PET > PET tumor imaging > General

PET Oncologic Imaging:

[18]F-fluorodeoxyglucose (FDG) Imaging:

Basic principles:

The transport of glucose into a cell is mediated by a family of structurally related glucose transporter proteins [23]. One of the biochemical characteristics of malignant cells in an enhanced rate of glucose metabolism due to increased number of these cell surface glucose transporter proteins (primarily Glut-1 and Glut-3 that are hypoxia responsive) and increased intracellular enzyme levels of hexokinase and phosphofructokinase which promote glycolysis [4,16,20,207]. Cancer cells can increase glucose metabolism and preferentially utilize glucose even in the presence of oxygen [326]. This enhanced glycolytic rate of malignant cells facilitates their detection utilizing PET FDG imaging. Increased glycolysis also leads to elevated levels of lactic acid (an acidotic environment) [326]. The resultant acidotic and hypoxic tumor microenvironment activates hypoxia-inducible factors that promote tumor cell proliferation and angiogenesis [326]. Rapid proliferation, poor lymphatic drainage, and increased extracellular matrix production all contribute to increased interstitial fluid pressure in the tumor microenvironment that can impede effective delivery of chemotherapeutic drugs [326].

The Warburg effect represents metabolic reprogramming of cancer cells to favor glycolytic metabolism [337]. Several processes determine FDG uptake in tumor cells [28]. Of major importance is the integrity of the vascular network that is necessary for supply of nutrients to the cell [28]. With an intact vascular supply, FDG enters the tumor cells by using the same facilitated transport mechanism as glucose (via cell surface proteins). The most common glucose transport protein over-expressed on the tumor cell membranes is Glut-1, which is insulin independent [28]. In-vitro studies have shown that FDG uptake is also determined by the number of viable tumor cells within a lesion (tumor-cell density) [16, 28]. Non-tumoral tissue such as necrotic and fibrotic tissue may reduce tracer uptake [16]. Increased cell proliferation in tumors (assessed by the mitotic rate) also results in increased glucose utilization [28]. Tumor hypoxia will also increase FDG uptake through hypoxia-inducible factor-1-alfa that up-regulates Glut-1 receptors [28]. The bottom line is that FDG accumulation within a tumor is likely related to a complex interaction between the cellular energy demand and the tumoral microenvironment [7].

Once inside the cell, FDG is phosphorylated by hexokinase into FDG-6-phosphate. FDG-6-phosphate does not enter into further metabolism and accumulates intracellularly [4]. Reduced levels of glucose-6-phosphatase (an enzyme which metabolizes FDG-6-phospahte) within tumor cells compared to normal and inflammatory cells permits longer intracellular retention of FDG-6-phosphate [22,110,207]. The signal derived from tumors represents an average of the FDG uptake throughout the lesion [16].

Unfortunately, FDG is not a cancer specific agent and its uptake has been described in a number of inflammatory lesions including sarcoid, tuberculosis, fungal infection, and cerebral abscess [1,20]. The increased accumulation is probably related to a markedly increased rate of glycolysis within activated inflammatory cells. Delayed or dual phase imaging may help to differentiate between benign and malignant processes [27]. A persistent or increased level of FDG accumulation within a lesion on delayed imaging is indicative of a malignant process [27].

Patient preparation:

FDG imaging is performed in the fasting state to minimize competitive inhibition of FDG uptake by glucose [14]. A minimum 4 hour fast is recommended prior to initiation of the PET FDG study. A 12 hour fast may decrease accumulation by the myocardium and improve detection of mediastinal metastases in cases of lung or breast cancer. Patients with early morning exams should not eat anything after midnight. Patients with afternoon exams should eat a light breakfast with minimal carbohydrate containing foods [143]. Patients should be well hydrated for the exam (while fasting patients should try to drink at least two to three 12 ounce glasses of water) and should avoid strenuous work or exercise for 24 hours before scanning [73,143]. Some recommend that patients also be on a low carbohydrate diet for 24 hours prior to the study [143]. For head and neck cancers, use of a benzodiazepine can aid in decreasing neck muscle activity [143]. Some authors recommend the use of a high-fat, low-carbohydrate, protein-preferred meal the night before the scan and a vegetable oil drink on the morning of the scan to more effectively suppress cardiac activity [199,202]. Using this protocol, the increased free fatty acid availability promotes FFA oxidation and inhibits glucose use [199,202]. This protocol may also aid in decreasing the incidence of brown fat activity compared to fasting patients (2.8% versus 6.3% of the patients, respectively in one study) [202].

If there is a possibility of an elevated serum glucose level, a serum glucose level is obtained prior to FDG administration. FDG uptake is significantly influenced by plasma glucose levels and uptake will be decreased when plasma glucose levels are elevated (elevated serum glucose levels can result in decreased FDG accumulation within the tumors) [4,14]. If the glucose level is higher than 150-200 mg/dL (8.3-11.1 mmol/L), the study should be delayed until the glucose level is under 200 mg/dL [3,76,195]. Although less well documented than acute hyperglycemia, chromic hyperglycemia is assumed to have a smaller negative influence on tumor uptake and tracer distribution [195]. Administering insulin at the same time as FDG should be avoided because it tends to increase accumulation in skeletal muscle and thus less FDG is available for accumulation in tumors [3]. In patients with diabetes, blood sugar control should be achieved with oral hypoglycemic agents or insulin (not administered near the time of FDG administration) [3]. Diabetic patients are best imaged early in the morning before the first meal and insulin or oral hypoglycemic medication should be titrated appropriately the night before and morning of the study [143]. Subjects with type I or II diabetes who cannot reliably attain acceptable glucose levels early in the morning should be scheduled for late morning imaging, should eat a normal breakfast at 7 AM, should take their normal morning diabetic drugs, and then should fast for at least 4 hours before the PET exam [300].  If possible, diabetic patients should test their ability to maintain reasonable glucose levels after fasting prior to the PET exam [143]. If required, some authors have found that insulin can be administered, but a waiting period of at least 90 minutes should be observed prior to administration of the FDG [195]. Even then, about 25% of patients will have unacceptable biodistribution of FDG and about 10% of patients can develop hypoglycemia [195].

Hyperinsulinemia: The patient below had a normal glucose level and was injected for an FDG PET scan. Imaging revealed intense cardiac uptake and a large about of muscular activity. The findings are consistent with a hyperinsulinemic state and the patient subsequently admitted to eating a small breakfast.

For specific imaging of the kidneys or pelvic region additional preparation can be performed. A foley catheter in the bladder will aid in reducing urine activity [143]. Administration of a diuretic (lasix 20-40 mg) 10-15 minutes after FDG administration and when possible IV hydration with 250-500 mL of saline (not dextrose containing solutions) will also aid in dilution and clearance of urinary activity [143].

For oncologic imaging, FDG-PET scans are performed approximately 60 minutes following the intravenous injection of 10-20 mCi of FDG (0.14-0.21 mCi/kg of body weight) [143]. For pediatric use, a dose of 0.15-0.30 mCi/kg has been recommended with a minimum dose of 1 mCi [125]. A normal PET acquisition is acquired from the base of the brain to the mid thighs [3]. For patients with melanoma, a whole body acquisition is performed from the top of the skull to the feet [235]. Some authors recommend that entire body imaging should be considered in all patients as unsuspected sites of malignancy may be found outside the normally scanned area in up to 4% of patients [235]. The standard PET exam previously required 45 minutes to 1 hour to acquire when performing attenuation corrected exams using a conventional BGO scanner [15].  LSO PET cameras and modern PET/CT scannsers can perform a similar 3D acquisition in a much shorter period of time.

In addition to standard body images, some centers acquire a 4-minute brain scan about 30 minutes following FDG administration using the three-dimensional acquisition mode [3]. However, routine CNS imaging is not universally performed [45]. The normal brain has substantial glucose uptake and metastatic foci may be difficult to detect on PET FDG images [42,43,44,45].

Overall efficacy:

PET/CT has been shown to be significantly more accurate (86%) in tumor staging compared to CT alone (63%) [235]. The results of a large number of studies has shown that the results of FDG PET imaging can have a major impact on oncologic patient management. Up to 15% of patients without clinical suspicion of recurrence or residual disease are found to have active tumor on PET imaging [47]. PET exam findings can change planned radiation therapy (dose, volume, or intent) in 27% of patients [47]. PET imaging can also detect unexpected sites of secondary malignancy (in 1.2 to 2% of patients) [75,113]. The identification of unexpected hypermetabolic foci on FDG PET imaging should prompt further evaluation as up to 71% of these foci can be malignant or premalignant [75]. Unfortunately, not all tumors will shown significant metabolic activity on FDG PET imaging [47]. PET exams are positive for tumor in about three-quarters of patients with known primary or residual tumor [47].

One other drawback of PET imaging is the underestimation of metabolic activity in tumors that are smaller than two times the spatial resolution of the scanner (partial volume effect) [6,118]. For a spherical lesion with a diameter 1.5 times the spatial resolution of the PET scanner at full width at half maximum, the measured maximum activity concentration is only 60% of the true activity (and the measured mean activity concentration on 30% of the true activity) [118]. Despite this limitation, using modern PET scanners, objects that measure as small as 5 mm can be visualized [1]. Assessment for malignancy and metastatic disease with PET FDG imaging is improved when supplemented by CT images [2]. PET imaging can also identify a more accessible tumor site for biopsy.

In cancer screening of asymptomatic individuals, FDG PET imaging can detect unsuspected malignancy in 1.1-1.2% of patients [113]. However, PET imaging is not recommended as a screening exam.

Monitoring response to therapy:

Individual tumors will vary widely in their response to a
 particular form of therapy [53]. These differences are likely multifactoral and related to disparities in tumor biology and the presence of drug and radio-resistance mechanisms [53]. The early identification of tumors that are not responding to conventional therapies would permit the timely institution of alternative treatment that may be more effective [53]. The World Health Organization (WHO) criteria define response as a decrease of at least 50% in the sun of the product of the longest perpendicular diameters of measured lesions [159]. The more recent RECIST criteria introduced by the National Cancer Institute defines response as a 30% decrease in the largest diameter of a tumor (for a spherical lesion this value is equivalent to a 50% decrease in the product of 2 diameters [159]. Unfortunately, conventional imaging modalities are somewhat limited in their ability to evaluate for treatment response as residual masses may persist on imaging studies despite resolution of disease activity [53]. In other words- anatomic changes often lag behind tumor cell mortality [53]. FDG PET imaging can evaluate tumor response to therapy before anatomic changes are observed [53]. PET imaging is currently the most sensitive and specific imaging method to obtain information about tumor physiology [53]. Decreased tumor FDG uptake following initiation of treatment is a complex biologic process linked to a decline in the number of viable tumor cells, reduction of the proliferative activity of tumors, and changes in glucose metabolism of viable tumor cells [196]. Studies indicate that a measurable decrease in tumor FDG uptake 1-3 weeks following chemotherapy is associated with effective treatment [118]. Therefore, post-treatment imaging should be performed 2 weeks following the end of a specific chemotherapy cycle, while waiting 6-8 weeks following radiation therapy [143]. Patients who do not demonstrate a change in FDG uptake should be considered for a change in treatment regimen [118]. By providing a more timely and accurate assessment of treatment efficacy, PET imaging can have significant impact on clinical treatment decisions [53].

