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PET-CT: Current Applications and New Developments in the Thorax Osama Mawlawi, PhD2

Brandon Howard, MD, PhD3

1 Department of Diagnostic Radiology, Division of Diagnostic Imaging,

The University of Texas MD Anderson Cancer Center, Houston, Texas 2 Department of Imaging Physics, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 3 Department of Radiology, Duke University Medical Center, Durham, North Carolina 4 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina

Edward F. Patz Jr., MD3,4

Address for correspondence Edward F. Patz Jr., Department of Radiology, Box 3808, Duke University Medical Center, Durham, NC 27710 (e-mail: [email protected]).

Semin Respir Crit Care Med 2014;35:145–156.

Abstract Keywords

► ► ► ► ► ►

PET imaging PET-CT pulmonary nodule lung cancer staging molecular imaging

Positron emission tomography computed tomography(PET-CT) imaging has emerged as an essential clinical diagnostic tool in the evaluation of thoracic abnormalities. Currently, its primary role is for tumor imaging; it helps to differentiate benign from malignant nodules, stage tumors, determine response, and follow patients after therapy is complete. It has also been used for nononcologic diseases, but the indications are less well defined. PET is a fundamental component of the molecular imaging initiative, and as new more specific imaging probes and better instrumentation are developed, PET-CT is certain to improve diagnostic accuracy and become even more integrated into the imaging armamentarium.

Early investigation of positron emission tomography (PET) imaging in the thorax focused on the evaluation of lung physiology with potential applications including asthma, chronic obstructive lung disease, pulmonary vascular disease and interstitial lung disease. At the same time the radiotracer, 18F-2-deoxy-D-glucose (FDG) was being evaluated as a quantitative methodology to assess glucose metabolism for a variety of indications. These studies were performed at academic institutions for research purposes, and it was not until the early 1990s, that FDG-PET began to emerge as a clinically relevant diagnostic tool in oncology. Over the subsequent 20 years, numerous studies using FDG-PET were performed, primarily to define its role in tumor imaging. These studies have provided insight into the benefits and limitations of PET, and PET has become an integral part of thoracic imaging. In addition, the concept that imaging could provide diagnostic information beyond traditional anatomy and morphology was a true paradigm shift, which resulted in the new field of molecular imaging.

Issue Theme Thoracic Imaging; Guest Editor, Martine Remy-Jardin, MD, PhD

Molecular imaging initiatives have focused on both designing better imaging probes and improving instrumentation. In this regard, novel radiotracers have been developed to evaluate specific biological properties including DNA synthesis, amino acid alterations, hypoxia and tumor receptors, and instrumentation has now incorporated CT for coregistration of anatomic and metabolic data. This article will review the current use of PET imaging in clinical practice, both oncologic and nononcologic, improvements in PET-CT technology and future applications.

Current Clinical Utility Oncologic Assessing Indeterminate Pulmonary Opacities The most common current indication for FDG-PET imaging in the thorax is the evaluation of an indeterminate pulmonary nodule (►Fig. 1). FDG is a measure of glucose metabolism, and is used to differentiate benign from malignant lesions.

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0033-1363459. ISSN 1069-3424.

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Jeremy J. Erasmus, MD1

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Fig. 1 A 65-year-old man with a lung nodule detected on routine evaluation. (A) Axial CT; (B) and whole body coronal integrated PET-CT; show increased uptake of FDG (SUV, 7.1) in 2 cm middle-lobe nodule (arrow). Biopsy revealed poorly-differentiated adenocarcinoma. CT, computed tomography; FDG, 18F-2-deoxy-D-glucose; PET, positron emission tomography.

When FDG uptake is increased, cancer is often of concern; when FDG activity is minimal, the likelihood of malignancy is low. This general principle provides a reasonable initial interpretation, but must be placed into clinical context, and other features including lesion size and appearance must be considered (e.g., solid, semisolid, or ground glass). In a metaanalysis of 40 studies, FDG-PET was found to have a sensitivity of 96.8% and specificity of 78%.1 However, in another study of 360 patients with lung nodules evaluated by FDG-PET, 43 patients had solid nodules with a standardized uptake value (SUV) > 2.5 and only 16 of these nodules were malignant.2 Furthermore, a prospective trial in 585 patients (496 malignant and 89 benign nodules) showed that while there was a 96% likelihood of malignancy when SUV > 4.1, a low SUV (< 2.5) was still associated with a 25% likelihood of malignancy.3 Nomori et al report a sensitivity (10%) and specificity (20%) for ground glass opacities (GGOs) that is significantly lower than that for solid nodules (90 and 71%, respectively).4 However, if the lesion proves to be lung cancer, low FDG uptake is associated with an indolent phenotype.5 While indolent behavior, small size and paucity of malignant cells are contributing factors for poor FDG avidity associated with subsolid nodules, particularly pure GGOs, technical factors associated with image acquisition can also result in a perceived or quantitative decrease in FDG uptake. In this regard, respiratory motion causes a misregistration between the FDG-PET and CT images and diminishes the perceived or measured semiquantitative uptake of FDG in small lung nodules. Respiratory-gated (four-dimensional [4D] PET/CT) or averaged CT (ACT) technique compensate for respiratory motion and improves the quantification of FDG uptake by eliminating the misregistration artifact from the longer PET acquisition time relative to the shorter CT time (see Motion Suppression). The usefulness of FDG-PET in determining whether a solitary pulmonary opacity is malignant is not centered on diagnostic accuracy alone, but also on clinical risk factors for malignancy, the radiologic appearance of the opacity and how patient management will be altered.1,6,7 For instance in a patient with a low pretest likelihood of malignancy (20%) Seminars in Respiratory and Critical Care Medicine

