PET and SPECT Imaging in Veterinary Medicine Amy K. LeBlanc, DVM, DACVIM,* and Kathelijne Peremans, DVM, DipECVDI, PhD† Veterinarians have gained increasing access to positron emission tomography (PET and PET/ CT) imaging facilities, allowing them to use this powerful molecular imaging technique for clinical and research applications. SPECT is currently being used more in Europe than in the United States and has been shown to be useful in veterinary oncology and in the evaluation of orthopedic diseases. SPECT brain perfusion and receptor imaging is used to investigate behavioral disorders in animals that have interesting similarities to human psychiatric disorders. This article provides an overview of the potential applications of PET and SPECT. The use of commercially available and investigational PET radiopharmaceuticals in the management of veterinary disease has been discussed. To date, most of the work in this field has utilized the commercially available PET tracer, 18F-fluorodeoxyglucose for oncologic imaging. Normal biodistribution studies in several companion animal species (cats, dogs, and birds) have been published to assist in lesion detection and interpretation for veterinary radiologists and clinicians. Studies evaluating other 18F-labeled tracers for research applications are underway at several institutions and companion animal models of human diseases are being increasingly recognized for their value in biomarker and therapy development. Although PET and SPECT technologies are in their infancy for clinical veterinary medicine, increasing access to and interest in these applications and other molecular imaging techniques has led to a greater knowledge and collective body of expertise for veterinarians worldwide. Initiation and fostering of physician-veterinarian collaborations are key components to the forward movement of this field. Semin Nucl Med 44:47-56 C 2014 Elsevier Inc. All rights reserved.
Historical Perspective: PET Imaging in Veterinary Medicine
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ET imaging is considered relatively new to veterinary medicine, with the first reports of its use in clinical patients dating to the early 1980s and 1990s.1-4 This is attributable to the limited access to PET scanners owing to their purchase and maintenance costs, reliance on discretionary income for pet owners to fund veterinary care for their pets, and the stillevolving knowledge of what role this technology plays in the management of common veterinary ailments. There is an ongoing need to validate the technique and increase the comfort level for veterinary radiologists and clinicians involved in reading such studies. The widespread fusion of PET with *Department of Small Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Veterinary Teaching Hospital, Knoxville, TN. †Department of Medical Imaging and Small Animal Orthopaedics, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium. Address reprint requests to Amy K. LeBlanc, DVM DACVIM, Department of Small Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, 2407 River Dr, Rm C247 Veterinary Teaching Hospital, Knoxville, TN 37996. E-mail: [email protected]
0001-2998/14/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semnuclmed.2013.08.004
computed tomography (PET/CT) assists in image interpretation, as CT is a common component of veterinary diagnostic imaging, and a review of both data sets can assist the clinician in characterizing areas of radiopharmaceutical uptake.5 The most logical and widely published studies for PET and PET/CT imaging, utilizing the commercially available tracer 18 F-fluorodeoxyglucose (18F-FDG), are in the field of oncology, where the most human PET studies are performed. Veterinary oncology is a growing field and a recognized specialty of the American College of Veterinary Internal Medicine, founded in 1972 (www.acvim.org). Currently, most veterinarians rely on standard anatomical imaging modalities such as radiography, ultrasonography, and computed tomography for detection and staging of cancer in veterinary patients. The use of PET offers an opportunity to evaluate the metabolic nature of malignancies in addition to anatomical data. Naturally occurring cancers in dogs and cats represent a great opportunity to validate PET and PET/CT imaging techniques, they benefit tumor-bearing pets while simultaneously advancing development of new imaging techniques for human cancers. This aspect of veterinary medicine is gaining traction in academic settings where research collaborations between veterinarians and physicians are established and growing. 47
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PET Imaging Protocols and Data Analysis for Companion Animals Several key differences exist in patient preparation for animals undergoing PET and PET/CT imaging. Veterinary PET scans involve preparation for general anesthesia, including 8-12 hours fast, which is required for proper positioning for the scan procedure, but also serves to limit physiological 18F-FDG myocardial uptake. Additionally, state-specific radiation safety guidelines may apply and must be followed to limit exposure to the animals and their excreta once they have been injected with the radiopharmaceutical of interest.6 Readers may refer to http://www.nrc.gov/material/miau/med-vet/html for additional details. In the case of 18F-FDG, artifactual uptake within skeletal muscle can occur if the animal is physically active in the uptake period before the scan, hence the use of a sedative or premedicant is recommended (Fig. 1). In addition, in the case of 18F-FDG and similarly to humans, animals should be normoglycemic so as not to interfere with tissue uptake of the radiopharmaceutical, which can lead to erroneous scan results. Other key components are adequate facilities for holding radioactive animals and protocols for transport to off-site facilities (if applicable), monitoring radiation exposure to staff, and release limits for pets to return home to their owners. Along with a greater body of experience in reading PET and PET/CT studies, there remains a need for standardized postimage processing and data analysis in veterinary PET imaging. The commonly used clinical indicator of radiopharmaceutical uptake is the standardized uptake value, which is influenced by many factors (scanner design and reconstruction parameters, patient body condition, scan protocol, etc.).7 Guidelines for objective evaluation of PET/CT–based responses (positron emission tomography response criteria in solid tumors) were recently reported for human patients in whom PET/CT is used to judge response to therapy.8 The use of such a uniform reporting method for factors affecting the generation of a PET image is needed so that data can be reproduced at other PET imaging centers and in support of multisite clinical trials that involve PET imaging.
PET Radiopharmaceutical Biodistribution Studies in Companion Animals In an effort to characterize the normal patterns of uptake for 18 F-FDG, studies in purpose-bred dogs and cats utilizing both PET and PET/CT have been published.9-11 An investigation of how various anesthetic protocols influence brain uptake of 18 F-FDG was also performed for future studies of 18F-FDG in neuroimaging.12 These studies act not only as valuable data sets for comparative studies between species and provide a reference for disease studies, but they also act as feasibility studies when human PET imaging facilities are used for animal work. Additionally, studies in birds have been performed and highlight the comparative differences for avian species.13,14
Figure 1 Maximal image projections (MIPs) of an 8-year-old mixedbreed dog with high-grade multicentric lymphoma, before (left) and after (right) receiving a CHOP-based induction chemotherapy protocol. Imaging was carried out with approximately 5 mCi 18F-FDG (PETNET Solutions, Knoxville, TN) allowing a 60-minute uptake time and using a Siemens mCT scanner (Siemens Molecular Imaging, Knoxville, TN). On the baseline scan, 18F-FDG uptake is present in affected lymph nodes (arrows, left image) with splenomegaly consistent with malignant infiltration (arrow head, left image). Physiological 18F-FDG uptake is present within the brain, heart, and salivary glands, which is difficult to discern with bulky head and neck lymphoma involvement. Normal excretion of tracer is evident in renal pelves and bladder. Notably within the remission scan, artifactual yet physiological uptake is noted within the musculature of the forelimbs, consistent with physical activity during the tracer uptake period (arrows, right image). Myocardial uptake is notably increased on the remission PET scan (arrow head, right image), indicating the variability of 18F-FDG myocardial uptake even in the fasting state. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone
Of particular interest for oncology, biodistribution data in dogs and cats with 18F-fluorothymidine (18F-FLT) is currently in progress. We believe this cellular proliferation tracer will provide valuable information for lesion discrimination when staging animals with cancer.
Application of Selected PET Radiopharmaceuticals to Veterinary Nuclear Medicine 18
F-FDG
18
F-FDG is the standard PET radiopharmaceutical for cancer imaging in humans, but it is also utilized for cardiac imaging
PET and SPECT imaging in veterinary medicine
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and neuroimaging purposes. Veterinary applications of 18 F-FDG-PET/CT in oncology are growing with increasing access to scanners, pet owners' growing requests for equivalent care to humans, and experience with PET imaging protocols. Several studies demonstrate the avidity of canine cancers for 18 F-FDG and emphasize the potential of whole-body PET and PET/CT as an efficient staging technique that can identify lesions not detected on physical examination that may represent additional sites of metastasis or additional unrelated malignancies or both.15-18 Serial 18F-FDG-PET/CT imaging is attractive for monitoring response to therapy in a single diagnostic procedure (Fig. 2). Investigations of this approach in canine cancers treated with a tyrosine kinase inhibitor showed discordance between standard response evaluation criteria in solid tumors and positron emission tomography response criteria in solid tumors applied to selected neoplastic lesions, emphasizing the need for larger clinical studies of serial 18 F-FDG-PET/CT in this area.19 Imaging of inflammatory processes with 18F-FDG is well established in humans and the application of this technique to veterinary medicine is ongoing, particularly in the field of neuroimaging for inflammatory central nervous system diseases.20 Fungal granulomas and other systemic infectious diseases could be tracked with serial PET/CT to determine the response to antimicrobial or antifungal therapy.3,4 18
F-FLT
18
F-FLT, is a substrate of the mammalian thymidine kinase, an integral part of the cellular DNA synthesis machinery and thus a reflection of cellular rate of proliferation. Many studies demonstrate a strong correlation between 18F-FLT uptake and cell proliferation, as assessed by the Ki-67 immunostaining technique.21 However, the consideration of the cell population of interest and other factors that may affect uptake of 18F-FLT, such as cellular thymidine and thymidine kinase 1 levels, are important when interpreting the validity of an 18F-FLT signal.22 Although 18F-FLT uptake in reactive lymphoid hyperplasia, mediated by B-lymphocyte proliferation in germinal centers does occur, some studies demonstrate the superiority of 18F-FLT over 18F-FDG for differentiation of a tumor from an inflammation23 and indicate that 18F-FLT could be a useful adjunct to 18F-FDG to improve diagnostic specificity.24 Clinical investigations using 18F-FLT are primarily in oncology, where response to therapy may be judged based on changes in tumor cell proliferation. Additionally, this technique may provide increased specificity over 18F-FDG in the evaluation of cancers that are metastatic to lymph nodes or may incite an inflammatory response, or both (Fig. 3). A study evaluating whole-body 18F-FLT-PET/CT as a noninvasive measure of response to a novel nucleoside analogue for canine lymphoma therapy demonstrated the utility of this proliferation tracer as an early marker of response or as an indicator of relapsed disease or both.25 Researchers at the University of Tennessee studied the whole-body biodistribution of 18F-FLT in normal cats and dogs and applied serial 18F-FLT imaging in a canine model of chemotherapy-induced myelosuppression.26 Physiological
Figure 2 Maximal image projections (MIPs) of a 6-year-old standard Poodle with stage V malignant oral mucosal melanoma, before (left) and after (right) receiving an investigational immunotherapy treatment protocol. Imaging was carried out with approximately 5 mCi 18 F-FDG (PETNET Solutions, Knoxville, TN), allowing a 60-minute uptake time, and using a Siemens mCT scanner (Siemens Molecular Imaging, Knoxville, TN). Uptake within the primary tumor of the maxillary mucosa is evident, along with bulky mandibular lymph node metastasis (arrow heads) and multiple pulmonary metastases (arrows). Physiological uptake is noted on both scans within the brain and gastrointestinal tract; minimal myocardial uptake is also present. Residual tracer is also present within the injection site on the distal forelimb. Excretion of 18F-FDG is evident within the renal pelves and urinary bladder. Comparison of the baseline and posttreatment scans is supportive of progressive disease, with no measurable response to therapy.
