Application of metabolic PET imaging in radiation oncology

Positron emission tomography (PET) is a noninvasive imaging technique that provides functional or metabolic assessment of normal tissue or disease conditions and is playing an increasing role in cancer radiotherapy planning. (18)F-Fluorodeoxyglucose PET imaging (FDG-PET) is widely used in the clinic for tumor imaging due to increased glucose metabolism in most types of tumors; its role in radiotherapy management of various cancers is reviewed. In addition, other metabolic PET imaging agents at various stages of preclinical and clinical development are reviewed. These agents include radiolabeled amino acids such as methionine for detecting increased protein synthesis, radiolabeled choline for detecting increased membrane lipid synthesis, and radiolabeled acetate for detecting increased cytoplasmic lipid synthesis. The amino acid analogs choline and acetate are often more specific to tumor cells than FDG, so they may play an important role in differentiating cancers from benign conditions and in the diagnosis of cancers with either low FDG uptake or high background FDG uptake. PET imaging with FDG and other metabolic PET imaging agents is playing an increasing role in complementary radiotherapy planning.     

Evaluation of 18F-labeled acetylcholinesterase substrates as PET radiotracers

Four 18F-labeled acetylcholinesterase (AChE) substrates, (S)-N-[18F]fluoroethyl-2-piperidinemethyl acetate (1), (R)-N-[18F]fluoroethyl-3-pyrrolidinyl acetate (2), N-[18F]fluoroethyl-4-piperidinyl acetate (3), and (R)-N-[18F]fluoroethyl-3-piperidinyl acetate (4), were evaluated for in vivo blood and brain metabolism in mice, brain pharmacokinetics in rats monkeys (M. nemistrina) using PET imaging. All 18F-labeled compounds were compared to N-[11C]methyl-4-piperidinyl propionate (PMP). Compound 1 was completely metabolized within 1 min in mouse blood and brain. This compound had relatively fast regional brain pharmacokinetics and poor discrimination between brain regions with different AChE concentration. Compound 4 showed relatively slower blood metabolism and slower pharmacokinetics than compound 1 but again poor discrimination between brain regions. Both compounds 1 and 4 showed different kinetic profiles than PMP in PET studies. Compound 3 had the slowest blood metabolism and slower pharmacokinetics than PMP. Compound 2 showed highly encouraging characteristics with an in vivo metabolism rate, primate brain uptake, and regional brain pharmacokinetics similar to [11C]PMP. The apparent hydrolysis rate constant k3 in primate cortex was very close to that of [11C]PMP. This compound has potential to be a good PET radiotracer for measuring brain AChE activity. The longer lifetime of 18F would permit longer imaging times and allows preparation of radiotracer batches for multiple patients and delivery of the tracer to other facilities, making the technique more widely available to clinical investigators.     

Quantification in oncologic FDG-PET: A scientific overview

F18-Fluorodeoxyglose Positron Emission Tomography (FDG-PET) has gained wide acceptance in cancer patient management for initial diagnosis, staging, prognosis and patient monitoring. FDG-PET is also of interest for radiotherapy treatment planning. FDG-PET imaging has the potential to yield a quantitative assessment of glucose metabolism in tumours, which might be extremely helpful for differential diagnosis, patient monitoring and delineation of the biologically active tumour volume. The most accurate approach to assess the glucose metabolic rate (GMR) is by combining dynamic PET imaging and kinetic analysis. However, this requires a lengthy acquisition and an estimate of the arterial input function, which make the approach unpractical for clinical use. Several alternative strategies have thus been proposed to assess the GMR in tumours more easily. The presentation will review these different approaches, from the simplest one (using the Standardized uptake values [SUV] as done almost in all clinical centres) to more advanced approaches (for instance requiring at least one blood sample drawing).     

早期动态18F-FDG PET/CT成像在实体肿瘤评估中的应用

~(18)F-FDG PET/CT常规代谢成像反应肿瘤的葡萄糖代谢及乏氧情况,而~(18)F-FDG PET/CT早期动态成像能反映PET/CT成像早期肿瘤的灌注情况。由于肿瘤的异质性,在早期动态~(18)F-FDG PET/CT成像,即~(18)F-FDG PET/CT灌注成像中,存在独立于常规60 min~(18)F-FDG PET/CT代谢成像的SUVmax(最大标准摄取值)高摄取区。因此,在临床工作中应用~(18)F-FDG PET/CT早期动态成像,能够进一步对实体肿瘤的活性区域进行评估,能够更好评价患者预后、完善治疗方案。当前~(18)F-FDG早期动态成像已经应用在肝癌、肾癌以及膀胱癌等实体肿瘤诊断中。早期动态~(18)F-FDG PET/CT成像结合常规标准~(18)F-FDG PET/CT代谢成像,对实体肿块进行一站式成像方法,能够更好的对肿瘤进行评估。     