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being considered for serial radiologic observation, a negative PET will reduce the likelihood of malignancy to 1% and thereby justify conservative management.1,6 However, in a patient with a high pretest likelihood of malignancy (80%) a negative PET will only reduce the likelihood of malignancy to 14%.1,6 Accordingly, biopsy or resection rather than a PET would be a more appropriate management strategy. Although the additional benefit of FDG-PET as a function of clinical pretest risk assessment for malignancy has not been clearly established, a cost-effectiveness analysis supports this diagnostic approach.8

Staging Lung Cancer Whole-body PET-CT has become an integral component of staging non-small-cell lung cancer (NSCLC), as it improves the detection of nodal and distant metastases and frequently alters patient management.9–14 FDG-PET is used together with CT because it integrates the metabolic activity with the exquisite spatial resolution of CT important for evaluation of tumor size, location and degree of locoregional invasion (T descriptor) and in the determination of the precise anatomic location of regions of focal increased FDGuptake (N and M descriptors).10,15 In a recent meta-analysis (17 studies, 833 patients) comparing PET and CT in nodal staging in patients with NSCLC, the sensitivity and specificity of FDG-PET for detecting mediastinal lymph node metastases ranged from 66 to 100% (overall 83%) and 81 to 100% (overall 92%), respectively compared with sensitivity and specificity of CT of 20 to 81% (overall 59%) and 44 to 100% (overall 78%), respectively (►Fig. 2).16 Because of the improvements of nodal staging when FDG-CT/PET is incorporated into the imaging algorithm of those patients with potentially resectable NSCLC, the performance of FDG-CT/ PET should be considered in all patients without CT findings of distant metastasis regardless of the size of mediastinal nodes, to direct nodal sampling as well as to detect distant occult metastasis. Importantly, although FDG-PET is costeffective for nodal staging and can reduce the likelihood that a patient with mediastinal nodal metastases (N3) that would preclude surgery will undergo attempted resection,

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Fig. 2 A 70-year-old woman with non-small-cell lung cancer presenting with a 1 month history of dyspnea. (A) Axial CT; (B) and axial integrated PET-CT; show increased uptake of FDG in a right upper lobe mass (M) and right paratracheal nodes (arrow). Biopsy confirmed metastatic nodal disease. CT, computed tomography; FDG, 18F-2deoxy-D-glucose; PET, positron emission tomography.

the number of false-positive results due to an infectious or inflammatory etiology are too high to preclude invasive sampling (►Fig. 3). Distant metastases (M1b) occur in 11 to 36% of patients in patients with NSCLC at presentation and common sites of metastases are the adrenal glands, liver, brain, bones, and abdominal lymph nodes.17 PET has a higher sensitivity and specificity than CT in detecting metastases to the adrenals, bones and extrathoracic lymph nodes. The American College of Surgeons Oncology Trial reports a sensitivity, specificity, positive predictive value, and negative predictive value of 83, 90, 36, and 99%, respectively, for M1 disease.12 Whole-body PET imaging stages intra- and extrathoracic disease in a single study, detects occult extrathoracic metastases in up to 24% of patients selected for curative resection and has been shown to be cost-effective.9,12,14,18,19 The incidence of detection of occult metastases has been reported to increase as the staging T and N descriptors increase, that is, 7.5% in early stage disease to 24% in advanced disease.19 In addition, two studies

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Fig. 3 A 41-year-old woman with non-small-cell lung cancer presenting with back pain. (A) Axial CT; (B) and whole body coronal integrated PET-CT; show increased uptake of FDG in a left upper lobe mass (M) and lumbar vertebral body (arrow). Note whole-body PET-CT is useful in detecting occult extrathoracic metastases and improves the accuracy of staging. CT, computed tomography; PET, positron emission tomography.

of patients with NSCLC considered resectable by standard clinical staging showed that FDG-PET prevented inappropriate surgery in one in five patients.12,18 It is important to emphasize that although whole-body FDG-PET imaging improves the accuracy of staging, false-positive uptake of FDG can mimic distant metastases and therefore all focal lesions with increased FDG-uptake should be biopsied if they potentially would alter patient management.