For proper interpretation of tumor response, it is important to have a baseline examination [53]. Imaging 10 days to 2 weeks after completion of chemotherapy is recommended to avoid transient fluctuations in FDG metabolism (tumor stunning) [53,158]. For radiation therapy a longer delay may be required (up to 60 days) prior to imaging. Generally, FDG uptake 6 months after radiotherapy is associated with tumor recurrence [53]. Assessment of tumor response to therapy can be determined by visual assessment of the images or by quantitative analysis using standard uptake values [53].

Standardized uptake ratio (SUR) or standardized uptake value (SUV):

A standardized uptake value (SUV), is used to determine if a lesion has increased ¹⁸FDG activity. The SUV normalizes the amount of FDG accumulation in a region of interest (ROI) to the total injected dose and the patient?s body weight in kilograms [60]. It provides a means of comparison of FDG uptake between patients [14]. The SUV is calculated by dividing the mean activity within a selected region (or volume) of interest (in mCi/ml) by the injected dose (in mCi/kg). Modifications of the SUV that may improve the semiquantitative evaluation of FDG uptake include using body surface area or the lean body weight instead of the weight of the patient; this is significant because the distribution of FDG is higher in muscle than in fat [4]. Specifically, in pediatric patients an SUV calculation based upon body surface area seems to be a more uniform parameter than SUV determined on body weight [125].

SUVmean=  Average selected region activity (mCi/ml)
                     Injected dose (mCi)/body weight (kg)

SUVmean can vary depending on the size of the region or volume of interest [254]. Because of this variability, there is not a consistent manner allowing SUVmean to be compared across sites and SUVmax has become the standard in quantification for PET studies [254].

The SUVmax is defined as the SUV derived from the single voxel showing the highest uptake within a defined ROI or VOI [254]. The SUVmax typically represents the most metabolically active part of the tumor and it is nearly free from observer variability and is less susceptible to partial volume effects [254,260]. A drawback of SUVmax is that because it is derived from a single voxel, it may not be an adequate surrogate marker for true tumor biology and it can be heavily influenced by image noise and voxel size [254,258,306]. Additionally, motion can result in blurring of the target volume resulting in a reduction in the measured SUVmax [306].

An SUVmax greater than 2.5 has been shown to be very sensitive and specific for malignant lesions [37]. Visual analysis of the amount of uptake within a lesion has also been shown to be effective in differentiating benign from malignant lesions [37,38]. Uptake greater than blood pool activity (i.e.: the liver and mediastium typically have SUV's of about 2.0) indicates a malignant lesion, while activity equal to or less than mediastinal blood pool suggests a benign lesion [38]. In fact, visual analysis may be more sensitive for nodules smaller than 1.5 cm in size (although, the improved sensitivity comes at a decreased specificity) [38].

It is important to remember that SUV values may change with time after FDG injection; thus, the time of acquisition after FDG injection must be standardized for the values to be useful [3]. Other factors that can affect the SUV include patient motion (due to lesion blurring), the blood glucose level at the time of injection, and partial-volume effects (scanner resolution) [16, 36]. Partial volume effects represent underestimation of metabolic activity in tumors that are smaller than two times the spatial resolution of the scanner [6]. An accurate SUV determination is more difficult for nodules smaller than 1.5 cm due to partial volume effects [85].

Factors affecting SUV measurement: (See also PET/CT discussion for the effects of contrast on SUV measurement)

1. Plasma glucose levels: High plasma glucose can decrease FDG uptake by competitive inhibition [111] and this will decrease the calculated SUV [110]. If the patients blood sugar is above 200 mg/dL the study should be postponed [111]. Chronic blood sugar elevation as seen in diabetic patients seems to have a less significant effect on tumor FDG uptake [111]. However, diabetic patients should have proper blood sugar control prior to PET imaging [111]. It is also important to note that insulin injection close to the time of FDG administration will increase skeletal muscle uptake of FDG and this can degrade scan quality by reducing the lesion-to-background ratio [111].
2. Time after administration that SUV is measured- FDG uptake in malignant tumors is time dependent and often increases for up to 90 minutes or longer after tracer injection [118,128]. SUV should be measured at a fixed time following injection to ensure accuracy.
3. Subcutaneous infiltration of the tracer: SUV is based upon the injected dose. Infiltration of the tracer will result in an error because of the decrease in the real dose available for distribution [110,118]. Incorrect measurement of the injected amount because of residual tracer in the syringe can also result in incorrect SUV measurements [306].
4. Body weight or body surface area- FDG distribution is weight dependent- heavier patients often have a body fat higher percentage and fat is less metabolically active than muscle tissue- hence, the SUV in obese patients is increased compared to thin patients [226,293]. A thin patient with relatively more muscle will likely have a lower SUV for a given lesion because muscle competes for the FDG [226]. Even SUV comparison between examinations of the same patient can be flawed if the patient has lost or gained weight [226]. The use of a lean body mass determination for SUV measurement in obese patients has been found to be a better representation of metabolic activity [293,306]. Lean body mass is calculated in male subjects as 1.10 x weight - 128 x (weight²/height²) and in females as 1.07 x weight - 148 x (weight²/height²), where weight is measured in kg and height in cm [306].
5. Size of the region of interest- because of partial volume effects, the measured mean tumor uptake will decrease when the size of the ROI used to define the tumor is increased [118].
6. Resolution of the scanner- image resolution affects the measured SUV of a small object because of partial volume effects [226].
7. Type of image reconstruction and attenuation correction: SUV measurements from filtered back projection (FBP)  images underestimate the true activity concentration by about 20%- this is much greater than iterative reconstruction (IR) images which underestimate activity concentration by about 5% [83]. The discrepancy is primarily related to the way transmission data is processed- measured attenuation correction for FBP images and segmented attenuation correction for IR images [83]. The number of iterations used for ordered-subsets expectation maximization (OSEM) reconstruction can also affect the measured SUV value [107]. For max SUV the value increases systematically with a 28% increase from 5 to 40 iterations [107]. The same field-of-view and reconstruction parameters should be used for all followup studies [226].

Because of some of the drawbacks associated with SUVmax, SUVpeak has been suggested as a better method for quantification [254]. SUVpeak is defined as a circular ROI or spherical VOI having a fixed predefined diameter that can be centered on the SUVmax or localized such that SUVpeak is highest across all locations within a tumor [254]. SUVpeak may be less sensitive to noise because it is based on the average value within a larger ROI or VOI [254]. However, a standard SUVpeak ROI/VOI diameter and a defined location for placement of the ROI have not yet been established [255].

The PERCIST response criteria suggest the use of a 1 cm³ ROI surrounding the voxel with the highest activity [306]. The mean value of the radiotracer activity within that ROI (SUVpeak) is then normalized to lean body mass and reported as peak SUL (SULpeak) [306]. The disadvantage of SULpeak is difficulty with the evaluation of small lesions and the need for specialized software [306]. For background activity, a 3 cm diameter spherical VOI is placed in the right side of the liver, midway between the dome and the inferior margin, excluding central ducts and vessels [310]. For a tumor to be measurable at baseline, the SULpeak must be greater than or equal to 1.5 times the mean SUL in the 3 cm diameter spherical VOI plus two times its standard deviation to have a minimum threshold for evaluation [310]. For follow up scans, the difference between the injection to imaging time between the baseline and followup study should be less than or equal to 15 minutes [310]. The injection to beginning of imaging should be greater than or equal to 50 minutes and less than or equal to 70 minutes [310]. Serum glucose levels must be less than 200 mg/dL [310].

PERCIST 1.0 criteria for response assessement:

- Complete metabolic response: Visual disappearance of all metabolically active tumor [310].
- Partial response: SULpeak decrease by 30% or more (between the most intense lesion at baseline and the most intense lesion at follow-up (not necessarily the same lesion). There should be no new lesions in a pattern suspicious for cancer and no increase in size greater than 30% in the target or non-target lesions [310].
- Stable disease: SUL peak decrease of less than 30% or increase of 30% or less
- Progressive disease: SULpeak increase of more than 30%, new lesions, or a lesion increase in size of greater than or equal to 30% [310].

A tumor-to-blood standardized uptake ratio (SUR= tumor SUV/blood SUV) may also be used to improve the prognostic value [332]. The SUR can also be corrected for uptake time variations by converting the measured uptake values to a preselected fixed scanning time point [332]. This scan time normalized SUR removes several shortcomings of SUVmax and results in decreased test-retest variability [332].

Three dimensional PET indices such as metabolic tumor volume and total lesion glycolysis have also been developed and may provide better prognostic information by providing a more accurate reflection of the total tumor burden [265]. Total lesion glycolysis (TLG) integrates both anatomic and biologic data and may also be useful for prediction of prognosis [256]. TLG is defined as the SUVmean multiplied by the metabolic tumor volume (MTV) [256]. The MTV represents the metabolically active portion of a mass as delineated by a specified threshold of the maximum SUV (above a minimum threshold). There is no standard definition for the metabolic tumor volume and various measures can be used to define an isocontour (for instance- the metabolic tumor volume could be defined by all voxels with an SUV above 2.5 or above a threshold of 41-42% of the SUVmax) [256,265,317]. However, use of 41-42% of SUVmax to determine MTV and TLG will underestimate lesion uptake with a high activity and overestimate lesions with an SUVmax close to background level [308]. Adaptive methods based on signal-to-background ratio have also been developed [332]. This is similar to the fixed threshold method, except that it adapts the threshold relative to the local average background activity, thereby correcting for the contrast between the tumor and local background.

The measurement of tumor texture/heterogeneity (corresponding to necrosis, fibrosis, and areas with higher cellular proliferation) has also been evaluated for prediction of tumor response to therapy [287]. Increased tumor heterogeneity often associated with adverse tumor biology, increased lesion aggressiveness and greater risk for treatment failure [287,291,301]. Exactly how tumor heterogeneity should be measured is not entirely clear [287]. Additionally, image reconstruction features (iteration number, grid size, FWHM of the gaussian filter) impact on the image features and this can affect heterogeneity/texture features [301].