PET imaging of redox and energy states in stroke-like episodes of MELAS

In stroke-like episodes of patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), changes in oxidative stress and glucose metabolism and their sequence remain obscure. We developed a novel double imaging method using positron emission tomography (PET) with [⁶²Cu]-diacetyl-bis(N4-methylthiosemicarbazone) (⁶²Cu-ATSM) and [¹⁸F]-fluorodeoxyglucose (¹⁸FDG) to visualize the regional oxidative stress, glucose metabolism and blood flow in brain lesions of stroke-like episodes non-invasively and rapidly. These PET imagings were performed on a MELAS patient with stroke-like lesions, and clearly demonstrated that oxidative stress following hyperemia along with increased glucose metabolism plays crucial roles in the pathogenesis of MELAS stroke-like episodes.     

Assessing skeletal muscle glucose metabolism with positron emission tomography

Insulin has a marked effect to stimulate the transport and metabolism of glucose in skeletal muscle in healthy individuals, whereas an impaired response, termed insulin resistance, is a major risk factor for diabetes mellitus and other metabolic diseases. Studies of the molecular physiology of insulin action in skeletal muscle indicate that a principal loci of control resides within the proximal steps of glucose transport and phosphorylation. Deoxyglucose, the metabolism of which is limited to these proximal steps, is widely used for in vitro studies of insulin action on glucose transport. The technologies of PET imaging provide a unique opportunity to carry out similar studies in vivo in human skeletal muscle. In this instance, a short-lived positron labeled tracer, [18F] FDG, can be given at sufficiently high specific activity to image not only glucose uptake, but by dynamic PET imaging, by monitoring the time course of [18F] FDG tissue activity, data can be generated to examine the kinetics of glucose transport and phosphorylation. The experimental procedures of this approach, including an overview of the mathematical modeling, are described in this review, along with some of the key findings of the initial applications of PET for the study of glucose metabolism in human skeletal muscle.     

TEP/IRM hybride en neuro-imagerie

The hybrid Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) is a newly available imaging modality combining the molecular and metabolic PET information with the morphological and functional data provided by MRI. Integrated PET/MRI tomographs were conceived in analogy to the current PET/Computed Tomography (PET/CT) technology, with specific properties linked to the intrinsic differences of MRI and CT imaging. In the field of neuro-imaging, in particular, MRI provides a larger panel of information, as compared with CT, and is already systematically fused and used as a support for PET images for diagnostic and research purposes. We summarize here our current experience with the first integrated PET/MRI tomograph installed in Switzerland, concerning specifically three clinical applications: brain tumors characterization, the diagnosis of neurodegenerative dementias and the presurgical evaluation of pharmaco-resistant epilepsy. With this sequential tomograph, we could combine the full range of diagnostic MR sequences (including diffusion tensor imaging, tractography, spectroscopy, functional MR) with PET imaging of brain glucose metabolism (by ¹⁸F-Fluorodeoxyglucose–FDG) and of amino acid transport (by ¹⁸F-Fluoroethyltyrosine–FET). We also summarize the main results obtained in neuro-imaging by the different groups working with these new hybrid tomographs. These data show that PET/MRI, acquired in a single imaging session, may represent the modality of choice for neuro-imaging.     

Application of positron emission tomography to neuroimaging in sports sciences

To investigate exercise-induced regional metabolic and perfusion changes in the human brain, various methods are available, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS) and electroencephalography (EEG). In this paper, details of methods of metabolic measurement using PET, [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) and [¹⁵O]radio-labelled water ([¹⁵O]H₂O) will be explained.Functional neuroimaging in the field of neuroscience was started in the 1970s using an autoradiography technique on experimental animals. The first human functional neuroimaging exercise study was conducted in 1987 using a rough measurement system known as ¹³³Xe inhalation. Although the data was useful, more detailed and exact functional neuroimaging, especially with respect to spatial resolution, was achieved by positron emission tomography. Early studies measured the cerebral blood flow changes during exercise. Recently, PET was made more applicable to exercise physiology and psychology by the use of the tracer [¹⁸F]FDG. This technique allowed subjects to be scanned after an exercise task is completed but still obtain data from the exercise itself, which is similar to autoradiography studies.In this report, methodological information is provided with respect to the recommended protocol design, the selection of the scanning mode, how to evaluate the cerebral glucose metabolism and how to interpret the regional brain activity using voxel-by-voxel analysis and regions of interest techniques (ROI).Considering the important role of exercise in health promotion, further efforts in this line of research should be encouraged in order to better understand health behavior. Although the number of research papers is still limited, recent work has indicated that the [¹⁸F]FDG-PET technique is a useful tool to understand brain activity during exercise.     