Assessing Treatment Response FDG-PET may allow an early and sensitive assessment of antitumor effect after therapy and may be predictive for treatment outcome and patient survival in patients with NSCLC (►Fig. 4).20–25 The degree of chemotherapy-induced changes in tumor glucose metabolism as determined by FDGPET has been used to stratify of patients with widely differing overall survival and progression-free survival probabilities into groups with similar outcomes. In a prospective study of 51 patients with advanced NSCLC receiving palliative Seminars in Respiratory and Critical Care Medicine

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PET-CT: Current Applications and Developments in the Thorax

Fig. 4 A 69-year-old man with non-small-cell lung cancer being evaluated for response after definitive chemoradiation therapy. (A) Axial integrated PET-CT prior to therapy shows increased uptake of FDG (SUVmax, 11.3) in large necrotic left upper lobe mass (arrow). (B) Axial integrated PET-CT after completion therapy marked decrease in FDG-uptake (SUVmax, 3.4) associated with only a slight decrease in size of the mass (arrow). Note there is generally a significant association between marked decrease in FDG-uptake within the primary tumor after therapy and patient outcome. CT, computed tomography; FDG, 18F-2-deoxy-D-glucose; PET, positron emission tomography; SUV, standardized uptake value.

chemotherapy, de Geus-Oei et al reported that patients with 35% or more decrease in SUV after the second or third cycle of chemotherapy had significantly longer times to progression (11 vs. 3 months) and longer overall survival (median, 17 vs. 9 months) compared with those with less of a decrease in SUV.20 Additionally, a recent study by Lee et al also evaluated the role of integrated FDG-PET/CT to predict early response to therapy in 31 patients with stage IIIB-IV NSCLC who received standard chemotherapy or molecular-targeted therapy and early metabolic response (after one cycle of systemic therapy) had a significant correlation with best overall response.21 FDG-PET has also been reported to be useful in the assessment of preoperative re-evaluation after neoadjuvant radiochemotherapy in stage III NSCLC (i.e., patients with positive FDG-PET results have a significantly worse prognosis and survival than patients with negative results).26,27 Moon et al recently reported that in patients with advanced NSCLC, FDG-PET can potentially be useful in identifying a subgroup of patients that would benefit from maintenance treatment Seminars in Respiratory and Critical Care Medicine

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after completion of first-line chemotherapy.27 Similarly, Choi et al, report that FGD-PET can be useful in personalizing therapeutic options in patients with advanced NSCLC receiving radiotherapy or chemoradiotherapy by identifying patients with a high risk of residual cancer who could receive salvage therapy soon after completion of standard therapy.28 Contrary to the widely held perception that FDG-PET has limitations in predicting early response in patients receiving radiotherapy, recent studies have reported that FDG-PET can be useful in the assessment of early response during radiotherapy with respect to overall survival in patients with NSCLC.28 In a small study, (34 patients with NSCLC) FDGPET/CT was performed before radiotherapy and repeated in the second week of radiotherapy. A decrease in SUV of 15% correlated with 2-year overall survival while changes in CTtumor volume did not correlate with overall survival. In terms of response assessment in cytostatic treatment regimens, FDG-PET/CT has been reported to predict histopathological response and outcome in patients undergoing neoadjuvant epidermal growth factor receptor (EGFR) inhibition therapy with erlotinib.29–31 In this regard, Benz et al, reported that there was a significant correlation of increased FDG uptake with shorter time to disease progression (47 vs. 119 days) and overall survival (87 vs. 828 days) compared with patients with stable or decreased FDG uptake.30 While FDG-PET/CT assessment may be useful in the prediction of early treatment response, progression-free survival and overall survival in NSCLC, the response to therapy and survival is multifactorial with stage at presentation being the strongest predictor. In addition, FDG-PET studies are often limited by small size, retrospective nature and variations in treatment protocols, particularly in patients with advanced-stage NSCLC. It is currently uncertain whether FDG-PET in patients with NSCLC will provide reliable and routinely applicable clinical prognostic information. In this regard, Patz et al, performed a retrospective review of 214 patients, with advanced-stage NSCLC who underwent FDG-PET at initial diagnosis. Univariate and multivariate analysis provided no evidence that survival for patient subgroups defined by SUVmax were significantly different, that is, median survival of the 106 patients with the primary tumor having a SUVmax < 11.1 was 16 and 12 months in the 108 patients with a SUVmax
11.1. Additionally, Tanvetyanon et al evaluated two phase II neoadjuvant chemotherapy trials and found that CT response (RECIST) was more accurate than FDG-PET. 32 Furthermore, in the prediction of histopathologic response in patients with locally advanced NSCLC who received neoadjuvant chemotherapy followed by curative surgery the accuracy for the prediction of histopathologic response was only 52 to 75% in metabolic responders.33

Nononcologic 18F-FDG is a measure of glucose metabolism. It can accumulate in sites of infection, inflammation and in autoimmune and granulomatous diseases possibly due to overexpression of glucose transporters in activated macrophages, neutrophils and lymphocytes. However, while FDG-PET is frequently