Determining metabolic response:

Changes in the SUV measurement also play a role in evaluating tumor response to therapy [126,226]. Studies have suggested that SUV has an in subject variation of approximately 10% [319]. A change of more than 20% is generally considered outside the range of spontaneous fluctuation and to represent a true change in the glucose metabolism of the tumor mass [126]. Studies indicate that most tumors responding to treatment show a 20-40% decrease in SUV early in the treatment course [226]. An important point to remember is that with current technology, PET can measure the first two logs of tumor cell kill (i.e.:  a negative PET result does not indicate a total eradication of disease, but it does imply a certain amount of cell killing (between 2 and 10 log units of tumor cell killing) [158]) [281]. Thus- a negative post-treatment PET scan at the end of therapy either means there are no cancer cells present or that there are fewer than 10⁷ cells [281]. Therefore, although a completely negative PET at the end of therapy is suggestive of a good prognosis, it does not necessarily correspond with compete eradication of cancer cells [281]. Thus, patients with negative mid or post treatment scans represent a heterogeneous group in terms of relapse risk [158]. A negative mid-treatment scans may imply a greater likelihood for cure as these patients will receive additional chemotherapy which will result in additional cell killing [158].

The European Organization for Research and Treatment of Cancer determines treatment response depending on the percentage change in SUVmax- % change SUVmax = (F/U - Baseline)/ Baseline x 100 [281]. They recommends that an increase in SUV measurement of 25% from the baseline scan or the appearance of new FDG positive lesions be classified as progressive disease, while a partial response is represented by a 15-25% decrease after one cycle of chemotherapy and greater than 25% after more than one treatment cycle [131,281]. Stable disease is defined as a decrease in activity of less than 15% or an increase in metabolic activity of less than 25% [281]. Complete metabolic response is defined as complete resolution of FDG uptake in the tumor [147] so that activity is less intense than the liver and indistinguishable from surrounding background blood pool levels [238].

PRECIST criteria (PET response criteria in solid tumors) have also  been published. For PRECIST a new metric the SUVpeak has been developed. The SUVpeak is defined as the mean FDG uptake within a spheric 1cm³ (other indicate a 12 mm diameter [295]) region around the tumor voxel with the highest SUV [283,295]. The SUVpeak is intended to provide a more reproducible parameter of maximal lesion uptake [283]. A CMR is defined as complete resolution of tumor uptake, a partial metabolic responder demonstrates a minimum reduction of 30% in a lesion (or 0.8 SUV units in absolute terms), progressive metabolic disease as an increase of a minimum of 30% in a lesion or development of new lesions, and stable metabolic disease as anything that does not meet the above criteria [252,295]. PRECIST defines a 3 cm spherical  ROI in the right hepatic lobe as a QA tool to assess the applicability of quantitative comparisons [296]. If the liver or blood pool is to be used for determination of tumor-to-background ratios to monitor therapy response, these values can vary between exams (in one study normal variability in SUV mean for blood pool was -0.8 to 0.9 and for the liver was -0.9 to 1.1 [277,296].

Additionally, in the presence of intense hypermetabolic tumors and/or bulky (extensive) neoplastic disease, the energy substrate requirements of the tumor may create a "reservoir" or "sink" effect which results in decreased radiopharmaceutical available for uptake in other organs [329]. This can affect the activity in the liver or blood pool (and brain) which are often used for semi-quantitative assessment of metabolic tumor therapy response [329]. Normalizing to a reference tissue, such as the blood, can remove this effect [329].

In patients with solid tumors treated by pre-surgical chemotherapy, a change in FDG uptake of 30-35% within the first few weeks of chemotherapy has been found to provide the highest accuracy for the prediction of histopatholgic complete or subtotal tumor regression [159]. Although there is interobserver variability in SUV max measurements, this variability has been shown to be significantly lower than the variability in CT size measurements for tumor response [206]. Variability in SUV max tends to be greater for treated tumors because of the challenge in selecting tumor ROI's when there is little FDG uptake above background tissues that results in greater statistical noise [206].

PET in Radiation Planning: See also individual tumors

The results of the PET examination can also be incorporated into radiation planning volumes [82]. However, there are several factors which affect PET images that can influence target edges or margins including partial volume effects (tumor size), patient motion, image resolution, heterogeneity of tracer uptake within the tumor, and window display level [82,253]. Most commonly, the tumor volume is delineated using a fixed percentage of the maximum FDG concentration/maximum voxel value (i.e.- 50% isocontours) [211]. Manually defined tumor volumes may be the most accurate way to delineate the tumor, but suffers from large intra- and interobserver variability and is time consuming [253].

PET in Radiofrequency ablation evaluation: See also individual tumors

Following radiofrequency ablation, activity within the tumor decreases to background levels as soon as one day following the treatment [145]. However, a ring-shaped area of increased activity around the site of the tumor can be seen due to inflammatory changes surrounding the zone of necrosis [145]. This activity will decrease in intensity over time, but PET imaging may need to be delayed 6-8 weeks following RF treatment to better evaluate for treatment response [145].

The normal distribution for FDG includes:

1- Head and neck:

The cortex of the brain- there is generally very intense tracer uptake in the brain because the brains only energy source is glucose. The total uptake in the brain is approximately 6% of the injected dose [20]. Metastatic CNS lesions generally have activity similar to gray matter [24]. During whole body scanning for the evaluation of patients with primary malignancy, unsuspected CNS metastases are detected in less than 1% of patients [24]. Some metastases may demonstrate decreased activity compared to normal brain (possibly related to edema) [45]. For the identification of cerebral metastases FDG PET has a sensitivity of 75% and a specificity of 83% [45]. Between 32% to 40% of cerebral metastases seen on MR imaging will not be detected on FDG PET exams [45,46]. Lesion size is an important determinant in the ability to identify a CNS lesion of PET [45]. The likelihood of detecting a 1 cm size metastatic CNS lesion is only about 40%, while a 1.8 cm lesion has a mean detection rate of about 90% [45]. It has been found that when scanning of the brain is included for oncologic FDG PET imaging a change in treatment occurs in fewer than 1% of patients [45]. Because FDG PET imaging detects few clinically relavent lesions in patients with primary malignancies, it should not be performed routinely [24].

Focal incidental uptake in the pituitary gland can be seen in about 0.8% of patients and should prompt further evaluation as an underlying abnormality can be found in up to 41% of cases- most commonly pituitary adenomas [244]. Using a cutoff SUVmax of 4.1 may be helpful in distinguishing pathologic uptake from physiologic uptake [244].

The tonsils are constantly exposed to antigens causing carious degrees of physiologic inflammation [220]. Low to moderate FDG uptake occurs in the lingual and palatine tonsils and at the base of the tongue because of physiologic activity associated with the lymphatic tissue in Waldeyer's ring [41]. However, tonsil uptake can be high (SUV 3.11 (lingual) to 3.48 (palatine)) [103], however, physiologic uptake is typically symmetric and asymmetric uptake should be regarded as suspicious for malignancy [220]. There is usually uptake in the lymphoid tissue of Waldeyer's ring [4]. The soft palate can also show tracer uptake [103]. Variable, but typically low, uptake can be seen in the salivary glands which secrete low amounts of glucose [41]. The parotids glands also show mild, symmetric tracer uptake. Due to this physiologic activity, low grade malignant lesions in the salivary and parotid glands may be obscured [157]. Additionally, PET imaging is not able to accurately differentiate benign from malignant parotid lesions as benign tumors such as pleomorphic adenoma, oncocytoma, and Warthin tumor are known to be FDG avid [312].

2- Myocardium- In the post-prandial state (following a meal), plasma insulin levels increase and there is marked cardiac activity (due to increased GLUT-1 and GLUT-2 transport activity) [251]. Little myocardial activity is generally noted in the fasting state as the myocardium preferentially utilizes fatty acids for energy generation [251]. However, uptake can be variable as even in the fasting state, glucose can still account for 30-40% of the energy derived from oxidative metabolism [25]. Even overnight fasting may be inadequate to reduce physiologic cardiac FDG uptake [251]. Fasting myocardial uptake tends to be nonuniform with a significant decrease in activity in the septum and anterior walls compared to the lateral and posterior walls (a posterolateral increased in cardiac FDG activity is a common normal physiologic pattern) [251]. Focal activity in the papillary muscles is also common [215]. This regional variation in FDG uptake likely reflects physiologic differences in local myocardial substrate utilization that may be related to variations in myocardial wall stress [251].

Certain drugs may also interfere with suppression of myocardial FDG uptake including beta-blockers and the antianginal drug trimetazidine (a FFA oxidation inhibitor) [199]. Bezafibrate, a drug used to treat hyperlipidemia, and levothyroxine (thyroid hormone) taken before FDG administration have also been shown to lower FDG cardiac uptake [251].

Some authors recommend the use of a high-fat, low-carbohydrate, protein-preferred meal the night before the scan and a vegetable oil drink on the morning of the scan to more effectively suppress cardiac activity [199,202]. Using this protocol, the increased free fatty acid availability promotes FFA oxidation and inhibits glucose use [199,202]. The use of unfractionated heparin (4000 units 15 minutes prior to FDG administration) has also been suggested to be effective in decreaing cardiac uptake [245]. Heparin causes the release of free fatty acids into the circulation and this works to reduce physiologic myocardial FDG accumulation [245]. However, the best suppression of myocardial uptake may be seen with a low carbohydrate (<5gm) dinner in the evening prior to the scan, and then fasting until the FDG injection [221].

Increased FDG localization in the atria is associated with atrial fibrillation [251]. The crista terminalis (a crescent-shaped muscle band located at the junction of the right atrium and right atrial appendage) may also occasionally demonstrate increased FDG uptake [251].

Increased FDG uptake has also been reported in lipomatous hypertrophy of the interatrial septum- mean SUV 5.6 [101]. Uptake can be seen in up to 82% of patients with LHIS [101]. The etiology for the uptake is not certain, but may be related to the presence of brown fat [101]. Fusion PET/CT helps to clarify the location of the uptake [101].

3- Renal/Urinary bladder- Unlike glucose, FDG is filtered by the glomerulus and not resorbed [54]. Hydration and frequent voiding promote diuresis and help to decrease the radiation dose to the genitourinary tract [4]. The use of IV hydration and IV lasix (0.5 mg/kg up to 40 mg with 3 successive urinary bladder voidings) can help to decrease/clear ureteral and urinary bladder activity in cases in where there are equivocal pelvic findings [153].

 

 

4- Liver- faint, heterogeneous activity is common. It has been reported that fatty liver changes can result in slightly decreased metabolic activity in the liver [217,240], but other authors have noted no significant change in SUV max between fatty and non-fatty livers [218] and even increased FDG uptake in hepatic steatosis has been reported and felt to be related to inflammatory cells (possibly reflective of nonalcoholic steatohepatitis or NASH) [272,321]. It is possible for both liver metastases and treated liver metastases to have liver-equivalent activity- as a result, such lesions cannot be reliably identified by PET imaging [17]. Acute cholangitis can demonstrate foci of tracer uptake along the course of the intrahepatic ducts, but this can be difficult to distinguish from true liver lesions [39]. Uptake can also be seen along biliary stents [39]. In patients with malignancies, focal uptake in the liver on PET imaging without corresponding abnormality on CT can be associated with malignancy in more than 75% of cases and should be further evaluated with liver MRI [333].