Microimaging characterization of a B16-F10 melanoma metastasis mouse model

Metastatic mouse models of melanoma have been characterized by gross necropsy examination, histopathology, and optical imaging. To determine if the time progression, extent, and metabolism of melanoma metastases could be monitored noninvasively, serial micro-CT and small-animal PET imaging studies were performed by using a mouse model of melanoma. Juvenile female C57BL/6 mice were injected intravenously with syngenic B16-F10 melanoma cells. Serial micro-CT imaging studies were performed on anesthetized mice. Mice were necropsied at the development of adverse clinical signs or at postinjection Day 30, and tissues were collected for histopathology. In a separate study of four mice, tumor viability was assessed with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) and studied by using small-animal PET imaging. A total of 59% of the mice developed metastatic tumors. Micro-CT image analysis was able to identify and follow up to 36% of metastatic lesions. Examples of metastatic lesions identified and followed up by micro-CT imaging included a lung metastasis, mandibular metastasis, subcutaneous metastasis, and tibial/femoral metastasis. Micro-CT and small-animal PET fusion imaging successfully correlated anatomic localization of glucose metabolism of the metastatic tumors. Micro-CT and small-animal PET imaging were found to be highly effective in detection and characterization of lesions produced by this metastatic melanoma model.     

Factor structure of regional cerebral blood flow and glucose metabolism rate as a tool to study the default mode of the brain

The functional connectivity of anatomical and functional brain structures in the state of operational rest was assessed on the basis of positron emission tomography (PET) data to study the so-called default mode of the brain, i.e., the brain’s spontaneous activity at rest. It is concluded that the possibility of identifying neuroanatomical systems of the default mode (default mode network) in routine clinical PET studies of the cerebral blood flow and glucose metabolism is important for studying the functional organization of the brain in the normal state and its rearrangements in pathologies.     

TEP/TDM au fluorure (18F) de sodium pour la détection des métastases osseuses du cancer de la prostate. Description de l’étude Fluprostic de comparaison de la TEP/TDM au fluorure (18F) de sodium à l’IRM corps entier dans cette indication

Fluorodeoxyglucose (¹⁸F) or FDG, the radioactive glucose analogue which is the reference radiopharmaceutical in oncologic PET, is not well suited for the detection of prostate cancer metastases the glucose metabolism of which is usually only slightly enhanced. Fluoride (¹⁸F) accumulates into the cortical bone, rapidly and intensely in reaction to a bony metastasis. In 2008, it has been granted a marketing authorisation in France, including imaging bone metastasis of prostate cancer. We report original clinical cases to illustrate its diagnostic performance. Whole-body MRI is developing and can also detect bone metastases. Recently diffusion-weighted MRI (DWI) has been proposed to increase the detection rate of metastases of the axial skeleton, which are largely predominant in prostate cancer. Using either hybrid PET/CT or MRI requires mobilising equipments, which are less available and more expensive than the gamma-cameras for classical bone scintigraphy, in the aim to achieve superior diagnostic performance. A clinical study protocol (STIC) has just been accepted for public funding. It aims to assess the impact on patient management of the discovery of the first macroscopic bony metastasis and the efficacy of diagnostic strategies including those innovations, individually and in association. In case of prostate cancer with a high risk of metastasis, but without any proven bone metastasis and no typical pattern on bone scintigraphy, fluoride (¹⁸F) PET/CT will be performed as well as whole-body MRI. Histopathology and/or data of a 6-month follow-up will be the standard of truth to evaluate the adequacy of impact on patient management and the benefit / cost ratio of those examinations. With this prospective national study, we hope to demonstrate in the real world a clinical role for this radiopharmaceutical, which was proposed several decades ago, but benefits from a renewed interest thanks to the development of PET/CT imaging.     