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Fever of Unknown Origin FUO is defined as a fever of 38.3°C or higher, that has been recorded on several occasions, has lasted longer than 3 weeks and is undiagnosed after appropriate inpatient or outpatient evaluation.34,35 Infections, autoimmune diseases and malignancy account for most FUO, although the relative importance of tumors as a cause of FUO is declining.36 The algorithms used in diagnosing the cause of FUO are not strictly evidence-based, but are predicated on a detailed clinical history, comprehensive physical examination, laboratory investigation and imaging. However, the diagnosis may not be established in up to 40% of patients.36 Although data are limited, FDG-PET has become widely accepted in the evaluation of patients with FUO when standard management fails to diagnose the etiology. In a multicenter prospective study with 70 consecutive patients with undiagnosed FUO after standard evaluation, FDG-PET contributed to the final diagnosis in 33% of the patients.37 In fact, FDG-PET has to a large extent, replaced other imaging techniques, including 111In-labeled white blood cells (WBC) and 67Ga-citrate, in the evaluation of patients with FUO. In a prospective study, 18 subjects with FUO patients underwent whole body FDG-PET with a double-head coincidence camera (DHCC) and single-photon emission tomography (SPET) 67Ga-citrate scanning.38 Sensitivity and specificity rates in detecting the focus of fever were 81 and 86% with transaxial FDG-PET compared with 67 and 78%, respectively, for 67Ga-citrate.38 Sensitivity of whole body FDG tomography was lower (36%); specificity was 86%. It was concluded that in the context of FUO, transaxial FDG tomography performed with a DHCC is superior to 67Gacitrate SPET. In another prospective study, 19 patients with FUO underwent both FDG-PET and 111In-labeled WBCs scintigraphy within 1 week.39 Sensitivity and specificity rates were 50 and 46% with FDG-PET compared with 71 and 92%, respectively, with 111In-labeled scintigraphy. The poorer performance of FDG-PET is in part attributable to a high percentage of false-positive scans, leading to a low specificity.39 However, compared with 111In-labeled WBC and 67Gacitrate, FDG-PET allows an earlier diagnosis than the 24 and 48 hours required for imaging with 111In-labeled WBC and 67Ga-citrate, respectively. Besides enabling the diagnosis of focal infection in the chest, abdomen and soft-tissues, FDGPET allows orthopedic prosthetic infections to be excluded with confidence in the absence of increased FDG uptake. In fact the high sensitivity of a negative FDG-PET in the setting of FUO excludes the need for further investigations or revision surgery.36 In patients with noninfectious inflammatory diseases, FDG-PET may have a role in the diagnosis and management of large-vessel vasculitis, sarcoidosis and idiopathic interstitial pneumonias (IIPs).

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Large Vessel Vasculitis Although many patients with large vessel vasculitis (giant cell arteritis, Takayasu arteritis) present with typical symptomatology that facilitates diagnosis, patients can have nonspecific symptoms, including FUO.40,41 FDG-PET is sensitive and highly specific in the diagnosis of large vessel vasculitis in patients presenting with FUO and is also reliable in monitoring disease activity and therapeutic response.42 Furthermore, FDG-PET can provide prognostic information regarding the likelihood of developing a thoracic aortic aneurysm in patients with giant cell arteritis.43 Specifically, the extent of aortic FDG uptake during the acute phase of giant cell arteritis correlates with the aortic diameter at late follow-up (i.e., patients with increased FDG uptake in the aorta are more prone to develop thoracic aortic dilatation than patients without this finding).43

Sarcoidosis Sarcoidosis, a noncaseating granulomatous multiorgan disease of unknown etiology with preferential involvement of intrathoracic organs and upper respiratory tract, can be difficult to diagnose.44 While a presumptive diagnosis is often possible on clinical and radiologic manifestations, a tissue biopsy is usually performed to confirm the diagnosis.45 Occasionally, a diagnostic site is not detected by physical examination or radiologic imaging. In this regard, FDG-PET can be useful in identifying potential diagnostic biopsy sites as FDG uptake is frequently increased in regions with active granulomatous inflammation in patients with sarcoidosis.46 In a large prospective trial of patients with sarcoidosis, FDGPET was useful in identifying potential diagnostic biopsy sites and detected occult disease sites in 15% of the patients imaged.47 Cardiac sarcoidosis is considered uncommon but may be undiagnosed in up to 25% of patients with systemic sarcoidosis.48,49 Because cardiac sarcoidosis can present acutely with fulminant congestive heart failure, ventricular arrhythmias, atrioventricular block as well as sudden cardiac death, the diagnosis is important. Unfortunately, the diagnosis of cardiac sarcoidosis can be difficult and is usually dependent on a combination of clinical and imaging findings.49 Although magnetic resonance imaging (MRI) is the modality of choice in the evaluation and diagnosis of cardiac sarcoidosis, FDGPET has high sensitivity for diagnosing cardiac sarcoidosis (87.5% compared with 75% for MRI).50,51 In fact, focal increased FDG uptake in the myocardium has been reported to be a characteristic feature of cardiac sarcoidosis.52,53 Currently, it is unclear whether FDG-PET and cardiac MRI will be complementary or mutually exclusive to one another in the investigation and follow-up of patients with cardiac sarcoidosis. Treatment of patients with sarcoidosis is typically restricted to those who are symptomatic.44 However, the decision to pursue treatment is restrained by the lack of understanding about the natural course of the disease. In a small study, Keijsers et al report that diffuse metabolic activity of the lung parenchyma imaged by FDG-PET predicts deterioration of diffusing capacity of the lung for carbon monoxide (DLCO) in Seminars in Respiratory and Critical Care Medicine