uptake of 18F-FLT within the bone marrow allows for the PET imaging of leukemias and other primary bone marrow disorders (myelodysplastic syndrome, aplastic anemia, and idiopathic marrow fibrosis) in which the patient's bone marrow 18F-FLT signal can be monitored noninvasively over time, thereby providing an early biomarker of treatment response.27,28 18F-FLT-PET/CT may also be applied to identify the bone marrow in external-beam radiotherapy planning so as to limit the dose in chemoradiation schemes, which carry a significant risk for myelosuppression.29 The use of 18F-FLT for the imaging of spontaneous tumors in dogs could be used to gather the necessary data for eventual Food and Drug Administration approval of 18F-FLT for human use in these and other clinical scenarios.
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Figure 3 MIPs of an 11-year-old neutered male dog with a large hepatocellular carcinoma with central necrosis, imaging done with both 18F-FLT and 18F-FDG (5 mCi for each radiopharmaceutical, allowing a 60-minute uptake time, and using a Siemens mCT scanner (Siemens Molecular Imaging, Knoxville, TN). Within the 18F-FLT-PET images, intense tracer uptake is evident within the bone marrow and the viable edges of the hepatic tumor, shown to be mitotically active on histopathology. As expected, no brain or myocardial uptake of 18F-FLT is seen. The borders of the hepatic tumor in this dog appear more sharply defined with 18F-FLT (SUVmax ¼ 13.1) compared with 18F-FDG imaging (SUVmax ¼ 4.5). In the 18 F-FDG-PET images, physiological tracer uptake is present within the left mandibular salivary gland, brain, myocardium, GI tract, and urinary tract. Although not confirmed with histopathology, a presumed reactive retrosternal lymph node (arrows) demonstrates avidity for 18F-FDG (SUVmax ¼ 10.7) but not 18F-FLT (SUVmax ¼ 1.8). GI, gastrointestinal; MIPs, maximal image projections; SUV, standardized uptake value.
18
F-Sodium Fluoride (18F-NaF)
F-NaF was first used for skeletal scintigraphy in the 1960s, but was replaced by 99mTc diphosphonate because of the cost and wide availability of clinical planar and SPECT gamma cameras in both human and veterinary medicine. Recently, 18 F-NaF has been reevaluated and is gaining popularity for bone imaging mainly because of the technological advances made possible with PET/CT. This technique provides greater sensitivity, resolution, and efficiency for whole-body skeletal studies. 18F-NaF has a high and rapid uptake in the bone with rapid blood pool clearance, producing high target-background ratios less than 1 hour after injection in both humans and dogs.30,31 Based on the human experience, 18F-NaF should be useful for characterization of primary and metastatic bone lesions. Additional work to support this technique over traditional bone scans for skeletal diseases in veterinary nuclear medicine is needed. 18
Investigational PET Radiopharmaceuticals and Their Applications 18
F-Misonidazole and 64CU-ATSM for Hypoxia Imaging Spontaneous canine malignancies offer a unique opportunity for radiopharmaceutical development. In the field of hypoxia
imaging, which has implications for radiotherapy dosimetry and development of therapies to specifically address cellular changes associated with hypoxia, both 18F-misonidazole and 64 CU-ATSM have been studied in an effort to garner data to support the commercialization of such tracers and their application to clinical situations. Radiation dose planning and prescription based on hypoxia imaging could complement traditional techniques by providing insight into areas of the tumor that may benefit from a boost of therapeutic radiation or novel intensity-modulated radiotherapy protocols or both. Canine tumor imaging with both 18F-misonidazole and 64CUATSM demonstrates the applicability of these naturally occurring cancer models for the development and refinement of such tracers.32-35 18
F-fluorothiaheptadecanoic acid (18F-FTHA)
The palmitate analogue 14(R,S)-(18F-FTHA) accumulates preferentially within the myocardium via betaoxidative metabolic trapping.36-38 Intense myocardial uptake, long myocardial retention, and rapid clearance from the bloodstream make 18F-FTHA a useful PET imaging agent, and it shows a vast improvement over previous efforts to interrogate the fatty acid oxidation pathway with C-11 labeled fatty acids, which were difficult to model and required on-site cyclotron facilities owing to the 20-minute half-life of C-11. Our group has studied the whole-body biodistribution of
PET and SPECT imaging in veterinary medicine 18
F-FTHA in the normal cat and has compared the uptake kinetics of both 18F-FTHA and 18F-FDG in this species. Based on the biodistribution of 18F-FTHA in the domestic cat, application of this PET tracer for cardiac, hepatic, and renal function seems plausible. Additional work is needed to define the role of 18F-FTHA for cardiac PET imaging in both humans and companion animals.
SPECT Planar gamma camera imaging has been used in veterinary medicine for decades, at first predominantly in the diagnostic workup of equine lameness cases but later for small animal application. However, tomographic studies (SPECT) have not received much enthusiasm in veterinary medicine despite the fact that many preclinical human medicine studies exist, mainly in dogs, but also in cats. This may be partially explained by the lack of suitable equipment (many veterinary gamma cameras are used for both large and small animal imaging but have been rebuilt to meet the specific requirements for equine imaging), specific software, and the necessity for anesthesia. In equipment also used to image horses, the size of the animal is an additional restriction as only limited areas are accessible to SPECT. Contrary to studies in man, anesthesia or sedation is an absolute prerequisite for SPECT investigations, which has further limited its use. Ischemic heart disease is not a clinical problem in our canine and feline patients, so there is not as high a demand for cardiac SPECT as in human medicine. Most functional imaging of the heart in veterinary medicine is carried out by echocardiography. There is not much interest in veterinary medicine for brain perfusion and neuroreceptor imaging where SPECT is essential. However, in the last decades, developments in small animal medicine, especially in oncology and behavioral medicine, prompted the introduction of more advanced diagnostic tools. Many owners regard their pets as part of the family and as such want the optimal (anthropomorphic) care for them. Because of the internet, owners have become increasingly aware of the variety in diagnostic and therapeutic possibilities. In addition, sophisticated processing software has become more accessible, thereby making coregistration with CT or MRI, or both, now part of the veterinary armamentarium. In this regard, diagnostic and therapeutic approaches in sick animals reflect, to a certain extent, those of human medicine but with financial restrictions, especially regarding some radiopharmaceuticals. In this section, the practical application of SPECT in different clinical settings has been expounded. New techniques, as applied in veterinary medicine, have also been briefly mentioned where applicable.
51 percentage due to thyroid carcinoma.39 In dogs, thyroid tumors are more likely to be malignant.40 Pertechnetate is the classic radionuclide used for diagnosis of thyroid disease in cats and dogs and planar imaging is usually sufficient for imaging of the primary lesion. Canine thyroid tumors tend to metastasize to regional lymph nodes and lungs at an early stage. Similar to human medicine, the sensitivity of planar imaging is much less than SPECT for metastasis detection except in an advanced stage. SPECT is not only used for diagnostic and staging purposes in dogs but also posttherapy to evaluate radioiodine uptake in the primary tumor and its metastasis (Fig. 4).
Insulinomas Insulinomas are rare tumors in dogs and cats.41,42 Clinical features can be vague and the presence of hypoglycemia in the face of increased insulin levels can be a diagnostic indication, but hypoglycemia as such is an aspecific sign and insulin levels may be normal. In 50% of the dogs insulinomas metastasize to the liver and lymph nodes.42 Ultrasonography is commonly used as the next diagnostic step but may be unrewarding to localize and characterize the primary tumor or its metastases. Somatostatin receptor scintigraphy, with radiolabeled octreotide or depreotide, has been successfully used in dogs suspected of an insulinoma (Fig. 5). Using SPECT and in-vitro autoradiography, Robben et al.43 demonstrated that uptake of the radiopharmaceutical was linked with overexpression of one type of somatostatin receptor as opposed
Oncology Thyroid Carcinoma In aging cats, hyperthyroidism is one of the most common endocrine disorders, with the majority due to benign adenomas or adenomatous hyperplasia and only a small
Figure 4 Coronal plane SPECT (summed slices) image acquired after radioiodine-131 treatment. There is an intense area of uptake in the cervical region from a thryoid carcinomal with 2 focal areas of less intense uptake (arrows) due to metastases in the thorax.