5- Musculoskeltal and soft tissue activity:

Exercise should be avoided on the day of scanning to avoid muscle uptake. The muscles of mastication or larynx can accumulate tracer if eating or talking [4]. Asymmetric uptake of FDG can be seen in the small internal laryngeal muscles in patients with laryngeal nerve palsy contralateral to the side of the nerve dysfunction and should not be misinterpreted as pathologic [29]. In patients with COPD, intercostal muscle uptake can be seen due to excessive contraction required to facilitate expiration [111]. Hyperventilation may induce uptake in the diaphragm [54] and stress-induced muscle tension is often seen in the trapezius and paraspinal muscles [4]. Benzodiazepines may be used to decrease paraspinal and posterior cervical muscle uptake in tense patients [20]. Insulin injection just prior to FDG administration will result in increased muscle uptake [111].

 

A moderate amount of uptake can be seen in the anterior part of the floor of the mouth due to the genioglosus muscle which prevents the tongue from fall back in supine patients [41]. In patients that chew uptake can be seen in the masticator muscles. Speaking or coughing produces tracer uptake in larynx (pharyngeal constrictor muscles and vocal cords larynx) [127]. Asymmetric muscular uptake can be seen in the inferior obliquus capitus muscle at the skull base [127].

 

 

Brown fat: Adipose tissue in mammals is composed of at least two functionally different types of fat: white and brown [259]. White fat serves as an insulator and as energy storage, releases hormones and cytokines that modulate whole-body metabolism and insulin resistance [259]. Brown fat (unlike white adipose tissue fat) contains a large number of mitochondria and has the capacity to generate heat [67,173,181]. Brown fat is stimulated by several factors, including exposure to cold (decreasing body temperature) which causes over-expression of glucose transporter 4 in brown fat [62]. Brown fat can also be stimulated by ingestion of food (diet-induced thermogenesis) [259]. The incidence of FDG uptake in brown fat has been shown to be increased during periods of cooler temperatures [62,259]. Heat generation in brown fat is initiated by activation of the sympathetic nervous system (catecholamine stimulation) [173,193]. Cold stimulated FDG uptake in brown fat is also more pronounced during fasting [264].

Prominent tracer uptake has also been described within the supraclavicular fat on PET/CT in about 2% to 5% of patients- the etiology is not well understood, but is felt to be related to the presence of "brown fat" (brown adipose tissue). [52,62,67,259]. Brown fat is most prominent in newborns and diminishes with age [67]. In adults, brown fat is significantly more common in women than men (5.9% versus 2.7%) and is also more common in patients with lower body weight and body mass index (the amount of brown fat in the body declines with age and as obesity increases and brown fat activity is generally found to be lower in older and overweight people compared to young or leaner controls) [259,305], however, this has not been found in all studies [323]. The incidence of tracer uptake in brown fat is also increased in women [62,91,259] and in pediatric patients [67].

Other areas in which brown fat uptake can less commonly be seen include the axillae, mediastinum, intercostal paravertebral, and perinephric regions [67,91]. Less common locations include the posterior neck, left paratracheal area, and retrocrural area [46]. Why brown fat persists in some adults is not presently known- although it is possible that brown fat may persist into adulthood more than was previously recognized [67]. SUV max measures can be as high as 27.8 [259]. Younger patients are more likely to have higher maximum SUV's in brown fat [259].

Brown fat is an active metabolic organ that plays an important part in the basal metabolic rate [311]. Brown fat is known to increase glucose uptake when the sympathetic nervous system is activated by cold stimulation and other causes [86]. Beta-adrenergic agonists increase fat oxidation and thermogenesis/brown fat activity [273]. Because brown fat is stimulated by the sympathetic nervous system and pretreatment with propranolol has been shown to reduce FDG uptake in an animal model [86]. Administration of fentanyl, diazepam, or the use of a low high-fat, low-carbohydrate, and protein permitted diet may also reduce FDG uptake in brown fat [205]. Nicotine has also been shown to increased brown fat activity in animals and this effect is increased when combined with ephedrine [168] and should be avoided prior to FDG administration [183]. The Hounsfield density measurements of active brown fat have been shown to be slightly higher than non-activated area of brown fat [213]. There is a negative correlation between brown fat and coronary artery atherosclerosis, and brown fat may be associated with fewer cardiovascular events [311]. The etiology for this protective effect is uncertain [311].

A hibernoma is a benign tumor of brown fat that can show elevated FDG accumulation on PET imaging [181]. The entity is rare and typically presents as a slow-growing painless mass in a subcutaneous or intramuscular location [315]. The most common location is the trunk, neck, and proximal extremity- particularly the thigh [315]. Hibernomas appear as a nonspecific echogenic mass on US and appear slightly denser than subcutaneous fat with clear margins on CT [315]. Similar to brown fat, the tumor appears to demonstrate fluctuation in the amount of tracer uptake when imaged on different dates and are more commonly seen in winter months [181,315].

There is normal tracer uptake in the skeletal growth centers- particularly long bone physes [125]. Uptake in benign bone lesions can be seen, such as Pagets disease and fibrous dysplasia can be seen during their active phases [39,176]. Benign fibro-osseous lesions such as non-ossifying fibromas, fibrous cortical defects, and cortical desmoids can also demonstrate tracer uptake [149,150]. Acute (fractures less than 3 months old [111]) or actively healing fractures also show increased FDG activity [39,92]. Sacral insufficiency fractures can also demonstrate increased tracer activity and may have a linear appearance [66]. Patients with osteoarthritis or bursitis of the shoulders can show diffuse uptake about the shoulder joint [124]. Decreased skeletal activity can be seen following radiation therapy [39].

FDG uptake around the head and neck of hip prosthesis can commonly be seen in non-infected prostheses [49] (whereas  increased tracer uptake along the interface between the bone and the prosthesis is suggestive of infection [50]). The artifact is related to differences in density at the interface between the metal prosthesis (high density) and the surrounding soft tissues (low density) [51]. Because of partial volume effects, the scanner records information along this interface as an average of the two densities [51]. This leads to over-correction of the low density soft-tissues adjacent to the prosthesis [51]. This finding can be caused by motion (even of only a few millimeters) between the emission and transmission scans [51]. The use of attenuation-weighted iterative image reconstruction or software based metal artifact reduction on the CT data can minimize this finding [51,299]. Also, this artifact should not be present on non-attenuation corrected images [51].

 

Similar to other nuclear medicine examinations, an intra-arterial tracer injection will result in a "glove phenomenon" with significant activity in limb distal to the arterial injection site.

6- Gastrointestinal tract- variable activity can be seen in the GI tract- partly due to smooth muscle activity associated with peristalsis, bacterial uptake, gastrointestinal lymphoid tissue, and metabolically active mucosa [20,30,54,95]. Small bowel activity is usually heterogeneous and of low intensity [156]. Inflammatory conditions such as Crohn's disease can produce areas of increased tracer activity [156].

Metformin:

Metformin is a biguanide drug used in the treatment of type II diabetes (by decreasing glucose transport from food to plasma, decreasing glucose output form the liver and increasing glusoce uptake in peripheral tissues and enhanced glucose consumption by enterocytes), but which is also being recognized for having antineoplastic actions [270,271]. Metformin directly and indirectly activates adenosine monophosphate-activated protein kinase (AMPK) through the inhibition of mitochondrial respiratory complex I [270]. AMPK activation results in the inhibition of energy-consuming processes (such as DNA synthesis, protein synthesis, and lipid synthesis) [270]. However, AMPK activation results in the upregulation of adenosine triphosphate-producing processes (such as glucose uptake from the circulation, glycolysis, and fatty acid oxidation) [270]. Hence, metformin can produce a dose-dependent increase in tumor glucose uptake, while decreasing cell proliferation [270]. In animal models and tumor cell lines, changes in FDG uptake following metformin treatment may be misleading [270].

 Increased tracer uptake within the bowel (particularly in the colon where the uptake is typically intense, diffuse and continuous) has been reported in diabetic patients taking metformin [233,271]. The effect appears after a relatively long period of treatment [271]. The exact reasons for the increased bowel activity is unclear, but metformin has been found to enhance the transfer of glucose from the vascular compartment into the intestinal mucosal cells and increase glucose utilization [318]. The tracer uptake is in the bowel wall and not in the bowel lumen and hence cannot be cleared with a bowel prep [271]. Stopping metformin for 2 to 3 days prior to imaging can result in clearance of the intense bowel uptake [234,236,330]. Stopping the medication for only 1 day does result in decreased activity compared to not stopping the medication, but is not as effective as 48 hour discontinuance [236,330]. A drawback is that longer periods of discontinuance of the medication can result in a few patients experiencing elevated glucose levels [330]. Metformin 48 hour withdrawal may aid in evaluation of patients with abdominal malignancies, especially when disease is suspected in or in close proximity to the bowel [330].

 

Large bowel activity is common and can be focal, segmental, or diffuse [40]. Focal intense uptake in the colon is an uncommon finding (1-2% of cases) and should be further evaluated with colonoscopy to exclude a neoplastic process which can be found in a large percentage of patients (61 to 86% of focal abnormalities are found to be premalignant or malignant) [40,93,96,114,123,2227]. The visualization rate of colorectal polyps increases with polyp size and the severity of histologic dysplasia [197]. Acute diverticulitis is an inflammatory condition that can result in focal colonic uptake [96]. Segmental colonic uptake is usually related to inflammation, while diffuse uptake is usually not associated with underlying bowel abnormality [40]. Areas of active Crohn's disease will also demonstrate FDG accumulation [170]. Uptake in the cecum and right colon is usually higher than in other colonic segments [4,40]. This may be related to abundant lymphoid tissue in this region [54]. FDG accumulation can also often occur in segments or large sections of the colon after colonoscopy- possibly due to a non-specific inflamation [20]. A perirectal area of artifactually increased curvilinear tracer uptake has been described and has been felt to be related to movement of gas within the rectum [230]. An air pocket present in the rectum during the PET acquisition where there was no gas during the CT exam results in overcorrection for attenuation at the margin of the rectum [230]. Adjacent extremely high tracer concentration in the urinary bladder is felt to contribute to the artifact [230].

 

 

 

 

The stomach is usually faintly seen, but uptake can be intense - activity is seen only in the wall of the stomach (possibly related to smooth muscle activity) giving it a "ring-like" appearance [4,99,111]. However, if the stomach is not distended, uptake can appear focal- particularly in patients with prior partial gastric resection surgery [116]. Drinking a glass of water (some authors recommend 250 mL [228]) will produce gastric distention and benign uptake will generally become less conspicuous [116]. Focal gastric uptake should prompt further evaluation to exclude an underlying mass [156].

