and would like to for the Tech Guide, the Technologists’ the achievements of fellow technologists Committee also plays an important role in thank you all for taking part in the success Committee had in mind the impact of non- like Dr Sebastijan Rep, who is not only an defining our communication strategy with of this project. PET hybrid imaging on nuclear medicine ambassador for the technologist’s role in patients in nuclear medicine, and we have practice. Moreover, SPECT-CT and the Tech quality assurance and quality control, but tried to include this new topic in this year’s Guide are of similar age, so we wanted to also a new PhD graduate. Other chapters Tech Guide. focus on collating conventional hybrid were co-authored by technologists and For us in the editorial team, publishing Marius Mada, MarieClaire Attard imaging practice in one concise and up- physicians or scientists, such as those this Guide is a way of saying thank you and Agata Pietrzak to-date guidance document. on myocardial perfusion imaging and to the nuclear medicine community Editorial team

6 EANM TECHNOLOGIST’S GUIDE EANM TECHNOLOGIST’S GUIDE 7 HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE PHYSICS AND RECONSTRUCTION METHODS FOR SPECT/CT by Anne Larsson Strömvall1 CHAPTER 1 CHAPTER 1 PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION INTRODUCTION and relatively slow CT provided 10 mm CT positions, for example with the detectors slices. Although somewhat rough, SPECT/ 180 degrees (H-mode, see Fig. 1) or 90 In scintigraphy, the distribution of an administered gamma - CT image fusion then became an option degrees (L-mode) apart. The detectors can emitting in vivo is visualised using external for routine clinical work, as well as CT-based usually also be flipped to point outwards detectors. The technique is sensitive and can image very small amounts attenuation correction. The Hawkeye was from the gantry, or can be arranged side of the injected radiopharmaceutical in the order of nanograms. Two- later upgraded to a 4-slice system with 5.0 by side if needed. It is possible to select dimensional images can be acquired using a stationary detector, while mm slices, which improved image quality whether both detectors or only one three-dimensional images can be acquired using single-photon emission and reduced CT acquisition time by a should be used in the imaging protocol. computed (SPECT). The phrase “single photon” indicates factor of 2. Nowadays there are several For a high image resolution, it is important that in SPECT, single emitted from the are traced manufacturers providing fully diagnostic that the detectors are positioned as close to their origin, in contrast to emission tomography (PET), where integrated CTs that can help to improve to the patient as possible. Their position two simultaneous annihilation photons are detected by rings of detectors nuclear medicine diagnostics and therapy. can be automatically adjusted using body in a coincidence circuit. In most cases SPECT images are used for visual For more information on the historical contour detectors mounted on the side of interpretation, but quantitative analyses are becoming increasingly development of SPECT and SPECT/CT, a the detectors. popular. well-written review on the subject (1) can The patient table can be adjusted in be recommended. height for loading and unloading the The SPECT/CT gantry consists of a CT patient, and to centre the patient in the SPECT is mostly used for diagnostic with a half-life of 6 h and a relatively pure bore and typically two scanner. Lasers can be used to help centre purposes but can also be used for gamma photon emission of 140 keV. The heads which are mounted on the front the patient correctly. Special solutions with planning and monitoring of radionuclide most common radionuclide for therapy side. An example can be seen in Fig. 1. cantilevered tables have been developed therapies. Radionuclides used for is [131I] for treatment of thyroid diseases, for a precise SPECT/CT registration in the diagnostics are primarily chosen to with a half-life of 8 days and mostly beta axial direction, since the two examinations have characteristics for high-quality emission. Emitted gamma are performed sequentially with different imaging and low radiation dose to the photons of relatively high energy, 364 keV, table positions. The table is usually patient, including a relatively short half- can however be used for imaging. equipped with a low-attenuation top of life. Therapy radionuclides, on the other Hybrid imaging has revolutionised fibre, with an imaging range in hand, should provide the target nuclear medicine with the addition of the order of 200 cm to be used for SPECT or tumours with a high dose, enough to the structural component from X-ray and whole-body imaging. A soft mattress treat the disease, and emit most energy in computer tomography (CT) to SPECT/CT and straps are used for patient comfort the form of alpha or beta particles. Image and PET/CT, or magnetic resonance (MR) and to prevent movements during the quality is a secondary objective, but SPECT imaging to PET/MR. The first commercial examination. The maximum permissible will of course benefit from at least some integrated SPECT/CT systems became Figure 1: Example of SPECT/CT gantry and table patient weight varies between scanners, fraction of gamma photons that can available in the late 1990s, with the release and needs to be borne in mind when be used for imaging. The most popular of the Hawkeye (GE Healthcare, WI, USA). The position of the detectors can be examining the heaviest patients. radionuclide used for diagnostics is [99mTc], In the beginning, this low-dose, low-cost, adjusted to a certain number of fixed

10 EANM TECHNOLOGIST’S GUIDE EANM TECHNOLOGIST’S GUIDE 11 HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE CHAPTER 1 CHAPTER 1

THE SCINTILLATION CAMERA PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION depend on the resolution/sensitivity of a series of lead cones with a small hole rear side of the crystal is optically coupled The traditional detector used for SPECT and the photon energy range for which at the apex, facing the imaged object. With to a light guide made of glass, which imaging is known as a scintillation camera the collimator is optimised. Collimators these pinholes, the size of the image will directs the light onto an array of closely or a gamma camera. It was developed in are crucial for identifying the point of depend on the distance from the object packed photomultiplier tubes (PM tubes). the late 1950s by Hal Anger (2) and has emission. To illustrate this, an image of to the pinhole, which is not the case for The PM tubes are relatively large, a few been a standard imaging device in nuclear a point source acquired both with and parallel-hole collimators. The multiple- centimetres wide, and there can be 50–70 medicine for a long time. The major without the collimator on can be seen in pinhole collimator is convenient when of them in a detector head of conventional components of the scintillation camera Fig. 3. the imaged objects are small, for example size. The PM tubes first convert the light today are in many cases similar to when it small animals or small organs like the heart photons into and then massively was invented, but its performance has of or the thyroid, since these objects can be amplify their number. This results in course improved over the years, especially magnified to produce a higher resolution. measurable electrical pulses from those through the introduction of digital There are also other types of collimators, for PM tubes that are hit by the light photons. electronics and multiple head systems. A example fan-beam, cone-beam and slant- The pulses are then processed to give schematic diagram of the intersection of a hole collimators. For more information the information on the location of the gamma scintillation camera detector can be seen collimator review by Van Audenhaege et photon interaction in X and Y direction in Fig. 2. al. (3) is recommended. and the energy deposited in the crystal. Figure 3: Left-hand side: point source image The detector material in the scintillation Due to non-linearities, correction tables with collimator. Right-hand side: point source camera is typically a sodium-iodide (NaI) are used to improve the accuracy of both image without collimator. crystal doped with a small amount of position and energy, and a uniformity thallium (Tl), which is needed in order for matrix is used to correct for irregularities High-resolution collimators have the crystal to generate scintillation light. in detector response. The interactions in thinner holes compared to general- It is coated with a thin protective layer the crystal that are to contribute to the Figure 2: The scintillation camera purpose or high-sensitivity collimators, on the front and edges to protect from image are sorted out by logical processes, and the reduced acceptance angle outside light and moisture. A scintillation comparing the measured energy with the The collimator, which can be of different leads to a smaller number of detected camera for diagnostic purposes usually energy window settings. types, is closest to the patient and sets the photons per unit of time and activity, i.e. has a crystal thickness of about 1 cm (3/8 acceptance angle for detection of the lower sensitivity. Collimators optimised inches), whereas a scintillation camera emitted gamma photons. The parallel- for higher energies, known as medium- used mainly for radionuclides emitting hole collimator is the most common energy or high-energy collimators, higher energies may need a thicker crystal, THE CZT CAMERA type and consists of a lead plate with have thicker septa to prevent septal for example 1.6 cm (5/8 inches) or even up The NaI scintillation crystal is a sensitive closely packed parallel holes, usually of penetration, which otherwise leads to to 2.5 cm (1 inch) in order to capture the detector material with many advantages hexagonal form like a honeycomb. The reduced contrast and star patterns around majority of the photons. When a gamma which has been in use for several decades. lead “walls” between the holes are called hotspots in the image. photon interacts in the crystal, light Recently, however, CZT-based gamma septa. The hole diameter, hole length Another relatively common collimator is photons are created, and their number is cameras have become increasingly (collimator thickness) and septal thickness the multiple-pinhole collimator. It consists proportional to the energy deposited. The popular. CZT was first introduced in pre-

12 EANM TECHNOLOGIST’S GUIDE EANM TECHNOLOGIST’S GUIDE 13 HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE CHAPTER 1 CHAPTER 1 PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION clinical and cardiac cameras but can now a few centimetres wide, it is easier to keV respectively) the peaks will be easier in a circular orbit, while the patient table also be found in some multi-purpose get a tight orbit around the patient’s to separate with a CZT system than with a moves through the gantry. The detectors SPECT/CT systems. Examples are the head. The removal of the PM tubes is conventional one. on the opposite side of the tube measure General Electric NM/CT 870 CZT, which is also advantageous for dedicated cardiac In contrast to NaI-based cameras, CZT the X-ray photons that are not attenuated a dual-headed camera relatively similar to cameras, which incorporate several cameras can be manufactured as pixelated in the patient. Collimators are used to a conventional system, and the Spectrum detectors pointing at the heart from systems, meaning that the detector limit the X-ray field to the detectors, Dynamics Medical Veriton SPECT/CT, different directions, allowing stationary surface is composed of a high number of defining the slice thickness. Bowtie filters which has a very special innovative design SPECT acquisition. This design would be small detectors. Each detector is mapped are needed to shape the X-ray beam by giving 360-degree coverage. very difficult to achieve if bulky PM tubes to a corresponding pixel in the image. This removing more of the low-energy photons CZT is short for Cd, Zn and Te, that is, an had to be connected to the detectors. has been reported to be advantageous in from the peripheral parts of the field, alloy of cadmium, zinc and telluride which Another advantage with semi- terms of resolution and contrast-to-noise, thereby reducing the radiation dose to can serve as a semi-conductor detector. conductor detectors is energy resolution, but it can also have disadvantages. For a the patient. The signals from the detectors When the gamma photon deposits which is a measure of uncertainty of the parallel-hole collimator, the collimator are converted into digital information, its energy in such a material, so-called measured gamma photon energy. In a holes need to be matched exactly to the and the tomographic images can then be -hole pairs are generated. A hole NaI-based system the energy resolution detector locations, and this means less calculated from the measured projections. is the name given to a missing electron, is usually in the order of 9–10% for 140 flexibility when it comes to resolution/ A complete scan can be acquired in a just and the combination serves as a pair of keV (calculated as the full width at half sensitivity considerations. If the system a few seconds. charge carriers. An electrical field over the maximum of the photopeak divided by includes a fixed collimator optimised for CT technology has evolved rapidly detector will pull the electrons towards an the peak energy), but with a CZT camera low-energy imaging, it is also difficult during the last decades, and advanced anode and the holes to a cathode, which it is usually better. Values in the order of to perform imaging with radionuclides multi-slice models have been developed will result in the formation of an electrical 3% have been reported for pre-clinical emitting higher energies such as [111In], in order to improve image quality, reduce pulse. In other words, the gamma photon systems, whereas many clinical systems [177Lu] or [131I]. scanning times, reduce the dose to the energy is directly converted into an seem to be closer to 6% in terms of energy patient, and freeze cardiac and respiratory electrical signal. No PM tubes are therefore resolution. A small percentage value (high motion. Top-of-the-range models are able needed in a CZT gamma camera, which energy resolution) is positive, since it to acquire up to 640 slices per rotation produces more compact camera heads means that a tighter energy window can COMPUTED TOMOGRAPHY (CT) with a rotation time of about 0.3 s. Dual- with less dead space outside the field of be used when collecting the primary CT is a technique which originated in the energy imaging has also been introduced, view (FOV). This is useful for SPECT/ photons. Less scattered photons will be early 1970s, and its developers, Cormack viewing the patient at two different kV CT studies, for example, where a tight registered within the energy window, and Hounsfield, were awarded the Nobel energies simultaneously, which allows orbit around the patient´s head is of which means higher contrast and less Prize in 1979. It is not difficult to imagine better classification of anatomical features great importance for a high geometrical need for scatter correction. The high what the introduction of 3D imaging and reduction of artefacts. However, the resolution. In a conventional SPECT/CT energy resolution is also a key factor in meant for at the time, and the top-of-the-range models are not typically with PM tubes, the rotation radius can some cases of dual- imaging. If explosion in research and development found in SPECT/CT systems, which are be limited by the patient’s shoulders, simultaneous imaging of [99mTc] and [123I] that followed. In CT, a motorised X-ray usually based on conventional 16–64 but if the frame outside the FOV is only is warranted (photon energy: 140 and 159 tube rotates rapidly around the patient slice CT systems. Advanced and expensive

14 EANM TECHNOLOGIST’S GUIDE EANM TECHNOLOGIST’S GUIDE 15 HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE CHAPTER 1 CHAPTER 1 PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION equipment needs a high patient because of the bowtie filters, which filter circular, orbit around the patient, and increase without an increase in resolution. throughput to be economically justifiable, the X-ray photons in proportion to the the number of projections usually varies In SPECT, the most commonly used matrix and for most SPECT/CT systems the CT is attenuation characteristics of the exposed between 60 and 128, equally distributed size is 128x128 pixels for both projections only used for a small fraction of the total region of the patient. The patient’s midline in space. and reconstructed images. If the whole scanning time. needs to be on the centre of the table, Early SPECT systems were based on FOV is used for imaging, i.e. if the zoom The CT scanner measures a number of and the table has to be adjusted so that a single gamma camera head rotating factor is set to 1, this usually means a pixel attenuated profiles around the patient, the centre of mass of the scanned part around the patient, but dual-headed, size in the order of 4–5 mm. In myocardial which can be reconstructed with methods of the patient’s body corresponds to the triple-headed and even four-headed SPECT the matrix size used is typically that are relatively similar to those used in centre point of the FOV. Lasers can aid the systems became available during the 64x64 pixels, and together with a zoom SPECT (to be described later). The images technologist when positioning the patient. 1990s. These systems lead to an n-fold factor of 1.3 this leads to a typical pixel size can have less than 1 mm resolution and are It has been shown that mispositioning of increase in sensitivity, where n is the of 6–7 mm. It should, however, be noted usually reconstructed into 512x512 pixel about 2 cm can result in a dose increase of number of gamma camera detectors, that SPECT resolution can be significantly matrices. The image information, which about 20% and an image noise increase of hence enabling higher image quality. better in systems dedicated to specific is based on attenuation, is recalculated to about 5–6% (5). Today, dual-headed systems are by far the tasks, for example the cardiac cameras a standard scale, Hounsfield numbers (H), most common systems used for clinical on the market. For pre-clinical SPECT the using the following equation: work. resolution can even be at sub-mm level. In SPECT using traditional equipment is these cases, matrices and pixel sizes have SPECT ACQUISITION often relatively slow, with examination to be adjusted to do justice to the higher (1) In SPECT, 2D projections are acquired times in the order of 10–30 min. Some resolution. at different angles around the patient. studies require several sequential SPECT where μ is the attenuation coefficient in A complete acquisition measures scans (FOVs) to cover a larger part of the

the voxel of interest and μw is the average projections over a 360° rotation, but a patient, which can make the examinations attenuation coefficient of for the restricted acquisition of 180° is usually even longer. The time per view will be RECONSTRUCTION OF SPECT X-ray photons (4). Air has a standard used for cardiac imaging or for other 20 s for a 20 min acquisition using a IMAGES H of -1000 and the H of water is 0. The lateralised uptakes. The projections are dual-headed camera measuring 120 In SPECT, the acquired projection images scale continues on the positive side for used for reconstruction of a 3D image projections. The time required for analysis measured at different angles around the tissues with higher attenuation, and bone volume, which ideally should correspond of the CT must also be added to the total patient are used to calculate the 3D activity can have H-values of 1000 or more. The to the activity distribution in the patient. time in the camera. distribution within the patient. On clinical acquired tomographic images build up a A continuous acquisition of data is Resolution in clinical SPECT is relatively work stations both analytical and iterative three-dimensional image volume that can possible but requires complicated data poor, and for traditional equipment it can methods are implemented, the iterative be sliced in any direction. management, and in most cases a “step be in the order of 8 –15 mm FWHM (full methods being the most commonly used For CT acquisition it is important that and shoot” technique is used instead, with width at half maximum), mostly limited by nowadays. In future, however, it is likely the patient is centred correctly in the no data collected during the detector the collimator. Using large image matrices that reconstructions will increasingly rely scanner, to ensure optimal image quality movements. The projection images are with small pixels is therefore usually on methods based on artificial intelligence and radiation dose to the patient. This is acquired in an elliptical, or sometimes counterproductive, since image noise will (AI).

16 EANM TECHNOLOGIST’S GUIDE EANM TECHNOLOGIST’S GUIDE 17 HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE CHAPTER 1 CHAPTER 1 PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION The classical analytical method of The probability matrix is very large, and is whole amount of acquired images when resolution and septal penetration can be image reconstruction is the filtered back- not usually stored in computer memory calculating a new update, and it has been incorporated into the reconstruction, i.e. projection (FBP) technique (6, 7), which but calculated on the fly during the proven to be stable. The MLEM method is, included in the probability matrix. This is based on the inverse of a transform reconstruction. The iterations start with an however, relatively slow and is seldom used implies that these effects are indirectly that was developed as early as 1917 (8). initial estimate of the activity distribution as it is. Hudson and Larkin (12) suggest a corrected for, and this will be discussed In this method, the measured projection in the patient, which for example can be a way of grouping the set of images into further in later sections. data (each row of pixels in the acquired blank image or a homogeneous phantom smaller subsets to reduce computing time. planar images) is filtered with a so-called image. This estimate is then improved in This method is called ordered-subsets ramp filter. The filtered projections are repeated steps (iterations) by comparing expectation maximisation (OSEM) and then added back from the acquired calculated projections with the acquired it is widely used and included in clinical ATTENUATION CORRECTION angles to give transaxial images. The ones. Usually, a pre-set number of software today. The subsets are comprised Attenuation correction is the correction ramp filter is used to remove blurring iterations is used, which should have of evenly spread projections around for the loss of counts in the images introduced by this back-projection step. been optimised for the SPECT analysis in the patient, and two projections is the due to attenuation in the patient and This filter will also amplify noise, and the hand, and the estimated and measured absolute minimum number per subset. In surrounding material in the field of view, projection images are therefore usually projections should be well matched. theory, however, it is much better to use at such as the table top. For the photon filtered with a noise-reducing filter before The optimisation is important, since least four projections per subset, since the energies used in SPECT, attenuation means reconstruction. Popular filters include, quantitative accuracy and image noise are sum of counts in the projections forming either photoelectric absorption, where for example, Butterworth, Hamming and dependent on the number of iterations. each subset should ideally be equal for the photon ceases to exist, or Compton Hann filters (9). FBP is a linear method If the iterations are too few, the activity all subsets, and this requirement is more scattering, where the photon continues which is simple to implement but can give distribution has not yet converged, and likely to be fulfilled with larger subset with a lower energy at a scattered angle. streak artefacts due to the limited number contrast and quantitative accuracy will sizes. When using OSEM, an update of the Most of the Compton-scattered photons of projections. The calculated transaxial be poor. With a high number of iterations, activity distribution is calculated for each will not be detected because of out- images build a 3D image volume that can the noise level may rise to unacceptable subset, but one iteration is defined as a scattering from the patient, photoelectric be sliced in any direction. levels. As in FBP, a filter is usually used pass through all the subsets. The reduction absorption in the patient or the energy Iterative techniques have long been to reduce the noise level. However, for in computing time in comparison with being outside the energy window. The known to possess some advantages over iterative techniques the filter is usually 3D the MLEM technique is roughly a factor of scattered photons that are detected the filtered back-projection technique. and is applied after the iteration process is the number of subsets used, so if we have contain less useful information and can be Image noise is handled in a better way, and finished. It is therefore called post-filtering. 120 projections and 12 projections/subset, corrected for using techniques described it is possible to incorporate corrections A well-known statistical iterative the computing time decreases by a factor in the next section. An example of a for image-degrading effects within the technique is the maximum likelihood of 10. OSEM has been shown to result in phantom reconstructed with and without reconstruction. The methods are based on expectation maximisation (MLEM) method images that are very similar to images attenuation correction can be seen in Fig. a probability matrix which describes the (10, 11), which iteratively maximises a using MLEM, using the same number of 4. probability of a photon originating from a likelihood function and takes the Poisson updates (which means fewer iterations). certain voxel in the patient being detected noise structure of the acquired images An advantage of iterative methods like in a specific pixel in a projection image. into account. For each iteration it uses the OSEM is that models for attenuation, scatter,

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Attenuation coefficient of 140 keV photons PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION

) 0,35 For the attenuation correction to work not meant for diagnostics, it is therefore -1 0,3 properly, the CT image volume must important to lower the CT dose so that the 0,25 correspond geometrically to the SPECT image quality fulfils the requirements of 0,2

0,15 image volume. Each voxel in the CT image the analysis, but no more. A very low CT 0,1 volume should point to the same piece of dose can usually be given if the images 0,05 anatomy as the voxel with corresponding are meant for attenuation correction Attenuation coefficient (cm 0 -1000 -500 0 500 1000 1500 2000 coordinates in the SPECT image volume. only. If used for image fusion, the CT Figure 4: Left-hand image has been Hounsfield number The patient therefore needs to stay on image quality needs to be high enough reconstructed with attenuation correction and Figure 5: Calibration curve for a Somatom Plus the table in exactly the same position to give the anatomical localisation of the right-hand image without. 4 Power (Siemens, Germany) CT scanner. throughout the two measurements. A functional information. A dialogue with mismatch due to patient movements or radiologists and physicists is important in CT images are based on attenuation soft tissue, since we have two fixed points scanner problems can usually be dealt order to find the optimal level of CT image of photons from an X-ray tube, and it is on the scale, air and water, for which we with in the reconstruction software, where quality for all protocols used for SPECT/CT therefore natural to base SPECT attenuation know the Hounsfield numbers and their the mismatch is manually adjusted. If the imaging. correction on the CT information for corresponding radionuclide attenuation mismatch is not corrected, the CT images SPECT/CT. The X-ray photon energies are, coefficients. A linear relationship is will introduce attenuation correction however, distributed in a spectrum whose usually assumed between these points. artefacts in the SPECT images, which average energy is considerably lower than However, for most radionuclides this linear could lead to faulty diagnostics and errors SCATTER CORRECTION the photon energies of most radionuclides relationship is not valid for the attenuation in quantitative analyses. It is therefore Compton scattering is a common used for SPECT. In order to be used for coefficients of bone, since photoelectric important that matching is carefully interaction process for the photon attenuation correction in SPECT, the absorption is more important for the X-ray checked during reconstruction using the energies in SPECT. When scattered, the Hounsfield numbers must be calibrated to photons than for the higher energy emission software tools available. Breathing motion photon interacts with an electron, which the attenuation coefficients of the SPECT photons. A calibration for the Hounsfield is a well-known problem, since the SPECT, leads to a loss of energy and a change in radionuclide. This conversion is not uniquely numbers above that of soft tissue is unlike the CT, is acquired during free direction. Most scattered photons will not defined, since attenuation coefficients therefore needed, and is implemented by breathing. It is therefore recommended be detected, but due to the relatively poor depend both on electron density and the SPECT/CT manufacturer. The calibration to also save images without attenuation energy resolution of the detector materials , but a reasonably accurate curve is specific to each radionuclide and correction which can be used for used for SPECT, some scattered photons approximation can be achieved (13). kV setting on the CT scanner, and each comparison if attenuation correction will be registered within the energy For Hounsfield numbers below that of setting requires its own calibration. An artefacts are suspected. window. For NaI detectors, the share of soft tissue, tissue can be assumed to be example of a calibration curve for the A CT scanner is capable of delivering scattered registrations can be in the order a mixture of soft tissue and air, and for 140 keV photons of 99mTc and for a 120 a relatively high dose to the patient, and of 30%. Scatter correction of SPECT images higher Hounsfield numbers tissue can be kVp CT protocol can be seen in Fig. 5. This the use of CT imaging for attenuation is used to remove these detections, in order seen as a mixture of soft tissue and bone. calibration was created by the author many correction purposes only can, of course, to improve image quality and quantitative This gives a straightforward calibration years ago using bone samples, before the be questioned as a routine basis for accuracy. Most of the detected scattered for the Hounsfield numbers below that of introduction of SPECT/CT equipment. diagnostic imaging. If the CT images are photons will have scattered in the patient,

20 EANM TECHNOLOGIST’S GUIDE EANM TECHNOLOGIST’S GUIDE 21 HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE CHAPTER 1 CHAPTER 1 PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION of scatter images, which, for example, can be estimated from measurements in separate energy windows. A more modern approach is to include scatter correction in the iterative reconstruction, to include 3D information when modelling scatter. It should, however, be noted that all scatter correction methods Figure 7: Contrast reduction due to scatter. are based on approximations, and severe Figure 6: Registration of a scattered photon far Scatter is included in the left-hand image but approximations may introduce image from the projected point of emission. not the right. artefacts. Furthermore, corrections based Figure 8: TEW window setting on subtraction of scatter images increase image noise, and methods included in but scattering from other parts of the the crystal does not correspond to iterative reconstructions can demand a something that needs to be optimised detector system and its environment the projected point of emission. This is lot of computing time. Nevertheless, if before implementation. This method is can also be detected. The amount of illustrated in Fig. 6, where a scattered implemented correctly, scatter correction often used for [99mTc] imaging. scattered registrations depends on the photon is detected relatively far from the has been shown to be beneficial for Another popular method is the size, density and composition of the expected perpendicular point (dashed both quantitative evaluation and visual triple energy window technique (TEW) part of the patient examined, and the arrow). Scatter will therefore reduce image interpretation of the images. introduced by Ogawa et al. (16). The distribution of the radiopharmaceutical contrast, but artefacts can also be induced, method is illustrated in Fig. 8. TEW is within that part of the body. Furthermore, for example in cardiac imaging. These based on two smaller sub-windows it depends on photon energy, the energy effects will also reduce the quantitative adjacent to the photopeak window, resolution of the gamma camera and accuracy. The effect of scatter in SPECT ENERGY WINDOW TECHNIQUES one at either side of the photopeak. The the size of the energy window used. A is demonstrated in Fig. 7 for the same A variety of different energy window scatter image to subtract is approximated smaller window, perhaps also centred water phantom as shown in Fig. 4. For techniques for scatter correction have by the triangular grey-shaded area in Fig. asymmetrically, reduces the number of the left-hand image no scatter correction been developed. The most common one 8 and is calculated taking the widths of scattered registrations at the expense of has been performed, but for the right- is the Compton window method (15), the different windows into account. The reduced sensitivity. Most of the detected hand image scatter is not included. Both where images are acquired at the same method can be recommended when scattered photons have scattered only images are corrected for attenuation. time in the photopeak window and a higher energy photons contribute to the once, but photons that have scattered 2 or The reduction in contrast in the image Compton window, usually adjacent to counts in the photopeak by scatter and 3 times will also contribute to the number including scatter can clearly be seen in the the lower energy limit of the photopeak septal penetration from the high-energy of scattered registrations (14). spheres without activity. window. A fraction of the Compton side. Examples of radionuclides with such Detected scattered photons carry A variety of scatter correction techniques window image is then subtracted from the characteristics are, for example, [123I] and false information about their emission have been developed and evaluated. photopeak image to give the corrected [131I]. sites, since their place of detection in Many methods are based on subtraction image. This fraction is constant, and is

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CORRECTION FOR PARTIAL PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION When using energy window techniques, emitted from the most recent update of is assumed, but when it is included a VOLUME EFFECTS scatter correction can be performed the calculated activity distribution and probability function is used for the point swiftly and without delay. Scatter from the resulting simulated projections are of origin of the emission photon. The The spatial resolution of SPECT can, sources outside the field of view will compared to the measured projections. technique is illustrated in Fig. 9. as mentioned, be in the order of 8–15 be included, in contrast to many other However, Monte Carlo simulations are mm, measured as the full width at half methods. A disadvantage is the increased a relatively time-consuming method of maximum (FWHM) of the point spread noise level resulting from the subtracted scatter modelling. function. The poor resolution causes spill- noisy scatter estimate. It should also be over between regions of different activity noted that these methods are based concentrations, affecting the quantitative on the assumption of identical spatial accuracy. Regions with high activity distribution of scatter in the different COMPENSATION FOR concentration will be underestimated due windows, which is an approximation. COLLIMATOR-DETECTOR to spill-out of registrations, while regions RESPONSE (CDR) Figure 9: CDR viewed as a cone. with lower activities will be overestimated Scatter correction in an iterative The poor spatial resolution in SPECT due to spill-in. CDR compensation reconstruction procedure is a problem for accurate quantification, When using CDR compensation, an increases spatial resolution, but for When scatter correction is included especially with small objects. However, increase in resolution of several mm has quantitative purposes it may be necessary in the iterative reconstruction, it is it is possible to compensate for this to been observed. If a resolution increase is to try to increase resolution even further, or possible to take 3D information from some degree if the spatial resolution desired, it is nevertheless important that to compensate for the quantitative effect the patient into account. The scattered as a function of the distance from the other factors that may limit resolution of the limited resolution. This is called photon can actually be mapped back collimator is known (17). This is called are adjusted, like the reconstruction post- correction for partial volume effects (PVE). to the point of emission of the primary “resolution recovery” or compensation filter. Not much is gained if one uses Many such techniques rely on an accurate photon, which results in a lower noise for collimator-detector response (CDR) the same smoothing post-filter as for definition of the organ or tumour contour level compared with energy window and can be implemented in the iterative conventional reconstructions. It should that is of interest for quantification. Some methods. This correction approach is reconstruction probability matrix. also be mentioned that the use of this applications try to find these contours from usually used in PET image reconstruction, Manufacturers of reconstruction software technique has been debated, especially the CT in the SPECT/CT hybrid equipment, but it is less common in the SPECT clinical offer different ingeniously named for quantitative analyses. Ringing but other segmentation techniques are workflow. The modelling of scatter in packages in which this type of correction artefacts (Gibbs artefacts) have been also in use. PVE is often quantified with iterative reconstruction techniques can is included. observed around sharp edges, resulting the recovery coefficient (RC), which is the be performed with different degrees of In CDR compensation the projection in disturbing patterns which also affect ratio between the activity concentration complexity. Methods relying on simple of a voxel in the activity distribution can the quantitative accuracy. Another thing measured in the image and the true activity models based on point or line source be seen as an “inverse cone” originating to take into account when implementing concentration. Approximate RC values can measurements are in use, but it is also in the projection pixel, which describes this technique is a clear increase in be calibrated in volumes of interest (VOIs) possible to simulate the scattering process the range of the detector response for a reconstruction time. using phantom measurements or Monte with Monte Carlo simulations. This means point in the projection data. Without CDR Carlo simulations and can then be applied that for each iteration, virtual photos are compensation a perpendicular projection to the measured quantitative values.