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Figure 5 Coronal plane SPECT images (summed slices) of the anterior abdomen following injection of 123I-MIBG. There are 2 focal areas of increased uptake within the liver and a patchy area of increased uptake (arrow) also within the liver. Postmortem examination confirmed nodular metastatic lesions (2 focal lesions) together with massive tumor infiltration in the liver.
to human insulinomas, where subtypes occur with lower affinity for octreotide. In a comparative study, the same authors compared CT, ultrasonography, and somatostatin receptor scintigraphy SPECT to evaluate their potential to demonstrate the primary tumor and metastatic disease.44 A higher number of primary tumors and metastases to the lymph nodes were found on CT images. However, because of the high number of false positives, CT was unreliable to provide a definitive diagnosis of metastatic involvement. The false-negative results of SPECT seemed to be predominantly related to low (spatial) resolution. Small lesions (median 15 mm) were missed and uptake was not always allocated to the correct anatomical area. The introduction of resolution recovering software and fusion with anatomical imaging may increase the preoperative value of CT and SPECT in the staging and characterization of canine insulinomas.
Pheochromocytoma These catecholamine-producing neuroendocrine tumors are uncommon in dogs and cats and the diagnosis can be a challenge. Clinical symptoms can be vague and hypertension may be phasic, thus failure to demonstrate hypertension does not exclude a pheochromocytoma. Diagnosis is often based on the detection of excessive catecholamines (epinephrine and norepinephrine) or their metabolites (metanephrine and normetanephrine). Urine concentrations of these products have been recently evaluated with the best promise associated with normetanephrinecreatinine ratios but these tests are not widely available.45 This tumor tends to be locally invasive and can metastasize to a range of organs. Ultrasonography is the first-line medical imaging tool and is useful to identify an adrenal associated mass; however it is not possible to differentiate pheochromocytoma from other types of adrenal masses. 123 I-metaiodobenzylguanidine (123I-MIBG) has been used in dogs for pheochromocytoma detection, however only planar imaging has been reported.46 We performed 123 I-MIBG SPECT studies in dogs suspected of a pheochromocytoma. In most of these dogs, the adrenal medulla was clearly recognized at 6 hours and remained visible 24
hours following injection. In humans, normal uptake in the medulla has been reported ranging from 30%-80% for 123 I-labeled MIBG.47,48 In 1 dog, focal uptake was seen in a caudal lung lobe at 6 hours but not at 24 hours. This area of uptake coincided with a patchy area of increased attenuation on CT scan. Lung biopsy revealed focal atelectasis. In humans, both decreased and increased pulmonary tracer washout has been reported to reflect changes in vascularization status of the lungs and endothelial integrity.49
Brain imaging Perfusion Imaging 99m Both Tc-hexamethylpropyleneamine oxime and 99m Tc-ethyl cysteinate dimer (ECD) with conventional collimated gamma cameras can be used for brain imaging in dogs. Injection of the tracers is performed in quiet surroundings with dimmed lights (similar to what is the standard protocol in human medicine) and before sedation and anesthesia. 99mTcECD studies have shown an influence of sedatives and anesthetics on regional cerebral blood flow (rCBF) when given before the tracer, with regional increases and decreases depending on the drug used.50,51 Dogs have a faster uptake and washout rate of 99mTc-ECD than men, therefore the optimal scan interval after tracer injection is 15-40 minutes.52,53 Comparison of the rCBF measured with 99mTc-ECD and 99m Tc-hexamethylpropyleneamine oxime revealed that, similar to man, regional distribution differences exist between both tracers, indicating that direct comparison of data obtained with these tracers is not possible.54,55 Most perfusion studies have been conducted in animals with behavioral disorders including impulsive aggression, pathologic anxiety, and compulsive behavior. In 2 recent studies, decreased left frontal and right temporal perfusion was found in impulsive-aggressive dogs and decreased left frontal, increased right temporal, and decreased subcortical blood flow was registered in dogs with anxiety disorders.56,57 The hypoperfusion in the frontal cortex, reflecting hypofunctionality, is consistent with the major involvement of this area in behavior in general and its control over limbic primary reactions, generated by structures located in the temporal and subcortical regions, in particular.58 Beside the fact that these data provide information on the pathophysiological mechanisms underlying canine behavioral disorders, the fact that parallelism is present with imaging findings in similar human psychiatric disorders59-63 renders the dog an interesting natural model. The use of 99mTc-ECD has also been described in epileptic dogs in the interictal phase and decreased perfusion in the subcortical region (a region that comprises a large part of the thalamus) was reported.64 This finding is of potential significance as the role of the thalamus has been described as causative, that is, involved in the initiation or propagation of seizures.65,66 The thalamic hypofunction has also been explained as a consequence of corticothalamic diaschisis.65 To increase resolution and allow further delineation of subcortical subdivisions a micro-SPECT system (HiSPECT) has
PET and SPECT imaging in veterinary medicine been tested, based on multipinhole collimation on a conventional triple-head gamma camera rendering a resolution of 2.5 mm (HiSPECT, Bioscan, France).67 The same system was successfully used in cats to evaluate feline rCBF and the effect of anesthetics.68,69
53 tailored treatment protocol. In addition, in cats, imaging of the serotonin-2A receptor has been reported using the aforementioned tracer and the HiSPECT system.84,69
Orthopedics Neuroreceptor Imaging Neuroreceptor imaging is used in dogs to investigate the pathophysiology of behavioral disorders and also to provide a means to predict the effectiveness of psychopharmacological therapy. Imaging using radioligands for the serotonin-2A receptor (with 123I-R91150), the serotonin transporter, and the dopamine transporter (with 123I-2β-carboxymethoxy-3 β-[4-iodophenyl]tropane and 123I-N-[3-fluoropropyl]-2βcarbomethoxy-3β-[4-iodophenyl]nortropane) has been reported in dogs for diagnostic purposes in behavioral disorders and for the evaluation of medicinal therapy (Fig. 6).57,70-76 A disturbed serotonergic system was demonstrated in impulsive-aggressive dogs, dogs with anxiety disorders, and compulsive dogs. Next to a deficient serotonergic system, an imbalanced dopaminergic system was found in compulsive dogs. These imaging findings again resemble those found in similar human disorders.7783 These studies can also guide the decision on which drug is best suited and are also helpful in monitoring therapeutic effectiveness.71,75 This could be the key to a patient-
The indication for a bone scan is usually lameness or pain of an unknown origin because clinical or radiographic examination is equivocal or when the temperament of the animal precludes clinical examination. Most bone scans in veterinary medicine are planar studies. SPECT imaging can reveal lesions that remain undetected on planar imaging (eg, spinal and pelvic lesions) and provide a better topographic overview of the suspected region. SPECT imaging of the canine elbow joint is an excellent example of the latter characteristic. Most cases of forelimb lameness are owing to elbow disease. Elbow dysplasia is the most commonly encountered diagnosis and may affect different anatomical structures within the joint. On planar images, it is often impossible to attribute increased uptake in the elbow joint to a specific anatomical structure. The limited resolution and the small size of the elbow hamper differentiation of the anatomical sites, especially when multiple areas within the joint are affected. Anatomical landmarks are definitely identified by conventional SPECT. The micro-SPECT system (HiSPECT, Bioscan,
Figure 6 Fused dorsal plane SPECT and MR images acquired following injection of 123I-β-CIT in a dog. Top row of images depicts activity in the raphe nuclei (small arrows) area (the small “tail”) where the serotonin transporters are located. The bottom row demonstrates uptake in the basal ganglia (large arrow), where high densities of dopamine transporters are found. CIT, carbomethoxy-3 β-(4-iodophenyltropane).
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Figure 7 (A) Ventral planar images acquired 3 hours following injection of 99mTc-MDP in a lame dog. There is asymetrical uptake associated with the elbows, with the left elbow being more intense. Further localization of the increased uptake within the joint is not possible. (B) HiSPECT images display increased uptake in the medial epicondylar region of the distal humerus, suggestive for flexor enthesopathy.
France) has superior resolution compared with conventional SPECT and has been used to evaluate normal and diseased canine elbows (Fig. 7).85,86 This micro-SPECT system with multipinhole collimation on conventional gamma camera heads allows adjustment of the gantry opening for larger animals as opposed to the dedicated rodent microsystems. A limitation of this system is the narrow range of the radius of rotation to ascertain optimal resolution, restricting the skeletal areas that can be investigated to the elbow and lower forelimb and to the stifle and lower hindlimb in dogs. Another major drawback is that the expense of the collimators and the dedicated reconstruction software hamper implementation in the classic veterinary setting. Recently, resolution recovery software has been commercialized, which may counter the aforementioned limitations of the HiSPECT system and offer an interesting alternative, as it allows the use of a conventional system for investigation of all regions of the body. In summary, PET and SPECT imaging in veterinary medicine is gaining in popularity for clinical and research applications. Challenges that veterinarians face with respect to access to necessary equipment and infrastructure to support companion animal imaging programs can be met in part by establishing collaborations with human imaging facilities. Spontaneous diseases in dogs and cats offer a unique opportunity to gather
data that could support the development and commercialization of novel PET imaging agents for human patients.