Les examens cardiaques en tomographie par émission de positons

Cardiac positron emission tomography (PET) is yet considered as a reference imaging technique but remains poorly used in clinical practice. At the present time, the advantages of cardiac PET investigations are far to be evident, when compared with conventional tomoscintigraphy (SPECT), except for perfusion imaging in the obese and for viability assessment in case of very severe cardiac dysfunction. However, this situation might quickly move because of an enhanced availability of PET imaging, dramatic technical progresses and promising new tracers. In particular, the last-generation PET-cameras allow reaching spatial resolutions and detection sensitivities, which are now spectacularly higher than those from conventional SPECT imaging. In addition, the list mode recording allows the subsequent images reconstruction to be synchronized to cardiac cycle but also to respiratory cycle; and the quantifications of myocardial perfusion flow and of coronary flow reserve are now available in clinical routine. Furthermore, new tracers labelled with fluorine-18 are under development, especially for perfusion investigations, and kinetics properties of these new tracers are dramatically enhanced when compared with current perfusion SPECT tracers.     

Glycolysis in cancer: a potential target for therapy

Clinical imaging of primary and metastatic cancers with Fluoro deoxy-d-Glucose Positron Emission Tomography (FdG PET) has clearly demonstrated that increased glucose flux compared to normal tissue is a common trait of human malignancies (Gambhir, 2002) This is a consequence of a shift of glucose metabolism to less efficient glycolytic pathways in response to regional hypoxia and evolution of aerobic glycolysis in many cancer phenotypes. This distinctive metabolic profile presents an inviting target for cancer treatment and prevention. Here, we summarize the therapeutic strategies under investigation to exploit or interrupt tumor glycolytic metabolism. Although a number of approaches are under investigation, none has been sufficiently successful to warrant widespread clinical application. We point out that the environmental heterogeneity and evolutionary capacity of tumor cells that likely led to development of upregulated glycolysis could also promote adaptive strategies that confer resistance to therapies designed to inhibit glucose metabolism.     

Synthesis and binding affinity of a fluorine-substituted peroxisome proliferator-activated gamma (PPARgamma) ligand as a potential positron emission tomography (PET) imaging agent

The peroxisome proliferator-activated receptor gamma (PPARgamma) is an important regulator of lipid metabolism and the differentiation of pre-adipocytes. Thus, imaging PPARgamma in vivo using positron-emission tomography (PET) might be useful in assessing lipid metabolism disorders and identifying tumor cell differentiation. A fluorine-substituted PPARgamma ligand from tyrosine-benzophenone class, compound 1, has a very high affinity for PPARgamma receptor (Ki = 0.14 nM). To develop this compound as a PPARgamma PET imaging agent, we investigated synthetic routes suitable for its labeling with the short-lived PET radionuclide fluorine-18 (t1/2 = 110 min). To obtain the high specific activity material needed for receptor imaging with this isotope, reactions need to proceed efficiently, within a short time, starting from fluoride ion at the tracer level. The most promising approach involves introduction of fluorine into a suitable benzophenone precursor, followed by efficient coupling of this intermediate with the heterocyclic tyrosine component using a copper-catalyzed Ullmann-type condensation.     

Les limites du SUV

The standardized uptake value (SUV) is the most used index to characterize the Fluorine-18-fluorodeoxyglucose (FDG) uptake in Positron Emission Tomography (PET). To better understand the potential of this index and its limitations, this article starts from the SUV definition, explains the different steps used to calculate the SUV, and shows the relationship between the SUV and the glucose metabolic rate. This analysis demonstrates the approximations and the sources of errors explaining why the SUV does not accurately represent the glucose metabolic rate. We also discuss why, despite the limitations of the SUV, it is useful in clinical routine and is currently the reference index used to roughly characterize the glucose metabolic rate. Finally, some ideas are presented that could facilitate the accurate characterization of the glucose metabolic rate from FDG PET scans in the future.     

PET-MRI in oncology

Hybrid positron emission tomography (PET)-MRI imaging enable the acquisition of functional information by PET, and structural as well as functional information by MRI. The two modalities are complementary: PET offers unparalleled sensitivity to molecular events, e.g. occupation of receptors, activity of glucose metabolism, during tumor or inflammation; while MRI offers high soft tissue contrast (including in highly mobile structures such as the heart) and other information (diffusion, blood flow, spectroscopy). Simultaneous acquisition is crucial for understanding brain function, the pathophysiology of cancer, mechanic cardiovascular dysfunction, and disorders of nutrition and metabolism.     