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REFERENCES PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION Theoretical calculations of RC values can and this is usually checked for and if acquisition of the images, since it can be 1. Hutton BF. The origins of SPECT and SPECT/ also be performed, for example by using possible corrected as a compulsory step used to compensate for missing data, CT, Eur J Nucl Med Mol Imaging 2014; 41:S3–S16 convolution methods (18). during image reconstruction. thus permitting acquisition of a reduced 2. Anger HO. Scintillation camera, Rev Sci Instr 1958; 29:27-33 number of SPECT or CT projections (23). If 3. Van Audenhaege K, Van Holen R, Vanden- less data is needed for an equivalent image berghe S, Vanhove C, Metzler SD, Moore SC. Review quality, this can also be used to reduce the of SPECT collimator selection, optimization, and fabri- IMAGE FUSION ARTIFICIAL INTELLIGENCE IN dose to the patient, both in SPECT and cation for clinical and . Med Phys 2015; 42:4796-4813 Image fusion means that the two sets SPECT CT. For all aspects of machine learning, 4. Curry, III TS, Dowdey JE, Murry, Jr RC. Chris- of images, SPECT and CT, are brought Artificial intelligence (AI) is a very broad validation is a key factor which requires tensen’s Physics of Diagnostic Radiology. Lea & Febiger together in an operation called registering topic that has been playing an increasing intensive effort before an algorithm can Philadelphia 1990 to make them correspond geometrically. role in our daily lives, and the number be implemented in clinical work. We can 5. Habibzadeh MA, Ay MR, Asl AR, Ghadiri H, Zaidi H. Impact of miscentering on patient dose and The images can then be displayed as an of possible applications seems endless. surely expect a lot more from this field in image noise in x-ray CT imaging: phantom and clinical overlap, with different colour scales. CT is In nuclear medicine, for example, AI has the future. studies. Phys Med 2012; 28:191-9. usually displayed in grey scale, whereas a shown success in segmenting different 6. Cormack AM. Representation of a function colour scale is used for SPECT. Different structures for determining volume and by its line integrals with some radiological applications. J Appl Phys 1963; 34:2722-2727 window settings are used for CT, such other parameters of interest for organs 7. Hounsfield GN. Computerized transverse as soft tissue window, lung window or and tumours (19,20). This is expected to axial scanning (tomography). Part I: Description of brain window, depending on type of evolve into efficient tools for diagnostics, system. Part II: Clinical applications. Br J Radiol 1973; 46:1016-1022 examination. The degree of transparency staging of disease and prognostics, using 8. J. Uber die bestimmung von funk- can usually be adjusted to make it possible advanced methods of machine learning tionen durch ihre integral-werte längs gewisser man- to cross-fade between SPECT and CT. (21) and preferably also taking the CT nigfaltigkeiten. Ber Verh Sächs Akad Wiss Leipzig, Math Image fusion can be used for images or MR into account. Promising results Phys 1917; 69:262-277 9. Van Laere K, Koole M, Lemahieu I, Dierckx R. from different scanners with the patient have also been presented showing Image filtering in single-photon emission computed in different positions, but this involves that AI can be used to speed up image tomography: principles and applications. Comput Med complicated geometrical transformations reconstruction and improve image Imaging Graph 2001;25: 127-133 of the image data to make it correspond. quality and quantitative accuracy (22). 10. Shepp LA, Vardi Y. Maximum likelihood re- construction for emission tomography. IEEE Trans Med In hybrid equipment such as SPECT/CT This involves training a neural network Imaging 1982; 1:113-22. the patient is usually positioned in the on thousands of images that should be 11. Lange K, Carson R. EM reconstruction algo- same way on the two sets of images, and relatively similar to those of the planned rithms for emission tomography. J Comput Assist To- this means that the image registration is application. It should then be possible mogr 1984; 8:306-331 12. Hudson HM, Larkin RS. Accelerated image just a factor of calibration. Factors that the to use the acquired projection images as reconstruction using ordered subsets of projection software needs to handle are differences input and get a high-quality SPECT image data. IEEE Trans Med Imaging 1994; 13:601-609 in matrix/pixel size, slice thickness, field volume as output, without the need for 13. Fleming JS. A technique for using CT im- of view and table positions. Patient the traditional reconstruction steps. AI ages in attenuation correction and quantification in SPECT. Nucl Med Commun 1989; 10:83-97 movement can result in a misregistration, also has the potential to speed up the

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14. Zaidi H, Koral KF. Scatter modelling and 20. Anita S, Priya PA. Three Dimensional

PHYSICS FOR SPECT/CT METHODS AND RECONSTRUCTION compensation in emission tomography. Eur J Nucl Analysis of SPECT Images for Diagnosing Early Par- Med Mol Imaging 2004; 31:761-782 kinson’s Disease using Radial Basis Function Kernel 15. Jaszczak RJ, Greer KL, Floyd CE, Harris CG, - Extreme Learning Machine. Curr Med Imaging Rev. Coleman RE. Improved SPECT quantitation using 2019;15(5):461-470. compensation for scattered photons. J Nucl Med 1984; 21. LeCun Y, Bengio Y, Hinton G. Deep learning. 25:893-900. Nature 2015; 521(7553):436-444 16. Ogawa K, Harata Y, Ichihara T, Kubo A, 22. Häggström I, Schmidtlein CR, Campanella Hashimoto S. A practical method for position-depen- G, Fuchs TJ. DeepPET: A deep encoder-decoder net- dent Compton-scatter correction in single photon work for directly solving the PET image reconstruction emission CT. IEEE Trans Med Imaging 1991; 10:408-412 inverse problem. Med Image Anal 2019; 54:253-262. 17. Pretorius PH, King MA, Pan TS, de Vries DJ, 23. Ryden T, Marin I, van Essen M, Svensson J, Glick SJ, Byrne CL. Reducing the influence of the partial Bernhardt P. Deep learning generation of intermediate volume effect on SPECT activity quantitation with 3D projections and Monte Carlo based reconstruction im- modelling of spatial resolution in iterative reconstruc- proves 177Lu SPECT images reconstructed with sparse tion. Phys Med Biol 1998; 43:407-420 acquired projections. J Nucl Med 2019; 60 1: 44 18. Soret M, Bacharach SL, Buvat I. Partial-Vol- ume Effect in PET Tumor Imaging. J Nucl Med 2007; 48:932–945 19. Wang T, Lei Y, Tang H, He Z, Castillo R, Wang C, Li D, Higgins K, Liu T, Curran WJ, Zhou W, Yang X. A learning-based automatic segmentation and quanti- fication method on left ventricle in gated myocardial perfusion SPECT imaging: A feasibility study. J Nucl Cardiol 2019; Jan 28. doi: 10.1007/s12350-019-01594- 2.

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QC OF HYBRID SYSTEMS

by Sebastijan Rep

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INTRODUCTION QC OF HYBRID SYSTEMS QC OF HYBRID SYSTEMS

The image reproduced by the SPECT/CT gamma camera shows the TEST RADIATION SOURCE TOLERANCES distribution of radiopharmaceutical activity in the body. The basis

of image quality is the ability to detect differences in the uptake of DAILY MONTHLY HALF-YEARLY into the lesion and the surrounding tissue. A high- Physical inspection X quality image is one that can reproduce this contrast in a way that enables In line with the initial benchmark. In a Background daily check, check the number on the X the right diagnosis. However, there are several factors that affect image monitor; take images in the annual test. quality. Some of them are impossible to influence, such as the size of Integral: CFOV ≤ 5%, UFOV ≤ 6% Intrinsic uniformity Point source 99mTc X the patient and the overlap and movement of the organs. Factors which Differential: CFOV ≤ 2.5%, UFOV ≤ 3% allow us to influence the quality of the image, on the other hand, include 99m Energy photo-peak Point source Tc, X a number of parameters and properties of the camera and the choice or the appropriate isotope of reconstruction algorithm. The user must have complete control over Integral: CFOV ≤ 5%, UFOV ≤ 6% Line source 153Gd X the properties of the gamma camera in order to optimise the image of Extrinsic Differential: CFOV ≤ 3.5%, UFOV ≤ 4% activity distribution. Regular control of the quality of the gamma camera is uniformity Integral: CFOV ≤ 5%, UFOV ≤ 6% Flat source 57Co X X critical to the reliability of the result. When the conditions are not optimal, Differential: CFOV ≤ 3.5%, UFOV ≤ 4% 99m In accordance with the initial reference misdiagnosis can occur, which means that the gamma camera can give The solution of Tc or X value false positive and false negative test results. Regular quality control is Sensitivity the appropriate isotope (for quantification) Reference sources; 75Se important in order to prevent such errors (1, 2). < 10% X in 57Co Bar phantom + Flat source In accordance with the initial reference X 57 value The Quality Control Programme evaluated (Table 1). QC programmes Spatial resolution Co and linearity (QC) is designed to maintain the high should follow international guidelines Micro capillary glass tubes 99m ≤ 7.5 mm (@10cm) X performance of equipment regardless of (IAEA, EANM, NEMA), taking into account filled with Tc 99m age. QC begins with an initial acceptance national guidelines and legislation as well Centre of rotation Point source Tc ≤2 mm X Point source: test based on a QC programme to assess as the manufacturer’s recommendations. SPECT/CT Tc-99m + contrast <5 mm misalignment X alignment whether or not the equipment meets The annual SPECT/CT QC tests and agent the specifications upon installation. The assessment should be performed by an Homogeneity (homogeneous part) <10%, 99m contrast (cold balls) and resolution (bar user (technologist or medical physicist) independent medical physicist (1, 3). Jaszczak phantom Solution of Tc in X Jaszczak phantom sectors) comparable to initial reference must subsequently perform routine QC measurements and published research measurements at regular intervals and also after major component changes, Table 1: Recommended routine QC tests (daily, monthly and half-yearly tests) manufacturer updates or repairs. In order to maintain long-term overall stability of operation, these measurements need to be specified, performed, recorded and

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QC OF HYBRID SYSTEMS 1 Daily tests 1.2. Intrinsic uniformity QC OF HYBRID SYSTEMS The operator must perform a daily In an intrinsic uniformity test, the visual and physical inspection of SPECT/ collimator is removed from the detector CT cameras to detect external mechanical system. The most commonly used or electrical defects or damage. If the measurement is the 99mTc point source detector collimator has a touch pad that Figure 1: Poor intrinsic uniformity (A) due to (Fig. 3), which is placed at a distance equal stops all movement when contact is made, contamination in the room (background) and to four times the detector’s field of view a touch pad test should be performed normal uniformity (B). diameter to ensure uniform detection every day and after each change of of the detector system. In the internal column restraints. An operational check evenness test, the impact of the collimator of the background count rates with 1.1 Extrinsic uniformity is not evaluated (4, 9). Figure 3: Implementation of intrinsic uniformity or without collimators and within one The system test evaluates the uniformity Extrinsic and intrinsic uniformity tests test with 99mTc point source. or more energy windows should be of the detector system with the collimator aim to verify the response of the gamma performed daily to detect radiation caused (Bolstad et al., 2011). A 57Co flat source camera to the steady flow of incident by possible radioactive contamination (Fig. 2) or a phantom flat filled with photons into the field of view of the 1.3 Assessment of uniformity of the scintillation camera, floor or 99mTc mixed with water may be used for detector system using a symmetrical We use visual assessment to check walls, radiation from any neighbouring implementation. Newer gamma cameras energy window, with and without changes in the distribution and density of unshielded source (Fig. 1) or an excess of use the 153Gd line source for the automatic collimators (4). pulses in the visual field of the image. electronic noise. Before using the SPECT/ QC system consistency test, which is The scintillation gamma camera For quantitative assessment of the CT cameras, the operator must check the designed to perform the test automatically displays the uniform field of view of the uniformity tests, the integral uniformity setting of the energy windows to confirm (5-8). system for all collimators used. If there are (IU) and differential uniformity (DU) in that all the pre-set energy windows of any significant differences in uniformity the usable field of view (UFOV) and the the pulse height analyser are correctly deviating from the reference values, an central field of view (CFOV) are calculated. oriented around the energy photo- intrinsic (internal) uniformity test must be The IU is calculated using the minimum peaks of the radionuclides, indicating performed by calibrating and adjusting and maximum counts/pixels, according to that the system energy calibration is the PMT (3, 4). the following equation: correct. The most sensitive parameter IE = 100 [(max - min) / max + min)] affecting changes to and performance For the DU the highest and lowest of the system is the uniformity of the pixel values are identified every five detector system. Factors potentially Figure 2: Implementation of extrinsic uniformity consecutive pixels in X and Y direction. affecting uniformity are changes in the test with a 57Co flat source photomultiplier (PMT), energy and linear corrections, hygroscopicity of the crystal and damage to the collimator, which affect the evenness of the image (1, 3, 4).

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QC OF HYBRID SYSTEMS Their differences are computed according clinical conditions and include the effects QC OF HYBRID SYSTEMS to the following equation: of the collimator. The quantitative measure DE = 100 [(high - low) / (high / low)] (4) of spatial resolution is given in millimetres as the full width at half maximum (FWHM) or full width at tenth maximum (FWTM) Figure 7: Test of spatial resolution (average of the peak of the imaged point or line FWHM = 4.26mm and FWTM = 7.76 mm) with line radioactive sources. This test must be source on the head of collimator (A) at a distance performed for all low-energy parallel-hole of 10 cm (average FWHM = 7.44 mm and FWTM Figure 8: COR test results and phantom position collimators. To perform the test, we use = 13.55 mm) (B). for performance of the test a bar phantom, a line source and a point source. The bar phantom is mounted on 3. Centre of rotation (COR) 4. SPECT resolution and homogeneity the collimator head (Fig. 6) at a distance The aim of this test is to ensure the test of 10 cm from the detector head. Align proper operation of the SPECT system and The Jaszczak phantom test is designed Figure 4: Daily report on extrinsic uniformity the phantoms with the X and Y axes of the to ensure that the distance from the centre to provide an assessment of the overall detector head. The estimated FWHM values of rotation is minimal. The SPECT system performance of the SPECT system. The for each collimator must be compared with must be precisely centred, since every Jaszczak phantom allows us to check the manufacturer’s worst-case values. If deviation from the axis of rotation reduces whether the system works satisfactorily, the lines on the surface of the collimator the spatial resolution. The COR test must be even in a high-repetition study. are straight and curved at a distance of 10 performed in all angular configurations of Phantoms should have at least one area cm (Fig. 7), this indicates that the bars and the SPECT system and for all the collimators for homogeneity assessment and one collimator are not parallel, which will result used. This test should be run as a reference area for cold lesions (Fig. 10). Place the in a decrease in resolution and contrast in test at weekly/monthly intervals, or if a phantom on a bed and align it with the the clinical images (3, 4, 10). problem is suspected. COR is measured axis of rotation, or use a special holder by 360 degree coverage around one or to align the phantom correctly with the Figure 5: Report on intrinsic QC tests for a more 99mTc point sources (Fig. 8). Most centre of rotation. The acquired images gamma camera manufacturers have software that analyses should be carefully examined, paying the acquisition to determine if the COR is particular attention to the appearance of within acceptable limits. It is important not any artefacts (Fig. 12). Adjust the profile of only to use the correct COR value, but also the phantom uniform region through the 2. Spatial resolution and linearity with to keep this value constant as a function incisions and measure the ratio of pixel the bar phantom of angle. When measured on a gamma counts in the centre to pixel counts at the The spatial resolution characterises the camera system at a radius of 20 cm, both X edge (Fig. 9). If attenuation correction is system’s ability to resolve spatially separated and Y values for COR must show less than 2 used, the profile across the uniform area sources of radioactivity. Extrinsic tests of Figure 6: Test of spatial resolution and linearity mm in a 360° orbit (3, 4, 10). of ​​the phantom must be straight or flat. spatial resolution are performed under performed with the bar phantom 57Co flat source Using the appropriate ROI, measure the uniformity (Fig. 11) and contrast of all

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QC OF HYBRID SYSTEMS visible spheres. Record acceptable values ​​ 5. SPECT/CT alignment especially important when SPECT/CT QC OF HYBRID SYSTEMS and compare with values when​​ the test Accurate registration of SPECT and CT quantification of uptake is required (6, 11). is performed routinely. The quality of the images is essential in order to achieve image is visually checked and the contrast accurate attenuation correction and 6. CT tests of the detected lesions recorded (3, 4, 10). merging of SPECT/CT images. After the Daily routine QC tests and phantoms SPECT/CT system has been installed for CT scanners are recommended and and calibrated, the match between the provided by the manufacturers. The daily SPECT and CT fields needs to be checked measurement of quality is based on at regular intervals. The frequency of three parameters. Measure the voltage testing depends on the stability of the in the tubes directly in the x-ray tubes. Figure 11: Calculated integral and differential system (EANM suggests that this be done Test the uniformity of a CT image of a uniformity in the homogeneous area and contrast monthly). The test can be performed using homogeneous object by measuring in the cold spheres area of the Jaszczak phantom. hollow spheres, which can be filled with the CT numbers (Hounsfield units - a solution of 99mTc (visible on SPECT) and HU) across the image of homogenous iodine contrast medium (visible on CT). phantom, and calculate pixel noise as a A SPECT/CT scan is then performed and standard deviation. The aim of the test is Figure 9: Profiles to check the accuracy of image fusion software is used for accurate to ensure that the relative calibration of attenuation correction. A profile was drawn alignment (Fig. 13). all CT numbers to water remains within across one of the transverse slices. A and A1: no When matching between SPECT and acceptable limits and that quantum attenuation correction. B and B1: CT attenuation CT images, attenuation correction is noise and electronic system noise do not correction appropriate, and an image with accurate increase. Too much image noise degrades reproduction of the radionuclide low-contrast detectability (3, 6, 11). distribution will be generated. This is

Figure 10: The Jaszczak phantom in three Figure 13: Spatial registration specific areas: homogeneous area (a), cold spheres Figure 12: Seven transverse slices of the phantom used in SPECT/CT. (b) and cold bars (c). homogeneous and sphere sections of the Jaszczak Reconstruction in sagittal, phantom, imaged with a 360° total angle of coronary and sagittal direction rotation and corrected for attenuation. Distinct on ten-point source vial filled with artefacts are seen in different slices. a solution of 99mTc and iodine contrast medium.

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THE INFLUENCE OF ABSOLUTE QUANTIFICATION IN QC OF HYBRID SYSTEMS QC OF HYBRID SYSTEMS RECONSTRUCTION SPECT/CT used isotope is the preferred method. Two quality control of SPECT/CT. In most 57 75 ALGORITHMS ON IMAGE point sources are available: Co and Se. cases, technologists are responsible for 57 QUALITY The accuracy of SPECT/CT The sensitivity calibration test with Co the routine tests which are performed quantification depends on many factors, and 75Se sources is performed at monthly daily and monthly. They may also be Image reconstruction allows the including the need for scatter correction intervals (Fig. 15) (21). responsible for conducting annual tests in provision of diagnostic information based and attenuation correction. In addition, collaboration with a medical physicist. on the distribution of activity in different absolute quantification is influenced by The technologist’s basic daily task is tissues. There are two reconstruction both the reconstruction algorithm and to evaluate images to exclude possible methods used in practice: analytical the settings. Recent developments in artefacts. Low-dose CT (10-40 mA) is used filtered back-projection (FBP) and the corrections for attenuation and scatter to make images of appropriate quality for iterative reconstruction method. The of photons, collimator modelling and 3D their intended purpose (16). CT imaging FBP method is simple, fast and easy to reconstruction with resolution recovery is used to obtain transmission folders that implement in research and clinical practice. and noise regulation have improved serve to correct attenuation in SPECT data However, there are some disadvantages reconstruction techniques, thereby (17). that can be eliminated through iterative enabling absolute SPECT quantification. Common artefacts that are generated techniques. Images reconstructed with The addition of an integrated computed in the reconstructed images are the result iterative techniques have been shown to tomography (CT) system not only of a misalignment of CT data and emission have better qualitative features, including provides anatomical reference, but also data. The reason for the formation of more accurate estimates of concentration enables accurate attenuation and scatter artefacts is the movement of organs due and improved image contrast, spatial correction and improves quantification. to breathing, which gives rise to major resolution and noise characteristics Hybrid SPECT/CT cameras have now Figure 15: Monthly test; sensitivity of 57Co and changes in attenuation coefficients. Metal compared with analytical methods. become standard clinical practice and 75Se point sources, which are used for absolute implants and patient movement during Advanced SPECT/CT reconstruction absolute quantification has thus become quantification in SPECT/CT. CT acquisition are another cause of poor algorithms include techniques to correct a reality (15, 16). image quality. The misalignment between for photon attenuation and scattering (Fig. In order to calibrate the sensitivity of the emission and transmission imaging, 14) (12-14). calculation of absolute quantification, use in addition to patient movement and of a standardised point source of a clinically THE ROLE OF THE breathing, also causes the table to bend TECHNOLOGIST as it enters the gantry. CT imaging takes Nuclear medicine technologists much less time than SPECT, resulting are health professionals who cover in a time mismatch. This is a problem, a wide range of tasks including especially when chest scanning, because radiopharmaceutical dispensing and the heart and lungs are moving organs. administration, patient care, image This temporal mismatch can produce Figure 14: NEMA body phantom reconstructions with FBP (A), iterative reconstruction (B), and iterative acquisition and processing, image unwanted artefacts on attenuation- reconstruction corrected by photon attenuation and scatter (C). evaluation to exclude artefacts and corrected images, which can lead to

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SUMMARY REFERENCES Ocean J Nucl Med Biol. 2017 Spring;5(2):120-133. doi: QC OF HYBRID SYSTEMS QC OF HYBRID SYSTEMS misinterpretation of results (16, 17, 18, 19). 1. Murph PH. Acceptance testing and quality 10.22038/aojnmb.2017.8708 To exclude artefacts due to attenuation This chapter has included examples control of gamma cameras, including SPECT. J Nucl 14. Berker Y, Li Y. Attenuation correction in emission tomography using the emission da- correction, it is important always to to give an insight into some of the Med. 1987, 1221-1227. 2. Zanzonico P. Routine quality control of ta--A review. Med Phys. 2016 Feb;43(2):807-32. doi: check uncorrected images as well. The procedures and practices associated with clinical nuclear medicine instrumentation: a brief re- 10.1118/1.4938264 anatomical accuracy of image fusion SPECT/CT cameras. Local practice and view. J Nucl Med. 2008 Jul;49(7):1114-31. doi: 10.2967/ 15. Peters SMB, van der Werf NR, Segbers M, must be verified before interpreting the recommendations from the manufacturer, jnumed.107.050203. van Velden FHP, Wierts R, Blokland KJAK, Konijnenberg MW, Lazarenko SV, Visser EP, Gotthardt M. Towards corrected scans. The responsibility of technologists and physicists will determine 3. Busemann Sokole E1, Płachcínska A, Britten A; EANM Physics Committee. Acceptance testing for standardization of absolute SPECT/CT quantification: the technologist includes the regular how and when QC tests are performed. nuclear medicine instrumentation. Eur J Nucl Med Mol a multi-center and multi-vendor phantom study. EJN- performance of quality control tests Performance of tests may vary between Imaging. 2010 Mar;37(3):672-81. doi: 10.1007/s00259- MMI Phys. 2019 26. dec.; 6 (1): 29. doi: 10.1186 / s40658- and the evaluation of scans to exclude different departments depending on the 009-1348-x. 019-0268-5 16. Ziegler SI, Dahlbom M, Sibylle I et al. Diag- potential artefacts (16, 20). clinical practices undertaken. 4. National Electrical Manufacturers Associa- tion (NEMA). Performance Measurements of Scintilla- nostic Nuclear Medicine. 2nd ed. Berlin: Springer. 2006. tion Cameras: Rosslyn, NU-1 NEMA. 2012. 277-88. 5. Bolstad R, Brown J, Grantham V. Extrinsic 17. Mariani G, Flotats A, Israel O, Kim E.E, Kuwert Versus Intrinsic Uniformity Correction for γ-cameras. J T. Clinical Applications of SPECT/CT: New Hybrid Nu- Nucl Med Technol. 2011. 39(3):208-12. clear Medicine Imaging System. Dunaj: Nuclear Med- 6. Siemens Operating Instructions Symbia icine Section International Atomic Energy Agency. System T16/T6/T2/T Series, Version VA60A. Quality 2008. Control and Assurance. 2010. 251-323. 18. Suzuki A, Koshida K, Matsubara K. Effects of 7. Busemann Sokole E, Kugi A, Bergmann H. Pacemaker, Implantable Cardioverter Defibrillator, and High count rates cause non-uniformities in -57 Left Ventricular Leads on CT-Based Attenuation Cor- flood images. Eur J Nucl Med.1993. 20: 896. rection. J Nucl Med Technol. 2014. 42: 37–41. 8. English RJ, Polak JF, Holman BL. An iterative 19. Apostolopoulos D, Savvopoulos C. What method for verifying systematic nonuniformities in re- is the benefit of CT-based attenuation correction in fillable flood sources. J Nucl Med Technol.1984. 12: 7-9 myocardial perfusion SPECT?. Hell J Nucl Med. 2016. 9. Elkamhawy AA, Rothenbach JR, Damaraju 19 (2): 89-92. S, Badruddin SM (2000). Intrinsic uniformity and rel- 20. Magdy M K Ed. Basic Sciences of Nuclear ative sensitivity quality control tests for single-head Medicine. London: Springer.2011. gamma cameras. J Nucl Med Technol.; 28(4):252-6. 21. www.siemens.com/healthcare 10. International Atomic Energy Agency. Quality assurance for SPECT systems. Human Health Series No. 6. 11. Jones DW, Hogg P, Seeram E. Practical SPECT/CT in nuclear medicine. London: Springer; 2013. 12. Bruyant PP. Analytic and iterative recon- struction algorithms in SPECT. J Nucl Med. 2002 Oct;43(10):1343-58. 13. Zeraatkar N, Rahmim A, Sarkar S, Ay MR. De- velopment and Evaluation of Image Reconstruction Algorithms for a Novel Desktop SPECT System. Asia

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QUANTITATIVE SPECT

by John Dickson

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INTRODUCTION QUANTITATIVE SPECT QUANTITATIVE SPECT From its very early days, nuclear medicine has been a quantitative modality. From probes counting the levels of radioactivity in the neck, through to quantifying thyroid uptake in planar imaging or looking at changes in activity distributions in the kidneys in dynamic renogram studies, the quantitative capability of nuclear medicine has been key to its success. Similarly, in SPECT, we’ve been performing quantification for many years. In myocardial perfusion imaging we can quantify relative perfusion in territories of the heart and determine wall motion and ejection fractions, while in the brain SPECT can be used to determine striatal specific binding ratios in I-123 imaging (Figure 1). What is noteworthy in all these SPECT examples is that this type of quantification is relative, i.e. relative to other areas of uptake in space, such as areas of the occipital lobe in I-123 ioflupane SPECT, or relative over time, as in SPECT determination of left ventricle ejection fraction.

While relative quantitative SPECT concentration, the technique has been has had its successes, because of its extrapolated to normalised quantitative historical inability to perform absolute measures such as standardised uptake quantification in terms of e.g. activity value (SUV) and used in a similar way to concentration, SPECT has been PET (2)(3). Absolute quantitative SPECT considered quantitatively inferior to PET. will be the focus for the rest of this chapter. This difference arose because of the long- established incorporation of corrections for physical factors such as scatter and attenuation in PET reconstruction, which until relatively recently were absent from routine SPECT imaging. However, with the introduction of SPECT/CT, together with improved reconstruction and correction algorithms, we now have the ability to Figure 1: Examples of relative SPECT quantification in (a) myocardial perfusion imaging and (b) I-123 perform absolute quantification in SPECT ioflupane SPECT. too (1). While this form of quantification was initially used to determine activity

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THE CLINICAL NEED FOR QUANTITATIVE SPECT QUANTITATIVE SPECT QUANTITATIVE SPECT performed using the MIRD scheme. Using dimensions, and where the incorporation up is performed with planar gamma this methodology, the time-activity curves of corrections for attenuation, scatter, camera and SPECT imaging using iodine- The initial need for absolute of tumours and/or organs are calculated resolution losses and an inbuilt sensitivity 123-labelled diagnostic versions of these quantification came with the growth to help derive overall radiation exposure, factor can produce time-activity curves radiopharmaceuticals. Having a body of theranostics (4). With the expansion before being combined with ’S’ values directly from an image (Figure 2). Because habitus normalised uptake value such as of molecular radiotherapies such as which estimate the dose to the organ of this, incorporating quantitative SPECT SUV in these diagnostic studies can be I-131 mIBG, Lu-177 dotatate and Lu-177 or tumour. Historically, the derivation into calculations is now well incredibly helpful in determining disease PSMA, together with the expansion of of time-activity curves was based on established (7), and the direct derivation extent and aggressiveness, and can be Y-90 microsphere therapy and its pre- anterior and posterior whole-body scans of voxel values of activity concentration is used in a similar way in which disease assessment with Tc-99m MAA (5), there (6). By drawing regions of interest around a clear benefit of this technique. progression is assessed using PET. As has been an increasing need to calculate relevant features on anterior and posterior A second clinical use of absolute can be seen in Figure 3, which shows a organ dosimetry. This has happened views, the geometric mean of the counts quantitative SPECT, again in theranostics, patient who has had imaging following because, as in external beam radiotherapy, in these regions is used to calculate is in disease assessment. Typically for multiple I-131 treatments for thyroid effective, safe radiation treatments require attenuation-compensated time vs. count radiotherapeutic interventions using e.g. , the SUVmax in the bone lesion has the maximum possible dose to the tumour curves before translation into activity iodine-131 for thyroid reduced slightly from 2.26 to 2.01 from site while minimising the dose given to (MBq) using a known activity standard or cancer and I-131 mIBG for neuroendocrine June to December. This small change in organs at risk. sensitivity factor. Although this approach tumours, initial staging or disease follow- SUV indicates that the last therapeutic For molecular radiotherapies using works, it does not have the accuracy agents such as I-131, I-131 mIBG, Lu-177 of quantitative SPECT, where organs/ dotatate and PSMA, dosimetry is typically tumours can be clearly defined in three

Figure 3. Quantitative SPECT on two occasions following Iodine-131 therapy for thyroid cancer. SUVmax in December 2018 (2.01) was only marginally lower than that measured in June 2018 (2.26), highlighting no Figure 2. Quantitative SPECT screen directly showing activity concentration within regions of interest. significant change in the metabolic activity in the lesion following therapy.

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OPERATIONAL REQUIREMENTS QUANTITATIVE SPECT intervention did not have the desired the field of view in the form of a Bone » The time of injection, to account for ra- QUANTITATIVE SPECT effect. Scan Index or total bone uptake (12,13). While quantitative SPECT has many dioactive decay from the time of the activ- One final area where quantitative SPECT This is analogous to total lesion glycolysis potential advantages, there is also an ity measurement is gaining interest is in orthopaedic and in FDG-PET. Publications in this area are overhead, and changes in practice are » The body habitus, i.e. the weight and/ oncological bone scanning (Figure 4). growing in number, so it is anticipated required to implement the technology or height of the patient depending on the Having the ability to calculate an SUV that this form of quantitative bone SPECT operationally. type of SUV normalisation. in bone SPECT is becoming useful in may become increasingly useful. While To calculate the activity or SUV in an While this is frequently performed in characterising bone disease (8–10). dosimetry, theranostic follow-up and bone image requires several input parameters. PET, the availability of weighing scales or However, an initial challenge with this scintigraphy are establishing themselves These input parameters work in much height measures may be an impediment technology is understanding the relevance as areas where quantitative SPECT is the same way as in PET (15). The first is for some, while the routine measurement of an SUV value where values relevant to becoming helpful, one can also envisage the sensitivity factor required to translate of activity in a syringe pre and post normal and indeed diseased bone are still other areas where quantitative SPECT may counts in the SPECT image into activity injection may not be routine or indeed not well established, and where normal be used. SPECT for parathyroid adenomas concentration. This requires a sensitivity possible in some nuclear medicine clinics uptake depends on the location of that and cardiac innervation, or indeed I-123 calibration to be performed, which should if a dose calibrator is not readily available. bone tissue (2,11). A further potential ioflupane or regional cerebral blood flow also be assessed periodically to ensure Introducing quantitative SPECT to a application of quantitative bone SPECT is SPECT have been suggested as areas consistency between the calibrations. nuclear medicine practice also brings with combining uptake in the diseased bone where the technology could be applied While this overhead is not onerous, it still it other overheads, such as the checking in terms of activity and volume across (14). requires some time on the scanner. and quality control of weighing scales and The second set of input parameters is height measures, and the availability and related to the determination of SUV. SUV synchronisation of clocks in injection areas is calculated using the following equation: to the clock on the scanner. A final factor that may not be as SUV = (activity concentration in area of well appreciated in SPECT compared interest) / (available activity concentration) to PET is the of the SPECT radiopharmaceutical, and the where available activity concentration patient status prior to injection. In non- can be the injected activity normalised quantitative SPECT, the interpretation of to body surface area, lean body mass, images is based on visual assessment of or, more commonly, body weight. The hot or cold features. With the introduction calculation of activity concentration of quantification, the quantitative values or SUV therefore requires several input may be dependent on drug interactions, parameters to be known: fasting/hydration status, and whether » The exact activity injected into the pa- the radiopharmaceutical status is

Figure 4. Bone SPECT quantification showing the uptake in a lumbar spine bone lesion in terms of SUVmax tient, i.e. the syringe activity pre and post in equilibrium. For the latter, when

SUVmean SUVmin together with the volume of the lesion. Also shown in the figure for reference is the SUV of the injection performing longitudinal comparisons it total segmented bone in the image data.