References 1. Larson SM, Weiden PL, Grunbaum Z, et al: Positron imaging feasibility studies. II. Characteristics of 2-deoxyglucose uptake in rodent and canine neoplasms: Concise communication. J Nucl Med 1981;22:869-874 2. Page RL, Garg PK, Garg S, et al: PET imaging of osteosarcoma in dogs using a fluorine-18-labeled monoclonal antibody Fab fragment. J Nucl Med 1994;35:1506-1513 3. Matwichuk CL, Daniel GB, Bowman LA, et al: Fluorine-18 fluorodeoxyglucose accumulation in blastomyces dermatitidisassociated inflammation in a Dog. Clin Positron Imaging 1999;2:217-221 4. Bassett CL, Daniel GB, Legendre AM, et al: Characterization of uptake of 2-deoxy-2-[18F]fluoro-D-glucose by fungal-associated inflammation: The standardized uptake value is greater for lesions of blastomycosis than for lymphoma in dogs with naturally occurring disease. Mol Imaging Biol 2002;4:201-207 5. Beyer T, Townsend DW, Brun T, et al: A combined PET/CT scanner for clinical oncology. J Nucl Med 2000;41:1369-1379 6. Martinez NE, Kraft SL, Gibbons DS, et al: Occupational per-patient radiation dose from a conservative protocol for veterinary 18 F-fluorodeoxyglucose positron emission tomography. Vet Radiol Ultrasound 2012;53:591-597 7. Keyes JW: SUV: Standard uptake value or silly useless value? J Nucl Med 1995;36:1836-1839
PET and SPECT imaging in veterinary medicine 8. Wahl RL, Jacene H, Kasamon Y, et al: From RECIST to PERCIST: Evolving considerations for PET response criteria in solid tumors. J Nucl Med 2009;50:122S-150S 9. LeBlanc AK, Jakoby BW, Townsend DW, et al: Thoracic and abdominal organ uptake of 2-deoxy-2-[18F]fluoro-D-glucose (18FDG) with positron emission tomography in the normal dog. Vet Radiol Ultrasound 2008;49:182-188 10. LeBlanc AK, Wall JS, Morandi F, et al: Normal thoracic and abdominal distribution of 2-deoxy-2-[18F]fluoro-D-glucose in adult cats. Vet Radiol Ultrasound 2009;50:435-440 11. Lee MS, Lee AR, Jung MA, et al: Characterization of physiologic 18F-FDG uptake with PET-CT in dogs. Vet Radiol Ultrasound 2010;51:670-673 12. Lee MS, Ko J, Lee AR, et al: Effects of anesthetic protocol on normal canine brain uptake of 18F-FDG assessed by PET/CT. Vet Radiol Ultrasound 2010;51:130-135. [Erratum in: Veterinary Radiology & Ultrasound. 2010 Nov-Dec;51(6):699] 13. Souza MJ, Wall JS, Stuckey A, et al: Static and dynamic (18F)FDG-PET in normal hispaniolan Amazon parrots (Amazona ventralis). Vet Radiol Ultrasound 2011;52:340-344 14. Jones MP, Morandi F, Wall JS, et al: Distribution of 2-deoxy-2-[18F] fluoro-D-glucose in the coelom of healthy bald eagles (Haliaeetus leucocephalus). Am J Vet Res 2013;74:426-432 15. LeBlanc AK, Jakoby BW, Townsend DW, et al: PET imaging in canine lymphoma and cutaneous mast cell tumor. Vet Radiol Ultrasound 2009;50:215-223 16. Ballegeer EA, Forrest LJ, Jeraj R, et al: PET/CT following intensitymodulated radiation therapy for primary lung tumor in a dog. Vet Radiol Ultrasound 2006;47:228-233 17. Ballegeer EA, Hollinger C, Kunst CM: Imaging diagnosis-multicentric lymphoma of granular lymphocytes imaged with FDG PET/CT in a dog. Vet Radiol Ultrasound 2013;54:75-80 18. Hansen AE, McEvoy F, Engelholm SA, et al: FDG PET/CT imaging in canine cancer patients. Vet Radiol Ultrasound 2011;52:201-206 19. LeBlanc AK, Miller AN, Galyon GD, et al: Preliminary evaluation of serial (18F) FDG-PET/CT to assess response to toceranib phosphate therapy in canine cancer. Vet Radiol Ultrasound 2012;53:348-357 20. Kang BT, Kim SG, Lim CY, et al: Correlation between fluorodeoxyglucose positron emission tomography and magnetic resonance imaging findings of non-suppurative meningoencephalitis in 5 dogs. Can Vet J 2010;51:986-992 21. Salskov A, Tammisetti VS, Grierson J, et al: FLT: Measuring tumor cell proliferation in vivo with positron emission tomography and 3′-deoxy3′-[18F]fluorothymidine. Semin Nucl Med 2007;37:429-439 22. Zhang CC, Yan Z, Li W, et al: [18F]FLT-PET imaging does not always “light up” proliferating tumor cells. Clin Cancer Res 2012;18:1303-1312 23. Lee TS, Ahn SH, Moon BS, et al: Comparison of 18F-FDG and 18F-FET and 18F-FLT for differentiation between tumor and inflammation in rats. Nucl Med Biol 2009;36:681-686 24. Van Waarde A, Elsinga PH: Proliferation markers for the differential diagnosis of tumor and inflammation. Curr Pharm Des 2008;14: 3326-3339 25. Lawrence J, Vanderhoek M, Barbee D, et al: Use of 3-deoxy-3-[18F] fluorothymidine PET/CT for evaluating response to cytotoxic chemotherapy in dogs with non-Hodgkin's lymphoma. Vet Radiol Ultrasound 2009;50:660-668 26. Rowe JA, Morandi F, Wall JS, et al: Whole-body biodistribution of 3′deoxy-3′-[18F]fluorothymidine (18FLT) in healthy adult cats. Vet Radiol Ultrasound 2013. ([Epub ahead of print]) 27. Vanderhoek M, Juckett MB, Perlman SB, et al: Early assessment of treatment response in patients with AML using [18F]FLT PET imaging. Leuk Res 2011;35:310-316 28. McGuire SM, Menda Y, Ponto LL, et al: A methodology for incorporating functional bone marrow sparing in IMRT planning for pelvic radiation therapy. Radiother Oncol 2011;99:49-54 29. Agool A, Slart RH, Kluin PM, et al: F-18 FLT PET: A noninvasive diagnostic tool for visualization of the bone marrow compartment in patients with aplastic anemia: A pilot study. Clin Nucl Med 2011;36: 286-289
55 30. Li Y, Schiepers C, Lake R, et al: Clinical utility of 18F-fluoride PET/CT in benign and malignant bone diseases. Bone 2012;50:128-139 31. Valdés-Martínez A, Kraft SL, Brundage CM, et al: Assessment of blood pool, soft tissue, and skeletal uptake of sodium fluoride F-18 with positron emission tomography-computed tomography in four clinically normal dogs. Am J Vet Res 2012;73:1589-1595 32. Bruehlmeier M, Kaser-Hotz B, Achermann R, et al: Measurement of tumor hypoxia in spontaneous canine sarcomas. Vet Radiol Ultrasound 2005;46:348-354 33. Black NF, McJames S, Rust TC, et al: Evaluation of rapid dual-tracer 64 Cu-PTSM þ 64Cu-ATSM PET in dogs with spontaneously occurring tumors. Physiol Med Biol 2008;53:217-232 34. Hansen AE, Kristensen AT, Jørgensen JT, et al: 64Cu-ATSM and 18FDG PET uptake and 64Cu-ATSM autoradiography in spontaneous canine tumors: Comparison with pimonidazole hypoxia immunohistochemistry. Radiat Oncol 2012;7:89 35. Hansen AE, Kristensen AT, Law I, et al: Multimodality functional imaging of spontaneous canine tumors using 64Cu-ATSM and 18FDG PET/CT and dynamic contrast enhanced perfusion CT. Radiother Oncol 2012;102: 424-428 36. DeGrado TR, Coenen HH, Stocklin G: 14(R,S)-[18F]Fluoro-6-thiaheptadecanoic acid (FTHA): Evaluation in mouse of a new probe of myocardial utilization of long chain fatty acids. J Nucl Med 1991;32: 1888-1896 37. Ebert A, Herzog H, Stöcklin G, et al: Kinetics of 14(R,S)-fluorine18-fluoro-6-thia-heptadecanoic acid in normal human hearts at rest, during exercise and after dipyridamole injection. J Nucl Med 1994;35:51-56 38. DeGrado TR, Kitapei MT, Wang S, et al: Validation of 18F-fluoro-4-thiapalmitate as a PET probe for myocardial fatty acid oxidation: Effects of hypoxia and composition of exogenous fatty acids. J Nucl Med 2006;47:173-181 39. Hibbert A, Gruffydd-Jones T, Barrett EL, et al: Feline thyroid carcinoma: Diagnosis and response to high-dose radioactive iodine treatment. J Feline Med Surg 2009;11:116-124 40. Wucherer KL, Wilke V: Thyroid cancer in dogs: An update based on 638 cases (1995-2005). J Am Anim Hosp Assoc 2010;46:249-254 41. Gunn-Moore D, Simpson KW: Insulinoma in cats. In: Rand J, (ed): Clinical Endocrinology of Companion Animals. (ed). Ames Iowa: John Wiley & Sons; 2013 42. Hess RS: Insulinoma in dogs. In: Rand J, (ed): Clinical Endocrinology of Companion Animals. (ed). Ames, IA: John Wiley & Sons; 2013 43. Robben JH, Visser-Wisselaar HA, Rutteman GR, et al: In vitro and in vivo detection of functional somatostatin receptors in canine insulinomas. J Nucl Med 1997;38:1036-1042 44. Robben JH, Pollak YW, Kirpensteijn J, et al: Comparison of ultrasonography, computed tomography, and single-photon emission computed tomography for the detection and localization of canine insulinoma. J Vet Intern Med 2005;19:15-22 45. Reusch CE: Pheochromocytoma in dogs. In: Rand J, (ed): Clinical Endocrinology of Companion Animals. (ed). Ames, IA: John Wiley & Sons; 2013 46. Berry C, Wright KN, Breitschwerdt EB, et al: Use of 123Iodine metaiodobenzylguanidine scintigraphy for the diagnosis of a phaeochromocytoma in a dog. Vet Radiol ultrasound 1993;34:52-55 47. Lynn MD, Shapiro B, Sisson JC, et al: Portrayal of pheochromocytoma and normal human adrenal medulla by m-[123I]iodobenzylguanidine: Concise communication. J Nucl Med 1984;25:436-440 48. Mozley PD, Kim CK, Mohsin J, et al: The efficacy of iodine-123-MIBG as a screening test for pheochromocytoma. J Nucl Med 1994;35:1138-1144 49. van Kroonenburgh M, Mostard R, Voo S: Metaiodobenzylguanidine scintigraphy in pulmonary and cardiac disease. Curr Opin Pulm Med 2010;16:511-515 50. Waelbers T, Peremans K, Vermeire S, et al: The effect of medetomidine on the regional cerebral blood flow in dogs measured using Technetium-99m-Ethyl Cysteinate Dimer SPECT. Res Vet Sci 2011;91:138-143