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used in the evaluation of oncologic patients, its use in the evaluation of fever of unknown origin (FUO), large-vessel vasculitis and inflammatory and connective tissue diseases (interstitial lung disease, sarcoidosis, dermatomyositis, etc.), is less well established.

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PET-CT: Current Applications and Developments in the Thorax untreated patients with sarcoidosis.54 In fact, the increased FDG-PET uptake by the lungs may indicate persisting active pulmonary granulomatous inflammation that is potentially reversible. In summary, FDG-PET can be useful in the diagnosis of sarcoidosis by identifying potential diagnostic biopsy sites and detecting disease in unsuspected anatomic locations as well as having a role in therapeutic management. However, because FDG-PET is expensive, cannot definitively diagnose sarcoidosis, and alone is not an indication to treat, it is not routinely performed in the evaluation of patients with sarcoidosis.

Idiopathic Interstitial Pneumonias IIPs are classified as idiopathic pulmonary fibrosis, which is defined histologically as usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), lymphoid interstitial pneumonia (LIP) and acute interstitial pneumonia (AIP).55 IIPs are usually diagnosed by a combination of clinical, physiologic, radiologic and histopathologic criteria. The high resolution CT (HRCT) manifestations of IIPs, particularly UIP, frequently allow a diagnosis without the need for histopathologic confirmation. However, HRCT determination of acute disease activity and need for therapy in patients with IIPs as well as potential response to therapy is lacking. In this regard, DIP and NSIP usually respond well to corticosteroids and cytotoxic therapy, whereas UIP, a primarily fibrotic process, tends to respond poorly to drug therapy and has a high 5-year mortality.56 Because FDG is a surrogate marker for inflammation, FDGPET has the potential to quantify pulmonary inflammation and provide an indication as to whether the IIPs will respond to treatment (i.e., the accumulation of FDG may reflect the inflammatory component of IIPs and the likelihood of responding to therapy). However, in a small prospective study, Nusair et al reported that patients with UIP had higher FDG uptake than patients with predominantly inflammatory IIPs.57 These findings are supported by a recent small prospective study using FDG-PET-CT that showed increased FDG uptake in all the patients with UIP and this uptake was higher in areas of reticulation/honeycombing on HRCT.58 The authors hypothesize that this finding may be due to increased cellular metabolism with increased glucose uptake and glycolysis within activated fibroblasts.

Cardiac Imaging Over the last few decades PET imaging has been used to evaluate cardiac perfusion and metabolism, and has had an important role in improving the understanding of myocardial physiology and pathophysiology. Currently, because of regulatory approval of PET radiopharmaceuticals for cardiac imaging and reimbursement, together with improved technical performance of current PET systems, the use of PET in cardiac evaluation is increasing. Because PET can quantify myocardial perfusion and detect changes in left ventricular function at rest and during peak stress, PET together with CT, is being Seminars in Respiratory and Critical Care Medicine