There can be normal mild FDG activity in the esophagus possibly due to swallowed saliva or smooth muscle activity and this can potentially obscure subtle lesions [11]. If the uptake in the distal esophagus is linear, but moderate to intense in activity- further evaluation should be performed to exclude Barrett esophagus [156]. There is usually a focus of moderate FDG uptake at the gastroesophageal junction- most likely related to normal contraction of the lower esophageal sphincter (which prevents reflux) [111]. Esophagitis in the distal esophagus is also a common cause of tracer accumulation [4]. However, even in patients without a specific history of esophagogastric disease, the gastric or gastroesophageal junction SUV can be as high as 4.0 (values higher than this should prompt further evaluation)[99]. None-the-less, uptake within the distal esophagus can be associated with underlying malignancy in 2-8% of patients [184]. Findings that are more suggestive of malignancy include focality (rather than linear), eccentric location, and more intense uptake [184].

 

For examinations that are co-registered with CT imaging, oral contrast can aid in confirming activity is located within bowel [30]. Oral contrast administration is associated with some increased FDG uptake in the ascending colon [30]. Also- because the contrast agent is traveling through the bowel the CT data may not exactly represent the distribution of contrast at the time of the FDG exam [30]. In principle, a mismatch of low CT density at the time of CT data acquisition and high CT contrast density at the time of FDG imaging could result in an artificially reduced FDG activity on attenuation corrected images [30].

7- Thymus: Thymic uptake is commonly seen in children (up to 73% of children prior to chemotherapy) with an SUVmax of 2.00 +/- 0.83 [98,257]. However, not all children will have visible thymic activity on FDG imaging [19]. The cause of this variability in pediatric thymic accumulation of FDG is unclear, but is likely related to physical and emotional stressors which influence thymic metabolism [19]. In general, physiologic uptake of FDG in the thymus disappears in adolescence in conjunction with involution of the thymus [19]. However, physiologic uptake in the thymus can be seen in patients well beyond puberty [98] and thymic FDG accumulation can also be seen in adult patients with a normal thymus [48].

The thymus responds to systemic stress (infection, neoplasm, chemotherapy, surgery) by rapid atrophy [257]. Once the stressful event has ended, the thymus may regrow beyond it's original size [257]. Thymic hyperplasia is one etiology for physiologic FDG accumulation in the thymus [98]. Thymic hyperplasia represents an immunologic rebound phenomenon following chemotherapy which is especially seen in young patients treated for malignancy [98]. Following chemotherapy, thymic FDG uptake can be seen in 75-80% of children and in 5% to 16% of adults [4,7,8,19,98,203]. Thymic enlargement can persist for up to 6 months (sometimes longer [257]) following completion of chemotherapy [7]. Occasionally, a lip of thymic tissue can extend above the left brachiocephalic vein- uptake in this tissue should not be confused for adenopathy [169]. [257]

There are several clues to non-pathologic thymic FDG accumulation. Normal thymic activity is usually triangular or "V" shaped (bilobed) and generally not very intense [98]- uptake values are typically less than 2.5 [48]. An SUVmax of greater than 3.4-4.0 is felt by some authors to be concerning for malignancy [257]. However, one study indicated that uptake associated with thymic hyperplasia demonstrated SUV max values of 3.73 =/- 1.22 [203]. On anatomic imaging studies, the thymus should also have a normal, homogeneous appearance [98]. Lack of uptake on the pre-therapy scan should also be a clue to post-treatment thymic hyperplasia [98].

FDG accumulation in the thymus suggests pathology when it does not have a typical triangular shape or if the activity is very intense (SUV max greater than 4.0 [98]) [19].

8- Bone marrow- faint activity is generally identified within the bone marrow [7]. The accumulation is generally homogeneous and has SUV ratios between 0.7 to 1.3 [7]. Bone marrow activity that is greater in intensity than the liver is considered abnormal [39]. Increased bone marrow activity can be seen with bone marrow recovery following chemotherapy, but this usually resolves by one month post-therapy [4]. Treatment with granulocyte stimulating factors (Filgrastim [Neupogen- daily dose] and Pegfilgrastim [Neulasta- single dose]) can also produce diffuse skeletal FDG accumulation [9,142] which can interfere with accurate PET imaging by decreasing the bioavailability of FDG to the tumor [79,142,167]. Both agents also result in increased splenic FDG accumulation [142]. Elevated marrow activity may persist in some patients for up to 20 days in some patients [79]. Both agents also result in increase splenic FDG accumulation [142]. Separating PET imaging from short acting colony stimulating factor therapy by a minimum of 5 days is recommended [79] and up to 30 days may be required for long acting agents [147].

Radiation treatment can also affect marrow activity. In an animal model following XRT, the irradiated bone marrow shows a significant increase in FDG accumulation over baseline on day 1, a significant decrease on day 9, and a return to normal between 18 and 30 days [12,13].

 

9- Thyroid- Normally, FDG uptake in the thyroid gland is low or absent as fatty acids are the primary metabolic substrate [166]. Incidental diffuse thyroid uptake can be seen in 0.6 to 3.3% of patients [166]. Diffuse uptake occurs in association with chronic lymphocytic thyroiditis (Hashimoto's) [166] or Graves' disease and is generally felt to be a benign finding [140]. It has also been suggested that diffuse increased tracer uptake is associated with decreased attenuation of the thyroid on CT- possibly related to inflammatory cellular infiltration of the thyroid gland (normally the thyroid is of higher attenuation due to the presence of iodine within the gland) [225].

Incidental focal uptake of FDG in the thyroid can be seen in about 2% to 4.3% of scans and is associated with autonomously functioning thyroid nodules and thyroid malignancies [31,120,140]. Patients with focal uptake should be further evaluated due to a higher risk of the finding being associated with thyroid malignancy (21-57% risk for malignancy and most commonly papillary carcinoma) [31,112,120,140,166,185,335]. However, the maximum SUV of thyroid cancer is not statistically higher than that of benign lesions [185]. Benign lesions associated with uptake include degenerate nodules, follicular adenomas, and adenomatous hyperplasia [327]. Oncocytic/Hurthle cell lesions demonstrate intense FDG uptake and this is related to an intrinsic mitochondrial defect driving inefficient glycolytic metabolism [327].

In patients with focal thyroid uptake, correlation with targeted thyroid ultrasound can provide additional information as nodules with benign sonographic features are much less likely to be malignant on biopsy [185]. Other authors recommend that a decision to pursue further evaluation of focal thyroid uptake should also be based on the patient's overall prognosis- which may be poor due to their underlying primary malignancy [327].

10- Lymph nodes- nodal uptake can occur if the agent extravasates into the soft tissues at the site of injection (always inject in arm opposite primary lesion) [4]. Lymphoid tissue can also demonstrate significant uptake- particularly the tonsils and adenoids [20]. Nodal uptake is also seen in patients with sarcoidosis- probably related to activated macrophages within granulomas [80,81]. In sarcoid, the degree of uptake has been related to disease activity and to document response to therapy [80,81].

11- Gonads/Ovary/Uterus/Endometrium-

Male gonadal activity can be seen and is quite variable. The normal prostate gland usually demonstrates homogeneously low level FDG uptake [324]. Incidental uptake in the prostate can be seen in about 1.2-2% of male patients without known prostate cancer and occult prostate cancer can be found in 5-23% of cases [261,314]. The likelihood of cancer in incidental focal prostate uptake has been shown to be related the patients PSA level (incidence of cancer was about 4% with PSA of less than 2.5 and almost 60% with a PSA greater than or equal to 2.5 [314]. Other authors suggest that incidental focal prostate uptake can be found in 1.8% of FDG PET exams and has a significant risk for malignancy of 62$ [324].

Faint uterine (endometrial) activity is common. In premenopausal patients, greater endometrial accumulation can be seen in the uterus during menstruation and ovulation (mid-cycle)- typically days 0-4 and approximately day 14, respectively [20,77,318]. Uptake is lower during the proliferative and secretory phases [77]. This is because the first half of the uterine cycle is characterized by increased glycolysis under the stimulation of estrogen and glycogen synthetase, while the second half is characterized by breakdown of glucose under glycogen phosphorylase activity [129]. Mean endometrial SUV in premenopausal women has been reported to be 5+/- 3.2 during menstruation, and 3.7 +/- 0.9 during the ovulatory phase [227].

Only mild endometrial activity may be seen in post-menopausal women (mean endometrial SUV is about 1.7 +/- 0.5) and does not seem to be significantly affected by hormone or anti-breast cancer hormone therapy [77]. Therefore, increased endometrial FDG uptake in postmenopausal women should be viewed as suspicious and may indicate malignancy [227,318].

Uterine fibroids usually show mild FDG uptake, however, they are also known to occasionally show increased FDG activity (up to 18%)  [176,227]. There can even be variable heterogeneous uptake within the same fibroid [318]. Fibroids with increased FDG uptake are more common in premenopausal than postmenopausal women [227]. In premenopausal women, fibroids tend to show higher uptake during the lureal phase than during the menstrual, follicular, and preiovulatory phases [227].

Adenomyosis generally shows mild FDG uptake in premenopausal women and the uptake is often higher during the menstruating and ovulating phases [227].

Increased ovarian uptake can be normal in premenopausal patients and is associated with ovulation and corpus luteal cysts- and is postulated to be due to an inflammatory reaction involving cytokines during the ovulatory process to increase glucose uptake to meet the metabolic demands of the growing follicle [77,214,218]. Ovarian uptake in post-menopausal women is associated with malignancy and should always prompt further evaluation [77]. Symmetric uptake in the fallopian tubes has also been described in premenopausal women at mid-menstrual cycle [223].

 

12- Degenerative joint disease and degenerative disk disease can be associated with increased tracer accumulation [146]. Incidental uptake suggestive of degenerative changes in the spine can be seen in up to 22% of patients [146]. The lumbosacral spine is the most common location and the severity of uptake correlates with the severity of the degenerative changes noted on CT [146]. The FDG accumulation is likely related to the inflammatory process that accompanies degenerative joint disease [146]. PET/CT aids in proper localization of the uptake so that it is not mistaken for metastatic disease [146].

13- Vascular activity- in scans not corrected for transmission, vascular activity in the large vessels in the thighs and pelvis can be seen in about 80% of patients [10]. On attenuation corrected images mild vascular activity can be seen in association with severe atherosclerotic disease or aneurysms [39]. Vascular uptake likely reflects active atherosclerosis [68,186,248] and is probably related to the presence of macrophages within the plaque [89,97,119,199,202]. FDG vascular uptake is rarely seen in areas of vessel calcification [248]. High carotid FDG uptake is commonly associated with increased clinical risk factors and the presence of vessels with ¹⁸F-FDG uptake has also been associated with greater atherogenic risk/acute plaque events such as stroke or MI [186,248,250,285]. This is because vulnerable plaques have a large, hypoxic, metabolically active core containing lipid, oxidized lipid, and inflammatory cells (predominantly macrophages) [199]. Vulnerable lesions have a thin fibrous cap that can be weakened by the secretion of proteolytic enzymes from the inflammatory cells [199].  Atherogenic uptake can be decreased with life style modifcation and the magnitude of decreased activity appears to correlate with increased plasma HDL [186]. Vascular uptake is also seen in association with thrombophlebitis (which can be very intense) [39], vasculitis [97,115], and has been described in pulmonary embolism [171].