56 51. Waelbers T, Polis I, Vermeire S, et al: The influence of ketamine on the regional cerebral perfusion and on the binding index of the selective 5-HT2A receptor radioligand 123I-R91150 measured with SPECT in the canine brain. Vet Anaesth Analg 2012;40:13-14. ([Abstract presented at the spring meeting of the Association of Veterinary Anaesthetists, Davos, Switzerland, March 22-23, 2012.]) 52. Waelbers T, Peremans K, Vermeire S, et al: Regional distribution of technetium-99m-ECD in the canine brain: Optimal injection-acquisition interval in adult beagles. J Vet Behav 2012;7:261-267 53. Ichise M, Golan H, Ballinger JR, et al: Regional differences in technetium99m-ECD clearance on brain SPECT in healthy subjects. J Nucl Med 1997;38:1253-1260 54. Asenbaum S, Brucke T, Pirker W, et al: Imaging of cerebral blood flow with technetium-99m-HMPAO and technetium-99m-ECD: A comparison. J Nucl Med 1998;39:613-618 55. Adriaens A, Polis I, Waelbers T et al: Normal regional distribution of cerebral blood flow in dogs: Comparison between 99mTc-ethylcysteinate dimer and 99mTc-hexamethylpropylene amine oxime single photon emission computed tomography. Vet Radiol Ultrasound (in press) 56. Vermeire S, Audenaert K, Dobbeleir A, et al: Regional cerebral blood flow changes in dogs with anxiety disorders, measured with SPECT. Brain Imaging Behav 2009;3:342-349 57. Vermeire S, Audenaert K, De MR, et al: Neuro-imaging the serotonin 2A receptor as a valid biomarker for canine behavioural disorders. Res Vet Sci 2011;91:465-472 58. Miller EK, Cohen JD: An integrative theory of prefrontal cortex function. Annu Rev Neurosci 2001;24:167-202 59. Kent JM, Rauch SL: Neurocircuitry of anxiety disorders. Curr Psychiatry Rep 2003;5:266-273 60. Kim SJ, Lyoo IK, Lee YS, et al: Decreased cerebral blood flow of thalamus in PTSD patients as a strategy to reduce re-experience symptoms. Acta Psychiatr Scand 2007;116:145-153 61. Engel K, Bandelow B, Gruber O, et al: Neuroimaging in anxiety disorders. J Neural Transm 2009;116:703-716 62. Wahlund K, Kristiansson M: Aggression, psychopathy and brain imaging—Review and future recommendations. Int J Law Psychiatry 2009;32:266-271 63. Anckarsater H, Piechnik S, Tullberg M, et al: Persistent regional frontotemporal hypoactivity in violent offenders at follow-up. Psychiatry Res 2007;156:87-90 64. Martle V, Peremans K, Audenaert K, et al: Regional brain perfusion in epileptic dogs evaluated by technetium-99m-ethyl cysteinate dimer SPECT. Vet Radiol Ultrasound 2009;50:655-659 65. Yune MJ, Lee JD, Ryu YH, et al: Ipsilateral thalamic hypoperfusion on interictal SPECT in temporal lobe epilepsy. J Nucl Med 1998;39:281-285 66. Henry TR, Mazziotta JC, Engel J Jr., et al: Quantifying interictal metabolic activity in human temporal lobe epilepsy. J Cereb Blood Flow Metab 1990;10:748-757 67. Martle V, Peremans K, Van HL, et al: High-resolution micro-SPECT to evaluate the regional brain perfusion in the adult Beagle dog. Res Vet Sci 2013;94:701-706 68. Waelbers T, Peremans K, Vermeire S, et al: Effects of medetomidine and ketamine on the regional cerebral blood flow in cats: A SPECT study. Vet J 2012;192:81-88 69. Waelbers T, Peremans K, Vermeire S, et al: Regional brain perfusion in 12 cats measured with technetium-99m-ethyl cysteinate dimer pinhole single photon emission computed tomography (SPECT). J Feline Med Surg 2013;15:105-110
A.K. LeBlanc and K. Peremans 70. Peremans K, Audenaert K, Coopman F, et al: Estimates of regional cerebral blood flow and 5-HT2A receptor density in impulsive, aggressive dogs with Tc-99m ECD and I-123 5-I-5-R91150. Eur J Nucl Med 2003;30:1538-1546 71. Peremans K, Audenaert K, Hoybergs Y, et al: The effect of citalopram hydrobromide on 5-HT2A receptors in the impulsive-aggressive dog, as measured with 123I-5-I-R91150 SPECT. Eur J Nucl Med Mol Imaging 2005;32:708-716 72. Peremans K, Goethals I, De VF, et al: Serotonin transporter and dopamine transporter imaging in the canine brain. Nucl Med Biol 2006;33: 907-913 73. Peremans K, De SB, Buntinx E, et al: Evaluation of serotonin-2A receptor occupancy with 123I-5-I-R91150 and single-photon emission tomography before and after low-dose pipamperone administration in the canine brain. Nucl Med Commun 2008;29:724-729 74. Vermeire ST, Audenaert KR, Dobbeleir AA, et al: Evaluation of the brain 5-HT2A receptor binding index in dogs with anxiety disorders, measured with 123I-5I-R91150 and SPECT. J Nucl Med 2009;50: 284-289 75. Vermeire S, Audenaert K, Dobbeleir A, et al: A Cavalier King Charles dog with shadow chasing: Clinical recovery and normalization of the dopamine transporter binding after clomipramine treatment. J Vet Behav 2010;5:345-349 76. Vermeire S, Audenaert K, De MR, et al: Serotonin 2A receptor, serotonin transporter and dopamine transporter alterations in dogs with compulsive behaviour as a promising model for human obsessive-compulsive disorder. Psychiatry Res 2012;201:78-87 77. Soloff P, Price J, Meltzer C, et al: 5HT(2A) receptor binding is increased in borderline personality disorder. Biol Psychiatry 2007;62:580-587 78. Audenaert K, Van Laere K, Dumont F, et al: Decreased frontal serotonin 5-HT2a receptor binding index in deliberate self harm patients. Eur J Nucl Med 2001;28:175-182 79. Biver F, Wikler D, Lotstra F, et al: Serotonin 5-HT2 receptor imaging in major depression: Focal changes in orbito-insular cortex. Br J Psychiatry 1997;171:444-448 80. Zitterl W, Aigner M, Stompe T, et al: [123I]-beta-CIT SPECT imaging shows reduced thalamus-hypothalamus serotonin transporter availability in 24 drug-free obsessive-compulsive checkers. Neuropsychopharmacology 2007;32:1661-1668 81. Perani D, Garibotto V, Gorini A, et al: In vivo PET study of 5HT(2A) serotonin and D(2) dopamine dysfunction in drug-naive obsessivecompulsive disorder. Neuroimage 2008;42:306-314 82. van der Wee NJ, Stevens H, Hardeman JA, et al: Enhanced dopamine transporter density in psychotropic-naive patients with obsessivecompulsive disorder shown by [123I]{beta}-CIT SPECT. Am J Psychiatry 2004;161:2201-2206 83. Hesse S, Muller U, Lincke T, et al: Serotonin and dopamine transporter imaging in patients with obsessive-compulsive disorder. Psychiatry Res 2005;140:63-72 84. Waelbers T, Polis I, Vermeire S et al: Ketamine decreases the brain 5-HT2A receptor binding index in cats measured with micro-single photon emission computed tomography. J Nucl Med (in press). 85. Peremans K, Vermeire S, Dobbeleir A, et al: Recognition of anatomical predilection sites in canine elbow pathology on bone scans using microsingle photon emission tomography. Vet J 2011;188:64-72 86. Peremans K, Duchateau L, Vermeire S, et al: The use of the HiSPECT bone scan in canine flexor enthesopathy and coronoid pathology. Res Vet Sci 2013;94:628-633
Historical Perspective: PET Imaging in Veterinary Medicine
P
ET imaging is considered relatively new to veterinary medicine, with the first reports of its use in clinical patients dating to the early 1980s and 1990s.1-4 This is attributable to the limited access to PET scanners owing to their purchase and maintenance costs, reliance on discretionary income for pet owners to fund veterinary care for their pets, and the stillevolving knowledge of what role this technology plays in the management of common veterinary ailments. There is an ongoing need to validate the technique and increase the comfort level for veterinary radiologists and clinicians involved in reading such studies. The widespread fusion of PET with *Department of Small Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Veterinary Teaching Hospital, Knoxville, TN. †Department of Medical Imaging and Small Animal Orthopaedics, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium. Address reprint requests to Amy K. LeBlanc, DVM DACVIM, Department of Small Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, 2407 River Dr, Rm C247 Veterinary Teaching Hospital, Knoxville, TN 37996. E-mail: [email protected]
0001-2998/14/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semnuclmed.2013.08.004
computed tomography (PET/CT) assists in image interpretation, as CT is a common component of veterinary diagnostic imaging, and a review of both data sets can assist the clinician in characterizing areas of radiopharmaceutical uptake.5 The most logical and widely published studies for PET and PET/CT imaging, utilizing the commercially available tracer 18 F-fluorodeoxyglucose (18F-FDG), are in the field of oncology, where the most human PET studies are performed. Veterinary oncology is a growing field and a recognized specialty of the American College of Veterinary Internal Medicine, founded in 1972 (www.acvim.org). Currently, most veterinarians rely on standard anatomical imaging modalities such as radiography, ultrasonography, and computed tomography for detection and staging of cancer in veterinary patients. The use of PET offers an opportunity to evaluate the metabolic nature of malignancies in addition to anatomical data. Naturally occurring cancers in dogs and cats represent a great opportunity to validate PET and PET/CT imaging techniques, they benefit tumor-bearing pets while simultaneously advancing development of new imaging techniques for human cancers. This aspect of veterinary medicine is gaining traction in academic settings where research collaborations between veterinarians and physicians are established and growing. 47
A.K. LeBlanc and K. Peremans
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PET Imaging Protocols and Data Analysis for Companion Animals Several key differences exist in patient preparation for animals undergoing PET and PET/CT imaging. Veterinary PET scans involve preparation for general anesthesia, including 8-12 hours fast, which is required for proper positioning for the scan procedure, but also serves to limit physiological 18F-FDG myocardial uptake. Additionally, state-specific radiation safety guidelines may apply and must be followed to limit exposure to the animals and their excreta once they have been injected with the radiopharmaceutical of interest.6 Readers may refer to http://www.nrc.gov/material/miau/med-vet/html for additional details. In the case of 18F-FDG, artifactual uptake within skeletal muscle can occur if the animal is physically active in the uptake period before the scan, hence the use of a sedative or premedicant is recommended (Fig. 1). In addition, in the case of 18F-FDG and similarly to humans, animals should be normoglycemic so as not to interfere with tissue uptake of the radiopharmaceutical, which can lead to erroneous scan results. Other key components are adequate facilities for holding radioactive animals and protocols for transport to off-site facilities (if applicable), monitoring radiation exposure to staff, and release limits for pets to return home to their owners. Along with a greater body of experience in reading PET and PET/CT studies, there remains a need for standardized postimage processing and data analysis in veterinary PET imaging. The commonly used clinical indicator of radiopharmaceutical uptake is the standardized uptake value, which is influenced by many factors (scanner design and reconstruction parameters, patient body condition, scan protocol, etc.).7 Guidelines for objective evaluation of PET/CT–based responses (positron emission tomography response criteria in solid tumors) were recently reported for human patients in whom PET/CT is used to judge response to therapy.8 The use of such a uniform reporting method for factors affecting the generation of a PET image is needed so that data can be reproduced at other PET imaging centers and in support of multisite clinical trials that involve PET imaging.