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used in patients with coronary artery disease (CAD) to assess myocardial perfusion, obstructive CAD and myocardial viability. PET myocardial perfusion imaging is recommended in the diagnosis and or risk stratification of patients with CAD who have had nondiagnostic imaging (SPECT, echocardiography (ECG), cardiac MR) or when the imaging and clinical diagnoses are discrepant.59 PET myocardial perfusion imaging can also be used in the initial detection and evaluation of the extent of myocardial ischemia.60 There are two Food and Drug Administration (FDA) approved radionuclides that are used clinically to assess myocardial perfusion: Rubidium-82 (82RB) and Nitrogen-13 (13N)-ammonia.50 82RB, a potassium analog with a physical half-life of 76 seconds, is the most commonly used radionuclide to assess myocardial perfusion as its kinetic properties allow rapid sequential perfusion imaging although the spatial resolution is not optimal. 13N-ammonia can also be used for myocardial perfusion PET imaging and although regional variability in uptake can complicate interpretation, the high extraction at first-pass perfusion simplifies perfusion quantification. Myocardial perfusion defects are characterized by their extent, severity and location. The extent of a defect can be small (5–10% of the LV), medium (10–20%) or large (> 20%) and the severity is characterized as mild, moderate and severe as compared with myocardium with the highest normal uptake.51 Two recent studies report that 82RB-PET myocardial perfusion imaging has high accuracy (87–89%) in detecting obstructive CAD with a 50% stenosis of one coronary artery or more and better clinical effectiveness compared with other modalities such as SPECT.61,62 In this regard, the accuracy of detecting a stenosis of 50% was 87% for PET and 71% for 99m-Technetium SPECT.61 However, although sensitive in detecting single-vessel stenosis, PET can underestimate the extent of diffuse CAD when multivessel stenoses are present. ECG-gated 82RB-PET/CT is also useful in the quantification of left ventricular function. Quantification of left ventricular ejection fraction at rest and peak stress can be used in risk prediction (survival, future cardiac events) and in the assessment of the degree of CAD.63,64 Specifically, a high LVEF reserve (stress ejection fraction–rest ejection fraction) has been reported to exclude left main/three-vessel CAD and a low reserve is directly related to the severity of ischemia and CAD.64,65 82RB-PET myocardial perfusion imaging and LVEF reserve have been reported to be have prognostic value of in predicting survival and future cardiac events (cardiac death, nonfatal myocardial infarction).63 In this regard, an increasing severity of ischemia on myocardial perfusion imaging is associated with an increase in the risk of cardiac events and cardiac events were higher in patients with an LVEF reserve < 0% compared with those with an LVEF reserve > or ¼ 0%.63,66 PET imaging combining perfusion with myocardial metabolism using FDG is clinically useful in patients with left ventricular dysfunction (LVD) and CAD. Myocardial viability and LVD in patients with CAD have important clinical and prognostic implications, that is, the amount of viable myocardium prior to a revascularization procedure correlates with survival after coronary bypass surgery.67 However,

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Fig. 5 The figure shows that with the conventional (non-TOF) PET imaging, no information is available about the origin of the annihilation event. Consequently, during image reconstruction, the origin of the event is given an equal probability to all voxels along the LOR between the two detectors that detected the annihilation gamma rays. With TOF imaging on the other hand, information about the arrival time of annihilation gamma rays helps in restricting this probability to a smaller number of voxels along the LOR and results in better SNR images. LOR, line of response; SNR, signal to noise ratio; TOF, time of flight.

noninvasive assessment of myocardial viability prior to planned revascularization can be difficult. 13N-ammonia and 82Rb-PET used in combination with FDG-PET for determination of viability are helpful in guiding management decisions regarding revascularization and or medical treatment. In this regard, decreased myocardial perfusion with associated FDG uptake in the myocardium (perfusion/metabolism mismatch) indicates function and viability of the myocardial muscle while absence of FDG uptake indicates scarring. The diagnosis of viable ischemic myocardium is important because these patients are at high risk for myocardial infarction and should be considered for myocardial revascularization. In addition, when FDG-PET is used to select patients for revascularization, perioperative complications are reduced and short-term outcomes are improved compared with patients where revascularization was performed without FDG-PET viability assessment.51 Furthermore, the quality of life in patients where FDG-PET is used to determine viability is better than those patients where treatment is not directed by FDG-PET.68

scan duration. A potential advantage of this option would be decreased patient motion during data acquisition and improved productivity.

Resolution Recovery Imaging Another relatively recent innovation in PET/CT imaging is the introduction of resolution recovery techniques, better known as point spread function (PSF) reconstruction. These techniques allow the recovery of resolution loss that occurs along the transverse FOV of a PET scanner. The correction is usually accomplished by modeling the resolution loss at different locations in the PET FOV during the image reconstruction process.71 PSF reconstruction is available as an option on the majority of new PET/CT scanners under commercial names such as “HD” or “Sharp IR.” With PSF reconstruction, lesions that are located off the central axis of the scanner will appear sharper and SUV will be more accurate than images without PSF correction. On the other hand, PSF reconstruction has been shown to introduce a Gibbs artifact resulting in an overshoot of FDG activity concentration along the periphery

New Developments in Technology and Probes Time of Flight Imaging One of the recent developments in PET imaging is the introduction of time of flight (TOF) data acquisition. With TOF imaging, information about the arrival time of an annihilation gamma ray at the corresponding detector pair is recorded (►Fig. 5). This information can be used to help better identify the location of the origin of an annihilation event within the PET field of view (FOV) which ultimately results in a superior reconstructed image signal to noise ratio (SNR). Currently most new PET/CT scanners have a TOF option and the improvement in SNR can be used to increase lesion detectability particularly when the lesion is small and or in large patients where image quality can be degraded due to increased photon attenuation (►Fig. 6).69,70 Furthermore, improvements in lesion detectability with TOF imaging can potentially be traded for a decrease in scan duration, that is, TOF images would have similar lesion detectability as non-TOF images but a shorter

Fig. 6 The figure shows PET images of a patient with (right) and without TOF (left) processing showing the improvement in lesion conspicuity with TOF imaging. PET, positron emission tomography; TOF, time of flight. Seminars in Respiratory and Critical Care Medicine

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Fig. 8 The figure shows a PET image of a patient with a lung lesion before (left) and after (right) motion suppression using 4D PET/CT. Motion suppression (4D PET/CT) results in the lesion being more conspicuous and having a higher SUV. CT, computed tomography; PET, positron emission tomography; SUV, standardized uptake value; 4D, four-dimensional.