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LIMITATIONS OF QUANTITATIVE QUANTITATIVE SPECT QUANTITATIVE SPECT may be necessary to scan at the same time SPECT correction assumes a uniform attenuation Figure 6 shows the value of uptake in post injection to ensure comparability. environment which does not work in a small feature (in this case the striata of While the issue of scanning time is an With a calibrated SPECT system and mixed- attenuation parts of the body a DaTSCAN™) with different corrections inconvenience rather than a challenge, knowledge of the injected activity and such as the chest, where soft tissue, lung applied. As a comparison, FBP and iterative the pharmacokinetic status at the time of body habitus of the patient, it is possible and bone may be present. The use of CT reconstruction with no corrections is also imaging and any possible drug interactions to perform quantitative SPECT. However, entails a small radiation exposure burden, shown. On visual assessment, the image of established radiopharmaceuticals may there are some caveats. To perform which may be an issue for some. Scatter with resolution modelling (ACSCRM), as need to be revisited. Figure 5 summarises quantitative SPECT, it is essential that and other corrections within the iterative expected, shows better resolution of the the operational issues associated with the data is corrected for physical factors. loop are also valuable for the highest separation of caudate and putamen, while quantitative SPECT. Given that the corrections should work level of accuracy. However, unlike in PET, the scatter-corrected data (ACSC and SC), in all environments, it is important corrections are not routinely used in which also corrects for septal penetration that measured rather than calculated SPECT, and while attenuation correction of high-energy photon emissions with attenuation correction is used, i.e. CT in iterative correction is relatively iodine-123, demonstrates superior image attenuation correction inside iterative common, corrections for scatter are not contrast between the striata and non- reconstruction rather than Chang as well developed on most software specific uptake elsewhere in the brain. calculation using filtered back-projection platforms, nor are they frequently used. Visually, attenuation correction appears to (FBP). This is because Chang attenuation Additionally, corrections for resolution have very little impact (AC vs. NC, ACSC vs. losses, known as point spread function SC), while iterative reconstruction without or resolution modelling, are not available corrections (NO) and filtered back- on some systems, or are not used. This projection with no corrections (FBP(NO)) correction is also prone to overshoot data have similar image appearance (Gibbs) artefacts, so should be used with with the lowest definition and contrast. care (16,17). As a consequence, not only Quantitatively, concentrating on striatal will the value of uptake be different for uptake, if it is assumed that correction users using different corrections, but for all physical effects (ACSCRM) correctly there will also be a loss of accuracy unless measures the striatal uptake; attenuation all corrections are applied. This is not an and triple energy window (TEW) scatter issue when performing non-quantitative correction (ACSC) gives 65.4% of the SPECT, where patterns or relative uptake ACSCRM count concentration; and are assessed. Also, in relative SPECT attenuation and scatter correction quantification, corrections are often not as individually give 77.3% and 24.9% of the relevant because they affect the different same count concentration, respectively. regions or time points in a similar manner. TEW scatter correction subtracts counts However, the choice of corrections is an from the data prior to reconstruction, Figure 5. Operational steps required to perform quantitative SPECT. issue in absolute SPECT quantification. which explains the low values when

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QUANTITATIVE SPECT the image, stopping the reconstruction Visual assessment of the data in Figure QUANTITATIVE SPECT early means that the quantitative values 7(a) shows the expected progress in the are not consistent within the image and formation of the image with increasing between imaging studies. Furthermore, numbers of iterations and subsets. In the stopping point may be different at the central panel which is at 5 iterations different imaging centres, or with different and 10 subsets, the image appears to be SPECT systems. Fortunately, these issues completely resolved. This is supported can be overcome by having a later by Figure 7(b), where striatal uptake has stopping point in the reconstruction plateaued. Typically, reconstructions are to ensure that the reconstruction stopped before this number of iterations consistently reaches the correct answer in and subsets. Figure 7(c) also shows the the image, with any excess noise handled increasing level of noise in the data, Figure 6. I-123 ioflupane SPECT images reconstructed with iterative reconstruction and: attenuation by a post- reconstruction smoothing although the use of a post-reconstruction correction, scatter correction and resolution modelling (ACSCRM); attenuation and scatter correction filter. Figure 7 shows how the change in filter controls the increasing levels of (ACSC); attenuation correction (AC); scatter correction (SC); and no corrections (NO). Filtered back-projection iteration number changes the quantitative noise to a point where it again plateaus reconstruction with no corrections (FBP (NO)) and striatal count concentrations normalised to the value value and the noise in the image. just beyond 5 iterations and 10 subsets. from all corrections (ACSCRM) are also shown.

scatter correction is used. The use of no uses multiple estimates of the image, corrections, be it with iterative or filtered making comparisons with the projection back-projection reconstruction, produces data that has been acquired (18). With low striatal count concentrations. While each iteration, the reconstruction updates it might be considered that calibration to a better estimate and provides a more using matching sets of calibrations would accurate quantitative value in the image. Figure 7 (a). I-123 ioflupane overcome the differences, it is clear from However, the technique gets noisier with SPECT images reconstructed with visual interpretation that such a calibration increasing number of iterations, so it is increasing number of iterations and would affect different regions in different normal to stop at a point at which the subsets in the OSEM reconstruction. ways. This creates considerable challenges image is acceptable from a noise and Charts showing the change in in terms of the choice of corrections and contrast perspective. As a consequence, quantitative value in the lesion (b), calibrations to be used. the value of uptake may not be accurate. and the increasing level of noise in A second area where quantitative SPECT Given that the convergence (the rate the background (c) with increasing can differ between users is in the use of at which the iterative reconstruction number of EM-equivalent iterations. iterative reconstruction. Reconstruction reaches the correct answer) changes EM-equivalent iterations is the using iterative techniques such as OSEM from image to image and indeed within product of iterations and subsets

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QUANTITATIVE SPECT Visually, the noise is acceptable throughout result in an underestimation of the SUV will also be a spill-in of counts from the motion in PET have been available for QUANTITATIVE SPECT the reconstruction series. This shows that it because of the partial volume effect, as surrounding area, but it does show the some time, solutions are more complex in is possible to iterate far enough to reach demonstrated in Figure 8a. Taking a profile known underestimation of volumes SPECT because of the rotating detectors convergence while keeping image noise through a small, medium and large feature within SPECT, and also why segmentation used. Nevertheless, algorithms are now to acceptable levels. represented by the solid box, the effect of techniques often define lesion boundaries starting to appear in this area too (21). One other aspect to be aware of spatial resolution represented by the red as around 40% of the maximum count with quantitative SPECT comes as a lines shows that for a large feature, the level. Figure 8(b) shows the effect on a

consequence of the limited spatial maximum intensity such as SUVmax will be NEMA image-quality phantom, where resolution available on such systems. For recovered, although the SUV mean will different-sized hot lesions containing ACCURACY AND PRECISION -99m imaging, reconstructed be reduced slightly because of the loss of the same activity concentration show Applying various corrections and spatial resolution is typically around resolution at the edges. In the medium- different visual and quantitative values using an increasing number of iterations 8-10mm, although when using medium or sized feature, the maximum value within of uptake. As a consequence, users of during the reconstruction may improve high-energy collimators with Lu-177 and the region will again be recovered quantitative SPECT must be aware that accuracy by reducing the bias in a value, I-131 respectively, the spatial resolution while the mean value in the region is the uptake of small features in an image but as a consequence they may reduce can be worse. Using resolution modelling significantly underestimated, and in the will be underestimated. Note that because the precision, i.e. they can increase the in the tomographic reconstruction can small feature both the maximum and of edge effects, the mean value within the noise/uncertainty in the value. Careful improve the spatial resolution a little. mean values are under-represented. This region is always less than the maximum decisions should therefore be made Imaging of features less than 2.5 times simple example does not demonstrate value. regarding what is needed from the the spatial resolution of the system will activity outside the region, where there Partial volume correction algorithms are imaging investigation. Figure 9 (a) shows available that help correct for these types a cross-sectional study where the data has of effects (19). Partial volume issues are been reconstructed using two methods – a challenge in both PET and SPECT, and one with low bias but low precision, and although correction algorithms have so the second with a larger bias (inaccuracy) far been used mostly for PET applications, but better precision (lower uncertainty). algorithms are now also being used in The lower normal range cut-off point for Figure 8 (a) Three rectangular profiles SPECT . However, these types of correction both reconstructions is shown by the representing small, medium and large are almost exclusively used for research dashed lines. The figure demonstrates features with increased activity. The red applications. Motion correction is another that a higher precision (lower uncertainty) lines demonstrate the effect on apparent growing area of research in quantitative clearly places the value above the normal maximum and mean uptake due to the SPECT. Respiratory and cardiac motion value, while with the lower precision result limited spatial resolution of SPECT (b) A can cause a significant degradation in the it is unclear whether the value is normal phantom experiment with technetium- achievable spatial resolution of a system, or not. Similarly, in Figure 9(b), which 99m showing the apparent differences in with the motion blurring out an image shows repeat longitudinal measurements visual and quantitative uptake in features taken over multiple respiratory and/or pre and post intervention, the lower due to the partial volume effect. cardiac cycles. Although corrections for uncertainty makes it clearer whether

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QUANTITATIVE SPECT there has been a real change in value. definition for quantitative SPECT. As a QUANTITATIVE SPECT Of course, the ideal would be very low consequence, quantitative image data bias and very high precision. In SPECT is proprietary to the system, and not as in PET, however, the incorporation of transferrable to PACS for reporting or reconstruction corrections and the use of review. While some independent software more iterations brings more uncertainty platforms are capable of reading this into the measurement. proprietary data, this issue needs to be resolved for the technology to be a success.

STANDARDISATION AND Figure 9 (a) Bar charts showing a cross-sectional measurement using a technique with low bias and low HARMONISATION precision (light blue), and high bias and high prevision (dark blue). The normal values for each measurement Having different values of uptake from CLINICAL IMPLEMENTATION OF are shown as a dashed line in each colour. While a low bias may give a more accurate value, low precision different sites and systems is clearly not QUANTITATIVE SPECT gives uncertainty whether the value is normal or abnormal, while higher precision clearly shows the value to helpful if normative comparative values At the time of writing there are four be normal. (b) The same low bias low precision and high bias high precision data shown in a longitudinal are required in cross-sectional studies, general quantitative SPECT platforms, study, pre and post intervention. Once more the low precision gives uncertainty in how the disease has nor is it helpful in follow-up studies if the which will be presented in alphabetical progressed while the high precision measurements show treatment response. results are acquired on different systems order below. or at different sites. As with PET, there is GE Healthcare have their Q.Volumetrix quantitative SPECT data irrespective of correction, motion correction and therefore a clear need for harmonisation. MI suite, which takes injected activity data the SPECT manufacturer so long as they resolution modelling are incorporated For centres involved in multi-centre trials, and body habitus data at the scanner have a sensitivity factor for the required into the iterative reconstruction, which or in single-centre research studies, core and a planar sensitivity factor for each radionuclide and collimator information together with volume sensitivity labs or principal investigators will often radionuclide to provide reconstructed data to perform resolution modelling. CT measurements for each radionuclide stipulate parameters to ensure consistency in terms of activity concentration and SUV. attenuation correction, Monte Carlo produces images of activity concentration in data (22). It has also been shown that this The reconstruction uses OSEM iterative scatter correction and motion correction or SUV. Operationally, injection information approach can work in quantitative SPECT reconstruction and applies CT attenuation, are also available. Here again, patient and body habitus information are entered (23). It is hoped that guidelines and/or dual/triple energy window scatter injection and body habitus information in the software. MIM also extend this accreditation such as that defined by EARL correction and resolution modelling. are required to create images of activity concept further to include dosimetry for PET applications will result in more Some of these factors can be turned off, concentration and SUV, which in this tools in their SurePlan software, which has consistent and comparable quantification but it is recommended that they are all instance are entered at the processing the capability to produce dose maps and of SPECT data. left on for the best quantitative value. This workstation (Figure 10b). dose-volume histograms for molecular A final issue that is hampering the software will only accept projection data MIM in their SPECTRA Quant product radiotherapy applications (Figure 10c). standardisation of quantitative SPECT is from appropriate GE scanners (Figure 10a). again offer software that works with all Siemens have two products for beyond the control of users and sites. At Hermes Medical Solutions offer their SPECT systems. CT-based attenuation quantitative SPECT: xSPECT Bone, which the time of writing there is no DICOM Hybrid Recon package, which can create correction, energy window scatter is optimised for bone SPECT studies,

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SUMMARY QUANTITATIVE SPECT and xSPECT Quant which extends the Figure 10 (a) An Iodine-123 mIBG QUANTITATIVE SPECT application into theranostics. Once more, Absolute quantitative SPECT has the SPECT/CT study showing SUV and reconstructions include corrections for potential to become a powerful tool tumour volume metrics using GE attenuation, scatter correction (TEW) and in nuclear medicine. Its advantages Q.Metrix. (b) Day 0 and Day 1 Lu- resolution, although in this instance a in theranostics are obvious, while its 177 DOTATATE SUV SPECT images, conjugate gradient rather than a standard possibilities in bone SPECT and other quantitative reconstruction OSEM algorithm is used. The choice of a SPECT applications are growing. There are performed with Hybrid Recon conjugate gradient algorithm results in some challenges, however. At the time from Hermes Medical Solutions, quicker convergence than standard OSEM. of writing, the lack of a DICOM standard images displayed in Affinity Viewer xSPECT bone also incorporates extra- for quantitative SPECT is an impediment. (Image courtesy of Hermes Medical modal information from the CT in the form The consequential loss of PACS and Solutions). (c) Dose contours and of zone maps to give sharper definition general compatibility across various dose volume histograms following and determination of uptake within bone workstations for this data is problematic, a radionuclide therapy using MIM tissue, while xSPECT Quant includes an although it does not prevent reporting on Sureplan (Image courtesy of MIM option for a NIST-traceable calibration manufacturer-specific or manufacturer- Software Inc.) (d) A longitudinal source that automatically calibrates the independent workstations. Other Tc-99m MDP series showing the system in terms of activity concentration. issues surrounding reconstruction and change in SUV in Rib and Scapula An alternative Tc-99m-based protocol is harmonisation are similar to those seen in bone lesions using xSPECT Quant also available for sensitivity calibrations PET, and operational issues are relatively (Image courtesy of Siemens (Figure 10d). easy to overcome. Healthineers). SPECT has been a feature of nuclear medicine for some time now. The addition of absolute quantification elevates its usefulness and is generating increased interest in the modality.

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REFERENCES 11. Kuji I, Yamane T, Seto A, Yasumizu Y, Shiro- 20. Erlandsson K, Thomas B, Dickson J, Hutton 23. Peters SMB, van der Werf NR, Segbers M, van QUANTITATIVE SPECT QUANTITATIVE SPECT 1. Ritt P, Vija H, Hornegger J, Kuwert T. Abso- take S, Oyama M. Skeletal standardized uptake values BF. Evaluation of an OSEM-based PVC method for Velden FHP, Wierts R, Blokland K (J ). AK, et al. Towards lute quantification in SPECT. Eur J Nucl Med Mol Imag- obtained by quantitative SPECT/CT as an osteoblas- SPECT with clinical data. IEEE Nucl Sci Symp Med Im- standardization of absolute SPECT/CT quantification: ing. 2011;38(SUPPL. 1):69–77. tic for the discrimination of active bone aging Conf. 2010;2686–90. a multi-center and multi-vendor phantom study. EJN- 2. Kaneta T, Ogawa M, Daisaki H, Nawata S, metastasis in prostate cancer. Eur J Hybrid Imaging. 21. Vija A, Cachovan M. Automated Motion MMI Phys. 2019;6(1). Yoshida K, Inoue T. SUV measurement of normal ver- 2017;1(1):1–16. Correction in Quantitative SPECT Reconstruction: A tebrae using SPECT/CT with Tc-99m methylene di- 12. Armstrong AJ, Anand A, Edenbrandt L, Feasibility Study of a Method Framework Applied First phosphonate. Am J Nucl Med Mol Imaging [Internet]. Bondesson E, Bjartell A, Widmark A, et al. Phase 3 as- to Bone Imaging. J Nucl Med. 2017;58(Supplement 2016;6(5):262–8. Available from: www.ajnmmi.us sessment of the automated bone scan index as a 1):703. 3. Brady SL, Shulkin BL. Analysis of quantita- prognostic imaging biomarker of overall survival in 22. Dickson JC, Tossici-Bolt L, Sera T, De Nijs R, tive [I-123] mIBG SPECT/CT in a phantom and in pa- men with metastatic castration-resistant prostate can- Booij J, Bagnara MC, et al. Proposal for the standardisa- tients with . EJNMMI Phys. 2019;6(1). cer a secondary analysis of a randomized clinical trial. tion of multi-centre trials in nuclear medicine imaging: 4. Ballinger JR. Theranostics and precision JAMA Oncol. 2018;4(7):944–51. Prerequisites for a European 123I-FP-CIT SPECT data- 13. Umeda T, Koizumi M, Fukai S, Miyaji N, base. Eur J Nucl Med Mol Imaging. 2012;39(1):188–97. medicine special feature : Review Article Theranostic Motegi K, Nakazawa S, et al. Evaluation of bone met- radiopharmaceuticals : established agents in current use. Br J Radiol. 2018;91(December 2017):20170969. astatic burden by bone SPECT/CT in metastatic pros- 5. Welsh JS, Kennedy AS, Thomadsen B. Se- tate cancer patients: defining threshold value for total lective internal (SIRT) for me- bone uptake and assessment in -223 treated tastases secondary to colorectal adenocarcinoma. Int patients. Ann Nucl Med [Internet]. 2018;32(2):105–13. J Radiat Oncol Biol Phys. 2006;66(SUPPL. 2):62–73. Available from: http://dx.doi.org/10.1007/s12149-017- 6. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, 1224-x Hays MT, Koral KF, et al. MIRD pamphlet no. 16: Tech- 14. Bailey DL, Willowson KP. An evidence-based niques for quantitative radiopharmaceutical biodistri- review of quantitative SPECT imaging and potential bution data acquisition and analysis for use in human clinical applications. J Nucl Med. 2013;54(1):83–9. radiation dose estimates. J Nucl Med. 1999;40(2):37– 15. Boellaard R, Delgado-Bolton R, Oyen WJG, 62. Giammarile F, Tatsch K, Eschner W, et al. FDG PET/CT: 7. Dewaraja YK, Frey EC, Sgouros G, Brill AB, EANM procedure guidelines for tumour imaging: ver- Roberson P, Zanzonico PB, et al. MIRD pamphlet no. 23: sion 2.0. Eur J Nucl Med Mol Imaging. 2014;42(2):328– Quantitative SPECT for patient-specific 3-dimensional 54. dosimetry in internal radionuclide therapy. J Nucl Med. 16. Rahmim A, Qi J, Sossi V. Resolution mod- 2012;53(8):1310–25. eling in PET imaging: Theory, practice, benefits, and 8. Suh MS, Lee WW, Kim YK, Yun PY, Kim SE. pitfalls. Med Phys. 2013;40(6):1–15. Maximum standardized uptake value of 99mTc hy- 17. Nuyts J. Unconstrained image reconstruc- droxymethylene diphosphonate spect/ct for the eval- tion with resolution modelling does not have a unique uation of temporomandibular joint disorder. Radiolo- solution. EJNMMI Phys. 2014;1:98. gy. 2016;280(3):890–6. 18. Hudson HM, Larkin RS. Ordered Sub- 9. Duncan I, Ingold N. The clinical value of sets of Projection Data. IEEE Trans Med Imaging. xSPECT/CT Bone versus SPECT/CT. A prospective com- 1994;13(4):601–9. parison of 200 scans. Eur J Hybrid Imaging. 2018;2(1). 19. Thomas BA, Cuplov V, Bousse A, Mendes 10. De Laroche R, Simon E, Suignard N, Williams A, Thielemans K, Hutton BF, et al. PETPVC: A toolbox T, Henry MP, Robin P, et al. Clinical interest of quantita- for performing partial volume correction techniques tive bone SPECT-CT in the preoperative assessment of in tomography. Phys Med Biol. knee osteoarthritis. Med (United States). 2018;97(35). 2016;61(22):7975–93.

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BONE SCINTIGRAPHY

by Vladimir Vukomanovic, Vesna Ignjatovic, Marija Jeremic, Nenad Mijatovic and Milos Stevic

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INTRODUCTION TO BONE SCINTIGRAPHY BONE SCINTIGRAPHY RADIONUCLIDE BONE IMAGING is usually performed 2-5 hours after tracer injection and reflects the rate of Various bone conditions, whether neoplastic or of other origin, lead to bone turnover. This delay allows optimal multifactorial and complex processes that involve reciprocal interplay clearance and higher uptake of the tracer, between osseous cells, surrounding tissue and the stroma itself. Early producing an adequate target/non-target detection of skeletal disorders is crucial for accurate staging and the ratio. implementation of adequate therapeutic options, in order to reduce the The most common bone scan risk of complications and improve quality of life. indications are primarily imaged using Over the past decades, advances in the understanding of osseous the delayed phase protocol only, which is pathology have led to the development of various diagnostic modalities. mainly used in oncology studies. Among the imaging techniques currently available, the most frequently A bone scan is usually acquired performed modality for detection of osseous involvement is radionuclide using a gamma camera in whole- bone scintigraphy. body scanner modality. Additionally, the nuclear medicine technologist can obtain planar anterior and posterior spot BONE SCINTIGRAPHY view images of the skeleton as needed. Skeletal scintigraphy, commonly make it a useful screening tool for many Single photon emission computed known as a “bone scan”, is a useful and pathological conditions of bones and tomography (SPECT) produces cross- Figure 1. Normal appearance of 99mTc-labelled versatile nuclear medicine method, and joints. sectional images in orthogonal planes, bisphosphonate “whole-body” scan has been established as a highly sensitive Although protocols vary among which facilitates both contrast and precise gold standard diagnostic tool for bone institutions, a bone scan is typically anatomical localisation. Although SPECT Normal scintigraphic findings pathology. One of the pathognomonic performed through three phases of is not generally performed as a stand- An understanding of the normal hallmarks of local bone remodelling imaging: alone modality, tomographic images are physiological distribution of radiolabelled is increased mineral turnover and the The 1st (dynamic) phase reflects the particularly useful for unequivocal imaging bisphosphonates is important for correct formation of calcium salts. A radionuclide angiogram and is obtained of skeletal tracer uptake, especially in interpretation of skeletal scintigraphy. bone scan is a special type of procedure for 60-90 seconds, immediately after anatomically complex structures such as Symmetrical and homogeneous tracer that uses technetium-99m-labelled i.v. administration of 99mTc-labelled spine and skull. The technologist should distribution throughout the osseous bisphosphonate compounds to pinpoint bisphosphonates (adults: 8-10 MBq/ repeat the procedure if the images are structures is the normal physiological the pathological condition which is kg/; children: EANM/SNMMI paediatric sub-optimal due to patient movement, finding in healthy adults, with clear causing increased osteoblastic activity. protocol). urinary contamination, or attenuation from delineation of the ribs and vertebral Although skeletal scintigraphy is not The 2nd (blood pool) phase is obtained jewellery, clothing or medical devices. structures. Furthermore, faint or specific (a wide range of pathological immediately after the flow phase for up to increased symmetrical areas of benign abnormalities produce osteoblastic 10 minutes, and reflects tracer activity that tracer uptake are present at the paired activity), its exceptional sensitivity, relative has extravasated into the soft tissue. joints (glenohumeral, acromioclavicular, inexpensiveness and wide availability The 3rd (delayed) phase of imaging sternoclavicular, sternomanubrial,

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BONE SCINTIGRAPHY sacroiliac and pubic symphysis, focal vs. linear or spindle-like. Since most Increased soft-tissue and extraosseous soft-tissue resolution of the marrow cavity BONE SCINTIGRAPHY acetabulofemoral, tibiofemoral and bone scans are performed as an integral tracer uptake of bisphosphonates must be and surrounding structures. patellofemoral, talocrural) and in the part of oncological disease staging taken into account, since the latter can be Since all bone imaging modalities have calvarial region, which corresponds and management, an experienced seen in various pathological conditions. strengths and weaknesses, hybrid imaging to hyperostosis frontalis in women technologist can precisely identify techniques such as SPECT/CT, PET/CT and (Figure 1). In children, intense symmetric patterns of osseous metastases. The Other bone imaging techniques PET/MR increase sensitivity, specificity and uptake in the physes of the long bones presence of multiple, randomly increased Although bone scan is highly sensitive accuracy. As a result, the technologist can represents the normal growth centres. tracer uptake, varying in size, shape and for skeletal disorders, the modality itself determine if abnormal radionuclide uptake The accumulation of tracer in the intensity, is highly suggestive of bone is not specific and may require further corresponds to suspicious osseous lesion above-mentioned anatomical structures metastases and requires no further clarification with other imaging modalities. on cross-sectional imaging. The highest generally decreases with age. clarification. Traumatic and degenerative Compared to conventional , diagnostic yield for skeletal pathology disorders can differ from metastatic bone scintigraphy is a sensitive technique can therefore be obtained by using a Critical scintigraphic findings disease by virtue of their characteristic which enables osseous lesions to be combination of these imaging modalities. Abnormalities on bone scan are distribution and location. detected up to several months earlier. indicated as areas of increased focal Extraosseous activity can be seen as Positron emission tomography (PET) is tracer uptake which reflect generally faint renal and minimal soft-tissue activity. superior to conventional bone scan in terms increased bone mineral turnover, with Due to the normal renal tracer excretion, of providing quantitative standardised RADIOPHARMACEUTICALS FOR higher sensitivity for osteoblastic than urinary bladder is also normally present uptake value (SUV) and a higher spatial BONE LESION ASSESSMENT for osteolytic bone lesions. Accurate on scans. Absence of renal and bladder resolution. The radiopharmaceuticals interpretation can be particularly difficult activity should raise suspicion of a so- which are most frequently used in PET 99mTc-diphosphonates without adequate clinical experience, called “superscan”, which corresponds bone studies are sensitive for osteoblastic 99mTc-labelled diphosphonates are the and should not be confidently assigned to diffusely increased osseous uptake and osteolytic bone lesions. PET skeletal most widely used radiopharmaceuticals. to a definite pathology. Bone scans throughout much or all of the skeleton imaging continues to evolve, and will 99mTc decays by isomeric transition with should therefore be performed under the due to metastatic disease. almost certainly become increasingly a half-life of 6.02 h to 99Tc by emitting supervision of a physician specialising in A variety of conditions can often important in the future. one 140.5-keV per decay. nuclear medicine. manifest as areas of decreased tracer To improve specificity, complementary The molecules most commonly used The nuclear medicine technologist, uptake, such as metastatic osteolytic imaging modalities such as computed for performing bone scintigraphy are however, must take into account the disease or the late phase of radiation tomography (CT) and magnetic methylene diphosphonate (MDP), shape and location of the tracer uptake osteitis after radiation therapy. On the resonance (MR) are often performed to hydroxymethylene diphosphonate (HMDP) in order to quickly recognise areas of other hand, chemotherapy affects bone provide additional structural anatomical or hydroxyethylene diphosphonate increased activity, so-called “hot spots”. scan findings by means of increased information on bone remodelling. (HDP), and 2,3-dicarboxypropane-1,1- Moreover, the technologist can assess intensity or the appearance of new foci Contrast-enhanced CT enables the diphosphonate (DPD). the tracer uptake pattern: monostotic as a result of bone matrix regeneration visualisation of cortical and trabecular Pharmacokinetics: The injected vs. polyostotic, axial vs. appendicular, responding to treatment (“flare” bone with high resolution, while MR radiolabelled diphosphonates adsorb to periarticular vs. metaphyseal-diaphyseal, phenomenon). imaging can be used to obtain excellent the surface of hydroxyapatite crystals in

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BONE SCINTIGRAPHY proportion to local bone vascularisation adults, but may be increased to 11–13 and etidronic acid: stop 2 weeks before hydroxyapatite crystal of bone to form BONE SCINTIGRAPHY and osteoblastic activity. After intravenous MBq/kg. For children, the administered scintigraphy. fluoroapatite. administration, the clearance from the activity is based on body weight according Tetracycline antibiotics: stop at least 2 h 2F- + Ca 10(PO4) 6(OH) 2 −> Ca 10(PO4)6F2 vascular compartment is fast, with half to the guidelines of the European before scintigraphy. + 2OH- times of 2–4 min. Peak uptake varies for the Association of Nuclear Medicine (EANM)/ Medication containing iron: increased The skeletal uptake of 18F- different agents, but is usually around 1 h. SNMMI Paediatric Dosage Harmonization extraossal accumulation of the (NaF) is quite high, approximately 70%, Four hours after injection, approximately Working Group. The typical paediatric radioisotope has been reported for iron- and 25% is excreted in the urine by 6 h. As 50 to 60% of the injected amount is fixed dose is 170–210 MBq (~4–6 mCi), with a containing ingredients. regards imaging time, the fluoride scan in the skeleton, the unbound fraction minimum of 20–40 MBq (0.5–1.0 mCi) and Drugs containing aluminium, notably can be completed within 2 h of 18F-sodium (34%) is excreted in the urine, and only 6% a maximum not exceeding the maximum antacids, may lead to abnormally fluoride administration. Since the plasma remains in circulation. for a healthy adult. high accumulation of 99mTc in the liver, protein binding of 18F-NaF is low, fluoride The diphosphonates listed above are Optimal imaging is 2–4 h after tracer presumably caused by the formation of ions are freely filtered in the glomeruli. commercially available and supplied in administration. At this time point about labelled colloids. Fluoride, however, also undergoes tubular a vial containing the diphosphonate, one third of the administered dose is reabsorption. As a result, renal clearance of a stannous reducing agent and other bound to bone, one third is excreted in the 18F-sodium fluoride 18F-NaF is dependent on overall urinary flow, excipients in the form of a powder ready urine and the remainder is associated with The mechanism of uptake of 18F-sodium because tubular reabsorption of fluoride for labelling. The radiopharmaceutical other tissues. Of the administered activity, fluoride is similar to other bone tracers increases with decreasing glomerular filtration is prepared by addition of the required approximately 30% is cleared within the used in nuclear medicine and depends rate. Therefore, it is recommended that amount of sodium first hour, 48% within 2 h and 60% within on regional blood flow and osteoblastic patients undergoing 18F-sodium fluoride PET diluted in sterile physiological saline 6 h. Renal excretion is the primary route activity. It is preferentially deposited be well hydrated to reduce radiation exposure. to the vial in accordance with the for elimination; the renal elimination rate by chemisorption onto bone surfaces, With 18F-sodium fluoride and manufacturer’s instructions. Because the of 99mTc-diphosphonates depends mainly exchanging with hydroxyl groups in dynamic PET imaging, certain radiopharmaceutical is susceptible to on glomerular function. Tracer elimination oxidation, care should be taken to avoid through the is PRINCIPAL ADMINISTERED introducing air into the multidose vial insignificant. PHYSICAL CHEMICAL RADIONUCLIDE PHOTON ACTIVITY IN during preparation or removal of doses. Adverse reactions to the injection of HALF- LIFE FORM ENERGY (KEV) ADULTS (MBQ) The radiopharmaceutical should be used the radiopharmaceutical are virtually non- within 6 h of preparation unless allowed existent. The reported incidents are usually otherwise by the manufacturer. For bone related to other agents in the kits that are 18F 1.8h Fluoride 511 110-370 scintigraphy in adults, the average activity necessary for stabilisation, e.g. pH buffers, administered by a single intravenous reducing agents to keep technetium in the 99m injection should be 300 – 740 MBq (8 – allowed valence state, and/or metabolites. Tc 6h MDP, HDP, HMDP 140 600-800 20 mCi). The administered activity usually Interactions: ranges between 8 and 10 MBq/kg for Bisphosphonates – clodronic acid Table 1: Diagnostic radionuclides for bone scintigraphy

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BONE SCINTIGRAPHY physiological and biochemical bone thalassaemia); BONE SCINTIGRAPHY parameters can be measured in vivo. » Rheumatology: rheumatoid arthritis, Figure 3. Primary bone These quantitative indices are the spondyloarthropathies and related dis- tumour of the left iliac measurement of local bone blood flow orders, osteoarthritis, osteonecrosis and bone, from its ridge to the and fluoride influx rate.18 F-fluoride is bone infarction; projection of the anterior injected intravenously; activity for adults is » Diagnosis of infectious lesions, such as inferior iliac spine. 185–370 MBq (5–10 mCi). A higher activity osteomyelitis and spondylodiscitis; A. “Whole-body” modality. may be used in obese patients. Paediatric » Exploration of unexplained symptoms. B. Spot scintigram of the activity should be weight-based: 2.22 Usefulness of each modality in terms of pelvic region. C. RTG of the MBq/kg (0.06mCi/kg), using a range of diagnosis left iliac bone D. MSCT of 18.5–185 MBq (0.5–5mCi) the left iliac bone.

SPECIFIC TECHNIQUES AND THEIR USEFULNESS IN ONCOLOGICAL AND NON- ONCOLOGICAL DIAGNOSIS List of most common indications for bone scintigraphy » Oncology: primary bone tumours and bone dysplasia (osteosarcoma, osteoid osteoma, osteoblastoma, fibrous dyspla- sia, giant tumour and osteopoikilosis) and metastatic disease (prostate, breast, lung, renal cancer and paraneoplastic syn- dromes); » Orthopaedics, sports & traumatology: periostitis, enthesopathies, spondylolis- thesis, stress-related and insufficiency fractures; » Paediatrics: osteochondritis of the hip (Legg-Calvé-Perthes disease) transient Figure 2. Multiple secondary deposits of synovitis of the hip, battered child syn- prostate adenocarcinoma. The multiple foci of Figure 4. Paget’s disease of the second Figure 5. Trauma to the anterior portions drome, bone infarction (sickle cell disease, high tracer uptake in the skeleton. "Whole-body" lumbar vertebra (Mickey Mouse Sign). “Whole- of the 7th, 8th, 9th and 10th ribs. “Whole- modality body” modality. body” modality.