PET Radiopharmaceutical Biodistribution Studies in Companion Animals In an effort to characterize the normal patterns of uptake for 18 F-FDG, studies in purpose-bred dogs and cats utilizing both PET and PET/CT have been published.9-11 An investigation of how various anesthetic protocols influence brain uptake of 18 F-FDG was also performed for future studies of 18F-FDG in neuroimaging.12 These studies act not only as valuable data sets for comparative studies between species and provide a reference for disease studies, but they also act as feasibility studies when human PET imaging facilities are used for animal work. Additionally, studies in birds have been performed and highlight the comparative differences for avian species.13,14
Figure 1 Maximal image projections (MIPs) of an 8-year-old mixedbreed dog with high-grade multicentric lymphoma, before (left) and after (right) receiving a CHOP-based induction chemotherapy protocol. Imaging was carried out with approximately 5 mCi 18F-FDG (PETNET Solutions, Knoxville, TN) allowing a 60-minute uptake time and using a Siemens mCT scanner (Siemens Molecular Imaging, Knoxville, TN). On the baseline scan, 18F-FDG uptake is present in affected lymph nodes (arrows, left image) with splenomegaly consistent with malignant infiltration (arrow head, left image). Physiological 18F-FDG uptake is present within the brain, heart, and salivary glands, which is difficult to discern with bulky head and neck lymphoma involvement. Normal excretion of tracer is evident in renal pelves and bladder. Notably within the remission scan, artifactual yet physiological uptake is noted within the musculature of the forelimbs, consistent with physical activity during the tracer uptake period (arrows, right image). Myocardial uptake is notably increased on the remission PET scan (arrow head, right image), indicating the variability of 18F-FDG myocardial uptake even in the fasting state. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone
Of particular interest for oncology, biodistribution data in dogs and cats with 18F-fluorothymidine (18F-FLT) is currently in progress. We believe this cellular proliferation tracer will provide valuable information for lesion discrimination when staging animals with cancer.
Application of Selected PET Radiopharmaceuticals to Veterinary Nuclear Medicine 18
F-FDG
18
F-FDG is the standard PET radiopharmaceutical for cancer imaging in humans, but it is also utilized for cardiac imaging
PET and SPECT imaging in veterinary medicine
49
and neuroimaging purposes. Veterinary applications of 18 F-FDG-PET/CT in oncology are growing with increasing access to scanners, pet owners' growing requests for equivalent care to humans, and experience with PET imaging protocols. Several studies demonstrate the avidity of canine cancers for 18 F-FDG and emphasize the potential of whole-body PET and PET/CT as an efficient staging technique that can identify lesions not detected on physical examination that may represent additional sites of metastasis or additional unrelated malignancies or both.15-18 Serial 18F-FDG-PET/CT imaging is attractive for monitoring response to therapy in a single diagnostic procedure (Fig. 2). Investigations of this approach in canine cancers treated with a tyrosine kinase inhibitor showed discordance between standard response evaluation criteria in solid tumors and positron emission tomography response criteria in solid tumors applied to selected neoplastic lesions, emphasizing the need for larger clinical studies of serial 18 F-FDG-PET/CT in this area.19 Imaging of inflammatory processes with 18F-FDG is well established in humans and the application of this technique to veterinary medicine is ongoing, particularly in the field of neuroimaging for inflammatory central nervous system diseases.20 Fungal granulomas and other systemic infectious diseases could be tracked with serial PET/CT to determine the response to antimicrobial or antifungal therapy.3,4 18
F-FLT
18
F-FLT, is a substrate of the mammalian thymidine kinase, an integral part of the cellular DNA synthesis machinery and thus a reflection of cellular rate of proliferation. Many studies demonstrate a strong correlation between 18F-FLT uptake and cell proliferation, as assessed by the Ki-67 immunostaining technique.21 However, the consideration of the cell population of interest and other factors that may affect uptake of 18F-FLT, such as cellular thymidine and thymidine kinase 1 levels, are important when interpreting the validity of an 18F-FLT signal.22 Although 18F-FLT uptake in reactive lymphoid hyperplasia, mediated by B-lymphocyte proliferation in germinal centers does occur, some studies demonstrate the superiority of 18F-FLT over 18F-FDG for differentiation of a tumor from an inflammation23 and indicate that 18F-FLT could be a useful adjunct to 18F-FDG to improve diagnostic specificity.24 Clinical investigations using 18F-FLT are primarily in oncology, where response to therapy may be judged based on changes in tumor cell proliferation. Additionally, this technique may provide increased specificity over 18F-FDG in the evaluation of cancers that are metastatic to lymph nodes or may incite an inflammatory response, or both (Fig. 3). A study evaluating whole-body 18F-FLT-PET/CT as a noninvasive measure of response to a novel nucleoside analogue for canine lymphoma therapy demonstrated the utility of this proliferation tracer as an early marker of response or as an indicator of relapsed disease or both.25 Researchers at the University of Tennessee studied the whole-body biodistribution of 18F-FLT in normal cats and dogs and applied serial 18F-FLT imaging in a canine model of chemotherapy-induced myelosuppression.26 Physiological
Figure 2 Maximal image projections (MIPs) of a 6-year-old standard Poodle with stage V malignant oral mucosal melanoma, before (left) and after (right) receiving an investigational immunotherapy treatment protocol. Imaging was carried out with approximately 5 mCi 18 F-FDG (PETNET Solutions, Knoxville, TN), allowing a 60-minute uptake time, and using a Siemens mCT scanner (Siemens Molecular Imaging, Knoxville, TN). Uptake within the primary tumor of the maxillary mucosa is evident, along with bulky mandibular lymph node metastasis (arrow heads) and multiple pulmonary metastases (arrows). Physiological uptake is noted on both scans within the brain and gastrointestinal tract; minimal myocardial uptake is also present. Residual tracer is also present within the injection site on the distal forelimb. Excretion of 18F-FDG is evident within the renal pelves and urinary bladder. Comparison of the baseline and posttreatment scans is supportive of progressive disease, with no measurable response to therapy.
uptake of 18F-FLT within the bone marrow allows for the PET imaging of leukemias and other primary bone marrow disorders (myelodysplastic syndrome, aplastic anemia, and idiopathic marrow fibrosis) in which the patient's bone marrow 18F-FLT signal can be monitored noninvasively over time, thereby providing an early biomarker of treatment response.27,28 18F-FLT-PET/CT may also be applied to identify the bone marrow in external-beam radiotherapy planning so as to limit the dose in chemoradiation schemes, which carry a significant risk for myelosuppression.29 The use of 18F-FLT for the imaging of spontaneous tumors in dogs could be used to gather the necessary data for eventual Food and Drug Administration approval of 18F-FLT for human use in these and other clinical scenarios.
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Figure 3 MIPs of an 11-year-old neutered male dog with a large hepatocellular carcinoma with central necrosis, imaging done with both 18F-FLT and 18F-FDG (5 mCi for each radiopharmaceutical, allowing a 60-minute uptake time, and using a Siemens mCT scanner (Siemens Molecular Imaging, Knoxville, TN). Within the 18F-FLT-PET images, intense tracer uptake is evident within the bone marrow and the viable edges of the hepatic tumor, shown to be mitotically active on histopathology. As expected, no brain or myocardial uptake of 18F-FLT is seen. The borders of the hepatic tumor in this dog appear more sharply defined with 18F-FLT (SUVmax ¼ 13.1) compared with 18F-FDG imaging (SUVmax ¼ 4.5). In the 18 F-FDG-PET images, physiological tracer uptake is present within the left mandibular salivary gland, brain, myocardium, GI tract, and urinary tract. Although not confirmed with histopathology, a presumed reactive retrosternal lymph node (arrows) demonstrates avidity for 18F-FDG (SUVmax ¼ 10.7) but not 18F-FLT (SUVmax ¼ 1.8). GI, gastrointestinal; MIPs, maximal image projections; SUV, standardized uptake value.