Longitudinal Evaluation of Lesion SUV Fig. 7 The figure shows a PET image with (right) and without (left) TOF þ PSF reconstruction and the difference in SUVmax when TOF and PSF reconstructions are applied. PET, positron emission tomography; PSF, point spread function; TOF, time of flight.

of a lesion particularly when the background has low FDG uptake such as the lungs.72 In such a case the maximum activity concentration or SUV in a lung lesion will be overestimated (►Fig. 7). Combining TOF and PSF during image reconstruction results in images with better SNR and resolution.69,70,73,74 However, because SUVmax is typically overestimated when TOF and PSF reconstruction is utilized, it is important that the same image processing techniques are used when studies are being compared with prevent image misinterpretation.

Motion Suppression Motion suppression is another novel tool in PET/CT imaging. Because PET imaging requires an average time per bed position of 3 minute, lesions that are affected by breathing or cardiac motion, will be blurred and will have an underestimated SUV. Motion suppression reduces this blurring and increases the SUV by 30 to 60% depending on the extent of motion and lesion size.75 Several approaches have been proposed and implemented on commercial PET/CT scanners to suppress motion blur.76–79 These techniques include 4D PET/CT data acquisition and deformable image registration to improve the resultant image. With 4D PET/CT the PET data are acquired into multiple bins using gated acquisition mode depending on different phases or amplitudes of the breathing cycle. A corresponding CT is also acquired for each phase/ amplitude and is used for attenuation correction. The result is a series of PET/CT images at different parts of the breathing cycle which can then be registered to one another to improve the resultant images. However, a limitation of 4D PET/CT data acquisition is an increase in imaging time. Other motion suppression techniques acquire PET data only during the quiescent state of the breathing cycle (usually end expiration) and a corresponding CT attenuation map is also be acquired during this part of the breathing cycle for proper attenuation correction. In either case, a motion tracking device is necessary to record the motion and to synchronize the PET and CT data acquisitions (►Fig. 8). Seminars in Respiratory and Critical Care Medicine

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The increase in PET/CT utilization for patient staging and treatment response evaluation has necessitated the development of a wide array of tools for lesion segmentation and tracking of SUV over multiple time points. Currently most, if not all, PET/CT viewers allow the measurement of SUV mean, max, and peak of a lesion. These can be based on SUV body weight, body surface area, or lean body mass. In addition, PET/ CT viewers from different vendors have a multitude of tools for lesion segmentation that are based on a fixed threshold, percentage threshold, or gradient techniques to allow the determination of a lesion size/volume and total lesion glycolysis (TLG). These viewers also have the ability to automatically align multiple PET/CT image sets from a longitudinal study using various image registration techniques and also enable the propagation of predefined regions of interest to all the registered PET/CT datasets. In addition, the majority of these viewers also offer automated tumor response trending tools using graphs and tables that highlight changes in tumor size and SUV to allow the monitoring of treatment using response criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) and PET Response Criteria in Solid Tumors (PERCIST).80 Collectively, these tools provide efficient and reproducible data analysis capabilities of PET/CT images.

Accurate Quantification The use of PET imaging for treatment response evaluation requires the SUV to be truly reflective of the underlying biological state of the disease between the pre- and posttreatment PET studies.75,80 However, SUV can be affected by several factors (technical, biological and physical) that can introduce errors upward of 50% and hence impacting the accuracy of response evaluation. In this regard, it is important that PET imaging for response evaluation be performed with strict adherence to predefined PET data acquisition and processing protocols to ensure comparable SUVs. This is particularly necessary when using TOF and PSF PET imaging techniques since such image acquisition and processing can significantly affect the SUV. The National Institutes of Health (NIH) as well as several other technical and professional societies (Radiological Society of North America [RSNA]; Society of Nuclear Medicine and Molecular Imaging [SNMMI]; American Association of Physicists in Medicine [AAPM]; American College of Radiology [ACR]; National Institute of Standards and Technology [NIST]) have recognized the need to standardize PET imaging particularly when conducting multicenter clinical

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Future Applications Novel PET tracers are currently being evaluated to determine their role in a variety of molecular processes including hypoxia, cell proliferation, cell surface receptors, and angiogenesis.