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THE SPECIFIC ROLE OF BONE SCINTIGRAPHY BONE SCINTIGRAPHY THE NUCLEAR MEDICINE water, and urinate regularly. After this TECHNOLOGIST IN BONE period, the patient is told to empty the SCINTIGRAPHY urinary bladder, and is called to a room with a gamma camera where whole-body The nuclear medicine technologist scintigraphy will be performed. performs an important role in skeletal Prior to scintigraphy, the patient should scintigraphy, starting from the patient remove all metal objects such as belt, reporting to the nuclear medicine watch, glasses, jewellery, etc. Then the department in order to confirm the patient is instructed to lie down on his/her correct diagnosis and the degree of back, with hands next to the body and legs urgency for performing the procedure. horizontal; he/she must remain motionless After completion of the examination, the and breathe normally. The technologist Figure 6. Monostotic fibrosis of the right iliac bone. (Jaffe-Lichtenstein Sy). A. "Whole-body" technologist obtains from the patient the checks whether the radiopharmaceutical modality. B, C and D. Three-phase bone scintigraphy basic information needed to determine has been administered using shield whether the procedure is feasible: partition as well as whether the patient » Does the patient suffer from claustro- has emptied his/her bladder. If the phobia?; radiopharmaceutical is administered » Can the patient lie on his/her back for 20 paravenously, the technician covers that min?; part of the arm with lead foil and checks » Is the patient pregnant or planning a if valid diagnostic information can be pregnancy, or is she breastfeeding a baby?; obtained. If a valid scintigram cannot be » Check if the patient is allergic to any obtained, a re-scan is scheduled. If the ; patient has not emptied his/her bladder, » Blood pressure and body temperature he/she is asked to urinate again. should be measured. Scanning usually takes 20 minutes. If, The technologist then explains due to inability to urinate, the bladder the procedure to the patient before has covered a large part of the pelvis, administering a specific dose of then scintigraphy in SPECT or SPECT/CT radiopharmaceuticals, based on body modality can be performed; this is decided weight and patient age. The patient by a nuclear medicine specialist. After the now has to wait in a separate room for scintigraphy has been completed, the a minimum of 2 hours before the scan patient is instructed on further behaviour takes place. During this time the patient for the next 24 hours: children and Figure 7. Three-phase bone scintigraphy. Left foot osteomyelitis and right ankle injury. A. “Whole- is allowed to eat, take his/her regular pregnant women should be avoided, body” modality. B, C and D. Three-phase bone scintigraphy modality. B, C and D. Three-phase bone therapy, preferably drink at least 1L of keeping a distance of at least 2 metres and scintigraphy

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BONE SCINTIGRAPHY not spending too long in the same room. Planar scintigraphy the contrast to facilitate the physician’s 512x512, the number of counts depending BONE SCINTIGRAPHY The toilet should be flushed twice every Planar scintigraphy has very wide analysis of the images. on the region under investigation: at time. If the patient is breastfeeding, she applications in almost all nuclear medicine least 700,000 to 1,000,000 counts for the must be told to delay breastfeeding for at procedures. Depending on the diagnostic Three phase bone scintigraphy thoraco-abdominal region, 250 000 to least 4 hours. information requested, various collimators Three phase bone scintigraphy starts 400 000 counts for the large joints and can be used. Low-energy, high-resolution with the so-called “angiographic phase”, skull, and 150 000 to 250 000 counts for parallel-hole collimators are most i.e. a fast dynamic scan immediately the distal joints, depending on the field of RESPONSIBILITIES OF commonly used in routine work, although after intravenous application of the view of the gamma camera. In this phase THE NUCLEAR MEDICINE other collimator types may be used for radiopharmaceutical. The technologist SPECT or SPECT/CT imaging can also be TECHNOLOGIST IN lower energies. The matrix size should places the patient in the correct position performed, depending on the type of PREPARATION OF THE IMAGING be 256x256 or 512x512. The nuclear on the gamma camera so that the area gamma camera available. EQUIPMENT medicine specialist (physician) decides of interest is in the centre of the detector whether or not to switch the zoom field of view. The dynamic scan starts at Whole-body scintigraphy option ON. The duration of the scan can the same moment as administration of the Whole-body (WB) scanning is a routine be determined by the number of counts radiopharmaceutical, using the following SPECT AND SPECT/CT SCANS and common procedure for bone registered, or by time. In routine work, the parameters: photo peak at 140 keV±10%, Depending on the requirements of scintigraphy for which low-energy, high- number of counts collected is usually 500 matrix size 128x128, 32 to 64 frames, the nuclear medicine specialist and the resolution, parallel-hole (or all-purpose) 000, but 300 000 counts can be used for duration of frames 2 to 3 s each. This phase available options on the gamma camera, collimators are used. The energy window arm, hand, foot or some another lateral is also called the “flow phase”. acquisition of SPECT or SPECT/CT scans should be centred at 140 keV with the patient positions. These specifications The second phase is also called the is sometimes necessary on some region window width between 15% and 20%. are for standard single-head or dual-head “blood pool phase “. Scanning starts 1 of the patient’s body. It is difficult to give The matrix size should be 1024x256 or gamma cameras. to 10 min after administration of the general recommendations for scanning 2048x512. A scan speed of 12 cm/min For some small lesions, the nuclear radiopharmaceutical. The recommended parameters in this situation. Depending on is recommended (although it can range medicine specialist can request a pinhole duration of the scintigraphy is 3 to 5 min, the kind of camera and its performance/ from 8 cm/min to 12 cm/min, depending collimator. These collimators have a with a matrix size of 256x256 or 512x512. the area to be scanned, parameters for on the manufacturer and performance high resolution and a small field of view. Quantification is performed using the a typical dual-head camera could be as of the gamma camera) with the auto- The following acquisition parameters region of interest (ROI) method, where follows: matrix size 256x256, 64 frames contour option ON. The scan is performed are recommended: photo peak at 140 uptake in target tissues is compared with per detector head, each with a duration of in anterior and posterior projections. Before keV±10%, matrix size 256x256 or 512x512, uptake in healthy surrounding tissues. 10 to 30 s for each detector position. The scanning, the technologist checks whether and total number of counts 100 000. The third phase is the “delayed phase “, duration of frame depends on the size of all criteria are fulfilled and adjusts the scan Planar images do not require special which is conducted 2 to 5 hours after initial the region, its anatomical localisation and length to the patient’s height. The majority processing, although contrast and colour administration of the radiopharmaceutical. uptake in the surrounding tissues and of devices are pre-set to a scan length of can be adjusted according to the nuclear Various imaging methods can be used organs. 200 cm, but this can be adjusted in order to medicine specialist’s instructions. The in this phase, one option being planar reduce the time required for scanning. option threshold can be used to adjust scintigrams with matrix size 256x256 or

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CHAPTER REFERENCES TP, Palestro CJ. Radionuclide bone imaging: an illustra- BONE SCINTIGRAPHY BONE SCINTIGRAPHY If the nuclear medicine specialist insists and milliamperes should be examined to 1. Agrawal K, Marafi F, Gnanasegaran G, Van tive review. RadioGraphics 2003;23(2):341-58. on SPECT/CT acquisition, CT should be assess how they affect the patient dose. der Wall H, Fogelman I. Pitfalls and limitations of radio- 13. Mattsson S, Johansson L, Leide Svegborn S, et al. Radiation Dose to Patients from Radiopharma- done immediately after SPECT if the Local diagnostic reference levels (DRL) planar and hybrid bone imaging. Semin Nucl Med 2015;45(5):347-72. ceuticals: a Compendium of Current Information Re- patient is still on the table. The field of view may be applied, if established in the 2. Bartel TB, Kuruva M, Gnanasegaran G, et al. lated to Frequently Used Substances. ICRP Publication (FOV) of hybrid devices is large, and the country or hospital in question. SNMMI procedure standard for bone scintigraphy 4.0. 128. Ann ICRP 2015;44(2 Suppl):7-321. default option is the same FOV for CT as for It is recommended that reconstruction J Nuc Med Technol 2018;46(4):398-404. 14. McDougall IR. Skeletal scintigraphy. West J Med 1979;130(6):503–14. SPECT acquisition. The nuclear medicine be performed with the three-dimensional 3. Blake GM, Park-Holohan SJ, Cook GJ, Fogel- man I. Quantitative studies of bone with the use of 15. Nakamoto Y, OsmanM, Wahl RL. Prevalence specialist should be consulted about the ordered-subset expectation maximization 18F-fluoride and 99mTc-methylene diphosphonate. and patterns of bone metastases detected with posi- FOV for CT, and if possible, the latter should iterative algorithm (OSEM), including Semin Nucl Med 2001;31:28–49. tron emission tomography using F-18 FDG. Clin Nucl be reduced to optimise the dose received corrections for attenuation and scattering. 4. Beheshti M, Mottaghy FM, Paycha F, et Med 2003;28:302–7. 16. O’Sullivan GJ, Carty FL, Cronin CG. Imag- by the patient during the examination. Typically, three or five iterations are al. (18)F-NaF PET/CT: EANM procedure guidelines for bone imaging. Eur J Nucl Med Mol Imaging ing of : an update. World J Radiol For SPECT/CT acquisition the following necessary and eight to ten subsets. 2015;42:1767–77. 2015;7(8):202-11. parameters are recommended: matrix Reconstructed images are shown as two- 5. Even-Sapir E, Metser U, Flusser G, et al. As- 17. Rager O, Nkoulou R, Exquis N, et al. Whole- Body SPECT/CT versus Planar Bone Scan with Target- size 256x256, 32 or 64 frames per detector dimensional cross-sections in the axial, sessment of malignant skeletal disease: initial experi- ed SPECT/CT for Metastatic Workup. Biomed Res Int head respectively, each with a duration of coronal and sagittal plane together with ence with18F-fluoride PET/CT and comparison be- tween 18F-fluoride PET and 18F-fluoride PET/CT. J Nucl 2017;2017:7039406. 10 s to 30 s, with a tube voltage of 80–130 the cross-section obtained by CT fusion Med 2004;45:272–8. 18. Sleiman Y. Naddaf, B. David Collier, Abdelha- kV and an intensity–time product of 2.5 to imaging, but they could also be shown 6. Fogelman I, Gnanasegaran G, Van der Wall mid H. Elgazzar, Magdy M. Khalil. Technical Errors in Pla- nar Bone Scanning. J Nucl Med Technol 2004;32:148- 300 mAs, depending on the anatomical separately. H. Radionuclide and hybrid bone imaging. Berlin: Springer; 2013. 53. region being scanned. Optimisation 7. Heindel W, Gübitz R, Vieth V, Weckesser M, 19. Talbot JN, Paycha F, Balogova S. Diagno- factors such as small variations in voltage Schober O, Schäfers M. The diagnostic imaging of bone sis of bone metastasis: recent comparative studies metastases. Dtsch Ärzteb Int 2014;111(44):741–7. of imaging modalities. Q J Nucl Med Mol Imaging 8. Helyar V, Mohan HK, Barwick T, et al. The 2011;55(4):374-410. added value of multislice SPECT/CT in patients with 20. Van den Wyngaert T, Strobel K, Kampen WU, equivocal bony metastasis from carcinoma of the pros- et al. The EANM practice guidelines for bone scintigra- tate. Eur J Nucl Med Mol Imaging 2010;37(4):706-13. phy. Eur J Nucl Med Mol Imaging 2016;43(9):1723-38. 9. Horger M, Bares R. The role of single-photon 21. Yang DC, Ratani RS, Mittal PK, Chua RS, Pate emission computed tomography/computed tomogra- SM. Radionuclide three-phase whole-body bone imag- phy in benign and malignant bone disease. Semin Nucl ing. Clin Nucl Med 2002;27:419–26. Med 2006;36(4):286-94. 22. Vaño E, Miller DL, Martin CJ, et al. Diagnostic 10. International Atomic Energy Agency. Safety reference levels in . ICRP Publication Standards for protecting people and the environment. 135. Ann ICRP 2017;46(1)1-144. and Safety of Radiation Sources: 23. Wu Q, Yang R, Zhou F, Hu Y. Comparison of International Basic Safety Standards. General Safety Re- whole-body MRI and skeletal scintigraphy for detec- quirements Part 3, Viena: IAEA; 2014. tion of bone metastatic tumors: a meta-analysis. Surg 11. International Atomic Energy Agency. Oncol 2013;22:261–6. IAEA-TECDOC-1782. Good Practice for Introducing Ra- diopharmaceuticals for Clinical Use. Viena: IAEA; 2016. 12. Love C, Din AS, Tomas MB, Kalapparambath

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LUNG IMAGING

by Bożena Birkenfeld, Jacek Iwanowski and Monika Gawron

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INTRODUCTION LUNG IMAGING in an adult human is approximately 5 benign pulmonary pathology, most often LUNG IMAGING The lungs are a pair of organs located in the chest, constituting the human litres. Bronchoscopy and endobronchial for pulmonary embolism. . Their primary function is gas exchange, i.e. providing ultrasonography (EBUS) are procedures 3. Lung hybrid imaging techniques. oxygen to the human body and removing carbon dioxide. They are also a used for direct assessment of the bronchial Metabolic/functional and morphological filter preventing pollution and other undesirable substances from entering tree, allowing sampling of abnormal or tomographic imaging techniques: single the body. Lungs are necessary for life. suspicious lesions for histopathological photon emission computed tomography The right lung consists of three lobes: upper, middle and lower, divided examination. A similar diagnostic (SPECT), SPECT combined with CT (SPECT/ by a horizontal and oblique fissure. The left lung is smaller than the right technique is percutaneous lung lesion CT), positron emission tomography one and consists of two lobes: upper and lower, separated by an oblique biopsy. combined with CT (PET/CT), positron fissure. Respiratory airways, the and the lymphatic Additionally, various imaging modalities emission tomography combined with MRI system with lymph nodes are located within the lungs. are used for the diagnostic assessment (PET/MRI) done with different radiotracers and subsequent monitoring of lung – usually performed for the diagnosis of diseases. These are able to visualise the focal benign or malignant lung lesions. The air enters the lungs through the within them is impaired. This may be morphological structure of the organs trachea, which subsequently branches due to inflammatory infiltration, cirrhosis, and/or their or function. Lung morphological modalities into the primary bronchi, lobar, segmental atelectasis, tumour lesions or pulmonary Pulmonary diseases which can be Chest x-ray is a simple diagnostic tool and interlobular bronchi, bronchioles, embolism. Pathological changes in visualised by imaging are usually those used in detection and diagnosis of lung and alveoli. Blood is transferred to each the lungs may occur in their individual affecting the parenchyma, the vascular diseases. It is cheap, widely available and lung through a large pulmonary blood components, the respiratory tract, blood and/or bronchial tree and the lymph involves low exposure to ionising radiation. vessel, the right and left pulmonary vessels and in the lymphatic system. Lung nodes. High-resolution computed artery and vein. These divide into lobar lesions can be benign or malignant. The following imaging modalities are tomography (HRTK) has revolutionised and segmental vessels and subsequently applied to diagnose lung diseases: the imaging of chest and lung lesions and into smaller vessels, which constitute 1. Lung morphological modalities: is currently the basic imaging modality. the capillary circulation surrounding the chest x-ray, high-resolution computed It is done in several variants: high-dose, alveoli where gas exchange occurs. IMAGING MODALITIES FOR THE tomography, computed tomography an- low-dose, and with or without contrast An anatomical unit of the lung smaller ASSESSMENT OF PULMONARY giography, pulmonary , lung medium. The technique images the lung than the lobe is the segment, supplied DISEASES ultrasound, magnetic resonance tomogra- parenchyma, vessels, heart, mediastinum, by its own bronchus and artery. The right Diagnosis of pulmonary diseases is phy – usually performed for assessment of pleura, and chest wall. It has a very good lung consists of ten segments and the left based on clinical examination, laboratory structural lung disorders. resolution, scan time is short and the one has nine. assays, functional tests and imaging 2. Lung metabolic/functional image provides detailed data about the The borders between segments are modalities. Spirometry is a common planar imaging techniques: nuclear size, shape and location of lesions and their not visible under normal conditions. pulmonary function test performed to medicine imaging done with different anatomical relation to the surrounding Bronchopulmonary segments are visible assess the vital capacity of the lungs. radiopharmaceuticals: lung perfusion organs. It is sometimes performed without in imaging tests when they become Spirometry provides an assessment scintigraphy, lung ventilation scintigraphy contrast due to patient contraindications, airless and/or when blood circulation of the total lung capacity (TLC), which – usually performed for diagnosis of mainly impaired renal function, hence it is

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LUNG IMAGING obligatory to measure serum creatinine mediastinal tumours. The disadvantage tract, allowing the imaging of lung the atmosphere passes through the LUNG IMAGING if the use of contrast medium is planned of the test is its higher cost, relatively aeration. The substances commonly used filters, which retain the remainder of during the procedure. long acquisition time, frequent cases of are Technegas™, 99mTc-DTPA radioaerosol the radioaerosol. After a few minutes of Computed tomography pulmonary claustrophobia in patients and numerous or krypton-81 gas. inhalation with radioaerosol, the image angiography (pulmonary angioCT or contraindications, including the presence Technegas™ is most often used for can be obtained with a gamma camera. CTPA) with contrast shows blood flow in of bone prostheses, pacemakers and ventilation studies in departments of The disadvantage of this method is that the pulmonary vessels and is done to detect metallic implants. nuclear medicine. The Technegas™ deposition of aerosol on bronchiole walls pulmonary embolism. It has almost generator is a specially designed machine is quite frequently seen. Also, due to ciliary completely replaced the previously which produces an ultrafine suspension movement the aerosol is transported applied technique of pulmonary of carbon nanoparticles 30-100 nm in higher, and as a consequence the bronchi angiography, which is an invasive LUNG METABOLIC/ diameter, labelled with technetium. This and trachea are sometimes visible in the procedure. FUNCTIONAL PLANAR IMAGING is done by heating 99mTc-pertechnetate scintigraphy images. Occasionally, the Transthoracic ultrasound (US) of the TECHNIQUES in a graphite crucible in a pure argon swallowed radioaerosol can also be seen lungs is a non-invasive procedure used for atmosphere at very high temperatures of in the oesophagus and stomach. diagnosis of lesions in the mediastinum, Lung perfusion scintigraphy up to 2700°C. The resulting microaerosol Krypton-81m is also used for ventilation lungs and pleura, fluid in the pleural The test involves intravenous is inhaled by the patient in several imaging. It is an inert radioactive gas with a cavities, pneumothorax, pulmonary administration of radiopharmaceutical, breaths from a dedicated nebuliser so very short half-life of 13 seconds, delivered oedema, and also to assess pulmonary usually labelled with 99mTc- that the particle suspension is deposited from a -produced 81Rb/81mKr embolism. It is an alternative to imaging macroaggregated human albumin (99mTc- uniformly in the small bronchi and the generator. The imaging procedure can be procedures using ionising radiation MAA) with particles 10-100 micrometres in alveolar region, showing ventilation. In done simultaneously with or immediately when diagnosing pregnant women. This diameter. When the pulmonary circulation contrast to krypton-81 imaging, there is following a perfusion study, because the technique is very effective in performing is normal the particles are evenly no rush in visualising its distribution. A gamma energy of 81mKr is higher than that targeted biopsies of lung lesions and distributed in the pulmonary circulation ventilation study can be done at any time of 99mTc – 190 keV versus 140 keV. During removing fluid from the pleural cavity. and stop in the capillary circulation of the if a Technegas™ generator and technetium the test, the patient breathes continuously Magnetic resonance imaging (MRI) is lungs, causing temporary microembolism are available. with a mixture of air and 81mKr. The an increasingly popular procedure for the and thus enabling the imaging of lung For ventilation studies performed with limitations of the technique are the short diagnosis of chest pathologies, despite perfusion. If the circulation is impaired, 99mTc-DTPA-labelled aerosol, the latter is half-life of 81mKr and the high cost of the the difficulties of lung imaging due to the scan shows segmental defects in the obtained from a nebuliser connected generator, which means that its on-shelf the air-filled spaces. The advantages of distribution of the radiopharmaceutical, to the oxygen, into which 99mTc-DTPA is availability is low. MRI are the lack of exposure to ionising usually projecting to the lung periphery. injected. Oxygen flowing through the Perfusion and ventilation scintigraphy radiation and the high resolution for nebuliser causes the liquid to break up and are performed using planar or other chest tissues. It can be useful for Lung ventilation scintigraphy form microparticles about 1-3 micrometres tomographic imaging techniques. A assessing lung tumours invading the Ventilation scintigraphy is based on in diameter. The patient inhales radioactive detailed description of the procedure chest wall, the mediastinum, including the administration of a substance which DTPA particles into the bronchi and can be found in the European Nuclear the blood vessels and heart, and posterior reaches the alveoli through the respiratory alveoli. During exhalation, the air entering Medicine Guide (1, 2). With the planar

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LUNG IMAGING method, scintigraphy is performed in metabolic and morphological devices, LUNG IMAGING anterior-posterior, posterior-anterior, both for example a SPECT gamma camera lateral, right and left posterior-oblique and combined with 64/128 row CT. Hybrid right and left anterior-oblique projections. imaging The main indications for ventilation/ techniques include SPECT/CT, PET/CT perfusion scintigraphy are benign lung and PET/MRI, all of which can be useful in disorders: benign and malignant lung disorders. » diagnosis and follow up of pulmonary The benign lung disorders they are most thromboembolism; often used for are pulmonary embolism » quantification of radiotracer uptake be- and infection, while the malignant disorder fore pulmonary resection; they are most commonly used for is lung » lung transplant evaluation; cancer. Different radiopharmaceuticals » assessment of the aetiology of pulmo- are applied, depending on the suspected nary hypertension; lung pathology. » assessment of chronic pulmonary pa- renchymal diseases. Figure 1: Segmental map of the two lungs in four coronal slices and two sagittal slices for each lung. Lung hybrid imaging techniques. UTILITY OF SPECT/CT, PET/ Courtesy of Prof. Marica Bajc. Bajc M, Schümichen C, Grüning T, Lindqvist A, Le Roux P-Y, Alatri A et al. EANM Metabolic/functional and CT AND PET/MRI IN THE guideline for ventilation/perfusion single-photon emission computed tomography (SPECT) for diagnosis of morphological tomographic imaging EVALUATION OF LUNG LESIONS pulmonary embolism and beyond. Eur J Nucl Med Mol Imaging 2019; 46(12):2429–51. techniques. Hybrid imaging equipment offers SPECT/CT scintigraphy in pulmonary Lung segments a combination of metabolic and diseases Right lung: Left lung: morphological imaging in a single device. SPECT and SPECT/CT imaging is Upper lobe: apical ap; posterior p; anterior an Upper lobe: apical ap; posterior p; anterior a; It has been shown that a single hybrid increasingly available in nuclear medicine Middle lobe: lateral l; medial m; superior lingular sl; lateral l imaging study gives more information departments. It is gradually becoming the Lower lobe: superior s; medial basal mb; Lower lobe: superior s; anterior basal ab; lateral about a patient’s pathology than several standard technique in metabolic imaging anterior basal ab; lateral basal lb; posterior basal basal lb; posterior basal pb studies performed separately. The of various organs, including lungs. SPECT pb basic idea in the beginning was to add imaging is based on coronal, transverse attenuation correction and localisation and sagittal slices and analysis of tracer information on lung aeration and allows Diagnosing pulmonary embolism with information for the metabolic lesions accumulation seen on a segmental map for more accurate interpretation of lung a perfusion/ventilation test is the standard visualised in scintigraphy, hence the of the lungs. scintigraphy. It significantly increases the procedure currently employed, but may morphological image quality was rather The use of SPECT perfusion/ventilation sensitivity of the test, as detailed in the new not be possible in some situations. In poor. Contemporary machines, however, images together with low-dose CT EANM guideline for diagnosis of pulmonary exceptional situations when a ventilation offer a combination of high-quality morphological images provides valuable embolism published in 2019 (3). study cannot be performed due to lack

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Figure 2: SPECT/CT study with 99mTc-MAA. Perfusion defect of left lung superior segment seen on transverse Figure 3: PET/CT study with 18F-FDG – transverse slices. A. Left-lung tumour with increased 18F-FDG slices and corresponding normal density in SPECT/CT lung scintigraphy hybrid imaging: images from left- accumulation – high probability of malignancy. B. Right-lung tumour with normal 18F-FDG accumulation lung CT, lung perfusion study, lung fusion image. Department of Nuclear Medicine, Pomeranian Medical – low probability of malignancy. Courtesy of PET/CT Center Starmedica, Szczecin University, Szczecin

of ventilation agent or lack of patient PET/CT scintigraphy in pulmonary may not be possible or is invasive and PET/MRI scintigraphy in pulmonary cooperation during the procedure, CT diseases highly risky, hence the widespread use of diseases information interpreted together with the Imaging with the PET/CT technique, metabolic PET/CT imaging, mostly after Hybrid PET/MRI imaging is a relatively lung perfusion pattern can be helpful. including lung pathology, is most often administration of 18F-FDG, for assessing new technique in clinical practice, but The SPECT/CT lung scan is also useful performed with 18F-FDG. Computed the nature of tumours. A focal lesion seen seems to be a promising diagnostic tool. in patients with lung neuroendocrine tomography of the lungs is a basic test on CT after the administration of 18F-FDG Using MRI instead of CT reduces the tumours. Somatostatin analogues for diagnosing pulmonary disorders, may or may not accumulate it. This tells radiation dose to the patient, which is labelled with 99mTc SPECT/CT or with including tumours of the lung and lymph us whether it is benign or malignant especially important in children, young 68Ga PET/CT are effective in diagnosing nodes. However, on the basis of CT only and facilitates decision-making with adults, and repeated imaging during suspected lung neuroendocrine tumours it is very difficult to assess the clinical regard to surgical resection and further follow-up. It does not replace PET/CT, or their metastases. 111In-labelled significance or origin of lung tumours. histopathological evaluation. More but for some indications like brain, head octreotide is also used, though rather The high incidence of lung cancer makes information is included in the EANM and neck, cervix and prostate tumours rarely. Depending on their histological it important to recognise malignant lung procedure guidelines for tumour imaging PET/MRI imaging may be done instead type, some neuroendocrine tumours may tumours as early as possible. Lung cancer (4) and in the technologist’s guide to or additionally. MRI has limited resolution not accumulate somatostatin analogues is the most common cause of death principles and practice of PET/CT (5). for lung pathology due to lung aeration. but may be visible in an 18F-FDG PET/CT among the neoplastic diseases, and an However, recent studies have shown scan. early diagnosis gives a chance of curing comparable results between PET/CT and the patient. At present, lung cancer PET/MRI in the detection of pulmonary tends to be diagnosed relatively late. In nodules and in lung cancer staging. It is many cases, biopsy from the focal lesion a very promising technique for detection

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LUNG IMAGING of mediastinal pleura involvement in gives very promising information about 2 cm when breathing calmly in a lying Correlation of the breathing cycle with LUNG IMAGING lung cancer, diagnosis and assessment 68Ga-FAPI PET/CT tracer (6). The latter is an position, significantly affects the accuracy PET/CT acquisition data of mediastinal tumours, and diagnosis of inhibitor of fibroblast activation protein of lung lesion evaluation, especially for Several compensation techniques are pleural mesothelioma. (FAP), which is highly expressed by rather small lesions localised in the lower used, combining acquisition data with tumour cells in various cancer types such lungs. Although computed tomography information from the respiratory gating as breast, head and neck and pancreatic images are very quickly recorded, only system. For this purpose, it is possible to cancer, but also in non-small-cell lung taking a few seconds, the acquisition time divide the respiratory cycle into several RADIOPHARMACEUTICALS cancer. It is more specific then18F -FDG for PET imaging, even for a single bed phases or to select a single phase. In USED FOR MALIGNANT LUNG imaging, no diet or fasting preparation position, rises to a few minutes. As a result, addition, time-based (phase-based) or TUMOUR IMAGING is required, imaging can be done a few PET images show the average movement amplitude-based methods can be used. The main, most widely used minutes after injection, and high-quality of hot spots and SUV values may be With the time-based method, some radiotracer for lung tumour imaging is images are obtained. Perhaps the most misread. In order to eliminate respiratory acquisition data may be lost due to 18F-fluorodeoxyglocose (18F-FDG), which interesting finding is that it has potential artefacts during PET/CT examination, differing lengths of the breathing cycle. is used for differentiation of benign for targeted therapy treatment when several methods have been developed However, a simple solution is to set a range from malignant tumours, lung cancer labelled with beta emitters. using external devices (respiratory gating) that is acceptable for a breathing cycle staging, radiotherapy planning and to record the respiratory cycle (7). in which short and long breath cycles follow-up. However, one disadvantage of Types of respiratory gating system: are not recorded. An important factor this radiopharmaceutical is that it is not » Pressure belt affecting the image quality is the number tumour specific and that false positive SPECIAL PROTOCOLS APPLIED A belt wrapping the patient at the height of registered respiratory phases, because a accumulation may be seen, mainly due to IN LUNG TUMOUR IMAGING of the diaphragm which records the small number of intervals can cause image inflammatory processes. Hybrid PET/CT imaging has become displacement of the abdominal wall in blur and a higher signal-to-noise ratio. On Additionally, there are other an extremely important technique in the course of pressure changes during the other hand, a large number of phases radiopharmaceuticals useful for imaging cancer staging, prognosis, follow-up inspiration and exhalation. The system yields a clear decrease in noise but can of lung tumours: cellular proliferation and assessment of treatment results. It allows image recording in a specific affect the detection of changes, because markers, metabolism tracers, is also used in the planning of radiation position for full inspiration or exhalation. the number of images determines the tumour hypoxia markers, angiogenesis treatment. The CT component of PET/ » RPM (real-time position management number of phases obtained. In addition, tracers, and pulmonary neuroendocrine CT imaging, apart from localisation of system) the diversity of internal tissues and their tumour tracers. There are reports that the lesions, also improves the accuracy of This device uses two infrared sensors movement can affect image noise due proliferation marker 18F-fluorothymidine attenuation correction and helps to located on the patient’s chest and to different tissue speeds in different (18F-FLT) can provide more information reduce motion artefacts. However, the synchronised with the camera located at respiratory cycles. It should be taken into about the pathophysiology of lung quality and accuracy of the image may the end of the patient’s bed. The camera account that the respiratory amplitude is cancer, and it seems to be more specific be affected by internal factors from the records the movement of the sensors not identical in all patients, which may also then 18F-FDG for lung tumour therapy patient (physiological factors). Respiratory along with the patient’s breathing rhythm. affect the image noise. The time-based assessment. movements and, above all, the movement method was introduced by the scanner A paper published in the JNM in 2019 of the diaphragm, which can move up to manufacturers, as it does not require access

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REFERENCES 5. van der Broek WJM, Testanera G. Principles LUNG IMAGING LUNG IMAGING to the breathing cycle. Information about Another method is deep inspiration 1. Bajc M, Neilly JB, Miniati M, Schuemichen C, and practices of PET: A technologist’s guide. Vienna: Eu- the breathing cycle is obtained by devices breath-hold (DIBH), where acquisition Meignan M, Jonson B. EANM guidelines for ventilation/ ropean Association of Nuclear Medicine; 2012. (Tech- nologist’s guide). additionally mounted before acquisition, data is obtained over a time interval of perfusion scintigraphy: Part 1. Pulmonary imaging with ventilation/perfusion single photon emission tomog- 6. Giesel FL, Kratochwil C, Lindner T, Mar- which are not available at work stations for fifteen seconds on a deep breath for CT raphy. Eur J Nucl Med Mol Imaging 2009; 36(8):1356– schalek MM, Loktev A, Lehnert W et al. 68 Ga-FAPI PET/ post-acquisition reconstruction purposes. and twenty seconds on a deep breath for 70. CT: Biodistribution and Preliminary Dosimetry Estimate The amplitude-based method PET. This results in aggregated images with 2. Bajc M, Neilly JB, Miniati M, Schuemichen C, of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various . J Nucl Med 2019; 60(3):386–92. determines the minimum and maximum attenuation correction, reconstructed Meignan M, Jonson B. EANM guidelines for ventilation/ perfusion scintigraphy. Eur J Nucl Med Mol Imaging 7. Pépin A, Daouk J, Bailly P, Hapdey S, Meyer thresholds and subdivides the respiratory using a standard conversion algorithm. 2009; 36(9):1528–38. M-E. Management of respiratory motion in PET/com- cycle into “bins” of the amplitude range. With this method, all data is obtained for 3. Bajc M, Schümichen C, Grüning T, Lindqvist puted tomography: The state of the art. Nucl Med However, the method is not very the same tissue position during a deep A, Le Roux P-Y, Alatri A et al. EANM guideline for ven- Commun 2014; 35(2):113–22. sensitive in terms of the reproducibility inspiration breath-hold. This guarantees tilation/perfusion single-photon emission computed tomography (SPECT) for diagnosis of pulmonary em- of the number of coincidences for each the accuracy of image fusion as well as bolism and beyond. Eur J Nucl Med Mol Imaging 2019; range. The condition for this method is accurate reproduction of attenuation 46(12):2429–51. continuous registration by the breathing correction. However, for patients with 4. Boellaard R, Delgado-Bolton R, Oyen WJG, cycle acquisition station. Although the shortness of breath or problems with Giammarile F, Tatsch K, Eschner W et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: ver- recording of respiratory amplitudes is a holding their breath, it may cause sion 2.0. Eur J Nucl Med Mol Imaging 2015; 42(2):328– better method than the time method, problems with acquisition. The DIBH 54. neither of the methods provides adequate method works well in routine lung absorption correction. CT images without imaging to detect small nodules and is respiratory gating also produces a large also useful in abdominal imaging. number of motion artefacts, which in turn contributes to errors in both recorded images.