18
F-Sodium Fluoride (18F-NaF)
F-NaF was first used for skeletal scintigraphy in the 1960s, but was replaced by 99mTc diphosphonate because of the cost and wide availability of clinical planar and SPECT gamma cameras in both human and veterinary medicine. Recently, 18 F-NaF has been reevaluated and is gaining popularity for bone imaging mainly because of the technological advances made possible with PET/CT. This technique provides greater sensitivity, resolution, and efficiency for whole-body skeletal studies. 18F-NaF has a high and rapid uptake in the bone with rapid blood pool clearance, producing high target-background ratios less than 1 hour after injection in both humans and dogs.30,31 Based on the human experience, 18F-NaF should be useful for characterization of primary and metastatic bone lesions. Additional work to support this technique over traditional bone scans for skeletal diseases in veterinary nuclear medicine is needed. 18
Investigational PET Radiopharmaceuticals and Their Applications 18
F-Misonidazole and 64CU-ATSM for Hypoxia Imaging Spontaneous canine malignancies offer a unique opportunity for radiopharmaceutical development. In the field of hypoxia
imaging, which has implications for radiotherapy dosimetry and development of therapies to specifically address cellular changes associated with hypoxia, both 18F-misonidazole and 64 CU-ATSM have been studied in an effort to garner data to support the commercialization of such tracers and their application to clinical situations. Radiation dose planning and prescription based on hypoxia imaging could complement traditional techniques by providing insight into areas of the tumor that may benefit from a boost of therapeutic radiation or novel intensity-modulated radiotherapy protocols or both. Canine tumor imaging with both 18F-misonidazole and 64CUATSM demonstrates the applicability of these naturally occurring cancer models for the development and refinement of such tracers.32-35 18
F-fluorothiaheptadecanoic acid (18F-FTHA)
The palmitate analogue 14(R,S)-(18F-FTHA) accumulates preferentially within the myocardium via betaoxidative metabolic trapping.36-38 Intense myocardial uptake, long myocardial retention, and rapid clearance from the bloodstream make 18F-FTHA a useful PET imaging agent, and it shows a vast improvement over previous efforts to interrogate the fatty acid oxidation pathway with C-11 labeled fatty acids, which were difficult to model and required on-site cyclotron facilities owing to the 20-minute half-life of C-11. Our group has studied the whole-body biodistribution of
PET and SPECT imaging in veterinary medicine 18
F-FTHA in the normal cat and has compared the uptake kinetics of both 18F-FTHA and 18F-FDG in this species. Based on the biodistribution of 18F-FTHA in the domestic cat, application of this PET tracer for cardiac, hepatic, and renal function seems plausible. Additional work is needed to define the role of 18F-FTHA for cardiac PET imaging in both humans and companion animals.
SPECT Planar gamma camera imaging has been used in veterinary medicine for decades, at first predominantly in the diagnostic workup of equine lameness cases but later for small animal application. However, tomographic studies (SPECT) have not received much enthusiasm in veterinary medicine despite the fact that many preclinical human medicine studies exist, mainly in dogs, but also in cats. This may be partially explained by the lack of suitable equipment (many veterinary gamma cameras are used for both large and small animal imaging but have been rebuilt to meet the specific requirements for equine imaging), specific software, and the necessity for anesthesia. In equipment also used to image horses, the size of the animal is an additional restriction as only limited areas are accessible to SPECT. Contrary to studies in man, anesthesia or sedation is an absolute prerequisite for SPECT investigations, which has further limited its use. Ischemic heart disease is not a clinical problem in our canine and feline patients, so there is not as high a demand for cardiac SPECT as in human medicine. Most functional imaging of the heart in veterinary medicine is carried out by echocardiography. There is not much interest in veterinary medicine for brain perfusion and neuroreceptor imaging where SPECT is essential. However, in the last decades, developments in small animal medicine, especially in oncology and behavioral medicine, prompted the introduction of more advanced diagnostic tools. Many owners regard their pets as part of the family and as such want the optimal (anthropomorphic) care for them. Because of the internet, owners have become increasingly aware of the variety in diagnostic and therapeutic possibilities. In addition, sophisticated processing software has become more accessible, thereby making coregistration with CT or MRI, or both, now part of the veterinary armamentarium. In this regard, diagnostic and therapeutic approaches in sick animals reflect, to a certain extent, those of human medicine but with financial restrictions, especially regarding some radiopharmaceuticals. In this section, the practical application of SPECT in different clinical settings has been expounded. New techniques, as applied in veterinary medicine, have also been briefly mentioned where applicable.
51 percentage due to thyroid carcinoma.39 In dogs, thyroid tumors are more likely to be malignant.40 Pertechnetate is the classic radionuclide used for diagnosis of thyroid disease in cats and dogs and planar imaging is usually sufficient for imaging of the primary lesion. Canine thyroid tumors tend to metastasize to regional lymph nodes and lungs at an early stage. Similar to human medicine, the sensitivity of planar imaging is much less than SPECT for metastasis detection except in an advanced stage. SPECT is not only used for diagnostic and staging purposes in dogs but also posttherapy to evaluate radioiodine uptake in the primary tumor and its metastasis (Fig. 4).
Insulinomas Insulinomas are rare tumors in dogs and cats.41,42 Clinical features can be vague and the presence of hypoglycemia in the face of increased insulin levels can be a diagnostic indication, but hypoglycemia as such is an aspecific sign and insulin levels may be normal. In 50% of the dogs insulinomas metastasize to the liver and lymph nodes.42 Ultrasonography is commonly used as the next diagnostic step but may be unrewarding to localize and characterize the primary tumor or its metastases. Somatostatin receptor scintigraphy, with radiolabeled octreotide or depreotide, has been successfully used in dogs suspected of an insulinoma (Fig. 5). Using SPECT and in-vitro autoradiography, Robben et al.43 demonstrated that uptake of the radiopharmaceutical was linked with overexpression of one type of somatostatin receptor as opposed
Oncology Thyroid Carcinoma In aging cats, hyperthyroidism is one of the most common endocrine disorders, with the majority due to benign adenomas or adenomatous hyperplasia and only a small
Figure 4 Coronal plane SPECT (summed slices) image acquired after radioiodine-131 treatment. There is an intense area of uptake in the cervical region from a thryoid carcinomal with 2 focal areas of less intense uptake (arrows) due to metastases in the thorax.
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Figure 5 Coronal plane SPECT images (summed slices) of the anterior abdomen following injection of 123I-MIBG. There are 2 focal areas of increased uptake within the liver and a patchy area of increased uptake (arrow) also within the liver. Postmortem examination confirmed nodular metastatic lesions (2 focal lesions) together with massive tumor infiltration in the liver.
to human insulinomas, where subtypes occur with lower affinity for octreotide. In a comparative study, the same authors compared CT, ultrasonography, and somatostatin receptor scintigraphy SPECT to evaluate their potential to demonstrate the primary tumor and metastatic disease.44 A higher number of primary tumors and metastases to the lymph nodes were found on CT images. However, because of the high number of false positives, CT was unreliable to provide a definitive diagnosis of metastatic involvement. The false-negative results of SPECT seemed to be predominantly related to low (spatial) resolution. Small lesions (median 15 mm) were missed and uptake was not always allocated to the correct anatomical area. The introduction of resolution recovering software and fusion with anatomical imaging may increase the preoperative value of CT and SPECT in the staging and characterization of canine insulinomas.