Vascular grafts also demonstrate mild tracer accumulation, as do sites of endarterectomy [39]. In one study, high FDG accumulation was identified in 75% of non-infected aortic vascular grafts placed by open surgery (and in one of 4 grafts placed endovascularly) [189]. In another study, diffuse FDG uptake was found in 92% of non-infected vascular prostheses and uptake was seen for up to 16 years with no change in intensity [286]. Uptake in vascular grafts is likely the result of a sterile foreign-body inflammatory reaction [286].

Injections performed via a port-a-cath will show retained activity in the hub and also along the course of the catheter [39].

 

 

14- Breasts- Incidental foci of tracer uptake in the breast can be seen in 0.36%to 1.1% of PET scans [247]. Any focal area of increased tracer accumulation in the breast should prompt further evaluation to exclude an underlying malignancy [144,334] (incidental focal breast uptake is associated with malignancy in 37.5 to 57% of patients (however, a malignancy rate as high as 83% has been reported)  [247]). Variable uptake can be seen within glandular tissue [20,61]. Higher FDG uptake is seen in women with dense breasts (larger amount of glandular tissue) and in women on hormone replacement [61]. The maximum peak SUV observed in dense breasts can be as high as 1.39 [61] (in another study the average SUVmax of dense breasts was 1.24 [215]). The average SUV is typically 0.50 to 0.69 [61,215]. The nipples also normally demonstrate FDG activity- especially on non-attenuation corrected images [111]. High uptake of FDG can be seen in the lactating breast due to intracellular trapping within active glandular tissue [21].

There is low excretion of FDG into breast milk and the estimated cumulative dose to a breast fed infant is approximately 0.085 mSv (well below the 1 mSv recommended for cessation of breast-feeding) [21,276]. The ICRP does not recommend interruption of breast feeding after FDG administration [276]. Although the amount of radioactivity within breast milk is low, the retained activity within the breast poses a direct and significant source of radiation exposure to the nursing infant [21].Therefore, close contact with the infant should be avoided for 12 hours following tracer injection [21,276]. It is recommended that the infant be breastfed just before injection, to maximize the time between injection and the next feeding [276]. Milk pumped from the breast may also be fed to the infant via a bottle [276].

15- Spleen- Diffusely increased splenic FDG uptake can be seen in association with granulocyte colony-stimulating factor treatment [32,33].

16- Benign adrenal lesions: Adrenal masses are not rare in the general population (2-9%), however, the adrenal is also a common site of metastases in cancer patients [190]. In general, lack of FDG uptake in an adrenal lesion is highly predictive of a benign etiology (NPV 93%). Unfortunately, benign adrenal adenomas and rarely adrenal myelolipomas (hematopoietic elements) can have uptake of FDG equal to or greater than the liver resulting in a false positive exam in (between 5% to 15% of adrenal adenomas/benign adrenal nodules demonstrate false positive FDG uptake) [135,137,155,165,176,190]. False negative exams can also occur with neuroendocrine metastases, small lesions, necrotic/hemorrhagic lesions, and in patients that have received previous therapy [135,155,190]. Generally, however, adenomas demonstrate only mild tracer accumulation that is less than liver activity, but greater than background [135], whereas malignant lesions will show uptake that is greater than liver activity [155].

The use of PET/CT can improve characterization of adrenal masses by improving the exams specificity [136,155]. Using activity equal to or greater than the liver to indicate malignancy, PET/CT imaging has a sensitivity of 83-100%, a specificity of 85-97%, a PPV of 67-87%, and an NPV of 93-100% for the characterization of adrenal lesions [190,198]. A cutoff SUV of 3.1 has been suggested to have a sensitivity of 98.5% and a specificity of 92% for characterization of malignant adrenal lesions [136].  However, between 3-10% of benign adrenal lesions will demonstrate increased FDG accumulation [198]. PET/CT permits further characterization of the lesion with an HU measurement of less than 10 indicative of a benign adrenal lesion [136,137,155].

17- Inflammation- FDG accumulation can be seen at sites of inflammation. The increased accumulation is probably related to a markedly increased rate of glycolysis within activated inflammatory cells. Talc pleurodesis produces a visceral and parietal pleural granulomatous inflammation. Increased FDG activity has been reported in sites of pleural talc (up to 3 years following the procedure)- presumably secondary to pleural inflammation [71,72]. Diffuse increased FDG accumulation in the lungs can be seen in association with bleomycin pulmonary toxicity [104]. Pulmonary accumulation of FDG has also been described in patients with idiopathic pulmonary fibrosis - particularly in regions of reticulation/honeycombing [201].

Mesh used for hernia repairs can also be associated with FDG accumulation and can be seen for several years (SUV max 2.8 to 5.6) [108]. The uptake is likely associated with a foreign body granulomatous reaction and it seems to be more intense with polypropylene mesh compared to polytetrafluoroethylene mesh [108].

18- Hilar uptake- bilateral hilar uptake of FDG has been reported in patients without lung cancer [187]. Findings that suggest a benign etiology include symmetric, low level (SUV max < 3) hilar uptake [187]. Asymmetric uptake and the presence of uptake in other mediastinal nodes should raise the degree of suspicion for malignancy [187].

Other agents used for oncologic imaging:

¹⁸F-Fluoride:

¹⁸F-fluoride (¹⁸F-NaF) is a bone imaging agent used for PET [78]. ¹⁸F-fluoride is produced by 11-MeV proton irradiation of ¹⁸O-water in a tantalum target body using a cyclotron [237]. The irradiated aqueous solution containing ¹⁸F-fluoride is diluted with sterile water and passed through cation and anion exchange cartridges to trap the ¹⁸F-fluoride [237].

¹⁸F-NaF is an analog of the hydroxyl group in hydroxapatite bone crystals (fluoride ions replace the hydroxyl ions in hydroxyapatite) [324,336]. After diffusing into the extracellular fluid of bone, the fluoride ion is exchanged for a hydroxyl group on the hydroxyapatite crystal bone and forms fluoroapatite which then incorporated into the bone matrix on the bone surface [78,122,180,324]. Tracer uptake correlates with bone remodeling and osteoblastic activity, as well as blood flow [324]. ¹⁸F-NaF has a biodistribution similar to Tc-99m-MDP, but it's lower protein binding in the blood (about 30% of the Tc-MDP is protein bound immediately after injection) allows a more rapid single pass extraction by bone (nearly 100% first-pass extraction by bone [336]) and fast clearance from the soft tissues (thus permitting earlier imaging- as early as one hour following injection) [249,289,294,336].

Ion exchange is the mechanism of uptake and blood flow is the rate limiting step in the transfer of fluoride ions from the blood to bone [313].  About 50% of the injected dose localizes to bone and essentially, all the ¹⁸F-fluoride that is delivered to bone is retained in the bone [177]. ¹⁸F ions exchange with hydroxyl ions (OH^-) on the surface of the hydroxyapatite to form fluoroapatite [294]. However, as the actual process of binding to bone takes hours to days, during one hour post injection imaging the agent is unlikely to have been incorporated into bone, but rather it is likely bound within the bone's extracellular fluid [263]. Bone uptake of the fluoride ion is two-fold higher than that of  ^99mTc-polyphosphonates and because it is not protein bound there is faster blood clearance (resulting in a better target-to-background ratio) [78,122,219,249]. Tracer uptake is higher in new bone because of higher availability of binding sites [232]. The concentration of ¹⁸F-NaF is 10 times higher in area s of regenerating bone, compared to areas of normal bone [294]. Local or regional hyperemia may also cause increased tracer localization in the skeleton [232]. Processes that result in minimal osteoblastic activity, or primaily osteolytic activity, may not be detected [232].

Following IV administration, the agent is rapidly cleared from the plasma in a biexponential manner [177] and excreted by the kidneys [237]. The first phase has a half-life of 0.4 hours and the second phase has a half-life of 2.6 hours [177]. The rate limiting step of ¹⁸F-NaF uptake is blood flow as almost all of the agent is retained in bone after a single pass [237,261]. One hour after administration, only about 10% of the injected dose remains in the blood [177,313]. There is negligible plasma protein binding of the agent [237,289]. Fluoride ions are freely filtered in the glomeruli, but fluoride also undergoes tubular resorption and the tubular absorption increases with decreasing GFR [275].

The rapid uptake and clearance allow earlier imaging (typically within one hour [as early as 30-45 minutes following administration]) with an improved target-to-background ratio and better image quality compared to Tc-MDP [177,219,249]. Another benefit of PET compared to gamma camera imaging is the improved spatial resolution (4-5mm) compared to 10-15 mm for Tc-MDP imaging [219,249]. On average, 15 +/- 5% of the whole body activity is excreted into the urinary bladder [263]. Urinary excretion of the agent can result in image artifacts that may obscure lesions in the sacrum or lower pelvis- hence patients should void prior to imaging [177]. The spatial resolution of ¹⁸F-fluoride is also superior to standard bone scanning [78]. ¹⁸F-fluoride imaging has been shown to be more sensitive and specific in detecting skeletal metastases than planar or SPECT MDP bone imaging [177,288,289]. In a meta-analysis comparing bone scan with ¹⁸F-fluoride PET, the pooled sensitivity and specificity for ¹⁸F-fluoride were 96 and 98%, respectively, compared to 57% and 98%, respectively for bone scan [288]. In the National Oncologic PET registry study, NaF PET scan results were associated with a change in management in 40% of patients - particularly prostate and breast cancer patients [297]. However, another study suggested that although ¹⁸F-fluoride PET/CT can result in a significant reduction in equivocal readings compared to planar bone scan, it may not have a significant impact on changing tumor staging [325].

¹⁸F-Fluoride is very sensitive for the detection of both lytic and sclerotic bone lesions, however, the agent is not tumor specific and benign bone lesions (degenerative change, fractures, Pagets disease, enchondroma, and osteoma) will also demonstrate increased tracer uptake [78]. ¹⁸F-fluoride is more likely to detect skeletal metastases from tumors that typically have low FDG activity [177]. FDG PET is more likely to detect bone marrow metastases or small osteolytic lesions (lesions with little or no increase in cortical turnover) [177].  Improved specificity is seen when the ¹⁸F-fluoride scan is interpreted with a fused CT exam [78,133]. Lesions that measure less than 3 mm have limited detectability on ¹⁸F-fluoride PET [177]. A combined ¹⁸F-fluoride and ¹⁸F-FDG scan protocol has been proposed to maximize the strengths of each agent [200]. A "flare" phenomenon can be seen in patients with breast cancer following initiation of therapy [177]. 3-phase imaging is not presently possible [177].