92 EANM TECHNOLOGIST’S GUIDE EANM TECHNOLOGIST’S GUIDE 93 HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE HYBRID IMAGING IN CONVENTIONAL NUCLEAR MEDICINE CHAPTER 6 CHAPTER 6 TUMOURS AND SENTINEL NODE IMAGING CLINICAL USE OF IMAGING SPECT/CT: OF NEUROENDOCRINE NEUROENDOCRINE TUMOURS AND SENTINEL NODE IMAGING CLINICAL USE OF IMAGING SPECT/CT: OF

CLINICAL USE OF SPECT/CT: IMAGING OF NEUROENDOCRINE TUMOURS AND SENTINEL NODE IMAGING

by Luka Lezaic

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METAIODOBENZYLGUANIDINE TUMOURS AND SENTINEL NODE IMAGING CLINICAL USE OF IMAGING SPECT/CT: OF NEUROENDOCRINE NEUROENDOCRINE TUMOURS AND SENTINEL NODE IMAGING CLINICAL USE OF IMAGING SPECT/CT: OF IMAGING Neuroblastoma imaging modality for neuroblastoma; Neuroblastoma is a most common according to available data, it consistently Metaiodobenzylguanidine (MIBG) is solid extracranial malignant paediatric shows superior diagnostic performance in a structural analogue of noradrenaline, tumour of neuroectodermal origin. In comparison to other an endogenous catecholamine which is over half of the patients, it is metastatic methods, including 123I-MIBG, and may be a neurotransmitter of the autonomous at diagnosis. Molecular imaging plays a considered an imaging method of choice nervous system. It is taken up by key role in staging, evaluation of response in the future. Skeletal scintigraphy with neuroendocrine cells through the NET to therapy and follow-up; in addition, it 99mTc-bisphosphonates no longer plays a transporter and stored in the secretory provides prognostic information and is relevant role in neuroblastoma imaging; granules within the cells via the VMAT1 used to select appropriate patients for a limited indication may exist for potential and VMAT2 transporters; alternatively, radionuclide therapy. evaluation of cortical lesions. in specific tumour tissue types (i.e. 123I-MIBG is an essential part of neuroblastoma), it may be stored in the evaluation of neuroblastoma patients. It is /paraganglioma cytoplasm. It is labelled with 123I or 131I. typically performed for staging purposes; Figure 1. Metastatic neuroblastoma. Planar Pheochromocytoma/paraganglioma While labelling with both can the number and distribution of lesions are 123I-MIBG imaging (left panel) demonstrates (PPGL) are also tumours of be used for diagnostic imaging, the used in validated scoring systems (Curie, multiple metastases throughout the body. SPECT/ neuroectodermal origin, located either former offers superior characteristics for SIOPEN) that are used to guide therapy CT (right panel) clearly differentiates between bone in the adrenals (pheochromocytoma, molecular imaging in terms of spatial and provide prognostic information. The marrow and soft tissue lesions. PHEO) or in the ganglia (sympathetic and resolution and dosimetry, while the latter investigation is highly accurate, with both parasympathetic). Those of sympathetic is typically used for therapy using its beta sensitivity and specificity around 90%. DOTATATE/TOC/NOC) tracers and PET/CT origin may present clinically with emission (123I/131I-MIBG theranostic pair). Nevertheless, the use of hybrid (SPECT/ with 18F-dihydroxyphenylalanine (DOPA). symptoms of catecholamine excess, while Common indications for imaging CT) imaging has been consistently shown 18F-FDG PET/CT is typically performed those of parasympathetic origin often with 123I/131I-MIBG are neuroblastoma, to increase the diagnostic performance in with (suspicion of) 123I-MIBG-negative present as mass/infiltrating lesions. Up neuroendocrine tumours of the comparison to planar imaging, typically lesions and/or in poorly differentiated to 10% of lesions may be hereditary, and autonomous nervous system identifying a greater number of lesions disease; its diagnostic performance is up to 10% of lesions may be malignant. (pheochromocytoma, paraganglioma), (increased lesion contrast, unmasking generally lower in comparison to 123I-MIBG. Molecular imaging plays a role in staging and, less frequently, other neuroendocrine lesions obscured by physiological uptake Similarly, the diagnostic performance of and follow-up, less often in diagnosis of tumours; it is also used for evaluation of – e.g. heart, liver, urinary system) and somatostatin receptor imaging is inferior the lesion. An increasing indication is autonomic myocardial innervation on allowing for differentiation between to 123I-MIBG due to variable expression patient selection for radionuclide therapy. suspicion of catecholamine-induced skeletal and soft-tissue lesions (Figure 1). of somatostatin receptors, but offers an 123I-MIBG accumulates in the secretory cardiomyopathy and differentiation of Other molecular imaging options in appropriate selection of patients when granules of neuroendocrine cells (see parkinsonian syndromes. neuroblastoma include PET/CT with peptide receptor radionuclide therapy above). Its sensitivity and specificity for 18F-fluorodeoxylucose (FDG), somatostatin (PRRT) is contemplated and 131I-MIBG localising pheochromocytoma is typically receptor imaging with SPECT (111In-DTPA- therapy is unavailable. 18F-DOPA PET/CT is high (around 85-100% and 90-100%, OC, 99mTc-HYNIC-TOC) or PET (68Ga- an emerging highly sensitive and specific respectively). It is lower for paragangliomas

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18 TUMOURS AND SENTINEL NODE IMAGING CLINICAL USE OF IMAGING SPECT/CT: OF NEUROENDOCRINE NEUROENDOCRINE TUMOURS AND SENTINEL NODE IMAGING CLINICAL USE OF IMAGING SPECT/CT: OF (overall around 50-75%), especially for of cases. F-DOPA exhibits sensitivity of those of parasympathetic origin (head around 80% and 18F-FDG of around 75% and neck; around 20-50%). in this context, while the sensitivity of Another single-photon imaging 123I/123I-MIBG was reported to be around option for PPGL is somatostatin receptor 40% (Figure 2). scintigraphy (111In-DTPA-OC, 99mTc-HYNIC- TOC). Generally, its sensitivity is inferior to 123I-MIBG, except for parasympathetic Somatostatin receptor scintigraphy (head and neck) PGL, where the sensitivity with single-photon emitting tracers typically exceeds 90% and it represents Somatostatin is a peptide hormone the single-photon imaging technique of and neurotransmitter with typically choice for the indication. However, the inhibitory action. Somatostatin Figure 3. Metastatic neuroendocrine , somatostatin receptor imaging with 99mTc-EDDA/HYNIC- diagnostic performance of single-photon receptor scintigraphy (SRS) utilises the TOC. Multiple metastases are demonstrated throughout the body on the MIP image (left panel); SPECT/CT tracers is inferior to that of newer positron- characteristic of neuroectodermally clearly localises the lesions and differentiates between liver and bone metastases. emitting tracers. 68Ga-DOTA-TATE/TOC/ derived tissues and (broadly NOC, the PET variant of somatostatin encompassed under the umbrella receptor imaging, detects metastatic term neuroendocrine tumours/ Depending on the NEN type, the expression The overall sensitivity of SRS for NEN pheochromocytoma and primary and/ neoplasms, NET/NEN) of expression of of somatostatin receptors can range from is generally high (reportedly between or metastatic paraganglioma in over 90% somatostatin receptors on their surface. very high and very dense to relatively low 70% and 90%). Somatostatin receptor and mild (e.g. glucagonoma, gastrinoma, scintigraphy therefore holds a central virtually 100%; ileal carcinoid, over 90%; position in the diagnostics of NEN due insulinoma and bronchial carcinoid, to its proven high sensitivity, specificity around 60%). In humans, five subtypes of and suitability for staging; it is also used somatostatin receptors are described. The for follow-up, evaluation of therapeutic most commonly and densely expressed effect and on suspicion of recurrence/ somatostatin receptor subtype is type 2 residual disease. Another benefit of SRS is (sstr2), which is also targeted by single- the ability to appropriately select patients photon-emitting tracers. Two are widely for radionuclide therapy (peptide receptor available: the traditionally used - radionuclide therapy, PRRT). Tomographic 111-labelled octreotide (111In-DTPA-OC), (SPECT) and hybrid (SPECT/CT) imaging commercially available as Octreoscan®, exhibits the typical advantages over planar targeting sstr2 and sstr5, and technetium- imaging of higher sensitivity, specificity and Figure 2. Different metabolic information provided by123 I-MIBG SPECT/CT (left panel) and 18F-FDG 99m-labelled octreotide (99mTc-EDDA/ localisation of lesions (Figure 3); in addition, PET/CT (right panel) in a paraganglioma. A “flip-flop” phenomenon of heterogeneity of metabolism in a HYNIC-TOC), commercially available as the increasing utility of quantitative centrally necrotic tumour (areas less active on 123I-MIBG are more active on 18F-FDG and vice versa). Tektrotyd®, targeting primarily sstr2. SPECT imaging allows for more accurate

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NEUROENDOCRINE TUMOURS AND SENTINEL NODE IMAGING CLINICAL USE OF IMAGING SPECT/CT: OF evaluation of therapeutic effect as well as the positron-emitting tracers labelled factor determining patient prognosis. By nodes; the combined approach was more accurate and elaborate dosimetry almost exclusively with gallium-68 (68Ga- definition, the sentinel node(s) is/are the shown to increase the diagnostic yield. assessment when PRRT is utilised. DOTATATE/TOC/NOC) exhibit significantly first lymph node(s) draining a specific The clinical entities where sentinel node 123I/131I-MIBG can also be used to image higher sensitivity (typically around 90-95% lymphatic watershed where the offending scintigraphy is most commonly used are NEN, but in contrast to its sensitivity for vs. 50-60% in direct comparison) with the malignant process is located. Sentinel breast cancer and malignant melanoma, entities originating from the autonomous added benefit of inherent tomographic node scintigraphy reproduces the path in which the procedure is integrated into nervous system (pheochromocytoma/ imaging, superior contrast and spatial of spread of malignant cells and allows the standard of care; its use in several paraganglioma; see above), its resolution; again, the tracer binding is the localisation of sentinel node(s), their other malignancies (in particular head sensitivity for gastroenteropancreatic most avid to sstr2 (-TATE), to a lesser extent subsequent removal and histopathological and neck cancer; gastrointestinal cancers neuroendocrine neoplasms (GEPNEN) also to sstr5 (-TOC) and only one tracer analysis. Confirmation of metastases in the – oesophagus, stomach, colon; urological and bronchial carcinoids is significantly (-NOC) also binds significantly to the sstr3 sentinel lymph node(s) typically involves cancers – prostate, penis; gynaecological lower (typically around 50%). The tracer subtype. Clinically, there is no significant dissection of regional lymph nodes in an cancers – vulva, cervix, uterus) is evolving is mostly used for imaging of mid-gut difference in the diagnostic performance attempt to attenuate further spread of the into the standard of care. GEPNENs, in particular when radionuclide of the tracers. Another positron-emitting disease. The overall diagnostic performance therapy is contemplated and PRRT is not option for NEN imaging is 18F-DOPA. In The radiopharmaceuticals used for of sentinel node scintigraphy is high: for available. contrast to PPGL imaging, the sensitivity sentinel node scintigraphy are technetium- most listed indications, the detection rate In comparison to single-photon tracers for NEN overall is lower (around 65%); 99m-labelled colloids (99mTc-colloids) (the identification of the sentinel lymph that target somatostatin receptors, it is currently the PET tracer of choice using particles of different size (3-1000 node) is around 90% and above, as is for imaging of biochemical recurrence nm) that spread through the lymphatics the sensitivity (detection of malignant of a specific NEN – medullary thyroid and localise passively in the lymph sentinel lymph nodes) and negative carcinoma (sensitivity around 65%). nodes; recently, a tracer that specifically predictive value, in particular when the 18F-FDG typically accumulates poorly binds to the mannose CD206 receptor dual-tracer approach is used; however, in well-differentiated neoplasms that on the surface of dendritic cells and somewhat discordant results are reported represent the majority of NEN; however, macrophages, technetium-99m- labelled for colon and uterine cancer (in part it is useful to confirm the suspicion of tilmanocept (99mTc-tilmanocept), was likely due to inhomogeneity of studies tumour dedifferentiation and provides introduced into clinical practice. Generally, and techniques). The use of SPECT and important prognostic information in this in studies directly comparing the tracers, SPECT/CT was shown to further increase Figure 4. Liver metastases, biopsy-proven context (Figure 4). no clinically significant differences were diagnostic accuracy. neuroendocrine neoplasm (high grade). Liver found in terms of accuracy; patient lesions are completely negative in somatostatin Sentinel node scintigraphy with tolerance may, however, be higher with the receptor imaging with 99mTc-EDDA/HYNIC- single-photon-emitting tracers receptor-based tracer. Frequently, sentinel TOC (left panel). 18F-FDG PET/CT (right panel) Sentinel node biopsy is a method node imaging is a combined procedure demonstrates multiple, partially necrotic, of staging malignant disease. In many using both a and a metabolically intensely active liver metastases – malignancies, the stage of the disease conventional (blue) dye with combined poorly differentiated neuroendocrine carcinoma. (including lymphatic spread) is the leading depiction of lymphatic vessels and lymph

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CONCLUSION LITERATURE TUMOURS AND SENTINEL NODE IMAGING CLINICAL USE OF IMAGING SPECT/CT: OF NEUROENDOCRINE

NEUROENDOCRINE TUMOURS AND SENTINEL NODE IMAGING CLINICAL USE OF IMAGING SPECT/CT: OF 1. Timmers HJ, Chen CC, Carrasquillo JA, et al. For the listed indications and Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxy- radiopharmaceuticals, the use of SPECT/ , and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocy- CT increases the diagnostic performance toma and paraganglioma. J Clin Endocrinol Metab. of imaging studies. When available and 2009;94(12):4757-67. technically and logistically feasible, 2. Koopmans KP, Jager PL, Kema IP, Kerstens SPECT/CT should be performed in MN, Albers F, Dullaart RP. 111In-octreotide is superior to 123I-metaiodobenzylguanidine for scintigraphic addition to or instead of planar imaging. detection of head and neck paragangliomas. J Nucl The added cost and time as well as the Med. 2008;49(8):1232-7. additional radiation exposure should also 3. Alrezk R, Suarez A, Tena I, Pacak K. Update of be considered (especially in the paediatric Pheochromocytoma Syndromes: Genetics, Biochem- ical Evaluation, and Imaging. Front Endocrinol (Laus- population), but will likely be offset by anne). 2018;9:515. the significantly enhanced diagnostic 4. Taïeb D, Hicks RJ, Hindié E, et al. European information obtained. Association of Nuclear Medicine Practice Guideline/ Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2019;46(10):2112-2137. 5. Brisse HJ, McCarville MB, Granata C, et al.; In- ternational Neuroblastoma Risk Group Project. Guide- lines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblasto- ma Risk Group Project. Radiology. 2011 Oct;261(1):243- 57. Bar-Sever Z, Biassoni L, Shulkin B, et al. Guidelines on nuclear medicine imaging in neuroblastoma. Eur J Nucl Med Mol Imaging. 2018;45(11):2009-2024. 6. Kjaer A, Knigge U. Use of radioactive sub- stances in diagnosis and treatment of neuroendocrine tumors. Scand J Gastroenterol. 2015;50(6):740-7. 7. Sundin A, Arnold R, Baudin E, et al; Antibes Consensus Conference participants. ENETS Consensus Guidelines for the Standards of Care in Neuroendo- crine Tumors: Radiological, Nuclear Medicine & Hybrid Imaging. Neuroendocrinology. 2017;105(3):212-244. 8. Moncayo VM, Alazraki AL, Alazraki NP, Aarsvold JN. Sentinel Lymph Node Biopsy Procedures. Semin Nucl Med. 2017;47(6):595-617.

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MYOCARDIAL PERFUSION HYBRID IMAGING

by MarieClaire Attard and Hein Verberne

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INTRODUCTION AND MYOCARDIAL PERFUSION HYBRID IMAGING MYOCARDIAL PERFUSION HYBRID IMAGING BACKGROUND or increased myocardial blood flow (i.e. flow patients must be able to exercise to result in inaccurate assessment of left higher resistance results in lower flow and a workload of at least 85% of age-adjusted ventricular ejection fraction. The coronary circulation is a strictly vice versa). maximum predicted heart rate (220-age). regulated system that matches its blood The coronary flow reserve (CFR) It is important to note that not all Hybrid Imaging flow with oxygen requirements through is a measure of the extent to which coronary arteries with a stenosis will cause As already stated in the 2015 EANM regulation of vascular resistance. In this coronary blood flow can increase from perfusion abnormalities. Among other procedural guidelines for myocardial respect it is important to realise that the the resting state to maximal vasodilation factors, this is driven by the geometry of perfusion imaging, hybrid imaging is vessels of the coronary circulation can be (i.e. stress). The CFR is expressed as the the given stenosis and is almost impossible defined as the combination and fusion categorised according to their diameter ratio of coronary blood flow at maximum to deduce from anatomical images only. of two datasets by which both modalities and subsequent related function. The stress to coronary blood flow at rest. However, in general it is safe to assume that significantly contribute to image proximal epicardial coronary arteries Since the coronary flow resistance is any stenosis of a coronary artery of more information [1]. Typically, hybrid imaging (conductive arteries) (size range 500 μm primarily determined by microvascular than 80% will most likely cause perfusion is synergistic, i.e. more powerful than the to 2–5 mm) mainly act as capacitance autoregulation, CFR is considered a abnormalities, and that a stenosis of sum of its parts, as it provides information vessels. The intermediate pre-arterioles measure of small vessel function. <20% will have no haemodynamic beyond that achievable with either data (size range 100–500 μm) act to maintain In the setting of coronary artery disease consequences. This means that a form of set alone, leading to improved sensitivity pressure in response to perfusion pressure (CAD), therefore, narrowed conductive functional testing is required to assess the and specificity [2]. or flow change, and the function of the arteries activate neuronal and metabolic impact on the myocardial flow in lesions The term hybrid imaging does not apply intramural arterioles (size <100 μm) is autoregulation processes leading to lower with a 20 to 80% stenosis. to the combination of nuclear cardiac mainly to match blood supply to the distal resistance and thereby maintain There are several ways to image imaging with X-ray-based attenuation degree of oxygen consumption. blood flow at rest. However, this means myocardial perfusion non-invasively. correction (AC), where the (low-dose) While the conductive arteries and that some of the CFR has been used to Among these techniques, myocardial CT images do not provide independent proximal pre-arterioles are responsive maintain resting conditions. The CFR of a perfusion imaging with radiotracers is a information, but only contribute to to flow-dependent dilation, the distal given stenosed epicardial coronary artery longstanding, proven and robust modality improving the image quality of the other pre-arterioles are more responsive to may thus fall short under stress, leading for (semi-)quantitative assessment of modality (PET or SPECT) [3]. perfusion pressure changes. On the other to perfusion abnormalities under stress. myocardial perfusion. As there is substantial inter-individual hand, arterioles are highly responsive Perfusion abnormalities are an early sign The addition of ECG-triggered anatomical variability in coronary arteries, to metabolic regulation as a result of an in the so-called ischaemic cascade, and acquisitions (i.e. gated SPECT) allows for the so-called standard distribution of increase in oxygen demand. This makes may lead to angina complaints at later the assessment of left ventricle volumes myocardial perfusion territories does not the distal pre-arterioles and arterioles stages of this cascade. and ejection fraction [2]. The ejection correspond with the patient’s individual (i.e. resistance vessels) the main site of Exercise stress testing (e.g. bicycle or fraction obtained is highly dependent anatomy in more than half of the patients coronary blood flow autoregulation. ergometer) provides a direct physiological on the regularity of the heart rate. An [4]. Most frequently, left circumflex artery Increasing or decreasing vascular link between exertional symptoms and irregular heart rate or one with several segments are erroneously assigned to resistance by respectively decreasing or coronary ischaemia, therefore dynamic premature ventricular contractions (PVC) the right coronary artery territory, and increasing the vascular diameter of these exercise is the first test of choice. However, will not permit accurate measurement standard left anterior descending artery resistance vessels results in decreased to allow for an adequate rise in coronary of ventricular volumes, and will therefore segments are erroneously assigned to the

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MYOCARDIAL PERFUSION HYBRID IMAGING left circumflex territory [5]. outcomes, guide patient management, and reperfusion treatment strategy. is positioned in the gantry in the same MYOCARDIAL PERFUSION HYBRID IMAGING Incidental cardiac and extra-cardiac CT and contribute to optimal downstream Selected lower-risk patients may position as during the SPECT acquisition. findings are not uncommon [6]. Although resource utilisation. be candidates for this study as well, Generally speaking, the additional CT most such findings are negligible, In general, the primary indications for particularly if they cannot exercise or if can be performed to improve image some may be of clinical relevance. It stress myocardial perfusion imaging are: the ECG is not interpretable (left bundle quality (attenuation correction) and/or is thus recommended that images are (1) for diagnostic purposes in patients with branch block, ventricular pacing, and to acquire anatomical information (i.e. additionally screened by a physician suspected CAD; and (2) for prognostic severe baseline ST segment abnormalities). calcium score and coronary artery lesion fully trained in CT readings, including purposes in patients with known CAD or This study may also be indicated for pre- diameter stenosis). As previously stated, non-contrast-enhanced CT scans for symptoms suggestive of CAD. operative risk stratification prior to high- the term hybrid imaging is reserved for attenuation correction and scouts. The major strength of the technique is risk non-cardiac surgery if the results of the latter indications only. The combined The integration of coronary anatomy its ability to provide powerful prognostic the study will impact on the peri-operative radiation burden associated with SPECT/ through CCTA and (quantitative) information in a wide range of patient management of the patient. CT depends strongly on the type of documentation of the true ischaemic populations, including patients with The most detailed criteria available scanner used (CZT vs. more conventional burden through SPECT/PET allows known CAD, at high risk of CAD, post- to select patients for this procedure are techniques, attenuation correction low- effective identification of: myocardial infarction, diabetes, advanced the “Appropriate Use Criteria for Cardiac dose CT vs. diagnostic CT, etc.). 1) patients with CAD benefiting age, obesity, and women. Radionuclide Imaging” published by the In order to improve image quality from optimal medical therapy versus American College of Cardiology and other related to attenuation of the detected those who should undergo coronary Clinical Applications of Myocardial cardiology or imaging societies. SPECT photons, a low-dose CT can be revascularisation, Perfusion Imaging performed. Generally speaking, a CT scan 2) the culprit stenosis in patients with The most appropriate patients for SPECT/CT is a reflection of tissue density and thus multiple coronary artery lesions, thereby whom this test should be considered SPECT/CT cardiac imaging is relatively a reflection of attenuation caused by the guiding clinicians to the appropriate include: non-invasive, and the technology and different tissue types [7]. The SPECT and method of revascularisation, (1) patients at intermediate-to-high risk method of scanning has advanced in the CT are usually matched and aligned using 3) patients with subclinical coronary of CAD who have symptoms suggestive last couple of years [2]. When performing dedicated (fully automated) software atherosclerosis where more aggressive of CAD; myocardial perfusion imaging with SPECT/ packages. However, manual correction prevention may be indicated, and (2) patients with known CAD who have CT, the patient usually undergoes the sometimes remains indispensable and it 4) patients with normal coronary new or recurring symptoms that may be SPECT first before the CT. One reason for is the task of the operator to ensure that arteries who can safely be deferred from attributable to myocardial ischaemia; this is that the SPECT examination should this is done properly. If manual correction any further cardiac testing. (3) patients with prior revascularisation first be checked for extra-cardiac activity is performed by an inexperienced person, In summary, the complimentary who have recurrent symptoms. that might interfere with the interpretation artefactual cardiac defects may occur, anatomical and functional information Finally, a less common group of patients of the perfusion imaging. This way, if the leading to an incorrect management of provided by hybrid SPECT/PET-CCTA that may be eligible for myocardial SPECT needs to be repeated, the patient the patient’s disease. Image 1 illustrates the imaging has been demonstrated to confer perfusion imaging are those who have had will not be exposed to an additional software fusion process when the nuclear added diagnostic value in CAD detection recent myocardial infarction and did not dose of radiation through an extra CT. medicine examination is matched with and to effectively stratify risk, predict undergo an early cardiac catheterisation When performing the CT, the patient the CT used for attenuation correction

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POST-PROCESSING DIAGNOSTIC CT MYOCARDIAL PERFUSION HYBRID IMAGING [2]. Dedicated cardiac scanners usually After the CT for attenuation correction, MYOCARDIAL PERFUSION HYBRID IMAGING offer reduced scanning times, allowing the patient might subsequently undergo Advances in processing software have The number of examinations performed for increased patient throughput but also an additional CT for calcium scoring. Still introduced very sensitive methods of by SPECT/CT combined with coronary CTA reducing patient discomfort. in the same position as for the SPECT and visualising myocardial perfusion. Data reduces the number of invasive coronary It is important to note that the CT- CT, a more accurate scout is performed sets from different imaging modalities can [7]. The technique is derived attenuation maps do not always in which the heart is scanned between also be matched and processed together, relatively inexpensive, readily available and have diagnostic quality [2]. Of course, top and bottom limits (set by the nuclear making imaging possible with no need for non-invasive. It provides good diagnostic reconstructions performed in the lung medicine technologist). repetition [2]. information on the presence of stenosis setting may reveal incidental findings Different cameras are available for due to calcified or soft plaques. which prompt further investigation. In the acquisition of myocardial perfusion A CT coronary angiogram requires the addition, and depending primarily on the images. A SPECT camera equipped with administration of intravenous contrast quality of the CT, the low-dose CT can also multi-pinhole collimators delivers high RADIATION BURDEN and specific imaging protocols, scanning be used to obtain a calcium score. sensitivity and shortened acquisition SPECT/CT is associated with radiation in step-and-shoot or helical mode. times [2]. exposure. Hybrid imaging techniques Furthermore, a CT coronary angiogram use radiolabelled tracers that enable requires a heart rate that does not visualisation of the myocardial perfusion. interfere with the acquisition of the CT The addition of CT will increase the images. By using beta-blockers (such as radiation exposure for the patient. Metoprolol™ or Bisoprolol™) the heart However, most modern CT scanners rate can be controlled, thereby improving are very effective in reducing radiation image quality. Patients with irregular heart exposure. The additional radiation rates should not be scanned for CTCA. In exposure of CTCA can be as low as 1 mSv. addition, in patients with high grades of Performing SPECT/CT together with calcified lesion the CTCA is less accurate, CTCA increases the chances of coronary leading to overestimation of lesion artery disease detection and acquires a full severity. A (nuclear medicine) physician examination using a one-stop approach. should decide whether to perform a CTCA The patient does not need to come back in patients with a Ca Score >300 [9]. for another appointment but continues For CTCA, the minimum number of to follow the trajectory intended for detectors involved in CT is 64 [2]. This treatment (if any). is because the spatial and temporal Image 1 resolution needs to be high in order to [2] Kaufmann P., Springer 23:327 diagnose coronary artery disease using CT [2]. CT coronary angiography should only be performed when the potential benefits outweigh the risk involved. It is important

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CONCLUSION MYOCARDIAL PERFUSION HYBRID IMAGING that the patient is well prepared before Motion or breathing artefacts still MYOCARDIAL PERFUSION HYBRID IMAGING the CTCA examination, the aim being to remain a problem when performing CTCA Hybrid and multimodal imaging scan once only and thus avoid a repeat [10]. Premature ventricular contractions provides detailed information regarding examination that would increase the (PVC) during the exact moment of CTCA myocardial perfusion studies and coronary patient’s radiation dose. scanning would result in an inconclusive artery disease. The results of these Another type of imaging, such as e.g. scan that might need to be repeated. examinations influence diagnosis, risk rubidium imaging, should be considered stratification of patients, the treatment in obese patients or in patients with high involved and patient management. and/or irregular heart rates [2]. The whole purpose of performing THE ROLE OF THE NUCLEAR the appropriate imaging test for a given MEDICINE TECHNOLOGIST patient is to improve patient outcome. Concise and careful planning by the High-quality images are essential in order DEVELOPMENTS AND technologist performing the scan is key. to arrive at the proper diagnosis and LIMITATIONS Details of the examination and instructions prognosis. The combination of techniques and Image 2 regarding relaxation and breathing need When seen together side by side, modalities reduces the incidence of false [2] Kaufmann P., Springer 23:329 to be explained to the patient prior to the CTCA and myocardial perfusion imaging positive results. The CT part of the SPECT The stress perfusion polar map shows procedure. provide comprehensive information provides the attenuation correction a defect in the basal inferior area which The technologist performing the CTCA about coronary artery disease, providing for the perfusion image but offers no is almost completely resolved during the should be trained to recognise any lesions the nuclear medicine physician and diagnostic quality. The SPECT part of resting examination (a). However, when a and report these to the nuclear medicine cardiologist with insight and guidance as the examination is an excellent detector CTCA was performed on the same patient, physician reporting the scan. Detection to the correct management of the patient. of perfusion abnormalities. If a CTCA there was found to be some calcification of a sub-occlusion may prevent the is performed, there is no detection of but no perfusion defects on the anterior patient suffering a coronary heart attack. ischaemia, only an assessment of the wall (b). The posterior volume-rendered A properly trained team and ongoing anatomy of the coronary arteries and the image (c) shows an occlusive lesion in the education enhance performance, patient surrounding anatomy. Together, however, left circumflex artery (LCX) which results interpretation and management and they make detection of coronary artery in the decrease in perfusion in the basal improve the accuracy of the examinations disease highly sensitive and specific. inferior area. performed. When performed separately, a normal The reporting nuclear medicine MPI does not exclude the presence of physician must be careful when assessing coronary artery disease [2]. Image 2 shows the images because a normal perfusion a clear example of this using polar maps SPECT still might not exclude coronary and a volume-rendered CTCA. artery disease and the result of the examination might end up being false negative [10].

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REFERENCES 6. Husmann L., Tatsugami F., Aepli U., Herzog [14] Seitun S., De Lorenzi., Cademartiri F., Bus- MYOCARDIAL PERFUSION HYBRID IMAGING MYOCARDIAL PERFUSION HYBRID IMAGING 1. Verberne H., Acampa W., Anagnostopoulos B., Valenta I., Veit-Haibach P., Buechel R., Pazhenkottil caglia A., Travaglio N., Balbi M., Bezante G P., (2018), CT C., BallingerJ., Bengel F., De Bondt P., Beuchel R., Cuo- A., Gaemperli O., Burkhard N., Wyss C., Kaufmann P., Myocarial Perfusion Imaging: A New Frontier in Cardiac colo A., van Eck-Smit B., Flotats A., Hacker M., Hindorf (2009), Prevalence of Noncardiac Findings on Low Imaging, Hindawi BioMed Research International, Arti- C., Kaufmann P., Lindner O., Ljungberg M., Lonsdale M., Dose 64-slice Computed Tomography Used for At- cle ID 7295460, 21 pages, online open access. Manrique A., Minarik D., Scholte A., Slart R., Tragardh E., tenuation Correction in Myocardial Perfusion Imaging [15] Varga-Szemes A., Meinel F G., De Cecco C N., de Wit T., Hesse B., EANM, EANM Procedural Guidelines with SPECT, International Journal Of Cardiovascular Fuller S. R., Bayer II R. R., Schoepf U. J., (2014), CT Myo- for Radionuclide Myocardial Perfusion Imaging With Imaging, 25(8):859-65 cardial Perfusion Imaging, Cardiopulmonary Imaging, SPECT and SPECT/CT: 2015 Revision, European Journal 7. Greulich S., Sechtem U., Multimodality im- Review, American Journal of Radiology, American Ro- of Molecular Imaging, (2015), 42(12): 1929-40 aging in coronary artery disease – “the more the bet- engen Ray Society, pages 487-497. 2. Kaufmann PA., Cardiac Hybrid Imaging: ter?”, (2015), Elsevier, Available at www.sciencedirect. [16] Matsuo S., (2016), Cardiac Hybrid or Fusions state-of-the-art, Annals of Nuclear Medicine, (2009), com Imaging of CT and SPECT, International Journal of Ra- 23(4): 325-31 8. Wann S., Tunio J., Current challenges and diology and Medical Imaging, 2:112, online open ac- 3. Flotats A., Knuuti J., Gutberlet M., Marcassa future directions in cardiac imaging, (2010), Journal cess. C., Bengel F., Kaufmann P., Rees M., Hesse B., Cardiovas- of the Saudi Heart Association, Available at www.sci- cular Committee of the EANM the ESCR and the ECNC., encedirect.com Hybrid Cardiac Imaging: SPECT/CT and PET/CT. A Joint 9. Gaemperli O., Kaufmann P., Alkadhi H., Car- Position Statement by the European Association of diac hybrid imaging, (2014), European Journal of Nu- Nuclear Medicine (EANM), the European Society of clear Medicine, 41 Supp 1, p91-103, Springer. Cardiac Radiology (ESCR) and the European Council of 10. Kauling R., Post M., Rensing B., Verzijlber- Nuclear Cardiology (ECNC), (2011), 38 (1): 201-12 gen J., Schaap J., Hybrid SPECT.CCTA Imaging in the 4. Javadi M., Lautamaki R., Merrill J., Voicu C., Work-up of Patients with Suspected Coronary Artery Epley W., McBride G., Bengel F., Definition of Vascular Disease, (2015), Current Cardiovascular Imaging Rep Territories on Myocardial Perfusion Images by Integra- 8:2, Springer Science+Business Media New York. tion With True Coronary Anatomy: A Hybrid PET/CT Analysis, (2010), 51 (2): 198-203 5. Gaemperli O., Bengel F., Kaufmann P., Car- diac Hybrid Imaging, (2011), 32 (17):2100-8, Eur Heart Journal

BIBLIOGRAPHY [11] Kauling R. M., Post M. C., Rensing B. J. W. M., Verzijlbergen F., Schaap J., Hybrid SPECT/CCTA Imaging in the Work-up of Patients with Suspected Coronary Artery Disease, (2015), Current Cardiovascular Imaging Rep, 8:2, Springer Science+Business Media New York. [12] Petretta M., Cuocolo A., (2016), Prediction Models for Cardiac Risk Classification with Nuclear Car- diology Techniques, Current Cardiovascular Imaging Rep 9:3, Springer Science+Business Media New York. [13] Prior J. O., Farhad H., Muller O., (2014), Mul- timodality Imaging in Ischaemic Cardiomyopathy, Current Cardiovascular Imaging Rep 7:9285, Springer Science+Business Media New York.