Current and future anatomical and functional imaging approaches to pheochromocytoma and paraganglioma

After establishing a biochemical diagnosis, pheochromocytomas and extra-adrenal paragangliomas (PPGLs) can be localized using different anatomical and functional imaging modalities. These include computed tomography, magnetic resonance imaging, single-photon emission computed tomography (SPECT) using 123I-metaiodobenzylguanidine or 111In-DTPA-pentetreotide, and positron emission tomography (PET) using 6-[18F]-fluorodopamine (18F-FDA), 6-[18F]-fluoro-l-3,4-dihydroxyphenylalanine (18F-DOPA), and 2-[18F]-fluoro-2-deoxy-d-glucose. We review the currently available data on the performance of anatomical imaging, SPECT, and PET for the detection of (metastatic) PPGL as well as parasympathetic head and neck paragangliomas. We show that there appears to be no 'gold-standard' imaging technique for all patients with (suspected) PPGL. A tailor-made approach is warranted, guided by clinical, biochemical, and genetic characteristics. In the current era of a growing number of PET tracers, PPGL imaging has moved beyond tumor localization towards functional characterization of tumors.     

A Dual Tracer 18F-FCH/18F-FDG PET Imaging of an Orthotopic Brain Tumor Xenograft Model

Early diagnosis of low grade glioma has been a challenge to clinicians. Positron Emission Tomography (PET) using ¹⁸F-FDG as a radio-tracer has limited utility in this area because of the high background in normal brain tissue. Other radiotracers such as ¹⁸F-Fluorocholine (¹⁸F-FCH) could provide better contrast between tumor and normal brain tissue but with high incidence of false positives. In this study, the potential application of a dual tracer ¹⁸F-FCH/¹⁸F-FDG-PET is investigated in order to improve the sensitivity of PET imaging for low grade glioma diagnosis based on a mouse orthotopic xenograft model. BALB/c nude mice with and without orthotopic glioma xenografts from U87 MG-luc2 glioma cell line are used for the study. The animals are subjected to ¹⁸F-FCH and ¹⁸F-FDG PET imaging, and images acquired from two separate scans are superimposed for analysis. The ¹⁸F-FCH counts are subtracted from the merged images to identify the tumor. Micro-CT, bioluminescence imaging (BLI), histology and measurement of the tumor diameter are also conducted for comparison. Results show that there is a significant contrast in ¹⁸F-FCH uptake between tumor and normal brain tissue (2.65 ± 0.98), but with a high false positive rate of 28.6%. The difficulty of identifying the tumor by ¹⁸F-FDG only is also proved in this study. All the tumors can be detected based on the dual tracer technique of ¹⁸F-FCH/ ¹⁸F-FDG-PET imaging in this study, while the false-positive caused by ¹⁸F-FCH can be eliminated. Dual tracer ¹⁸F-FCH/¹⁸F-FDG PET imaging has the potential to improve the visualization of low grade glioma. ¹⁸F-FCH delineates tumor areas and the tumor can be identified by subtracting the ¹⁸F-FCH counts. The sensitivity was over 95%. Further studies are required to evaluate the possibility of applying this technique in clinical trials.     

Joint SFMN/ANOCEF focus on 18F-FDOPA PET imaging in glioma: Current applications and perspectives

18F-FDOPA PET has demonstrated its additional value during the clinical course of glioma, at initial diagnosis, for treatment planning or follow-up. The aim of the current review was to summarize current applications of 18F-FDOPA PET in gliomas and constitute, as a perspective, a first step in harmonizing clinical practices in French centers. In France, the indication for 18F-FDOPA PET is restricted to the assessment of primary brain tumor recurrence. According to the literature, this indication could be expanded to primary diagnosis and, to a lesser extent, treatment monitoring. There is a real need to harmonize standard procedures among French centers. The objective is to increase the availability of data for this rare entity of glioma and to develop multi-parametric PET analyses (static, dynamic and textural), also known as radiomics, by using artificial intelligence algorithms. For this purpose, kinetics analysis with dynamic PET acquisition should be implemented in routine practice because it has demonstrated its additional value for initial diagnosis in gliomas. Therefore, this review proposes a workflow based on acquisition and reconstruction parameters that can be implemented in each center to increase the amount of standardized 18F-FDOPA PET data in neuro-oncology imaging in France. This would help in creating a national database and developing national multi-center studies that can respond to the challenge of using multi-parametric PET in glioma.     

Application clinique des nouveaux traceurs TEP en oncologie. La vision d’un médecin nucléaire en Espagne

PET is an excellent and sensitive molecular imaging technique using positron-emitting radioisotopes coupled to specific ligands. Many biological targets of great interest can be imaged with these radiolabelled ligands. ¹⁸F-FDG is the most widely tracer PET used, but is not a oncospecific tracer and many malignancies are poorly imaged by FDG-PET. In the last years, the investigation and development of novel ligands will be an alternative to the limitations of FDG in clinical oncology. This review describes the current status of non-FDG PET tracers that have a potential clinical effect in the management of patients affected by cancer.