Patients should be well hydrated for the exam to promote rapid renal excretion of the agent- decreasing radiation dose and improving image quality [232]. Unless contraindicated, patients should drink 2 or more 8-oz glasses of water within 1 hour before the exam, and another 2 or more glasses of water after tracer administration [232]. No fasting is necessary and patients may receive their usual medication [294].  The bladder should be emptied immediately prior to imaging [232]. Scanning is performed 60 +/- 30 minutes minutes after the injection of 8-12 mCi (2.1 MBq/kg) of ¹⁸F-fluoride [78,177,262]. The SNM practice guidelines indicate that the adult dose should be 185-370 MBq (5-10 mCi) with the higher dose being used in obese patients [232]. Pediatric activity should be weight based (2.22 MBq/kg or 0.06 mCi/kg) using a range of 18.5-185 MBq (0.5-5 mCi - the pediatric dose should not exceed 5 mCi) [232,294]. To obtain high quality images of the extremities, a longer delay (90-120 minutes) may be required [232,263]. The total imaging time is 15-30 minutes- therefore an entire exam can be completed in approximately one hour [177]. The SNM guidelines indicate that in patients with normal BMI, good images of the axial skeleton can be obtained with an acquisition time of 3 min/bed position starting 45 minutes after the injection of 5 mCi of ¹⁸F [232]. Good whole body imaging can be obtained with using 3 min/bed position starting 2 hours after injection of 10 mCi of ¹⁸F [232].

Radiation dosimetry: There is little overall difference in the estimated radiation dose for ¹⁸F-fluoride and Tc-MDP scintigraphy [177], however, other authors indicate that the dose from a ¹⁸F-NaF bone scan is higher than that from a Tc-MDP bone scan [294]. Although the radiation absorbed dose from the agent is higher, a lower dose can be used and the actual absorbed dose is similar to that from MDP bone scanning [249]. ¹⁸F-fluoride delivers radiation from both the emitted positron (mean energy 250 keV) and the two 511 keV annihilation protons [177]. The proton will deposit essentially all of its kinetic energy in the source organ, while the 511 keV photons have a soft-tissue half value layer of 7.3 cm- meaning energy will be delivered to, as well as distant from, the source organ (140 keV photons of Tc-99m deposit most of their energy in the source organ) [177]. However, ¹⁸F has a shorter half-life than Tc99m (110 minutes versus 6 hours) so there is a shorter period of exposure [177]. For a 70 kg patient the effective dose from a ¹⁸F-fluoride exam is about 4.0 mSv (compared to 3.0 mSv from a Tc-MDP exam) [177], although other authors report the dose from a 10 mCi scan to be 8.9 mSv (compared to 5.3 mSv from a 25 mCi Tc-MDP scan) [275,294,324]. An additional 1.0-4.0 mSv dose is incurred if CT is used for attenuation correction and anatomic localization [289,294]. The urinary bladder receives the highest dose, followed by the bone surfaces and red marrow (compared to Tc-MDP in which the bone surface receives the highest radiation dose) [262,275,289,294].

In the National Oncology PET registry trial, ¹⁸F-fluoride PET/CT changed management from non-treatment to treatment in 47% of patients at initial staging, 44% of patients with suspected first bone metastasis, and 52% of patients with suspected progressive disease [336].

Both benign and malignant bone lesions will demonstrate ¹⁸F-NaF uptake, including fibrous dysplasia and vertebral hemagiomas [294,309]. Extraosseous uptake of ¹⁸F-NaF can be seen in the arterial vasculature (likely related to atherosclerotic calcification), gastrointestinal tract, and genitourinary tract (due to urinary bexcretion) [294]. Uptake can be seen in large and small bowel and the etiology is uncertain [294]. Similar to MDP, NaF imaging can be subject to a flare phenomena associated with successful systemic therapy [297].

Combined ¹⁸F-Fluoride and ¹⁸F-FDG PET/CT scanning: Co-injected combined ¹⁸F-Fluoride and ¹⁸F-FDG imaging has been studied as an optimum method for the detection of both lytic and blastic bone metastases [267,268,303]. Both agents are injected simultaneously using approximately 10-15 mCi of FDG and 5 mCi of ¹⁸F-Fluoride [268,303]. In patients with breast and prostate cancer, combine imaging has been shown to be superior to Tc-MDP scintigraphy and whole body MRI for the evaluation of skeletal disease [303]. However, certain lesions may become less conspicuous on comboned imaging exams [268]. Small lung nodules seen on FDG imaging, may become less evident on combined imaging and metastatic foci in the skull may also not be identified [268]. Another limitation is that, it is not possible to determine if ¹⁸F-Fluoride positive/ ¹⁸F-FDG negative bone lesions represent viable tumor versus an osteoblastic response to therapy, unless a baseline scan is available for comparison [267,268].

Somatostatin receptor imaging agents:

⁶⁸Ga-DOTA-Tyr³-Octreotide (⁶⁸Ga-DOTA-TOC), ⁶⁸Ga-DOTA-Tyr³-Octreotate (⁶⁸Ga-DOTA-TATE), ⁶⁸Ga-DOTA-[1-naI3]-Octreotide (⁶⁸Ga-DOTANOC):

These agents specifically bind to somatostatin receptors and can be used for imaging neuroendocrine neoplasms which are frequently not well evaluated on FDG imaging due to a low proliferation rate [161,162,216]. Most well-differentiated neuroendocrine tumors express a high density of surface somatostatin receptors that allow imaging with somatostatin receptor scintigraphy [208].

 ⁶⁸Ga is conveniently produced by a ⁶⁸Ge/⁶⁸Ga generator [175].  ⁶⁸Ge with a long half-life (270.8 days) produces the short-lived ⁶⁸Ga (T_1/2= 67.71 min) [162,175]. ⁶⁸Ga is an excellent positron emitter with 89% positron branching accompanied by a low photon emission 1,077 keV, 3.22%) that decays to stable ⁶⁸Zn [175]. Labeling is straightforward and can be performed in a very short time (under 30 minutes) with good labeling efficiency [161,162]- although the eluate from the commercial generator still contains measurable activities of long lived ⁶⁸Ge [175].

Prior to performing PET imaging with ⁶⁸Ga, it is important to be sure that the PET system is properly calibrated for the agent (most PET systems are calibrated for ¹⁸F), otherwise, SUV measurements can be underestimated by an average of 15% [328]. ⁶⁸Ga has a higher energy positron than ¹⁸F (1.9 MeV vs 0.63 MeV) and will travel further prior to an annihilation reaction [328]. Additionally, ⁶⁸Ga is accompanied by a prompt 1.08 MeV gamma emission of approximately 3% abundance which complicates the emission spectrum [328].

⁶⁸Ge-labeled somatostatin analog peptides clear rapidly from the blood, with reported peak tumor uptake occurring at about 70 minutes and no radioactive metabolites detected in the serum at 4 hours [278].The normal biodistribution of the agent is the spleen, liver, and GU tract due to excretion [161]. Uptake is also seen in the pituitary, adrenal glands, and in the normal pancreatic head (up to 68% of patients) [161]. Faint activity can be seen in the salivary tissue and GI tract [161].  ⁶⁸Ga-DOTANOC uptake has also been reported in the fibrotic areas of the lungs in patients with interstitial lung disease [239]. The optimal imaging time is 100 minutes following injection [161]. The agent shows a very high affinity for somatostatin receptors 2 and 5 [162].  The agent has been shown to be superior to conventional CT imaging and octreotide SPECT imaging for the evaluation of neuroendocrine tumors with a sensitivity of 97%, specificity of 92%, and an accuracy of 96% on a per patient basis [161]. ⁶⁸Ga-DOTA-TOC imaging can provide further clinically relevant information in up to 14% of patients compared to SPECT, and up to 21% of patients compared to conventional CT imaging [161]. Uptake does not appear to be influenced by the functional status of the tumor [162].

Interestingly, the agent ⁶⁸Ga-DOTA-TATE can also demonstrate macrophage active plaque within vessels- even the coronary arteries [212]. This is related to the expression of somatostatin subtype 2 receptors on macrophages and the lack of physiologic cardiac uptake of the agent [212].

Gluc-Lys ([¹⁸F]FP)-TOCA:

Gluc-Lys ([¹⁸F]FP)-TOCA is an agent that can be used for somatostatin receptor imaging [139]. [¹¹¹In]DTPA-octreotide imaging is limited by delayed imaging, high physiologic uptake in the liver and kidneys, and the low spatial resolution of SPECT imaging [139]. ([¹⁸F]FP)-TOCA has low lipophicity, rapid renal tracer elimination, low liver and intestinal uptake, and rapid tumor uptake (by about 30 minutes) resulting in excellent tumor-to-non-tumor ratios [139]. Imaging should be initiated between 30-40 minutes following tracer injection [139]. Whole body radiation exposure is about 1.3 mSv/100MBq (compared to 8 mSv/100 MBq with [¹¹¹In]DTPA-octreotide) [139]. In a comparison with [¹¹¹In]DTPA-octreotide imaging, PET detected over twice as many lesions [139]. The drawbacks of the agent are that it requires a long multi-step preparation and there is limited radiochemical yield (20-30%) [139].

 Amino Acids and Other Agents:

Amino acid transport and protein synthesis are generally increased in malignant cells and amino acid imaging is less influenced by inflammation [18,56]. Amino acid transporters mediate transfer of amino acids across cell membranes [280]. Two amino acid transporters, the system L transporter type I (LAT1, SLC7A5) and the system ASC transporter type 2 (ASCT2, SLC1A5) are upregulated in a wide range of human cancers, are associated with a worse prognosis, and are potential targets for tumor therapy [280]. The replacement of a carbon atom by ¹¹C does not chemically change the molecule [18]. Amino acid agents can cross an intact BBB and typically have low CNS uptake which provides good contrast with tumor uptake (compared to FDG which has significant CNS activity) [18,280,290]. The uptake is mediated by increased type L amino acid carriers (facilitated transport is upregulated due to increased transporter expression in tumor vasculature and does not depend on a breakdown in the blood-brain barrier [290]. Images are usually performed within the first hour after tracer administration and patients should be fasting prior to the exam [18]. However, the optimal dietary state for imaging has not yet been clearly defined and tumor uptake of certain amino acids may be promoted by preloading with other amino acids such as tryptophan [34]. Tumor hypoxia decreases uptake of amino acids (unlike FDG uptake which is increased by tumor hypoxia) [26].