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ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC PETPOPULATION RADIOPHARMACEUTICALS

by Pietro Zucchetta by Lei Li Corrigan

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ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC POPULATION Many factors contribute to quality in paediatric nuclear medicine, from reception area to the scanning table a small, temporary one, with decorations, ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC POPULATION a correct referral to a clear and timely report. Scan planning, radiotracer can enhance fear and stress, giving the games, TV set, etc. Hospitals often administration, and image acquisition are probably the most relevant impression that the patient is being seem cold and sometimes downright aspects involving the nuclear medicine technologist. It is a significant treated like an object. As a rule of thumb, frightening places for younger children: a challenge, because standard imaging strategies fall short of the target paediatric scans need twice as long as couple of pencils and a sheet of paper can due to the many differences between adult and child, including disease adult ones. Each exam is unique with work magic. spectrum. regard to technical aspects (i.e. venous The technical aspects of most paediatric nuclear medicine examinations access, positioning, etc.) and emotional are detailed in a number of guidelines and textbooks. Still, there are some requirements. Therefore, scheduling of general issues worth discussing because they shape the foundations paediatric scans needs to be flexible; it RADIATION PROTECTION of the approach to the paediatric patient. Moreover, they quite often is highly preferable to have a dedicated Radiation protection is a key point in the represent a significant obstacle in setting up a regular paediatric schedule. room, and to avoid intermixing adult day-to-day activity of a nuclear medicine and child scans or setting a too-tight department. Ethical and legal constraints schedule. A frequent solution is to reserve require strict control of exposure to The most relevant issue with a large or other family members in the team in a room for paediatric activities once or radiation for patients, staff, and the general number of paediatric patients is probably charge of the examination. twice a week. Adequate time is probably public. the lack of cooperation, with the resulting Teamwork is a mainstay of paediatric the most relevant requisite to reduce The concern over radiation-related problems in radiotracer administration, nuclear medicine: a single operator, even sedation requirements. Cooperation can health risk is even higher in children, patient positioning, etc. Nevertheless, if highly skilled and experienced, can be obtained in most cases if the time because data from the population paediatric nuclear medicine offers seldom manage all the steps. The goal constraints are adapted to the paediatric of atomic bomb survivors suggests invaluable data in many clinical situations is to create a safe, friendly environment environment, from explanations to increased susceptibility with decreasing and has an established track record as a that reduces anxiety, fear, and stress for venepuncture and immobilisation. In most age. Therefore, paediatric nuclear medicine powerful and safe technique. everyone involved, including the staff. cases a window of opportunity opens at examinations require rigorous measures to The experience of dedicated centres Including the family in the work of the some point, but that point is difficult to keep radiation exposure to the lowest level shows that an integrated approach is team is of paramount importance, and identify in advance. On the other hand, compatible with a useful exam. key to obtaining high-quality nuclear every effort is required to establish a however, the window will not remain The activity administered to the adult medicine examinations in paediatrics. sound relationship, avoiding barriers and open indefinitely, because boredom, fear patient has to be scaled down in children, This integrated strategy relies on careful considering doubts and the need for or hunger can swiftly turn cooperation using body weight or body surface as a consideration not only of the technical information and reassurance. A gentle, into active opposition. reference. The “Paediatric Dose Calculator” aspects but also of the complicated open attitude and a lot of patience Scheduling should allow a little extra (available on the EANMMI website or as a emotional and social relationship with can work wonders, even in the most time and dedicated space for the first stand-alone app) simplifies the calculation the child and his/her parents. The family challenging situation. encounter: creating the right environment based on the body weight and offers can be a powerful ally or a significant This approach requires an adequate in the preparatory phase will save time a quick estimate of the radiation dose drawback, and experienced staff will allotment of time, because rushing and trouble during the scan. It is highly associated with the proposed activity. It is make any attempt to include the parents the child and his/her parents from the advisable to set up a child-only space, even worth reiterating that the recommended

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ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC POPULATION activity should be adapted to the specific gathered from a nuclear medicine exam because temperature-dependent brown- underrated, but they are usually well aware ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC POPULATION exam, considering e.g. the equipment cannot be obtained easily or with fewer fat activation can interfere heavily with of their situation and want to be reassured. used (detector technology, collimator, risks using other diagnostic methods. image interpretation, particularly in Infants and babies cannot understand etc.), scan duration (3 vs. 4 minutes per The level of detail given in the lymphoma patients. verbal commands, but voices, handling bed position in PET imaging) and sedation explanation should be adapted to the The patient’s information is provided and general attitude can have a profound time constraints and risks. knowledge level of the parent(s), but before the scan, covering the indication influence on their reactions. Smiling, a The expanding role of hybrid imaging, reticence and oversimplification should for the examination, approximate soothing tone, and uninterrupted contact mainly SPET/CT and PET/CT, has further be avoided. A clear description of the scan duration, injection technique with a cooperative parent can facilitate complicated the issue, because the CT balance between potential risks and and institutional policy regarding the most complex procedure. Simple part of the exam requires additional care clinical benefits is essential information venepuncture attempts, radiation explanations can be given to children to avoid unnecessary exposure. The latest and plays a pivotal role in communication exposure and immobilisation. Open starting at about 3 years old, with the child scanners and cameras offer dedicated between the treatment team and the questions are preferable (i.e. “Do you know sitting on a parent’s lap. Try to keep your paediatric protocols, which should be family. why/how/…?, Have you been told…? ”) eyes at the same level as the child’s: it is used whenever possible because they because they allow for doubts or practical often difficult to trust a towering white- allow a significant reduction of the dose requirements. The health professional clad adult. Explanations should be brief to the patient. should steer the talk, keeping it to and adapted to the child’s attention span Every exam should be tailored to the COMMUNICATION reasonable time limits, but it is essential and level of understanding. individual patient and the clinical setting, Communication is the key to obtaining to focus on the conversation and avoid Open, honest communication with avoiding standardised presets. the cooperation of the family and, where multitasking. Room preparation, computer parents is essential in order to obtain Careful observance of the radiation possible, the child. Preliminary facts set-up, etc. should have been performed their cooperation and establish a good protection rules will also help reassure the should be provided to the family before already or put off until the end of this technologist–parent relationship, but parents about the safety of the nuclear the procedure, via leaflets, e-mail, relevant critical phase. honesty is also vital in gaining the trust of medicine examination. Even the most sections on the institutional website, Key points should be summarised and the child. It is not necessary to underline relaxed and trusting parent has some etc. Only a few of the common nuclear repeated to avoid misunderstandings due unpleasant details, but one has to be doubts about the radiation-related risks, medicine procedures in paediatrics to emotional pressure or time constraints. truthful, if reticent. Crying should not which must be discussed explicitly before require specific preparation (i.e. fasting It is crucial to deliver a coherent message; be frowned upon, because it is a normal the start of the scan. We do not really for some GI studies, avoiding interfering therefore the whole staff need to know the reaction to stress and pain, particularly know if diagnostic doses increase the risk drugs before an MIBG scan or a brain FDG relevant details of the procedure. when the child is incapable of verbal of developing cancer, but the technologist PET/CT). The most relevant exception is Parents are not the only object of the communication. Recognising stress and should clearly state that this risk, if present, probably whole-body FDG PET/CT, where information effort. The child is at the fear often helps to reduce weeping and is very low and that the information image quality requires fasting, avoidance centre of the action, and even young sobbing when pain and discomfort are gained from the examination is essential of physical activity in the day(s) before the children should be involved and informed, experienced. to the clinical management of the child. scan and prevention of exposure to cold adapting the approach to their stage of Offering choices helps the child to The explanation is usually straightforward, during the hours preceding the injection. cognitive and psychosocial development. gain some control over her/his situation: because most of the functional data The last point is particularly relevant, Children’s attention span is often choosing the position of the parent beside

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SEDATION ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC POPULATION the scanning bed, selecting videos or Patient preparation and requirements MAG-3 renography, 3-phase bone scan) ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC POPULATION music on a tablet, etc. It is possible to perform most of are subject to local regulations and has to start before injecting a central line, The injection is probably the most the nuclear medicine procedures in institutional policies, often including an because the bolus will arrive in the field significant source of fear for the child, and paediatric patients without sedation. anaesthesiologic evaluation in the days of view very quickly. After the injection a proper injection technique is essential Many departments sedate only a small before the examination. Strict adherence it is essential to flush the line thoroughly to avoid unnecessary distress. Anaesthetic proportion of children undergoing to the preparation protocol and absence to avoid radiopharmaceutical retention, creams can be used to reduce pain standard planar imaging. Lengthy of contraindications to sedation (i.e. febrile particularly at the tip of the device. and fear, but the most relevant aspect examinations (mostly PET/CT, SPET/CT, illness, acute disorders, etc.) need to be Butterfly needles fitted with a three- remains a good relationship with the PET/MR) usually require sedation, when verified before injecting the radiotracer. way stopcock are preferred when an IV child and the parents. Tactful explanation immobility is essential and repeated It is also worth remembering that the line is not available. A saline syringe or of the various steps, underlining what is acquisitions are contraindicated and occupation time of the scanning room is an IV line is connected to one port and absolutely painless, will keep the negative cumbersome. often longer than for conscious patients, the radiopharmaceutical syringe to the anticipation to a minimum. Bandages and The age range varies slightly, depending particularly if no recovery room is available. remaining one. A first saline flush will verify medication removal are often perceived on local resources and skills, but the vein patency, and after the radiotracer as unpleasant, so it is useful to ask for the most frequent indication for sedation is injection a second flush will complete child’s cooperation. between 8-9 months and 4-5 years. dose delivery, leaving the line in place if The explanations to the child are a good Imaging of babies and small children INJECTION required (diuretic test, etc.) opportunity to reinforce some of the can often rely on the induction of natural The injection is the critical step in many At least in smaller children, a second messages to the parents and give them sleep. An earlier wake-up and avoiding paediatric scans, and the time required to operator should help in immobilising the another chance to ask supplementary naps before the examination are useful identify the optimum site and position a injection site; parents should mainly try to questions. strategies, as is feeding before the scan, safe access can be as long as 30 minutes, soothe the child, but they can help control The final phase of the conversation most often after an IV line has been placed. even in a dedicated environment with the other limbs if they are willing to do should cover instructions for the Dimmed lights and a quiet environment experienced staff. so. This is a critical point in the procedure, management of the child after the scan. (beware of phones, intercoms, etc.) can The most favourable situation is because even small children or babies They usually include free oral hydration facilitate sleep induction. having an IV line already established can be difficult to control when they are and frequent voiding to reduce the Sedation should not be a routine option, on the inpatient’s hospital ward. Use of overwhelmed by fear, particularly if they radiation dose to the bladder, as well therefore, because it carries some definite indwelling central catheters or ports may are surprised by the venepuncture. On the as advice on the proper disposal of risks, but is reserved for selected cases be allowed, and in many oncological other hand, it is essential to avoid a brute radioactive nappies. after careful cost-benefit analysis. Sedation patients this is the only available access. In force approach. Careful evaluation and usually requires specialised professionals this case, the injection is usually reserved planning are therefore required during the for administration and monitoring, and to trained personnel using scrupulous previous phase to identify the role of each all the equipment needed (vital signs sterile technique. It is highly advisable team member. monitors, infusion pumps, resuscitation to use the shortest line available and to tools) must be available and checked flush it before injecting the radiotracer. before starting the procedure. The acquisition of a dynamic scan (i.e.

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IMAGING ENVIRONMENT ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC POPULATION child, with better positioning, supervision, often they need to be directed and helped appreciated by adolescents as well. ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC POPULATION The imaging environment and immobilisation. Moreover, the child by the technician. Stickers, bravery awards, etc., presented encompasses not only the scanning room will not be frightened by the impending Safety straps or some other kind of to the patient before discharge, can help but also the reception area, the waiting camera and will have unobstructed access gentle restraint should always be used, reduce any negative feelings. The child room, and the corridors. It is important to his/her parents and distractions such as because they guarantee the safety of the and his/her parents should always be to introduce child-friendly elements such videos, phones, etc. when supine. child. They are no substitute for careful reassured, even in difficult and prolonged as cartoon posters or wall decorations to Some manufacturers offer dedicated uninterrupted monitoring, because quiet examinations. make the atmosphere less intimidating. cradles, which are mounted on the children can become agitated within a few Finally, it is useful to point out that If a dedicated waiting room is available, standard table. These offer some seconds due to noise or simply boredom, follow-up examinations will also run a TV set or a computer/tablet showing advantages in SPECT imaging, but their and even sedated children can awake more smoothly if they can build on an movies or children’s shows may help, practical utility is debated. Different types suddenly. Therefore, the technologist established good relationship between particularly for longer post-injection of vacuum cushion are also used, with should never leave a child unattended the technologist, the child, and the waiting times. Toys and games need good results. Whatever the method, the on the imaging table, and it is prudent to parents. appropriate cleaning to avoid spreading child cannot be left unattended. have a member of staff on hand to help infection, but the information leaflet can It is advisable to have the parents the parent. suggest that families bring one favourite remove any unnecessary clothing and, The staff should demonstrate the use of toy from home. The toy can participate where applicable, to change the child’s the restraints before the examination, both IMAGE ACQUISITION in the scanning procedure, staying with nappy just before positioning the patient. to the parents and to the child, whenever As a general rule, the acquisition the child on the imaging table to provide This should happen in a different room, possible. It must be made clear that they protocol should be adapted to each comfort and reduce apprehension. or at least on separate stretcher/bed, are for the child’s protection and are not patient, not only with regard to the Child-friendly decorations can also help to prevent urine contamination of the a way of avoiding contact with the child. obvious parameters related to body on the scanning room walls and ceiling, imaging table or the detector. At the end of the acquisition, it is habitus, weight, etc. (i.e. acquisition zoom or on the gamma camera and the PET/ When the child lies on the table under better to check the whole scan before or pixel dimensions), but to the general CT gantry. Needles, syringes, scissors, and the camera head, it is mandatory to allowing the child off the table. It is often approach. The goal is not to achieve the other menacing equipment should be reassure him/her and avoid direct contact a challenge to convince the child to return best image quality possible, but to acquire kept out of view whenever possible. between the camera and the body of to the gamma camera or the PET scanner, the image(s) needed to resolve the clinical The single-head gamma camera is the the patient. A parent or member of staff even for a single one-minute image. question. This goal should be achieved in best solution for imaging of babies and should keep the child under direct and The technologist should anticipate the shortest time possible, keeping stress young children. The camera should be continuous control, to prevent sudden table and detector movement in order to to a minimum for the child and for the configured head face up underneath movements and bumping of the head reassure both the child and the parents. parents. the imaging table. In some models it or limbs on the camera. Gentle restraint Good communication must continue Motion correction software can help in is possible to fit an adapter over the is necessary for babies and younger for the whole duration of the scan, reducing motion artefacts, particularly in collimator surface, allowing the direct children, to avoid movement artefacts maintaining empathy and preventing SPET/CT acquisition. However, it cannot positioning of the baby on it. This set-up and keep the patient safe. Parents should anxiety. Encouragement and praise can substitute for careful positioning, clever has the advantage of direct access to the cooperate in keeping the child still, but motivate older children and are often use of mild restraint and meticulous

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SUGGESTED READING ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC POPULATION ACCOMPLISHING GOOD DIAGNOSTIC EXAMINATIONS FROM THE PAEDIATRIC POPULATION watching throughout the entire scan. 1. Gordon I. Issues surrounding preparation, Many distraction techniques have information and handling the child and parent in nu- proven useful, from reading stories to clear medicine. J Nucl Med. 1998;39(3):490–494. 2. Pintelon H, Jonckheer MH, Piepsz A. Paedi- DVD players, smartphones, and tablets. atric nuclear medicine procedures: routine sedation The parents can usually identify the or management of anxiety? Nucl Med Commun. best solution and should be warmly 1994;15(8):664–666. encouraged to deploy their skills in this 3. Ljung B. The child in diagnostic nuclear medicine. Eur J Nucl Med. 1997 Jun;24(6):683-90. crucial task. As a positive side effect, 4. Borgwardt L, Larsen HJ, Pedersen K, Hø- they will also feel more in control of the jgaard L. Practical use and implementation of PET in situation. children in a hospital PET centre. Eur J Nucl Med Mol Imaging. 2003;30(10):1389–1397 5. Gelfand MJ, Clements C, MacLean JR. Nu- clear Medicine Procedures in Children: Special Consid- erations. Semin Nucl Med. 2017;47(2):110–117. CONCLUSION 6. Lassmann M, Treves ST; EANM/SNMMI Paediatric nuclear medicine poses many Paediatric Dosage Harmonization Working Group. Paediatric radiopharmaceutical administration: har- challenges to the nuclear medicine team, monization of the 2007 EANM paediatric dosage and the technologist is deeply involved in card (version 1.5.2008) and the 2010 North American most steps of the procedure. Obtaining consensus guidelines. Eur J Nucl Med Mol Imaging. 2014;41(5):1036–1041 quality images while keeping physical 7. Parisi MT, Bermo MS, Alessio AM, Sharp SE, and emotional discomfort to a minimum Gelfand MJ, Shulkin BL. Optimization of Pediatric PET/ requires sounds technical knowledge, CT. Semin Nucl Med. 2017;47(3):258–274. empathy, flexibility, and a lot of patience. On the other hand, this can be one of the most rewarding professional activities because the patients and their parents feel the engagement and are usually very grateful. At the end of the day, smiles usually overcome tears and whining.

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INFLAMMATION AND INFECTION STUDIES

by Andor W.J.M. Glaudemans

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INTRODUCTION INFLAMMATION STUDIES AND INFECTION In this chapter, the most commonly Generally, the bone scan consists of INFLAMMATION STUDIES AND INFECTION Molecular imaging of and inflammatory diseases has seen a used radiopharmaceuticals and imaging three phases (perfusion, blood pool, dramatic growth in interest in the last decade due to improvements in our techniques for gamma-camera imaging and late phase with incorporation of knowledge of the pathophysiology of infections and inflammatory diseases, of infection and inflammation will be the radiopharmaceutical into the bone as well as to recent development in imaging modalities. Nuclear medicine discussed, with a focus on the correct matrix) and all phases are necessary when imaging offers unique possibilities to differentiate between infections and acquisition and interpretation of the a bone infection is suspected. Recently, sterile inflammation and between infections and tumours, but it has also scans. The most often used technique is a procedural guideline was published important added value in defining the extent of an infection, in selecting white blood cell scintigraphy. The other on how to perform bone scintigraphy the best location for biopsy, and in monitoring treatment efficacy. Hybrid commonly used conventional imaging correctly 14. camera systems allowing combinations of pathophysiology and anatomy techniques (bone scan, bone marrow The three phase bone scintigraphy can have led to better diagnostic accuracy. Nuclear medicine has positioned scintigraphy, 67Ga-citrate) only play a minor be used as an initial screening method itself as a key player in the field of infections and inflammatory diseases. role these days, but will also be discussed. to exclude the presence of peripheral In the second part of this chapter, an bone infection in case of negativity, overview will be given of all available because of its good availability (it can Different nuclear medicine imaging particular topic: [1] guidelines on how to radiopharmaceuticals for conventional mostly be performed within 24 hours of techniques and radiopharmaceuticals label autologous white blood cells 2,3, [2] nuclear medicine imaging and some the request from the referring clinician), are available for imaging infection and guideline on the correct acquisition and experimental radiopharmaceuticals will be relatively low costs and high negative inflammation. However, all of them have interpretation criteria for white blood discussed. Finally, some clinical examples predictive value. After recent fracture and/ their pros and cons, not all techniques cell imaging 4, [3] guideline on the use will be shown. or surgery and if there is high suspicion of are available in every centre, and there is of FDG in infection/inflammation5 , [4] an infection the role of bone scintigraphy widespread variation in how the scans are guideline on multimodality imaging for is negligible, since the specificity is rather acquired and the results interpreted. Over infective endocarditis 6, [5] guideline for low, and uptake can be seen in all sites of the last decade, the EANM Committee vasculitis and polymyalgia rheumatica 7, RADIOPHARMACEUTICALS FOR increased bone metabolism irrespective of on Inflammation and Infection has [6] guideline for cardiac sarcoidosis 8, [7] GAMMA-CAMERA IMAGING the underlying disease. Furthermore, in a worked hard on three main goals: [1] guideline on peripheral bone infection 9, low-grade infection the first two phases the standardisation of nuclear medicine [8] guideline on prosthetic joint infection Bone scintigraphy can even be negative, so the late phase is techniques for the diagnosis of infection 10, [9] guideline on spinal infections 11, [10] The bone scan is one of the oldest essential and when positive it may be the and inflammation and their interpretation guideline on vascular graft infections 12, existing nuclear medicine techniques and only indication of an existing infection. criteria, [2] the dissemination of these and [11] guideline on cardiac amyloidosis is still one of the cornerstones of nuclear The time frame in which the bone scan techniques amongst nuclear medicine 13. Many of these guidelines focus on FDG- medicine practice in many centres, is confirmed positive after fracture and/ practitioners, and [3[ the publication of PET/CT imaging as the nuclear medicine despite the increasing use of the PET or surgery is not known, but increased joint diagnostic guidelines with clinicians imaging technique of choice, but some bone scan (NaF-PET) in some hospitals. osteoblastic activity probably remains 1. of them also still include conventional Gamma-camera bone scintigraphy is visible within the first 2 years of the trauma The following guidelines are available nuclear medicine imaging (gamma- performed by intravenous administration or surgery. During this time period there now for those with an interest in a camera imaging). of diphosphonates labelled with 99mTc. is no role for bone scintigraphy. There

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INFLAMMATION STUDIES AND INFECTION might be a role in chronic latent bone White blood cell scintigraphy radiation energy of 173 and 247 keV that uptake in suspected regions over time, an INFLAMMATION STUDIES AND INFECTION infections, but even then, a positive Scintigraphy with labelled autologous increases the radiation burden, whereas important criterion of positivity for bone bone scintigraphy must be interpreted white blood cells (WBC scintigraphy) is 99mTc has a short half-life of 6 h and ideal infections and most soft tissue infections 4. with caution and when positive other another of the oldest existing nuclear radiation energy of 140 keV. A scan should be considered positive for imaging methods are necessary to better medicine imaging techniques (developed Due to the different biodistribution an infection when there is an increase in differentiate between real infection and back in the 1970s), though thanks to and kinetics of white blood cells (WBC) size or intensity over time. When there is other causes of increased osteoblastic better and hybrid imaging systems and in blood, bone marrow, inflammation a decrease in size or intensity over time, or activity. improved acquisition and interpretation and infection, 3 sets of images should when the uptake is stable over time, then Indications for the use of bone criteria it is still the gold standard in preferably be acquired: “early” images the scan should be considered negative. scintigraphy in infections and nuclear medicine techniques for several (between 30 minutes and 1 hour after If the correct acquisition protocols inflammatory diseases are: (1) To exclude infections. injection), “delayed” images (2-4 h after and interpretation criteria are used, the presence of an infection in the Scintigraphy with autologous injection) and “late” images (20-24 h after this technique yields excellent overall musculoskeletal system, and (2) to look for leukocytes is characterised by high injection) (Figure 1). In order to reduce diagnostic accuracy. Guidelines regarding viability of the involved bone or to see if specificity, because the latter only operator dependence in image display indications, acquisition and interpretation there are sequestra. When this is the only accumulate as a consequence of active and final interpretation, image acquisition of WBC scintigraphy were recently question from the referring trauma or migration into inflamed tissues. After times should be corrected for isotope published 4. orthopaedic surgeon, then a three-phase injection, radiolabelled WBCs show rapid decay. If early images are acquired for a WBC scintigraphy has a high bone scintigraphy is required. When clearance from the lungs and blood set number of counts or a set period of diagnostic accuracy for infections in performing a conventional bone scan, all pool, with progressive migration into the time, delayed and late images should be the musculoskeletal system (except three phases are necessary to see if there spleen, liver, bone marrow and sites of corrected for the isotope half-life. With in spondylodiscitis) 9,10. However, the is perfusion and osteoblastic activity of infection where a neutrophilic infiltrate this acquisition modality, different images procedure itself has several limitations: the the involved bone. When looking for a predominates. can be compared on the same intensity full analysis requires several scans over 2 sequester (which can be rather small) Radiolabelled WBCs first adhere to the scale, in absolute counts (and not in % days, blood manipulation is necessary, the SPECT/CT is required for exact location vascular endothelium and then migrate of maximum activity), thus avoiding any labelling procedure takes time (2-3 hours) and in order to see a small “cold” spot in toward the infected area through the operator bias. This method also allows and the technique is not available in the case of a sequester. This is really the endothelium and basal membrane. Thus, correct detection of a true increase in every nuclear medicine department. WBC only question for which bone scan is the radiolabelled WBCs are a specific indicator absolute best option in patients after for leukocytic infiltration15 . Figure 1. Accumulation of white blood cells is trauma and/or bone surgery. However, The white blood cells can be labelled a dynamic process. In infections, uptake increases since the spatial resolution in conventional with either 99mTc-exametazine (HMPAO) or over time, while in inflammation there is uptake bone scintigraphy is rather limited (to 111In-oxine. 99mTc-labelled white blood cells in the 1st (early) and 2nd (delayed) phase, but a approximately 8 mm), smaller sequestra have replaced 111In-labelled white blood decrease in the 3rd (late) phase. Bone marrow may be missed. cells for most indications, because of their uptake remains stable over time. Due to this more suitable radiation characteristics. dynamic process, imaging at several time points is 111In has a long half-life of 67 h and necessary. The diagram is adapted from 17.

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INFLAMMATION STUDIES AND INFECTION scintigraphy can already be performed There are two antibodies commercially only a minority of patients still require a citrate scintigraphy is becoming obsolete INFLAMMATION STUDIES AND INFECTION at an early stage after the trauma and/or available: a Fab fragment, Sulesomab BM scan. and has been replaced by FDG-PET/CT. surgery. Furthermore, use of antibiotics (Leukoscan®) and a whole murine However, it may still find applications in does not influence the results of WBC IgG, Besilesomab (Scintimun®). Image 67Gallium-citrate scintigraphy fever of unknown origin, sarcoidosis or scintigraphy 16. protocols differ between complete and 67Ga-citrate binds in ionic form to spondylodiscitis in centres that are lacking Currently, radiolabelled white blood fragmented antibodies. Images with circulating transferrin as an analogue of a PET-CT scanner. cell scintigraphy is the gold standard complete antibody (Besilesomab) should iron. It uses transferrin receptors (CD71) to nuclear medicine imaging technique for be performed 2-4 h and 16-24 h post access the cell and then becomes highly Role of hybrid imaging infections in the musculoskeletal system injection. Planar images can be performed stable within the cells. Increased blood The advent of hybrid imaging (peripheral bone infection, prosthetic joint with the same acquisition protocol as WBC. flow and increased vascular membrane technologies combining molecular/ infection, diabetic foot infection), but can Images with the fragmented antibody permeability result in increased delivery functional and anatomical information also be used as a good alternative for FDG- (Sulesomab) should be performed 1-3 and accumulation has significantly increased the diagnostic PET/CT in endocarditis and vascular graft and 6-8 h post injection. Guidelines of transferrin-bound 67Ga in infected accuracy of conventional nuclear imaging infections. regarding indications, acquisition and areas. 67Ga also binds to lactoferrin, which is examinations by increasing sensitivity and interpretation of AGA scintigraphy were present in high concentrations in infected specificity and reducing the number of Anti-granulocyte antibody recently published 4. foci. Some 67Ga may be transported bound equivocal lesions. This hybrid technology scintigraphy to leukocytes. Direct uptake by certain has redefined the diagnostic work- As an alternative to WBC scintigraphy, Bone marrow scintigraphy bacteria has also been observed, due to up of patients and influenced patient labelled anti-granulocyte antibodies Bone marrow (BM) scintigraphy can be the high affinity of siderophores and low- management. Hybrid imaging techniques (AGA) can be used. The advantages of used in patients with suspected infection molecular- weight chelates produced by have improved image properties because using radiolabelled antibodies against of the musculoskeletal system when bacteria for 67Ga. The siderophore–67Ga of (1) advances in detector designs and surface present on granulocytes WBC (or AGA) scans are doubtful. 99mTc- complex is presumably collimator modelling inherent to newer are that they are easier to use than colloids (colloids larger than 500 nm are transported into the bacterium, devices, (2) incorporation of CT data into radiolabelled autologous WBCs and do recommended) are injected intravenously where it remains until phagocytosed by SPECT reconstruction, and (3) fusion of not require the handling of potentially and images of the region of interest are macrophages. Approximately 25% of the anatomic and functional data, allowing hazardous biological specimens. acquired after a minimum of 30 minutes total injected dose is excreted through the more accurate localisation and assessment Disadvantages, on the other hand, include and a maximum time of 6 h post injection. urinary system, whereas the rest is retained of disease extent. SPECT/CT should be an the high molecular weight (resulting in When there is concordance between WBC in the bone, bone marrow, liver and soft integral part of a conventional scintigraphy, slow diffusion into sites of inflammation), and BM scan (uptake in the same region) tissues. The best target-to-background the main aim being to better distinguish a long plasma half-life, slow concentration this is probably due to physiological bone ratio is normally achieved after 48–72 bone infections from soft tissue infections in the affected site, uptake in the liver marrow activity; discordant findings h. 67Ga-citrate has a very low specificity, and to more accurately assess the extent due to clearance by the reticuloendothelial (positive on WBC scan, negative on BM and its long physical half-life (78 h) and of the infectious or inflammatory process. system, and in some cases the induction scan) point to an infection. However, if high-energy radiation are unfavourable of human antimurine antibodies, a host the correct acquisition and interpretation characteristics for scintigraphic imaging 15. response to foreign antigens. criteria are used for WBC/AGA imaging, Although still used in some countries, 67Ga-

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INFLAMMATION STUDIES AND INFECTION Other available radiopharmaceuticals however, were not successful. Most fast renal clearance with low hepatic, INFLAMMATION STUDIES AND INFECTION for conventional infection and attempts were made to radiolabel bone marrow or gastrointestinal uptake. inflammation imaging antibiotics, such as 99mTc-ciprofloxacin, The results obtained were controversial, Many efforts have been made in the which was the first radiolabelled antibiotic however, which may have been the result past to develop other, more specific, tested in humans to image infections. of different bacterial strains imaged, radiopharmaceuticals. Most of them, The first studies were promising, showing ongoing antibiotic therapy, and a lack of standardisation in acquisition and interpretation. Other compound groups that were radiolabelled included antifungal agents, antimicrobial peptides, vitamins, endothelial cell components, antibodies, cytokines, peptides, etc. In recent years, radiolabelled interleukin-2 (99mTc-IL2) showed good results in vulnerable atherosclerotic plaques 18, for rejection after lung transplantation 19 and to visualise the lymphocytic infiltration in metastatic melanoma 20. A PET variant is now under investigation 21. A complete overview of available radiopharmaceuticals is shown in Figures 2 and 3.

Figure 3. Available radiopharmaceuticals for inflammation imaging. Source: Signore A, Glaudemans AW. The molecular imaging approach to image infections and inflammation by nuclear medicine techniques. Ann Nucl Med 2011; 25(10):681-700.

Figure 2. Available radiopharmaceuticals for infection imaging. Source: Signore A, Glaudemans AW. The molecular imaging approach to image infections and inflammation by nuclear medicine techniques. Ann Nucl Med 2011; 25(10):681-700.

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INFLAMMATION STUDIES AND INFECTION CLINICAL EXAMPLES INFLAMMATION STUDIES AND INFECTION 36-year-old male patient. Several 46-year-old female patient. Several 47-year-old male patient. Pain surgical operations in the past for distal surgical operations in the past for distal complaints several years after surgery for tibia fracture and pseudoarthrosis. tibia fracture and pseudoarthrosis. a tibia fracture. CT scan was inconclusive. Now wound complaints. Because of Because of suspected infection WBC Because of suspected infection WBC suspected infection WBC scintigraphy was scintigraphy was performed. scintigraphy was performed. performed.

Figure 6: WBC scintigraphy (upper row: delayed images (4 h after injection of the radiolabelled cells) anterior and posterior views, middle row: late images (24 h after injection) anterior and posterior views, lower Figure 5: WBC scintigraphy (upper row: delayed row: fused SPECT/CT images. The planar images (4 h after injection of the radiolabelled images (corrected for decay and showed in cells) lateral views, lower row: late images (24 h counts intensity) show high focal uptake, Figure 4: WBC scintigraphy (upper row: delayed after injection) lateral views. The planar images increasing over time, suspected infection. The images (4 h after injection of the radiolabelled (corrected for decay and showed in counts SPECT-CT images show that the infection is cells) anterior and posterior view, middle row: intensity) show only physiological uptake in the located at the metallic implant in the medial late images (22 h after injection) anterior and delayed images, but increased uptake in the late malleolus. posterior view, lower row: SPECT/CT images at the images, so increase in size over time, suspected delayed time point). The planar images (corrected infection. for decay and showed in counts intensity) show increased uptake in size over time, suspected infection. SPECT/CT reveals that the infection is located outside the bone. Scan conclusion: soft tissue infection, no bone involvement.