Hypoxia Hypoxic (oxygen concentrations of < 1,000 ppm) can increase activation of transcription factors that support cell survival and metastatic potential of solid tumors. In this regard, it is well established that hypoxia is an important factor in the resistance of a tumor to radiotherapy and or chemotherapy. Visualization of tumor hypoxia prior to therapy could potentially facilitate dose escalation or modification of chemotherapy with an improvement in patient outcome. Imaging of hypoxia can be performed with 18Ffluoromisonidazole (18F-FMISO) and Cu-labeled diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM). The main advantage of 18F-FMISO is that it is directly affected by tumor oxygenation. However, 18F-FMISO has limitations in that the contrast ratio between hypoxic tumors and normal tissues is poor and the low cellular washout of this tracer delays imaging and results in poor image quality. Although a feasibility study of eight patients with NSCLC treated with chemoradiation showed an association between a decrease in 18FFMISO uptake after treatment and favorable outcome, a small study of patients with suspected or biopsy-proven NSCLC showed a poor correlation between 18F-FMISO uptake and hypoxia.81,82 Recently, Cu-ATSM has been shown to be selective for hypoxic tissue. Cu-(II)-ATSM is biochemically reduced to unstable Cu-(I)-ATSM and retained in hypoxic cells. CuATSM accumulates avidly in hypoxic tissues and a small study of patients with NSCLC showed that Cu-ATSM was predictive of tumor response to therapy.83

Cell Proliferation and Apoptosis 18F-fluorothymidine (18F-FLT), a thymidine analogue, can be used to assess tumor proliferation because after phosphorylation by thymidine kinase 1, a key enzyme of the salvage pathway of DNA synthesis, 18F-FLT is trapped in the cell. Additionally 18F-FLT uptake in NSCLC correlates with the Ki67 index in NSCLC, an independent prognostic indicator.84 18F-FLT-PET has the potential to determine early response to therapy as well as prognosis. A prospective FLT-PET/CT pilot study of five patients with locally advanced NSCLC showed that uptake of 18F-FLT can be used to monitor the biologic responses of cancers.85 Other clinical studies have reported

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that 18F-FLTmay be useful in predicting therapeutic response.86–88 Scheffler et al reported that in 40 patients with advanced NSCLC treated with a tyrosine kinase inhibitor (erlotinib), low FLTuptake (SUVmax < 3.0) prior to treatment was associated with significantly longer survival compared with high-FLT uptake.88 18F-FMISO is a tracer which images apoptosis, and is being investigated currently, particular in radiation therapy and in multimodality strategies along with FDG and FLT. Most of the studies involve a small number of patients but appear promising.81,89

Cell Surface Receptors Protein and peptide compounds show great promise in being able to characterize a particular tumor’s phenotype, particularly cell surface receptors. Although monoclonal antibodies have been studied, their large size (150 kDa) limits tumor penetration. Additional potential limitations are a prolonged half-life in the blood, and there susceptibility to Fc-mediated cellular effects. Thus they are likely not feasible imaging agents clinically. A better option is the VHH domain, sometimes called nanobody, a 15-kDa fragment of the unique heavy chain-only antibody produced naturally by camels and llamas. Libraries of VHH from animals immunized with tumor antigens can be generated with cloning procedures and screened using a technique called phage display. These VHH have high stability and avidity, and are also rapidly cleared via renal excretion from the blood-qualities which are desirable for an imaging agent. VHH specific for the EGFR were recently identified and further investigation is ongoing.90

Angiogenesis Angiogenesis has an important role in tumor growth and the integrin αvβ3, a receptor involved in adhesion and migration of cells, is highly expressed on activated endothelial cells during this pathologic process. 18F-galacto-RGD is a new tracer for PET imaging of αvβ3 and may provide information for planning and response evaluation of antiangiogenic therapies.91,92

Conclusion FDG-PET/CT has become an invaluable component in evaluating thoracic disease. While the dominant focus of PET/CT imaging has been in oncology, nononcologic use of PET/CT is evolving. PET/CT may have a limited role in the management of patients with fever of unknown origin, large-vessel vasculitis, sarcoidosis, and idiopathic interstitial pneumonias. Cardiac applications on the other hand are increasing and in patients with CAD, PET is used to assess myocardial perfusion, obstructive CAD, and myocardial viability. While the appropriate clinical utility of PET/CT evolves, current developments/research interests including new processing techniques such as 4D CT/PET and partial volume correction as well as new scanning techniques, such as time of flight, have potential advantages and clinical utility. Additionally, molecular imaging initiatives have focused on Seminars in Respiratory and Critical Care Medicine

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trials where the bias and variance in PET SUV measurements are the largest due to differences in scanner performance and imaging protocol. Task groups and alliances have been established such as the quantitative imaging network (QIN) and the quantitative imaging biomarker alliance (QIBA) with collaborations from various PET/CT vendors in an effort to mitigate this challenge. These efforts will hopefully further propel the utilization of PET imaging through more robust and accurate quantitative measurements.

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PET-CT: Current Applications and Developments in the Thorax improving instrumentation and designing better imaging probes. Furthermore, there are numerous new agents that could allow an improvement in the management of oncologic patients. In this regard, agents with a potential for clinical utility that target cell proliferation/DNA synthesis, hypoxia, angiogenesis and tumor receptors such as EGFR are currently being developed and evaluated. Overall, with new molecular targets and improved technology, PET/CT is assured an ever increasing role in oncologic and nononcologic imaging in the thorax.

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