Pheochromocytoma These catecholamine-producing neuroendocrine tumors are uncommon in dogs and cats and the diagnosis can be a challenge. Clinical symptoms can be vague and hypertension may be phasic, thus failure to demonstrate hypertension does not exclude a pheochromocytoma. Diagnosis is often based on the detection of excessive catecholamines (epinephrine and norepinephrine) or their metabolites (metanephrine and normetanephrine). Urine concentrations of these products have been recently evaluated with the best promise associated with normetanephrinecreatinine ratios but these tests are not widely available.45 This tumor tends to be locally invasive and can metastasize to a range of organs. Ultrasonography is the first-line medical imaging tool and is useful to identify an adrenal associated mass; however it is not possible to differentiate pheochromocytoma from other types of adrenal masses. 123 I-metaiodobenzylguanidine (123I-MIBG) has been used in dogs for pheochromocytoma detection, however only planar imaging has been reported.46 We performed 123 I-MIBG SPECT studies in dogs suspected of a pheochromocytoma. In most of these dogs, the adrenal medulla was clearly recognized at 6 hours and remained visible 24
hours following injection. In humans, normal uptake in the medulla has been reported ranging from 30%-80% for 123 I-labeled MIBG.47,48 In 1 dog, focal uptake was seen in a caudal lung lobe at 6 hours but not at 24 hours. This area of uptake coincided with a patchy area of increased attenuation on CT scan. Lung biopsy revealed focal atelectasis. In humans, both decreased and increased pulmonary tracer washout has been reported to reflect changes in vascularization status of the lungs and endothelial integrity.49
Brain imaging Perfusion Imaging 99m Both Tc-hexamethylpropyleneamine oxime and 99m Tc-ethyl cysteinate dimer (ECD) with conventional collimated gamma cameras can be used for brain imaging in dogs. Injection of the tracers is performed in quiet surroundings with dimmed lights (similar to what is the standard protocol in human medicine) and before sedation and anesthesia. 99mTcECD studies have shown an influence of sedatives and anesthetics on regional cerebral blood flow (rCBF) when given before the tracer, with regional increases and decreases depending on the drug used.50,51 Dogs have a faster uptake and washout rate of 99mTc-ECD than men, therefore the optimal scan interval after tracer injection is 15-40 minutes.52,53 Comparison of the rCBF measured with 99mTc-ECD and 99m Tc-hexamethylpropyleneamine oxime revealed that, similar to man, regional distribution differences exist between both tracers, indicating that direct comparison of data obtained with these tracers is not possible.54,55 Most perfusion studies have been conducted in animals with behavioral disorders including impulsive aggression, pathologic anxiety, and compulsive behavior. In 2 recent studies, decreased left frontal and right temporal perfusion was found in impulsive-aggressive dogs and decreased left frontal, increased right temporal, and decreased subcortical blood flow was registered in dogs with anxiety disorders.56,57 The hypoperfusion in the frontal cortex, reflecting hypofunctionality, is consistent with the major involvement of this area in behavior in general and its control over limbic primary reactions, generated by structures located in the temporal and subcortical regions, in particular.58 Beside the fact that these data provide information on the pathophysiological mechanisms underlying canine behavioral disorders, the fact that parallelism is present with imaging findings in similar human psychiatric disorders59-63 renders the dog an interesting natural model. The use of 99mTc-ECD has also been described in epileptic dogs in the interictal phase and decreased perfusion in the subcortical region (a region that comprises a large part of the thalamus) was reported.64 This finding is of potential significance as the role of the thalamus has been described as causative, that is, involved in the initiation or propagation of seizures.65,66 The thalamic hypofunction has also been explained as a consequence of corticothalamic diaschisis.65 To increase resolution and allow further delineation of subcortical subdivisions a micro-SPECT system (HiSPECT) has
PET and SPECT imaging in veterinary medicine been tested, based on multipinhole collimation on a conventional triple-head gamma camera rendering a resolution of 2.5 mm (HiSPECT, Bioscan, France).67 The same system was successfully used in cats to evaluate feline rCBF and the effect of anesthetics.68,69
53 tailored treatment protocol. In addition, in cats, imaging of the serotonin-2A receptor has been reported using the aforementioned tracer and the HiSPECT system.84,69
Orthopedics Neuroreceptor Imaging Neuroreceptor imaging is used in dogs to investigate the pathophysiology of behavioral disorders and also to provide a means to predict the effectiveness of psychopharmacological therapy. Imaging using radioligands for the serotonin-2A receptor (with 123I-R91150), the serotonin transporter, and the dopamine transporter (with 123I-2β-carboxymethoxy-3 β-[4-iodophenyl]tropane and 123I-N-[3-fluoropropyl]-2βcarbomethoxy-3β-[4-iodophenyl]nortropane) has been reported in dogs for diagnostic purposes in behavioral disorders and for the evaluation of medicinal therapy (Fig. 6).57,70-76 A disturbed serotonergic system was demonstrated in impulsive-aggressive dogs, dogs with anxiety disorders, and compulsive dogs. Next to a deficient serotonergic system, an imbalanced dopaminergic system was found in compulsive dogs. These imaging findings again resemble those found in similar human disorders.7783 These studies can also guide the decision on which drug is best suited and are also helpful in monitoring therapeutic effectiveness.71,75 This could be the key to a patient-
The indication for a bone scan is usually lameness or pain of an unknown origin because clinical or radiographic examination is equivocal or when the temperament of the animal precludes clinical examination. Most bone scans in veterinary medicine are planar studies. SPECT imaging can reveal lesions that remain undetected on planar imaging (eg, spinal and pelvic lesions) and provide a better topographic overview of the suspected region. SPECT imaging of the canine elbow joint is an excellent example of the latter characteristic. Most cases of forelimb lameness are owing to elbow disease. Elbow dysplasia is the most commonly encountered diagnosis and may affect different anatomical structures within the joint. On planar images, it is often impossible to attribute increased uptake in the elbow joint to a specific anatomical structure. The limited resolution and the small size of the elbow hamper differentiation of the anatomical sites, especially when multiple areas within the joint are affected. Anatomical landmarks are definitely identified by conventional SPECT. The micro-SPECT system (HiSPECT, Bioscan,
Figure 6 Fused dorsal plane SPECT and MR images acquired following injection of 123I-β-CIT in a dog. Top row of images depicts activity in the raphe nuclei (small arrows) area (the small “tail”) where the serotonin transporters are located. The bottom row demonstrates uptake in the basal ganglia (large arrow), where high densities of dopamine transporters are found. CIT, carbomethoxy-3 β-(4-iodophenyltropane).
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Figure 7 (A) Ventral planar images acquired 3 hours following injection of 99mTc-MDP in a lame dog. There is asymetrical uptake associated with the elbows, with the left elbow being more intense. Further localization of the increased uptake within the joint is not possible. (B) HiSPECT images display increased uptake in the medial epicondylar region of the distal humerus, suggestive for flexor enthesopathy.
France) has superior resolution compared with conventional SPECT and has been used to evaluate normal and diseased canine elbows (Fig. 7).85,86 This micro-SPECT system with multipinhole collimation on conventional gamma camera heads allows adjustment of the gantry opening for larger animals as opposed to the dedicated rodent microsystems. A limitation of this system is the narrow range of the radius of rotation to ascertain optimal resolution, restricting the skeletal areas that can be investigated to the elbow and lower forelimb and to the stifle and lower hindlimb in dogs. Another major drawback is that the expense of the collimators and the dedicated reconstruction software hamper implementation in the classic veterinary setting. Recently, resolution recovery software has been commercialized, which may counter the aforementioned limitations of the HiSPECT system and offer an interesting alternative, as it allows the use of a conventional system for investigation of all regions of the body. In summary, PET and SPECT imaging in veterinary medicine is gaining in popularity for clinical and research applications. Challenges that veterinarians face with respect to access to necessary equipment and infrastructure to support companion animal imaging programs can be met in part by establishing collaborations with human imaging facilities. Spontaneous diseases in dogs and cats offer a unique opportunity to gather
data that could support the development and commercialization of novel PET imaging agents for human patients.
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A.K. LeBlanc and K. Peremans 70. Peremans K, Audenaert K, Coopman F, et al: Estimates of regional cerebral blood flow and 5-HT2A receptor density in impulsive, aggressive dogs with Tc-99m ECD and I-123 5-I-5-R91150. Eur J Nucl Med 2003;30:1538-1546 71. Peremans K, Audenaert K, Hoybergs Y, et al: The effect of citalopram hydrobromide on 5-HT2A receptors in the impulsive-aggressive dog, as measured with 123I-5-I-R91150 SPECT. Eur J Nucl Med Mol Imaging 2005;32:708-716 72. Peremans K, Goethals I, De VF, et al: Serotonin transporter and dopamine transporter imaging in the canine brain. Nucl Med Biol 2006;33: 907-913 73. Peremans K, De SB, Buntinx E, et al: Evaluation of serotonin-2A receptor occupancy with 123I-5-I-R91150 and single-photon emission tomography before and after low-dose pipamperone administration in the canine brain. Nucl Med Commun 2008;29:724-729 74. Vermeire ST, Audenaert KR, Dobbeleir AA, et al: Evaluation of the brain 5-HT2A receptor binding index in dogs with anxiety disorders, measured with 123I-5I-R91150 and SPECT. J Nucl Med 2009;50: 284-289 75. Vermeire S, Audenaert K, Dobbeleir A, et al: A Cavalier King Charles dog with shadow chasing: Clinical recovery and normalization of the dopamine transporter binding after clomipramine treatment. J Vet Behav 2010;5:345-349 76. Vermeire S, Audenaert K, De MR, et al: Serotonin 2A receptor, serotonin transporter and dopamine transporter alterations in dogs with compulsive behaviour as a promising model for human obsessive-compulsive disorder. Psychiatry Res 2012;201:78-87 77. Soloff P, Price J, Meltzer C, et al: 5HT(2A) receptor binding is increased in borderline personality disorder. Biol Psychiatry 2007;62:580-587 78. Audenaert K, Van Laere K, Dumont F, et al: Decreased frontal serotonin 5-HT2a receptor binding index in deliberate self harm patients. Eur J Nucl Med 2001;28:175-182 79. Biver F, Wikler D, Lotstra F, et al: Serotonin 5-HT2 receptor imaging in major depression: Focal changes in orbito-insular cortex. Br J Psychiatry 1997;171:444-448 80. Zitterl W, Aigner M, Stompe T, et al: [123I]-beta-CIT SPECT imaging shows reduced thalamus-hypothalamus serotonin transporter availability in 24 drug-free obsessive-compulsive checkers. Neuropsychopharmacology 2007;32:1661-1668 81. Perani D, Garibotto V, Gorini A, et al: In vivo PET study of 5HT(2A) serotonin and D(2) dopamine dysfunction in drug-naive obsessivecompulsive disorder. Neuroimage 2008;42:306-314 82. van der Wee NJ, Stevens H, Hardeman JA, et al: Enhanced dopamine transporter density in psychotropic-naive patients with obsessivecompulsive disorder shown by [123I]{beta}-CIT SPECT. Am J Psychiatry 2004;161:2201-2206 83. Hesse S, Muller U, Lincke T, et al: Serotonin and dopamine transporter imaging in patients with obsessive-compulsive disorder. Psychiatry Res 2005;140:63-72 84. Waelbers T, Polis I, Vermeire S et al: Ketamine decreases the brain 5-HT2A receptor binding index in cats measured with micro-single photon emission computed tomography. J Nucl Med (in press). 85. Peremans K, Vermeire S, Dobbeleir A, et al: Recognition of anatomical predilection sites in canine elbow pathology on bone scans using microsingle photon emission tomography. Vet J 2011;188:64-72 86. Peremans K, Duchateau L, Vermeire S, et al: The use of the HiSPECT bone scan in canine flexor enthesopathy and coronoid pathology. Res Vet Sci 2013;94:628-633