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CONCLUSIONS 3. Roca M, de Vries EF, Jamar F, Israel O, Si- kler H, Gheysens O, Vanhoenacker FMHM, Petrosillo tro evidence that 99mTc-HYNIC-interleukin-2 is able INFLAMMATION STUDIES AND INFECTION gnore A. Guidelines for the labelling of leucocytes N, Jutte PC. Consensus document for the diagnosis of to detect T lymphocytes in vulnerable atherosclerotic INFLAMMATION STUDIES AND INFECTION In conclusion, nuclear medicine with (111)In-oxine. Eur J Nucl Med Mol Imaging 2010; prosthetic joint infections: a joint paper by the EANM, plaques of the carotid artery. Eur J Nucl Med Mol Imag- 37(4):835–841. EBJIS, and ESR (with ESCMID endorsement). Eur J Nucl ing 2014; 41(9):1710-1719. modalities play a very important role 4. Signore A, Jamar F, Israel O, Buscombe J, Med Mol Imaging 2019; 46(4):971-988. 20. Telenga ED, van der Bij W, de Vries EF, Ver- in patients with suspected infection or Martin-Comin J, Lazzeri E. Clinical indications, image 12. Lazzeri E, Bozzao A, Cataldo MA, Petrosillo N, schuuren EA, Timens W, Luurtsema G, Slart RH, Signore inflammation. For most infectious or acquisition and data interpretation for white blood Manfre L, Trampuz A, Signore A, Muto M. Joint EANM/ A, Glaudemans AW. 99mTc-HYNIC-IL-2 scintigraphy to inflammatory diseases FDG-PET/CT is the cells and anti-granulocyte monoclonal antibody scin- ESCR and ESCMID-endorsed consensus document for detect acute rejection in lung transplantation patients: tigraphy: an EANM procedural guideline. Eur J Nucl the diagnosis of spine infection (spondylodiscitis) in a proof-of-concept study. EJNMMI Res 2019; 9(1): 41. preferred nuclear imaging technique, but Med Mol adults. Eur J Nucl Med Mol Imaging 2019; 46(12):2464- 21. Markovic SN, Galli F, Suman VJ, Nevala WK, there is still a role for conventional nuclear 5. Imaging 2018; 45(10):1816-1831. 2487. Paulsen AM, Hung JC, Gansen DN, Erickson LA, Mar- medicine in several infectious diseases, 6. Jamar F, Buscombe J, Chiti A, Christian PE, 13. Chakfe N, Diener H, Lejay A, Assadian O, Be- chetti P, Wiseman GA, Signore A. Non-invasive visualiza- and particularly for white blood cell Delbeke D, Donohoe KJ, et al. EANM/SNMMI guideline rard X, Caillon J, Fourneau I, Glaudemans AW, Koncar I, tion of tumor infiltrating lymphocytes in patients with for 18F-FDG use in inflammation and infection. J Nucl Lindholt J, Melissano G, Saleem B, Senneville E, Slart RH, metastatic melanoma undergoing immune check- scintigraphy in peripheral bone infections Med 2013; 54(4):647-658. Szeberin Z, Teebken O, Venermo M, Vermassen F, Wyss point inhibitor therapy: a pilot study. Oncotarget 2018; and prosthetic joint infections. When 7. Erba PA, Lancellotti P, Vilacosta I, Gaem- TR. European Society for Vascular Surgery (ESVS) 2020 9(54):30268-30278, performing nuclear medicine imaging, perli O, Rouzet F, Hacker M, Signore A, Slart RH, Habib Clinical practice guidelines on the management of vas- 22. Di Gialleonardo V, Signore A, Glaudemans G Recommendations on nuclear and multimodality cular graft and stent graft infections with the endorse- AW, Dierckx RA, de Vries EF. N-(4-18F-fluorobenzoyl)in- practitioners should be aware of existing imaging in IE and CIED infections. Eur J Nucl Med Mol ment of the European Association of Nuclear Medicine terleukin-2 for PET of human-activated T lymphocytes. guidelines on how to correctly acquire Imaging 2018; 45(10):1795-1815. (EANM). Eur J Vasc Endovasc Surg 2020, in press. J Nucl Med 2012; 53(5):679-686. and interpret the images and existing 8. Slart RH, Glaudemans AW, Chareonthai- 14. Dorbala S, Ando Y, Bokhari S, Dispenzieri A, diagnostic flowcharts showing when to tawee P, Treglia G, Besson, TL, Bley TA, et al. FDG-PET/ Falk RH, Ferrari VA, Fontana M, Gheysens O, Gillmore JD, CT(A) imaging in large vessel vasculitis and polymyal- Glaudemans AW, Hanna MA, Hazenberg BP, Kristen AV, use which technique for which indication. gia rheumatica: joint procedural recommendation of Kwong RY, Maurer MS, Merlini G, Miller EJ, Moon JC, Fortunately, several guidelines and the EANM, SNMMI, the PET Interest Group (PIG), and Murthy VL, Quarta CC, Rapezzi C, Ruberg FL, Shah SJ, diagnostic flowcharts for infections and endorsed by the ASNC. Eur J Nucl Med Mol Imaging Slart RH, Verberne HJ, Bourgque JM. J Card Fail 2019; inflammatory diseases are now available 2018; 45:1250–1269. 25(11):e1-e39. 9. Slart RH, Glaudemans AW, Lancelotti P, 15. Van den Wyngaert T, Strobel K, Kampen and technicians, nuclear medicine Hyafil F, Blankstein R, Schwartz R, et al. A joint proce- WU, Kuwert T, van der Bruggen W, Mohan Hk, et al. The specialists and clinicians should be aware dural position statement on imaging in cardiac sar- EANM practice guideline for bone scintigraphy. Eur J of these new guidelines and adhere to coidosis: from the cardiovascular and inflammation Nucl Med Mol Imaging 2016; 43:1732-1738. them in practice. and infection committees of the European Association 16. Signore A, Glaudemans AW. The molecular of Nuclear Medicine (EANM), the European Associa- imaging approach to image infections and inflamma- tion of Cardiovascular Imaging (EACVI), and the Amer- tion by nuclear medicine techniques. Ann Nucl Med ican Society of Nuclear Cardiology (ASNC). Eur Heart J 2011; 25(10):681-700. REFERENCES Cardiovasc Imaging 2017; 18(10):1073–1089. 17. Glaudemans AW, Israel O, Slart RH. Pitfalls 1. Signore A, Lazzeri E, Glaudemans AW. In- 10. Glaudemans AW, Jutte PC, Cataldo MA, Cas- and limitations of radionuclide and hybrid imaging fection and inflammation imaging standardization: sar-Pullicino V, Gheysens O, Borens O, Trampuz A, Wör- in infection and inflammation. Semin Nucl Med 2015; the EANM guidelines. Clin and Transl Imaging 2018; tler K, Petrosillo N, Winkler H, Signore A, Sconfienza LM. 45(6):500-512. 6(4):253-255. Consensus document for the diagnosis of peripheral 18. Glaudemans AW, Galli F, Pacilio M, Signore 2. De Vries EF, Roca M, Jamar F, Israel O, Signo- bone infection in adults: a joint paper by the EANM, A. Leukocyte and bacteria imaging in prosthetic joint re A. Guidelines for the labelling of leucocytes with EBJIS, and ESR (with ESCMID endorsement). Eur J Nucl infections. Eur Cell Mater 2013; 25:61-77. (99m)Tc-HMPAO. Eur J Nucl Med Mol Imaging 2010; Med Mol Imaging 2019; 46(4):957-970. 19. Glaudemans AW, Bonanno E, Galli F, Zee- 37(4):842–848. 11. Signore A, Sconfienza LM, Borens O, bregts CJ, de Vries EF, Koole M, Luurtsema G, Boersma Glaudemans AW, Cassar-Pullicino V, Trampuz A, Win- HH, Tuarino M, Slart RH, Signore A. In vivo and in vi-

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PARATHYROID AND THYROID IMAGING

by Martin Gotthardt

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INTRODUCTION PARATHYROID AND THYROID IMAGING scintigraphic imaging techniques for glands is less reproducible. They can PARATHYROID AND THYROID IMAGING Nuclear medicine plays a relevant role in imaging of thyroid and validation of scintigraphic findings, adding sometimes be found in an intrathyroidal parathyroid disease. Ever since the principle of radionuclide imaging to the specificity of image diagnosis. Still, location, in the (most often upper was introduced by Nobel laureate George de Hevesy, nuclear medicine the approach to image interpretation, anterior) mediastinum, in the thymus or, has used radionuclides to track physiological and pathophysiological treatment and follow-up of patients if they have not migrated properly during metabolic processes in the human body. I-131 was first used for therapy with thyroid nodules and/or parathyroid embryological development, clearly of Grave’s disease in 1941. The isotope was used to determine iodine adenoma may depend on the presence of above the thyroid. In addition, the lower uptake in the thyroid, and calculation of therapeutic doses via the thyroid multinodular goitre. parathyroids can also be located in the uptake was already described back in 1948. Although imaging/uptake Here, a concise overview will be given middle behind the thyroid lobes or at the measurements of the thyroid with radioactive thus has a of anatomy/physiology, diseases and upper poles. Normally, they are the size of long tradition, the role of nuclear medicine for diagnosis of thyroid disease diagnostic imaging of the thyroid and a grain of rice, and although the spatial varies between countries throughout Europe and is often determined by parathyroid glands. The aim is not to resolution of ultrasound, for example, is medical traditions that have developed over the last century. replace guidelines or deliver protocols but sufficient to visualise such small structures, to give an overview of the current state of they usually cannot be distinguished the art in thyroid and parathyroid imaging. from surrounding tissue by imaging. Factors influencing the role of nuclear common. Based on such traditions, we see However, some general recommendations Incidentally, one parathyroid gland may medicine include the incidence of thyroid considerable differences across Europe in for imaging protocols are given. be missing or an additional gland may be disease as well as how actively nuclear the role that thyroid diseases play in the present, mostly in the thymus. medicine has acquired patients with perception of healthcare professionals The role of the thyroid is production thyroid diseases. Diagnosis and treatment and the general population, although of the three thyroid hormones, of thyroid disease may be fully in the the regional differences in iodine supply ANATOMY AND PHYSIOLOGY triiodothyronine (T3), thyroxine (T4), and hands of nuclear medicine (as in Germany are much reduced compared to 50 years OF THE THYROID AND THE calcitonin. T3 and T4, produced in the or Austria, obviously excluding surgical ago. However, in many countries the PARATHYROIDS thyroid cells (thyrocytes), are responsible treatment) but can also be limited to average daily uptake of 200 micrograms The thyroid is a gland consisting of two for the metabolic rate of the body and are diagnosis and I-131 treatment on behalf of of iodine as advised by the WHO has not lobes lying on the left and right side of also essential for growth and development endocrinologists (as in many parts of the yet been reached (WHO 2004). This results the trachea with the so-called isthmus in during childhood. For production of Netherlands). Also, the view on diagnosis in a moderate iodine deficiency in parts between, a relatively thin layer of thyroid thyroid hormones, iodine is required. Lack and treatment may vary in countries of the population, so that nodular goitres tissue connecting both lobes. The thyroid of thyroid hormones during childhood with traditional iodine deficiency leading (enlarged with thyroid nodules) is located just above the sternum and (as a result of severe iodine deficiency or to high incidence of enlarged thyroids, are still common. As we will see later below the larynx. Behind the thyroid lobes, because the thyroid has not developed so-called goitres (as, for example, in the in this chapter, this has a considerable the four parathyroid glands are found – in the embryo) leads to so-called regions around the Alps), as compared to influence on diagnosis and localisation normally one each behind the upper and cretinism, characterised by retardation of regions where high amounts of iodine- of thyroid nodules and hyperplastic lower poles of each thyroid lobe. While development, small size and low cognitive containing sea fish were available as food parathyroid glands. In this context, the location of the thyroid itself does not function. Calcitonin is produced in the and thus iodine-deficient goitres were not ultrasound can play a major role alongside usually vary, the location of the parathyroid C-cells in the thyroid and is responsible for

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PARATHYROID AND THYROID IMAGING calcium metabolism. In the parathyroid daily iodine requirement may vary, so that hormones. Another autoimmune disease case of lung metastases. Therapy consists of PARATHYROID AND THYROID IMAGING glands, parathyroid hormone (PTH) is different individuals, although having an leading to is Hashimoto’s surgical removal of the thyroid (as well as produced. The latter also plays a major role identical daily iodine supply, may develop disease, in which the thyrocytes are cervical lymph nodes in case of metastases) in the calcium metabolism of the human a goitre or not. The maximal normal destroyed by the autoimmune process. followed by therapy with I-131, which is body, as well as influencing vitamin D and volume of a thyroid gland is 18 grams for Thus, hyperthyroidism in this case is not given for ablation of thyroid remnants as phosphate levels. Calcitonin is responsible women and 25 grams for men. In enlarged caused by overproduction of thyroid well as tumorous tissue. Although uptake for lowering calcium levels in the blood, thyroids, nodules develop frequently and hormones, but by release of thyroid of I-131 in thyroid carcinoma is lower than while PTH increases blood calcium levels. nodules resulting from iodine deficiency hormones that were stored in the thyroid. in healthy thyroid tissue with an efficient Secretion of T3 and T4 is stimulated by may also develop in thyroids of normal Medication reducing thyroid hormone uptake of iodine from the bloodstream, it is the thyroid-stimulating hormone (TSH) size. Nodules that have grown as a result production (thyrostatic medication) is usually still sufficient to achieve a cure. Only secreted from the anterior pituitary gland. of iodine deficiency may become cystic, in therefore not efficient in this case, while it in poorly differentiated thyroid carcinoma TSH is regulated by the thyrotropin- which case they can grow rapidly or even works very well if autonomous nodules or or Hürthle cell carcinoma (a subtype of releasing hormone (TRH) produced by the become acute within a couple of days as Graves’ disease are present. follicular carcinoma) there is no iodine hypothalamus, and high levels of thyroid a result of bleeding into the cystic nodule. Thyroid malignancies: The most uptake in most cases, so that adjuvant hormone in the blood suppress TRH Such patients may be afraid of having common thyroid carcinomas derived therapy with I-131 is not effective; cure production via a feedback loop. cancer, which frequently can be excluded from the thyrocytes are papillary and rates and 5- and 10-year survival rates here if a cystic nodule is present. Enlargement follicular thyroid carcinoma. Papillary are thus significantly reduced. of the thyroid or growth of nodules tends thyroid carcinoma preferably metastasises A particularly aggressive subtype of to start during puberty or pregnancy/ to the lymph nodes, whereas follicular thyroid carcinoma is anaplastic thyroid THYROID DISEASES breastfeeding. carcinomas have a tendency to spread via carcinoma, which despite extensive surgery Thyroid diseases can be classified into Diseases changing the function of the the bloodstream. Both tumours have a high and external beam radiation of the cervical diseases leading to enlargement of the thyroid gland: Hyperthyroidism may occur rate of cure, and both 5-year and 10-year area leads to death within months in most thyroid gland or formation of nodules as a consequence of autonomous function survival rates are among the highest for all cases. (adenomas), changes in function with of one or more thyroid nodules, which is malignancies. Nearly all early-stage patients Medullary thyroid carcinoma is derived hyper- or hypofunction, combinations usually caused by iodine deficiency. This are cured, and most patients can still be from the C-cells and produces calcitonin, thereof, and malignant diseases. Thus, is more common in countries with low cured even if lymph node metastases are which together with carcinoembryonic the size of the thyroid and its function iodine supply, while in countries with high present; even if metastasised to the lungs, (CEA) serves as a tumour marker do not necessarily correlate: a large average iodine intake, Graves’ disease is a cure is still possible. Thyroid carcinoma may after therapy. Radical surgery with extensive goitre may have a normal function, while more common cause of hyperthyroidism. also occur in childhood, especially after removal of metastatic lymph nodes is the hyperproduction of thyroid hormones Graves’ disease is an autoimmune disorder exposure to ionising radiation, as was the treatment of choice. As C-cells do not take may occur in a small thyroid. in which autoantibodies against the TSH case, for example, after the nuclear accident up iodine, adjuvant therapy with I-131 is Anatomical changes in the thyroid receptor expressed in the thyrocytes in Chernobyl in 1986. Although thyroid not an option. External beam irradiation gland: As a consequence of insufficient are produced. This antibody is able to carcinoma is more aggressive during may be considered in selected cases, also iodine supply, the thyroid can be enlarged stimulate the TSH receptor, resulting in childhood, the tumours respond very well to for reducing lymphogenic spread. while the function is normal. The individual continuous overproduction of thyroid therapy and cure rates are high, even in the

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PARATHYROID DISEASES PARATHYROID AND THYROID IMAGING the parathyroids are enlarged as a result nodules; to define the metabolic activity is not stimulated and hyperthyroidism is PARATHYROID AND THYROID IMAGING Parathyroid disease of overproduction of PTH in an attempt of a lesion or the thyroid as a whole; and caused by thyroid hormone release from (hyperparathyroidism, HPT) is usually to normalise blood calcium levels, thus to characterise lesions, i.e. identification of the progressively destroyed thyroid, thus characterised by an overproduction of PTH, usually more than one or all parathyroids malignancy. All these indications require uptake is low. In the case of Graves’ disease, leading to increased calcium levels in blood are enlarged. Chronic sHPT will lead to different approaches. TSH receptor- stimulating antibodies cause and urine. As a result, nephrocalcinosis, autonomous overfunction of the enlarged Anatomical pathology can most easily hyperthyroidism, leading to high uptake. urolithiasis, bone disease, gastrointestinal (hyperplastic) parathyroids, so-called be diagnosed by ultrasound, which allows Thyroid scintigraphy is sometimes used if and neuromuscular symptoms may occur. tertiary hyperparathyroidism (tHPT). measurement of the size of the whole thyroid nodules are detected, to measure Nowadays, the diagnosis is usually made Primary hyperparathyroidism may also thyroid, identification of nodules and also whether uptake of the radionuclides in based on elevated calcium levels in the occur as part of multiple neuroendocrine determination of the size of the nodules the lesion is normal or not. If so, the lesion blood, diagnosed when laboratory tests neoplasia (MEN) syndrome (MEN1 or for further follow-up. Thyroid scintigraphy is considered to be benign while in case are performed. Therefore, the diagnosis is MEN2A), leading to a combination of was formerly used for this purpose, but this of missing uptake, malignancy should often made in a subclinical state (Gotthardt endocrine tumours, usually of pancreas, indication is obsolete when ultrasound is be ruled out by fine needle aspiration et al 2013). If not diagnosed early, clinical thyroid and parathyroids (Hindie et al available. In the case of very large goitres, cytology. Thyroid scintigraphy is not symptoms may include urolithiasis, bone 2009, Greenspan et al 2012; Gotthardt et CT scanning may be required for complete generally used for this indication in Europe, or stomach pain, but there are also cases al 2013). imaging of the entire gland, especially if part but it is in some countries. The same is with neuropsychiatric symptoms (ranging of the thyroid is located in the retrosternal true for determination of thyroid nodule from slight behavioural changes to severe compartment, or if compression of the uptake with radiopharmaceuticals such as cases with coma). trachea is suspected. 99mTc-labelled MIBI, which in case of high There are three forms of this so- THYROID AND PARATHYROID Scintigraphic imaging of the thyroid uptake may indicate malignancy. However, called hyperparathyroidism: a primary, IMAGING is usually performed to determine the the specificity of such scans is limited and a secondary and a tertiary form. Primary The indications for imaging of the thyroid metabolic activity of either the whole further work-up with ultrasound or fine hyperparathyroidism (pHPT) is usually differ significantly from those for the thyroid or individual nodules. For this needle aspiration may be required, so that caused by one enlarged hyperfunctioning parathyroids. The aim of thyroid imaging purpose, I-131 or I-123 may be used, or the added value of such examinations is parathyroid, a so-called adenoma. In is usually not to localise a particular lesion, as an alternative, Tc-99m. For diagnosis of often limited. about 10-15% of cases, two parathyroid but to characterise it or to determine the autonomous thyroid nodules, scintigraphy adenomas may be found. Parathyroid metabolic activity of the thyroid or nodules. is usually performed with suppressed TSH, Parathyroid imaging – indications carcinoma is usually also associated with Parathyroid imaging is used to localise an meaning that the thyroid is not stimulated. As mentioned above, parathyroid hyperparathyroidism, but is very rare adenoma or hyperplastic glands, e.g. in Under such conditions, high uptake scintigraphy is performed for localisation of (fewer than 1% of cases). preparation for surgery. indicates autonomously functioning diseased parathyroids, thus the diagnosis Secondary hyperparathyroidism thyroid tissues, which can be one or of HPT should be confirmed biochemically (sHPT) is the result of chronically low Thyroid imaging – indications more nodules causing hyperthyroidism. prior to imaging. Elevated levels of PTH and calcium levels, most often caused by Imaging of the thyroid can be performed Differentiation between Hashimoto’s calcium usually point towards a diagnosis renal failure but they can also result for several reasons: to diagnose anatomical disease and Graves’ disease is also possible, of HPT (Hindie et al 2009; Greenspan et al from the use of certain drugs. In sHPT, pathology, such as goitre or thyroid because in Hashimoto’s disease the thyroid 2012).

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PARATHYROID AND THYROID IMAGING The indication for parathyroid in the case of sHPT caused by hyperplastic values above 2% are considered suspicious compared to the thyroid, hence images PARATHYROID AND THYROID IMAGING scintigraphy and its combination with parathyroids, where the surgeon may for autonomously functioning tissue. In are obtained 10 and 120 minutes after other imaging modalities may again vary prefer bilateral neck exploration and Graves’ disease, uptake values of 3-5% injection of the radiotracer. In this setting, between countries, but also between the potential contribution of imaging are commonly reached. In Hashimoto’s sestamibi has the advantage of quicker hospitals in the same country. Usually, may be limited. On the other hand, the disease, the uptake in the thyroid usually washout from thyroid tissue and longer it depends on the preferences of the combination of preoperative imaging remains below 0.2%. Also, after exposure retention in parathyroid adenomas, while surgeon and the experience of the nuclear with an intraoperative PTH assay may of the thyroid to a larger amount of iodine tetrofosmin has a slow washout from both, medicine physician. If bilateral neck help to determine the need for further (as is the case after application of contrast which may mask parathyroid adenomas exploration is performed, in which the exploration after removal of lesions agents containing iodine), uptake of 99mTc (Fjeld et al 1997). Sestamibi should surgeon looks for enlarged parathyroids identified by imaging prior to operation in the thyroid may be blocked, producing therefore be preferred over tetrofosmin. in the usual locations and also explores (Hindie et al 2009). results resembling those found in However, if dual-tracer imaging is areas where ectopic parathyroids may Hashimoto’s disease. If 123I is used, images performed, tetrofosmin is an option. occur, localisation diagnosis prior to are usually obtained after 3h. Normal It should also be borne in mind that operation may not be required. However, uptake values with suppressed TSH are hyperplastic parathyroid glands in sHPT minimally invasive surgery is commonly RADIOTRACERS AND IMAGING below 10%, while autonomy is present have a quicker washout than parathyroid used nowadays as it results in lower PROCEDURES if values are >20-30%. For scintigraphic adenomas in pHPT. These differences can morbidity and shorter operation times, The radiotracers used for thyroid imaging, activities of 10MBq for 123I and be observed in larger cohorts of patients. and in this case the value of preoperative imaging are radioactive iodine isotopes 37MBq for 99mTc will usually suffice. However, it should be mentioned that imaging in HPT is evident. If no (123I and 131I) or 99mTc. The choice of In preparation for I-131 therapy, a 24h parathyroid adenomas and thyroid can parathyroid adenoma can be identified radiotracer depends on the indication uptake measurement is usually obtained. have the same sestamibi washout, so that by imaging, bilateral neck exploration for the procedure. For scintigraphic Measurement of 24h uptake values no retention of sestamibi in parathyroid may be required. Another indication for imaging aimed at diagnosis of thyroid requires a radionuclide with a longer adenomas is observed. Therefore, SPECT imaging is patients with persistent or disease and simultaneous uptake half-life, and in this case a low amount images should always be obtained early recurrent HPT, who have been operated measurement, 99mTc can be used. 99mTc is of I-131 should be used. The quality of (45-60 minutes p.i.) to achieve a good on previously. Surgery in such patients is taken up by the thyroid via the sodium- scintigraphic images obtained with I-131 sensitivity. Usually, 500-700MBq of 99mTc more complex and associated with higher iodine symporter, the same molecule with a high-energy collimator is usually sestamibi or tetrofosmin are administered, morbidity, thus preoperative localisation that is also responsible for iodine uptake limited, but probe measurement is which results in adequate image quality diagnostics help to reduce operation in the thyrocytes. Unlike iodine, 99mTc is sufficient for determination of uptake, so (Gotthardt et al 2016). time and complication rates. Parathyroid not stored inside the thyrocytes, so it is lower activities can be applied. The principle of dual-tracer imaging is scintigraphy should therefore be washed out of the thyroid – scintigraphy 99mTc- labelled tetrofosmin or sestamibi based on planar imaging of the thyroid performed in all patients before minimally is therefore performed 20 minutes after are used for parathyroid scintigraphy, and and the parathyroids with different tracers. invasive or unilateral neck exploration, and injection. Normal thyroid uptake for 99mTc both accumulate in thyroid tissue as well The thyroid is imaged with 123I or 99mTc in all patients undergoing reoperation if TSH is suppressed (i.e. the thyroid is not as in parathyroid adenomas. Dual-phase (as described above) and the resulting for persistent or recurrent HPT. However, stimulated by TSH) is up to 1% with a grey imaging relies on higher retention of the images are subtracted from sestamibi parathyroid scintigraphy is less sensitive zone between 1% and 2%, and uptake radiotracer in parathyroid adenomas as or tetrofosmin images. The remaining

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PARATHYROID AND THYROID IMAGING activity will then represent the parathyroid D as well as calcimimetics should be Dual-phase parathyroid scintigraphy: injected 2-3 hours after administration of PARATHYROID AND THYROID IMAGING adenoma. The activity recommended for discontinued. It has been recommended In dual-phase scintigraphy, early and the 123I. Again, the patient is placed in supine 99mTc is 35-75 MBq, whereas around 10MBq that active vitamin D be discontinued late planar images are obtained (~10 position. Five to fifteen minutes after 99mTc- may be used for 123I with its higher target- for 1 week and native vitamin D for and 120 minutes post injection) with the sestamibi/tetrofosmin injection, planar to-background ratios. Officially, higher 3-4 weeks. Calcimimetics should be patient in supine position. The gamma images of the head and neck are obtained activities may be used (recommendations discontinued for 2 weeks. In addition, camera should be equipped with a low- in analogy to what has been described in the guidelines mention a maximum of consider discontinuing any drugs that energy, high-resolution parallel-hole or above. Because this examination is done 370MBq for 99mTc and around 20MBq for may suppress parathyroid (hyper)function cone-beam collimator with a 128x128 as a simultaneous dual-tracer acquisition, 123I), but the image quality obtained with for a few days before scintigraphy (Hindie or 256x256 matrix. It is important that symmetrical 10% energy windows (140 the activities mentioned here usually et al 2009, Greenspan et al 2012). the field of view is large enough to cover keV±5% for 99mTc and 159 keV±5% for 123I) suffices. the area where parathyroid adenomas are used. A low-energy, high-resolution For an activity of 500MBq, the resulting can usually be found, including ectopic parallel-hole collimator is recommended, effective radiation doses will be approx. adenomas (i.e. from the salivary glands to with a 256x256 matrix. Although pinhole 4.5mSv for sestamibi and 3.8mSv for IMAGE ACQUISITION AND the myocardium). SPECT images should images may improve spatial resolution, tetrofosmin in men, while the effective PROCESSING be obtained from the same area starting SPECT/CT images may be preferred for doses for women are 20-30% higher. For 45-60 minutes after injection of the improved anatomical localisation. For 10MBq of 123I and 37MBq of 99mTc, the Thyroid scintigraphy: radiopharmaceutical. Use of a low-energy, reduction of cross-talk, the planar images effective doses are 2.2mSv and 0.5mSv, If 99mTc is used, planar images of the high-resolution parallel-hole collimator may be acquired using a 14% energy respectively (Valentin 1998, Hindie et al thyroid should be obtained 20 minutes with a 128x128 matrix is recommended. window instead of 10% (140 keV-10%/+4% 2009, Greenspan et al 2012). after injection, usually covering the area In many cases, higher matrix sizes do not for 99mTc and 159 keV+10%/-4% for 123I) from the salivary glands to the upper thorax. add to image quality as reconstruction If 99mTc is used for delineation of the An external source with a defined amount software packages will reduce larger thyroid, dual-isotope imaging is not of 99mTc can be used for quantification of matrix sizes to 128x128 – it is advisable to possible. Sequential protocols are used PATIENT PREPARATION thyroid uptake, in which case the syringe check with the vendor whether 256x256 instead, which may differ in details but For thyroid imaging, patients under should be measured before and after is supported. Acquisition of 120 views of generally follow the recommendations thyrostatic treatment should discontinue injection to determine the exact activity 20-30 seconds each is recommended. put forward here. First, the thyroid is this medication (thiamazole, methimazole injected. In principle, the same protocol SPECT/CT is highly recommended to imaged with 99mTc approx. 20 minutes or propylthiouracil) for 3 days. As contrast can be used with 123I, but image acquisition enable optimum anatomical localisation after injection, followed by application of media containing iodine suppress the should take place later, around 3h after (Gotthardt et al 2016). 400mg of chloride to induce uptake in the thyroid, administration administration. A low-energy parallel- washout of the 99mTc from the thyroid. The should be at least 6 weeks ago, or even hole collimator should be used, with a Subtraction parathyroid scintigraphy: patient lies in a supine position and may longer if possible. This also applies for matrix size of 256x256. A calibrated probe Combined 123I/99mTc-sestamibi/ not move during the procedure. Then, parathyroid imaging if a dual-tracer measurement can be performed for uptake tetrofosmin scintigraphy can be performed 99mTc-sestamibi/tetrofosmin is injected and protocol is used. measurement, as this avoids calculation of as a simultaneous planar imaging image acquisition starts 5-15 minutes later For parathyroid imaging in sHPT, vitamin uptake based on camera measurements. procedure. Sestamibi/tetrofosmin is (Hindie et al 2009, Gotthardt et al 2016).

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IMAGE INTERPRETATION PARATHYROID AND THYROID IMAGING Processing of parathyroid For all imaging protocols (dual-phase, or both. In contrast to SPECT imaging, PARATHYROID AND THYROID IMAGING scintigraphy: dual-tracer, different imaging time points), they most often lie inside the contour of It is important to avoid oversubtraction, Thyroid scintigraphy all sites of sestamibi/tetrofosmin uptake the thyroid. An increased uptake, even which leads to white areas in the images. The thyroid should be symmetrical in either in unusual locations or protruding if minor, in the upper or lower part of a Also, if the patient has moved, artefacts shape. Size differences between the lobes from the contour of the thyroid (even thyroid lobe can potentially represent a may occur, including false positive results. may occur, but are more common if goitre if uptake is lower than in the thyroid, cf. parathyroid adenoma. However, they can As interpretation of parathyroid SPECT is present. If autonomously functioning partial volume effects!) are suspicious for also be located clearly above or below the images requires highly sensitive reading, nodules are present and TSH is parathyroid adenoma. Also, it should be thyroid lobes. the interpretation of the images is prone suppressed, the thyroid will not be visible borne in mind that ectopic adenomas As stated above, early SPECT images to reconstruction artefacts that may but only the autonomous nodule(s). If may be present. Focal areas of high are advised to allow for detection of vary between reconstruction software the whole thyroid shows a high uptake uptake which are located in blood vessels parathyroid adenomas with quick washout. packages. Practitioners should therefore of the tracer while TSH is suppressed, (retention in veins) or in tumours (head Furthermore, detection of parathyroid be aware that the choice of optimum Graves’ disease should be considered. If and neck or breast carcinoma) can lead to adenomas may be complicated by the reconstruction settings and differences thyroid scintigraphy is complemented false positive findings. SPECT/CT imaging activity in the thyroid gland. Therefore, between the software packages have by ultrasound, misinterpretation of allows correct interpretation of such all inconsistencies in the contour of the a significant impact on sensitivity and scintigraphic images due to differences lesions, which may be clinically relevant. thyroid gland are potential parathyroid specificity of the method (van Hoorn et al in thryoid lobe size, unusual uptake Also, parathyroid adenomas located adenomas, especially if located in the 2014). patterns caused by anatomical factors high in the neck may be misinterpreted dorsal contour. Parathyroid adenomas can and unexpected hot or cold areas can be as salivary gland uptake, which can be thus be visualised as small protrusions. avoided. correctly identified by SPET/CT imaging. Changing the scaling of the images during In dual-phase scintigraphy, parathyroid interpretation will help to correctly identify Parathyroid scintigraphy adenomas may show up on early planar lesions (Hindie et al 2009, Gotthardt 2016). Parathyroid scintigraphy should images as inhomogeneities in the uptake On dual-tracer scintigraphy images, be read in an “over-sensitive” manner. of the thyroid, while on the late images the thyroid-specific 99m( Tc or 123I) scan is Compared to other types of scintigraphy, they should be characterised by higher compared to the scan with uptake in the target-to-noise ratios are often lower retention of radioactivity. As stated above, both thyroid and parathyroid (tetrofosmin and the lesions visualised are often especially when tetrofosmin is used, or sestamibi). Discrepancies between below the spatial resolution of the SPECT parathyroid adenomas may show the the two scans indicate the presence of a technique, leading to partial volume same retention/washout characteristics parathyroid adenoma, which may be seen effects. Therefore, correct interpretation as thyroid tissue. Therefore, sensitive clearly on subtraction images. However, a of parathyroid scintigraphy is highly interpretation of the images is required. very slight increase in uptake of 99mTc or dependent on expertise and experience. Most parathyroid adenomas are located 123I can sometimes be seen in parathyroid Here too, its combination with ultrasound behind the thyroid gland in the lower half adenomas, which can lead to incorrect will help to improve results (see below, of the lobes and thus may appear as slightly interpretation of the scans. Also, one parathyroid ultrasound) (Gotthardt 2016). darker areas on either early or late images, needs to be aware that suboptimal fusion

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PARATHYROID AND THYROID IMAGING of the 99mTc/123I and sestamibi/tetrofosmin detection of growing lesions as well as adenomas or hyperplastic glands, and in areas, calcifications and, if deemed useful, PARATHYROID AND THYROID IMAGING images may result in false positive or being more cost effective. combination with parathyroid scintigraphy blood flow by Doppler measurements. false negative findings caused by over-/ Although successful localisation of it allows us to differentiate thyroid nodules The patient is then asked to turn his/her undersubtraction or patient movement. If parathyroid adenomas with FDG-PET has with sestamibi/tetrofosmin uptake or head to the left and the right cervical area fusion is done correctly, the uptake in the been described, it does not seem to be other cervical structures from parathyroid is examined from mandible to clavicle thyroid region of the fusion images should an appropriate procedure for standard adenomas (deFeo et al 2000). with respect to presence of enlarged be comparable to background uptake in parathyroid imaging due to its lower lymph nodes and other findings. The the neck, and critical assessment of the sensitivity and higher cost compared to Thyroid ultrasound: patient then turns his/her head to the quality of the image fusion is essential parathyroid scintigraphy. An alternative In the assessment of thyroid disease, right and the same procedure is repeated (Hindie et al 2009, Gotthardt et al 2016). may be C-11- imaging, as it ultrasound is more reliable than palpation on the left side of the neck. It is helpful seems to enable localisation of adenomas and scintigraphy for the assessment to follow a standardised procedure, and that have not been identified by of anatomical thyroid pathology. For also to have clear protocols for the exact parathyroid scintigraphy and ultrasound. assessment of function, however, determination of the size of lesions in PET IMAGING OF THYROID AND The use of C-11 is limited to centres that scintigraphy is preferable, thus these order to achieve high reproducibility. PARATHYROID ADENOMAS have a cyclotron available and produce methods are complementary. When Lymph nodes should also be assessed FDG-PET is able to identify malignant this tracer regularly (Chicklore et al 2014). ultrasound of the thyroid is performed, based on their ultrasound features: if they nodules in the thyroid. When FDG- the patient is in a supine position with are oval in shape, hypoechogenic and a PET is performed for other indications, a pillow beneath her/his shoulders and hilum is present, they are usually benign. FDG-positive nodules may be found neck and the head in a reclined position. The size is not a very sensitive or specific incidentally in the thyroid. Such nodules ULTRASOUND IMAGING This position may not be very comfortable predictor of malignancy, except if lymph may be sent for further work-up using Ultrasound imaging is a fast and for the patient, but it allows assessment nodes are very small. A small axis diameter ultrasound and fine needle aspiration safe method for obtaining anatomical of the lower poles of the thyroid, which of up to 5mm is considered normal. If a cytology. A possible alternative indication information about the thyroid, thyroid may, at least in part, be located behind slightly larger lymph node is found but for FDG imaging in thyroid nodules may nodules, parathyroid adenomas, lymph the sternum. In addition, paratracheal it has benign features, malignancy is be distinguishing between malignant nodes or other structures in the cervical or retroclavicular lymph nodes may be unlikely. Submandibular lymph nodes and benign nodules. If FNA delivers area. Thyroid ultrasound aims to identify missed if the head is not reclined. may be much larger in size, hence their indeterminate results normally requiring thyroid size, shape and nodules but also The thyroid is imaged in axial and echographic features are more important diagnostic hemythyroidectomy, FDG-PET allows assessment of the character of sagittal view, with thickness and width to assess. The lymph node findings should may be able to identify the malignant nodules based on their echogenicity being measured in the axial plane and also be documented. nodules and avoid unnecessary diagnostic and ultrasound features. In addition, length in the sagittal plane. Nodules in Based on ultrasound patterns, the surgery. The question of the utility of FDG- diseases such as Hashimoto’s or Graves’ the thyroid are measured accordingly and character of nodules in the thyroid can PET for identifying malignant lesions is not disease display typical patterns which, in are documented with respect to shape, be determined according to the TI- yet answered (Castellana et al 2019), but the context of clinical symptoms, often echogenicity (hypo-, hyper-, normal, RADS classification (Tessler et al 2017). it should be borne in mind that follow-up allow a diagnosis to be made. Parathyroid echo free), delineation, presence of a halo This classification also gives advice with of lesions using ultrasound may enable ultrasound aims to localise parathyroid (a black rim around the nodule), cystic respect to which nodules require fine

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PARATHYROID AND THYROID IMAGING needle aspiration (FNA). FNA is performed regressive nodules in multinodular goitres parathyroid scans can easily be verified by contour and thus appear as if located in PARATHYROID AND THYROID IMAGING under ultrasound guidance: a fine needle resulting from iodine deficiency may ultrasound in such a setting. The results the thyroid. However, in such cases the is inserted in a thyroid nodule (23 or have features of malignancy. As a result, of the procedure will, however, always thyroid capsule can often be identified as 25 gauge give the best results), moved in countries with widespread iodine depend on the presence of physicians a white rim of connective tissue separating gently back and forth, and if no material deficiency, strict adherence to the TI-RADS experienced in imaging of parathyroid the parathyroid adenoma from thyroid becomes visible in the plastic conus of the classification may result in over-aggressive pathology. tissue. As such a lesion may be identified aspiration needle, vacuum may be applied therapy. In such cases, and perhaps if FNA Parathyroid adenomas can have as a thyroid nodule on the scintigraphic with a syringe attached to the needle. results are equivocal, an experienced (!) different shapes (oval, lobular, etc.) and images, ultrasound can be very helpful in If blood is aspired, interpretation of the ultrasonographer may advise ultrasound are in most cases hypoechogenic, though order to correctly differentiate between findings by the pathologist may become follow-up of nodules and perform FNA or they can also be echo free (black) or thyroid nodules and parathyroid adenoma more difficult. The acquired material is operate only if they grow. have ultrasound patterns comparable to if there are (multiple) suspicious findings in then fixated and prepared for examination Hashimoto’s and Graves’ disease show thyroid nodules in multinodular goitres. In the SPECT images (Gotthardt et al 2013). by the pathologist. The aim of the a typical pattern of multiple hypoechoic most cases, they are located at the lower procedure is not to acquire histological lesions which may be located in a part pole of the thyroid or in a dorsal position samples, but to acquire cells that will of the thyroid or found throughout the behind the lower half of the thyroid. If allow the pathologist to classify them gland. In the late stages of Hashimoto’s located behind the trachea, they can be CONCLUSION according to the Bethesda classification disease, when patients are hypothyroid difficult to visualise, and it is essential to Imaging of thyroid and parathyroid as benign, malignant or suspicious. The as a consequence of autoimmune let the patient turn his/her head in order pathology is optimised when anatomical advised therapy will depend on the destruction of the thyroid, the thyroid to assess the space between the vertebrae and functional imaging are combined, findings, the options being no follow- is mostly hypoechoic, sometimes with and the trachea. Many parathyroid and scintigraphy and ultrasound are highly up, repeat FNA, follow-up by ultrasound, hyperechoic stripe-like patterns of fibrosis. adenomas have an artery originating efficient in this context. The addition diagnostic hemithyroidectomy, and total from the inferior or superior thyroid of ultrasound data about echographic thyroidectomy. Parathyroid ultrasound: artery that can be visualised by Doppler patterns provides valuable information It should be borne in mind that In a perfect scenario, parathyroid imaging. If a parathyroid adenoma is echo about characteristics of thyroid nodules most thyroid malignancies have an scintigraphy and ultrasound are free and located alongside the inferior and helps to increase the specificity of excellent prognosis and (except for performed simultaneously by the same thyroid artery (which does not happen parathyroid scintigraphy. In the optimum dedifferentiated/anaplastic carcinomas, experienced person. Physicians with a often but can be the case), it may be scenario, the same experienced physician which can usually be diagnosed based on lot of experience in performing both missed because it is taken for a blood will perform and/or interpret scintigraphic clinical features, palpation and ultrasound) procedures together will be considerably vessel. However, on Doppler imaging the and ultrasonographic images. grow very slowly. In countries with better at correctly identifying lesions. blood flow in the artery is much higher, suboptimal iodine supply, the TI-RADS If there is no physician experienced allowing correct identification of the classification (developed in the US, which in reading both examinations, joint lesion, and parathyroid scintigraphy will has optimum iodine supply and thus low examinations by the nuclear medicine help to identify such lesions. Furthermore, incidence of multinodular goitres) may specialist and the ultrasonographer are a parathyroid adenomas located behind thus be applied more conservatively, as preferred solution. Suspicious findings on the thyroid may impress the thyroid

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REFERENCES 8. Hindie E, Ugur O, Fuster D, O’Doherty M, PARATHYROID AND THYROID IMAGING PARATHYROID AND THYROID IMAGING 1. Castellana M, Trimboli P, Piccardo A, Grassetto G, Ureña P, Kettle A, Gulec SA, Pons F, Rubel- Giovanella L, Treglia G. Performance of 18 F-FDG lo D.al. 2009 EANM parathyroid guidelines. Eur J Nucl PET/CT in Selecting Thyroid Nodules With Indeter- Med Mol Imag. 2009;36(7):1201-1216 minate Fine-Needle Aspiration Cytology for Surgery. 9. Tessler NT, Middleton WD, Grant EG, Hoang A Systematic Review and a Meta-Analysis. J Clin Med JK, Berland LL, Teefey SA, Cronan JJ, Beland MD, Desser 2019;8(9):1333-1344 TS, Frates MC, Hammers LW, Hamper UM, Langer JE, 2. Chicklore S, Schulte KM, Talat N, Hubbard Reading CC, Scoutt LM, Stavros AT. ACR Thyroid Imag- JG, O’Doherty M, Cook GJ. 18F-FDG PET rarely pro- ing, Reporting and Data System (TI-RADS): White Pa- vides additional information to 11C-methionine PET per of the ACR TI-RADS Committee. J Am Coll Radiol imaging in hyperparathyroidism. Clin Nucl Med. Mar 2014;17(5):587-595 2014;39(3):237-242. 10. Valentin D. recalculated dose data for 19 3. De Feo ML, Colagrande S, Biagini C, Tonarel- frequently used radiopharmaceuticals from icrp pub- li A, Bisi G, Vaggelli L, Borrelli D, Cicchi P, Tonelli F, Amo- lication 53. Radiation dose to patients from radiophar- rosi A, Serio M, Brandi ML. Parathyroid glands: combi- maceuticals (Addendum 2 to ICRP Publication 53) ICRP nation of (99m)Tc MIBI scintigraphy and US for demon- 801997; 1998 stration of parathyroid glands and nodules. Radiology 11. van Hoorn RA, Vriens D, Postema JW, Arens 2000;214(2):393-402 A, Pfestroff A, Oyen WJG, Gotthardt M. The influence 4. Fjeld JG, Erichsen K, Pfeffer PF, Clausen OP, of SPECT reconstruction algorithms on image quality Rootwelt K. Technetium-99m-tetrofosmin for parathy- and diagnostic accuracy in phantom measurements roid scintigraphy: a comparison with sestamibi. J Nucl and 99mTc-sestamibi parathyroid scintigraphy. Nucl Med. Jun 1997;38(6):831-834. Med Com 2014;35(1):64-72 5. Gotthardt M, Franzius C, Zielke A, Roth- 12. WHO - Iodine status worldwide. WHO Global mund M. Primärer Hyperparathyreoidismus: Lokali- Database on Iodine Deficiency. de Benoist B, Andersson sationsdiangostik beim Hyperparathyreoidismus. In: M, Egli I, Takkouche B, Allen H. 2004. https://apps.who. Rothmund, ed. Praxis der Viszeralchirurgie. Vol 2. 3 ed. int/iris/bitstream/handle/10665/43010/9241592001. Heidelberg, Germany Springer; 2013:266-276. pdf;jsessionid=47150107A7320ABDF69F575AB8B- 6. Gotthardt M. Parathyroid gland scintigrao- 834B7?sequence=1 (URL accessed April 20th 2020) hy. In Esser/van den Heuvel/van Dalen (edts). Proce- dure Guideline Nuclear Medicine. Dutch Society of Nuclear Medicine. Kloosterhof, Neer, The Netherlands, 2016; 52-58 7. Greenspan BS, Dillehay G, Intenzo C, Lavely WC, O’Doherty M, Palestro CJ, Scheve W, Stabin MG, Sylvestros D, Tulchinsky M. SNM practice guideline for parathyroid scintigraphy 4.0. J Nuclk Med Technol 2012;40(2):111-118.

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THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY

by Paul Gape, Carla Abreu, Glenn Flux and Jan Taprogge

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INTRODUCTION

THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY AVERAGE THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY RADIO- HALF- THERAPEUTIC RANGE INDICATION The combination of functional imaging in nuclear medicine (SPECT, PET) PHARMACEUTICAL LIFE EMISSION IN TISSUE with anatomical imaging in CT, in what is referred to as hybrid imaging, (MM) Benign thyroid disease β- provides undoubted diagnostic value. Many of these benefits can also be I-131 NaI 8.1 Thyroid cancer (E = 0.61 MeV, 0.4 appreciated in the application of hybrid imaging to radionuclide therapy. max days Recent developments in radiopharmaceutical production have I-131 MiBG Neuroendocrine tumours Eav = 0.192 MeV) increased the scope of radionuclide therapy, and implementation of a Y-90 DOTA- Neuroendocrine tumours β- multidisciplinary approach in the clinic has facilitated improvements in Non-resectable hepatoma 64 hours (Emax = 2.28 MeV, 3.9 therapeutic efficacy, patient comfort and radiation safety. These factors Y-90 microspheres Liver metastases have contributed to efforts to move towards personalised treatment. Eav = 0.934 MeV) Lu-177 DOTA- Neuroendocrine tumours β- Metastatic castration- 162 hours (Emax = 0.498 MeV, 0.23 HOW DOES RADIONUCLIDE of applications in the clinic. Examples of Lu-177 PSMA resistant prostate cancer E = 0.133 MeV) THERAPY WORK? radiopharmaceuticals used for therapy, av Radionuclide therapy involves the along with some of their properties which Metastatic castration- 11.43 days α 0.04 – 0.05 Ra-223 Cl2 resistant prostate cancer process of administering radioactive make them suitable candidates, are given (E = 5–7.5 MeV) substances that mimic naturally occurring in Table 1. Auger-electron emitters have substances in the body to target disease. shorter ranges in tissues of several nm [2]. Table 1: Common radiopharmaceuticals used clinically for therapy [22],[23], [24]. These radioactive substances are often The action of radiation on tissue is often delivered to the target (i.e. malignant characterised using the linear energy with the surrounding medium (primarily WHAT IS THE RATIONALE FOR or benign disease) via the blood transfer (LET) which describes the amount cellular fluid) to produce free radical ions. COMBINING IMAGING AND circulation. In the case of malignant of energy deposited into the tissue per These free radicals are highly reactive and THERAPY? disease, the ionising radiation emitted unit length the particle travels through can in turn damage the DNA. Double There is growing interest in the nuclear by the radionuclide has the aim of killing tissue. A higher LET is usually associated strand breaks are considered more likely medicine community in what has come to cancer cells. This is primarily achieved via with more severe damage to tissue. Beta to lead to cell death as they are more be known as the ‘theragnostic principle’. interaction between the radiation and the emitters have a lower LET when compared difficult for the cell to repair. As such, alpha Underpinning this principle is the concept DNA, causing irreparable damage which to Auger-electron or alpha emitters. Alpha emitters, which have a higher LET than that diagnostic imaging can be used to ultimately means the cell is no longer able particle emitters are associated with the beta or Auger-electron emitters, cause inform, guide and evaluate therapeutic to reproduce itself [1]. highest LET [3]. more double strand breaks and thus have treatment [5]. In practice, this is achieved Radionuclides used for therapy emit Radiation damage to tissue is caused a greater cell killing effect. by using the same radiopharmaceutical, or Auger electrons, beta particles or alpha by indirect or direct damage to DNA [4]. two radiopharmaceuticals with very similar particles and therefore differ from the Direct damage results from single or uptake, for both imaging and therapy [6]. radionuclides usually used for imaging. double strand breaks of the DNA caused The distribution of the Various targeting agents can be bound to by the radiation, whereas indirect damage radiopharmaceutical within the patient the same radionuclide, enabling a range is caused when the radiation interacts depends on the specific biokinetics of

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THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY the individual. In order to investigate this diagnostic companion show the uptake THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY of the therapeutic radiopharmaceutical RADIO- OPTIONS FOR PRE-THERAPY OPTIONS FOR POST-THERAPY distribution, pre-therapy and post-therapy PHARMACEUTICAL IMAGING IMAGING imaging is necessary. in tissue. An image of the patient can In pre-therapy imaging, a tracer amount therefore be created in which the number I-131 NaI of either the therapy radiopharmaceutical of counts in each region of the image I-131 NaI I-124 NaI or a diagnostic tracer with (ideally) identical relates to the activity in that anatomical I-123 NaI uptake can be imaged quantitatively region. Gamma-camera imaging of I-131 364 keV γ emission and used to inform the therapeutic The scope for theragnostic imaging I-131 MiBG administration. In post-therapy imaging, has increased rapidly, and an imaging I-131 MiBG I-124 MiBG the therapeutic radiopharmaceutical or option is available for most therapies. I-123 MiBG a diagnostic radionuclide attached to The possibilities for imaging the Ga-68 DOTA- [26] the therapeutic radiopharmaceutical is radiopharmaceuticals listed in Table 1 are SPECT/CT of Y-90 Bremsstrahlung Gamma-camera imaging of In- Y-90 DOTA- Y-86 DOTA- imaged and can be used for dosimetry. given in Table 2. 111 173 and 247 keV γ emissions (administered simultaneously) This allows the absorbed dose to target Planar images acquired using a In-111 DOTATATE and non-target tissues to be calculated conventional gamma camera can SPECT/CT of Y-90 Bremsstrahlung Y-90 microspheres Tc-99m MAA and compared to a prescribed dose. characterise the activity distribution. This Y-90 PET [27] enables the whole body to be included Radio-labelled somatostatin analogues, Lu-177 DOTA- e.g. Ga-68, In-111 in the image within an acceptably short Gamma-camera imaging of Lu-177 duration. However, as a 2D representation Lu-177 PSMA [28] 113 and 208 keV γ emissions Lu-177 PSMA HOW CAN WE IMAGE THE of a 3D activity distribution within the Ga-68 PSMA patient, planar imaging is not always the THERAPY? Tc-99m MDP Gamma-camera imaging of Ra-223 The most applicable imaging most appropriate method for imaging Ra-223 Cl 2 82, 154 and 270 keV γ emissions [30] method depends on the radionuclide. post therapy [7]. Tissues which overlie the F-18 fluoride [29] Radiopharmaceuticals used for therapy imaging plane are not distinguishable, so may emit characteristic secondary that it is impossible to determine whether Table 2: Pre- and post-therapy imaging options for commonly used radionuclides [25]. radiation in the form of gamma photons counts in a region of interest have arisen in addition to the emissions responsible from tissues above or below the ROI. image to accurately represent the activity from the various tissues within the body. for the majority of the cell killing effect. Attenuation correction can be applied in the tissue, corrections must be applied The attenuation map is necessary for These secondary emissions penetrate the when using simultaneous anterior/ for photon attenuation, scatter as the several of the corrections required in patient’s body and can thus be detected posterior imaging by application of the emissions interact with the patient and hybrid imaging. with a scintillation camera or an external conjugate view method [8]. the imaging equipment, and several other counter. Tomographic imaging enables 3D effects which degrade image quality and If a diagnostic radionuclide is attached visualisation of the activity distribution, affect quantification. Conventionally, a CT to the therapeutic radiopharmaceutical, thereby avoiding the problem of overlying scan is used to create a voxel attenuation the primary photons emitted by the tissues. However, for the counts in the map to indicate the degree of attenuation

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QUANTITATIVE UPTAKE EXTENDING QUANTITATIVE WHAT DO WE NEED FOR THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY MEASUREMENTS IMAGING TO DOSIMETRY DOSIMETRY? of the target volume. The absorbed frac- tion depends on the size, shape and sep- Quantitative pre-therapy imaging at a Whilst a single quantitative image is a The MIRD scheme [13] provides a aration of the source and target volumes. single time point may be used to inform useful indicator of the distribution of the framework for calculating the radiation The product of these two quantities a subsequent therapy. An example of radionuclide, dosimetry is required to dose from a source volume to a specific gives the absorbed dose to the target this is the acquisition of a pre-therapy determine the absorbed dose delivered to target volume. The source and target region from the source region in units radioiodine uptake scan to personalise tumours and to normal organs. volumes can be at the organ, sub-organ of Joules per kg. Mathematically, this is radioiodine treatment of benign thyroid Absorbed dose is defined as the energy or voxel scale. The calculation requires described by the basic MIRD equation: disease [9]. Marinelli et al [10] developed deposited in a tissue, divided by the accurate knowledge of: a formula to deliver a prescribed absorbed mass of the tissue. Calculation of patient- 1. The ‘cumulated activity’ within the [2] dose to the thyroid, which is routinely specific absorbed doses is essential, with source, which represents the total num- used in many centres around the world to the assumption that treatment outcome ber of events over the Where D = Absorbed Dose, Ã =

calculate the activity to be administered, is dependent on the absorbed doses course of the therapy. Cumulated Activity, S = S-factor and rS,T = as: delivered to target volumes and to healthy 2. The ‘S-factor’, which represents the source and target region, respectively. organs [11]. Treatment optimisation and mean dose to the target volume per unit The total dose to the target region is [1] personalisation may be achieved using activity in the source volume. This is de- the sum from each of the separate source pre-treatment dosimetry or by adapting pendent on the energy of the radionu- regions. Figure 2 shows one method of Where C is a unit conversion factor, the treatment based on dosimetry during clide emissions, the ‘absorbed fraction’, combining the various elements required

AA is the activity to be administered treatment. Post-treatment dosimetry may which is the fraction of energy emitted in to determine the cumulated activity and (MBq), D is the prescribed radiation dose be used to verify the dose delivered and the source volume and subsequently ab- the S-factor, and is discussed below.

to the thyroid (Gy), mT is the mass of to inform the associated risk, as required sorbed in the target region, and the mass

the thyroid (g), U24h is the percentage under recent EU legislation [12]. uptake of radioiodine in the thyroid at

24 hours (%), and Teff is the effective half- life of radioiodine in the thyroid (days) (accounting for both physical decay and biological clearance). If only a single scan is acquired, the same effective half-life in the thyroid is assumed Figure 2: Schematic for all patients. Such assumptions can representation of the various produce clinically useful information, but steps in the dosimetry chain the associated large inaccuracies should allowing cumulated activity be considered when applying them to and S-factor to be calculated. individual patients. Figure 1: Key points to understand in dosimetry.

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THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY Steps to determine cumulated to account for the fact that some of the time correction if imaging of high activities Area under TAC THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY activity using hybrid imaging: photons originating within the patient is required. The activity measured in the image will be attenuated before reaching the PET imaging specifically requires a represents the activity in the source region Hybrid imaging at multiple time points detector, resulting in fewer counts than correction for random coincidences. at a single time point. The total number Nuclear medicine (NM) images, e.g. would have been obtained if the activity There is no analogous correction for this of decays in the source organ over the SPECT or PET, are acquired at several were in air. A CT scan can be used to in SPECT. entire duration of the treatment, which time points following administration produce a map of tissue density within the is the quantity we require to calculate of the radionuclide, as well as a CT scan patient. This makes it possible to estimate Outlining volumes of interest (VOIs) absorbed dose, is obtained from the area to provide anatomical information. the specific amount of attenuation for Source and target volumes must under the TAC, as shown in Figure 3. This is These images give a snapshot of the radiation arising at any point within the be delineated on CT, which gives an the cumulated activity, or time-integrated distribution of the radionuclide within the patient. Attenuation correction implies ‘anatomical’ volume, or on the NM image, activity. This is calculated by fitting a curve patient at the time of image acquisition. correcting for this loss of signal due to guided by the CT. Outlining requires good representing the activity as a function of Extending NM imaging to hybrid imaging tissue attenuation. knowledge of the relevant anatomy and a time to the observed data points in the by incorporating the CT improves A scatter correction may also be multi-professional approach to ensure that TAC, then calculating the integral of this visualisation and the accuracy with applied to correct for photons that have inter-operator variability in volumes is kept function from t = 0 to t = ∞. which the images can be quantified. The changed energy and trajectory due to a minimum. Since biological clearance in many accuracy with which the biokinetics within to interactions within the patient, but If the scans at different time points are processes has been shown to be the patient are known is dependent on which are still detected by the scanner. If registered, it is possible to copy the regions approximated by exponential patterns, the number of images acquired. unaccounted for, these photons will be from one image to another. However, the it is common to fit combinations of misplaced in the reconstructed image. user should take care to adjust the VOIs to exponential functions to the observed Image registration There are several methods to correct for account for misalignment, patient motion, data [7]. The NM data is registered to the CT data. scatter. Traditionally, this is achieved with or any other effect. Image registration refers to the process by the Triple Energy Window (TEW) method which two images are aligned such that [14], but modern systems may model Time – activity curve the corresponding pixel in each image the expected contribution from scatter Once the necessary corrections have represents the same anatomy, thereby based on an attenuation map from CT been applied, activity in the source organ allowing the anatomical information from and by including this estimate in the can be plotted against time. These points CT and the functional information from reconstruction process. together produce the time–activity curve. NM to be viewed simultaneously. The partial volume effect causes the The amount of activity in the regions over activity of objects that are of the order time depends on both the radioactive Correction factors for quantification of the spatial resolution of the imaging decay and the biological clearance of the To convert from counts per second to system or smaller to be underestimated radiopharmaceutical. Therefore if enough Figure 3: Sample time-activity curve showing units of activity (MBq) in the image, several [15]. A correction may be applied to time points are collected, this curve activity in source region at a series of 4 time points. An corrections are required. account for this. describes the pharmacokinetics of the exponential function is fitted to the data to estimate An attenuation correction is applied It may also be necessary to apply a dead radiopharmaceutical within an individual A(t) at all time points, and the area under this curve = patient. cumulated activity.

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THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY STEPS TO DETERMINE THE target region. The only therapy for which pre-therapy NaI dosimetry is validated in the clinical THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY S-FACTOR: However, as discussed above, pre- dosimetry is routinely performed in some trial against post-therapy I-131 NaI calculated S-factors will be based on a countries is still I-131 NaI for benign dosimetry. Anatomical model reference anatomical model. The mass of thyroid diseases. The EANM Dosimetry A different approach is inter-cycle or The gold standard method for S-factor the target organs for the specific patient Committee has published standard post-therapy dosimetry. In many cases determination is to use a simulation to can be determined from CT, allowing the operational procedures for pre-therapy radionuclide therapy involves multiple estimate the energy deposited in the pre-calculated S-factors to be scaled to dosimetry of benign thyroid diseases [9]. therapy cycles with intervals of several target organ by emissions originating the patient-specific tissue weight. The process often involves a tracer amount weeks between the cycles. Dosimetry after within the source organs, based on Once the cumulated activity and the of I-131 NaI and single or multiple uptake the first or after each cycle can be used to the size, shape and separation of the S-factor have been determined, absorbed measurements to assess the biological estimate normal tissue absorbed doses. specific patient’s organs. However, this is doses are calculated simply by applying retention of I-131 NaI in the thyroid. Based Subsequent cycles of the treatment can computationally intensive and generally Equation. on the estimated absorbed dose to the then be planned to ensure healthy organs not practical for clinical dosimetry [16]. thyroid gland from the tracer amount, the are not irradiated over a certain threshold Therefore, S-factors for nuclear medicine therapeutic activity required to deliver limit. Post-therapy dosimetry can be used are generally pre-calculated based on a PRE- OR POST-TREATMENT the prescribed radiation dose to the to confirm lesion absorbed doses and ‘mathematical phantom’. This is a reference DOSIMETRY USING IMAGING thyroid gland can be estimated. Another assess doses received by organs at risk. patient, with organ mass and geometry Pre-therapy dosimetry describes the example of pre-treatment dosimetry is the An example is I-131 MIBG for the based on population reference data [17]. process by which the activity to be SELIMETRY clinical trial, a UK based multi- treatment of neuroblastoma. The However, for research studies the gold administered in the therapy is planned centre study to investigate the potential treatment is performed using two standard method may be preferred, in based on a pre-therapy estimation of of the MEK inhibitor Selumetinib to allow administrations given two weeks apart, which case a CT of the patient is required the absorbed doses to either lesions, to further treatments with radioiodine in whereby the activity administered for the to create the anatomical model on which maximise the therapeutic effect, or to advanced radioiodine refractory thyroid second cycle is adjusted based on the to base the simulation. healthy organs, to ensure safety limits are cancer patients, when radioiodine is whole-body absorbed dose measured not exceeded. Furthermore, pre-treatment no longer taken up by lesions [18], [19]. during the first administration [20]. A Simulation of radioactive decays dosimetry may be used to decide if Patients in this study are given 4 weeks further example of inter-cycle dosimetry Once the anatomical model has been a patient is suitable for radionuclide of Selumetinib before I-123 NaI SPECT/ is ILUMINET, a multi-centre clinical trial in defined, the effect of the radiation can therapy based on the estimated absorbed CT imaging is used to assess lesion uptake Lund, Sweden involving Lu-177 Dotatate be simulated based on the mathematics doses delivered to lesions. Pre-treatment of radioiodine. Sequential hybrid images for neuroendocrine tumours (EudraCT describing the interaction of the radiation dosimetry requires a good estimate of at 4, 24, 48 and 72 hours are used to No. 2011-000240-16) [21]. Dosimetry is with the tissues within the patient. The the mass of the target, and it must be estimate lesion absorbed doses for the performed after each cycle to determine result gives the S-factor, which has units assumed that the distribution during subsequent treatment with I-131 NaI. The the absorbed dose to the kidneys, the of absorbed dose per MBq of activity. This the pre-treatment scan is comparable CT component of the imaging is used major organ at risk. The subsequent value is the total energy deposited in the to the therapy administration, where throughout in order to apply corrections, treatment cycle is only performed if a pre- target region from the source region for 1 higher activities and sometimes other for visualisation and to aid outlining of defined limit for renal toxicity has not been MBq of activity, divided by the mass of the radionuclides and tracers are used. volumes of interest. Pre-treatment I-123 reached.

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CONCLUSION REFERENCES the dangers arising from exposure to ionising radiation THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY THE CONTRIBUTION OF HYBRID IMAGING TO RADIONUCLIDE THERAPY 1. Pouget, J.-P., et al., Introduction to Radiobi- and repealing Directives 89/618/Euratom, 90/641/Eur- Increasingly, the theragnostic principle ology of Targeted Radionuclide Therapy. Frontiers in , 96/29/Euratom, 97/43/Euratom and 2003/122/ Euratom. . OJ of the EU, 2014. L13(57): p. 1 - 73. and dosimetry are being applied to Medicine, 2015. 2(12). 2. O’Donoghue, J.A. and T.E. Wheldon, Target- 13. Bolch, W.E., et al., MIRD pamphlet No. 21: a radionuclide therapy treatments. The ed radiotherapy using Auger electron emitters. Physics generalized schema for radiopharmaceutical dosime- additional information provided by in medicine and biology, 1996. 41(10): p. 1973-1992. try--standardization of nomenclature. Journal of nu- hybrid imaging can significantly impact 3. Sgouros, G., et al., MIRD Pamphlet No. 22 clear medicine : official publication, Society of Nuclear Medicine, 2009. 50(3): p. 477-484. the patient pathway and should be (abridged): radiobiology and dosimetry of alpha-par- ticle emitters for targeted radionuclide therapy. Journal 14. Ogawa, K., Simulation study of triple-ener- utilised as much as possible. To achieve of nuclear medicine : official publication, Society of Nu- gy-window scatter correction in combined Tl-201, Tc- this will require a coordinated effort clear Medicine, 2010. 51(2): p. 311-328. 99m SPECT. Annals of Nuclear Medicine, 1994. 8(4): p. from technologists, physicists and 4. Hubenak, J.R., et al., Mechanisms of injury to 277-281. 15. He, B., et al., Evaluation of quantitative im- clinicians working towards a shared normal tissue after radiotherapy: a review. Plastic and reconstructive surgery, 2014. 133(1): p. 49e-56e. aging methods for organ activity and residence time objective, with common techniques and 5. Pene, F., et al., Toward theragnostics. Critical estimation using a population of phantoms having standard operating procedures between Care Medicine, 2009. 37(1): p. S50-S58. realistic variations in anatomy and uptake. , 2009. 36(2): p. 612-619. centres. This should provide the basis 6. Yordanova, A., et al., Theranostics in nuclear 16. Huizing, D.M.V., et al., Dosimetry methods for personalised treatments, resulting in medicine practice. OncoTargets and therapy, 2017. 10: p. 4821-4828. and clinical applications in peptide receptor radionu- improved outcomes for patients. 7. Ljungberg, M. and K.S. Gleisner, Hybrid Im- clide therapy for neuroendocrine tumours: a literature aging for Patient-Specific Dosimetry in Radionuclide review. EJNMMI research, 2018. 8(1): p. 89-89. Therapy. Diagnostics (Basel, Switzerland), 2015. 5(3): p. 17. Stabin, M.G., R.B. Sparks, and E. Crowe, OLIN- 296-317. DA/EXM: The Second-Generation Personal Computer 8. Minarik, D., K. Sjögreen, and M. Ljungberg, A Software for Internal Dose Assessment in Nuclear Med- new method to obtain transmission images for planar icine. Journal of Nuclear Medicine, 2005. 46(6): p. 1023- whole-body activity quantification. Cancer biotherapy 1027. & radiopharmaceuticals, 2005. 20(1): p. 72-76. 18. Wadsley, J., et al., SELIMETRY-a multicentre 9. Hänscheid, H., et al., EANM Dosimetry Com- I-131 dosimetry trial: a clinical perspective. The Brit- mittee series on standard operational procedures for ish journal of radiology, 2017. 90(1073): p. 20160637- pre-therapeutic dosimetry II. Dosimetry prior to radio- 20160637. iodine therapy of benign thyroid diseases. European 19. Gregory, R.A., et al., Standardised quanti- journal of nuclear medicine and molecular imaging, tative radioiodine SPECT/CT Imaging for multicentre 2013. 40(7): p. 1126-1134. dosimetry trials in molecular radiotherapy. Physics in 10. Marinelli, L.D., Dosage determination in the medicine and biology, 2019. 64(24): p. 245013-245013. use of radioactive isotopes. The Journal of clinical in- 20. Buckley, S.E., et al., Whole-body dosimetry vestigation, 1949. 28(6 Pt 1): p. 1271-1280. for individualized treatment planning of 131I-MIBG ra- 11. Strigari, L., et al., The evidence base for the dionuclide therapy for neuroblastoma. Journal of nu- use of internal dosimetry in the clinical practice of clear medicine : official publication, Society of Nuclear Figure 4: Summary points for the chapter. molecular radiotherapy. European Journal of Nuclear Medicine, 2009. 50(9): p. 1518-1524. Medicine and Molecular Imaging, 2014. 41(10): p. 1976- 21. Sundlov, A., et al., Individualised (177) 1988. Lu-DOTATATE treatment of neuroendocrine tumours 12. European Council Directive 2013/59/Eura- based on dosimetry. Eur J Nucl Med Mol Imag- tom on basic safety standards for protection against ing, 2017. 44(9): p. 1480-1489. 22. Stokkel, M.P.M., et al., EANM procedure

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