¹⁸F-fluorodeoxythymidine:

Tumor growth rate is a useful prognostic indicator of tumor aggressiveness and tumor response to therapy [70]. Cell lines and tissues with a high proliferation rate require high rates of DNA synthesis [70]. Thymidine is incorporated into DNA, but not RNA [279]. PET imaging can be used to measure tumor cell proliferation using thymidine analogs.

¹⁸F-fluorodeoxythymidine (¹⁸F-FLT) is an amino acid agent labeled with ¹⁸F that can be used to measure tumor cell proliferation [35,63]. The agent is transported into the cell by the same nucleoside carriers as thymidine [84]. The agent is then phosphylated within the cell by thymidine kinase-1 (TK₁) which is upregulated in rapidly dividing tumor cells especially during the S-phase of the cell cycle (thymidine kinase activity is a marker of cellular proliferation and TK₁ activity increased almost 10-fold during DNA synthesis) [35,69,151,274]. There is prolonged intracellular retention of ¹⁸F-fluorodeoxythymidine because it is polar and cannot cross the cell membrane and it is also very resistant to catabolism by thymidine phosphorylase [35]. Only minimal amounts of  ¹⁸F-FLT is incorporated into DNA (0.2% to less than 1%) because the agent lacks a 3'-hydroxyl group which is essential for chain propagation [100,102,152, 279]. Imaging is started approximately 60 minutes following tracer administration [138].

Normal ¹⁸F-FLT high uptake can be seen high proliferating tissue such as the bone marrow [279]. High liver activity is seen because FLT anabolism occurs primarily in the liver to produce a glucuronide conjugate that is exported to the blood and cleared by the kidneys (which results in renal and genitourinary activity) [152]. The organs receiving the largest radiation dose from ¹⁸F-FLT are the urinary bladder (abour 650 mrad/mCi) and the liver (about 200 mrad/mCi) [65]. The effective dose equivalent is about 100-120 mrad/mCi [65].

¹⁸F-FLT has limited ability to image the bone marrow (because of intense uptake associated with normal cellular proliferation) and the liver (because of glucuronidation) [64,69]. Minor intestinal uptake can be observed [69]. Generally, there is no uptake within the brain (the agent does not cross the blood brain barrier) or myocardium [69,94,279]. Therefore, FLT may be more favorable than FDG for imaging brain metastases [109]. However, one must keep in mind that breakdown of the blood brain barrier can lead to increased activity in the absence of cell proliferation [279]. Because of the high marrow uptake, FLT imaging can actually be used to measure health and proliferative marrow- especially in patients undergoing bone marrow transplantation [279].

Overall, however, uptake of ¹⁸F-FLT within malignant lesions appears to be less than ¹⁸F-FDG uptake and there is an increased risk for false negative exams (tumor uptake of FLT, as measured by SUV values, is only about half that of FDG) [63,138,224,279]. Unfortunately, due to it's lower sensitivity compared to FDG, FLT is not useful for staging and restaging lung cancer [94,138] and esophageal cancer [105]. It has also been shown to have low specificity and low positive predictive value in the evaluation of lymph node metastases in patients with head and neck cancers due to non-specific accumulation in reactive nodes [165]. However, ¹⁸F-FLT appears to have utility in the imaging of CNS neoplasms due to its low basal CNS uptake which allows better delineation of lesions compared to FDG CNS imaging [117]. See also CNS tumor imaging

Unlike FDG, there is little accumulation of FLT in areas of inflammation [84]. However, accumulation at inflammatory sites has been reported and can lead to false positive exams [138]. Inflammatory lung disease can be associated with lymphocytic infiltrates and involve growth factors that lead to increased proliferation [138]. FLT accumulation at sites of inflammation appears to be related to: 1) High proliferation rates of B-lymphocytes and macrophages; and 2) Nonspecific increased accumulation due to increased perfusion and vascular permeability [138,229]. Non-tumoral uptake has also been described in reactive lymph nodes- likely due to the proliferation of reactive B-lymphocytes [].

¹⁸F-2'-fluoro-5-methyl-l-beta-D-arabinofuranosyluracil (FMAU):

¹⁸F-FMAU is a thymidine analog that is phosphorylated by thymidine kinase and incorporated in DNA [261]. FMAU is preferentially phosphorlyated by the mitochondrial TK2 in comparison with cytosolic TK1 [261]. The agent is useful for imaging tumor proliferation and for imaging reporter gene expression using herpes simplex virus type 1 TK system [261]. FMAU is resistant to degradation, undergoes rapid blood clearance, and has very little accumulation in bone and in the urinary bladder [261].

¹⁸F-fluoro-L-tyrosine:

¹⁸F-fluoro-L-tyrosine (¹⁸F-TYR) is an agent that can be used to assess the rate of protein synthesis within malignant lesions [56]. The agent is not actually incorporated into proteins, but exhibits high uptake in tumor cells due to increased transport via the amino acid transport system [106,132]. The agent has low uptake in inflammatory conditions thus promising a higher specificity for the detection of malignancy [106,132]. There is high uptake in the pancreas, the salivary glands, and to a lesser extent within the liver which can hamper detection of lesions in these areas [56]. FDG PET imaging is superior to ¹⁸F-TYR for staging NSCLC, head and neck tumors, and lymphoma [56,132]. Overall, ¹⁸F-TYR has been shown to be inferior to FDG for general tumor evaluation [106], but can be used for CNS tumor evaluation [163]. The agent is also taken up in meningiomas [164].

¹⁸F-fluoroacetate:

¹⁸F-fluoroacetate may be an alternative to ¹¹C-acetate for prostate cancer imaging [160]. However, fluoroacetate is a toxic compound that occurs naturally- the human median lethal dose (LD₅₀) is approximately 2-10 mg/kg [160]. Fortunately, the amount given in association with ¹⁸F PET imaging is 10^-6 times BELOW the human LD₅₀ [160].

¹⁸F-fluorodihydroxyphenylalanine (DOPA):

¹⁸F-FDOPA (an analog of L-DOPA) is an agent being explored for imaging of neuroendocrine tumors (APUD tumors- amine precursor utake and decarboxylation) [87,172]. The agents use is based on the capacity of endocrine tumor cells to take up, decarboxylate (via amino acid decarboxylase- an enzyme that is strongly expressed in neuroendocrine tumors [182]), and store amino acids such as dihydroxyphenylalanine [148]. The agent enters the cell through the amino acid transport systems for large neutral amino acids [182]. For the examination, patients should fast for at least 6 hours prior to the study [148]. The dose is 5MBq/kg body mass. Immediately following injection a set of images over the abdomen is obtained prior to excretion of FDOPA by the biliary tree which is seen on images obtained after 1 hour [148]. Normal tracer uptake can be seen in the striatum and pancreas, and there is elimination via the biliary (resulting in gallbladder visualization), digestive, and urinary tracts (kidneys and urinary bladder are seen) [148,182]. Liver and myocardial uptake are generally faint [173]. Low level uptake can be observed in the small intestine and peripheral muscles [182]. In children, some uptake in the growth plates can be seen [182]. Pancreatic uptake can be nearly completely blocked by the administration of carbidopa [182]. There is minimal uptake in the normal adrenal medulla [182]. The radiation dose is estimated to be 0.02 mSv/MBq [182]. The agent has demonstrated superior performance for lesion identification compared to somatostatin receptor scintigraphy (overall sensitivity for ¹⁸F-FDOPA about 85% compared to 58% for SRS) [87]. ¹⁸F-FDOPA has been shown to be superior to CT in the detection of skeletal metastases [87]. ¹⁸F-FDOPA exam findings can alter patient management in up to 30% of cases [87].

¹⁸F-FDOPA has also been shown to be highly accurate for the evaluation of CNS neoplasms [141] due to the excellent visualization of both high-grade and low-grade brain tumors [231]. ¹⁸F-FDOPA is brought into tumor cells via amino acid transporters [231]. ¹⁸F-FDOPA uptake is higher in high grade compared to low grade lesions [231].

Carbidopa is routinely used for ¹⁸F-FDOPA neurologic imaging as it increases striatal uptake, mainly by increasing the agents plasma concentration via decreased renal excretion [182].

¹⁸F-17beta-estradiol (FES):

The agent is an analog of estradiol and binds with high affinity to the antigen receptor in breast cancer [196].

¹⁸F-fluciclovine: The agent is a leucine analog that depicts amino acid transport into cells [322]. It has been used for the detection of recurrent prostate cancer [322]. The agent demonstrates rapid tumor uptake and gradual decrease avidity over time that may be due to tracer clearance from tumor cells as the agent is not modified intracellularly [322]. The agent has prominent physiologic hepatic uptake that can degrade detection of liver metastases [322]. See also discussion in prostate cancer section.

¹⁸F-fibroblast activation protein inhibitors (FAPI): Cancer-associated fibroblasts play a role in the development of an immunosuppressive tumor microenvironment by creating a dense desmoplastic stroma that excludes T-cells from tumor deposits and through secretion of various chemokines that recruit myeloid-derived suppressor cells and regulatory T cells [338,341]. Fibroblast activation protein (FAP) has been shown to be up-regulated in the stroma of more than 90% of epithelial cancers [340]. FAP expression is associated with increased local tumor invasion, increased risk of lymph node metastases, and decreased survival [340]. However, FAP can also be expressed in benign diseases and in normal tissues during remodeling including stromal cells and mesenchymal cells during embryogenesis, wound healing, fibrotic reactions, and inflammatory conditions such as arthritis, atherosclerotic plaques, and fibrosis (such as following myocardial infarction) [340].

FAPI's are peptidomimetic quinoline derivatives that bind with high affinity to fibroblast activation protein expressed on cancer-associated fibroblasts [338]. Hence, these agents will depict the tumor stroma, whereas FDG imaging shows tumor cell glycolysis [338].

FAPI sensitivity is affected by the amount of tumor stroma (the supporting tumor stroma is typically significantly larger than the tumor volume) and the level of FAP expression [338]. Specificity is limited by FAP expression in wound healing, active inflammation, fibrosis (such as in the liver in cirrhosis and in the lung with ILD), and high fibroblastic activity in normal tissues (such as the endometrium) [338]. Background organs with low FAPI uptake (but high FDG uptake) include the brain, liver, digestive system, and the head and neck mucosa [338].

While changes in FDG uptake reflect viability of tumor cells after treatment, stromal changes with treatment are more complex [339]. More information will be required about modulation of fibroblastic activity, particularly following radiation, which can induce fibrosis [339].

¹⁸F-Fluciclatude:

The agent is used for imaging angiogenesis in tumors and can be used as a biomarker of response to antiangiogenic therapies [302]. It contains the RGD sequence that binds with high affinity to integrins alpha_v-beta₃ and alpha_v-beta₅ both of which are upregulated in tumor-associated vasculature [302].

¹¹C- half-life is approximately 20 minutes

¹¹C-L-methylmethionine:

¹¹C-L-methylmethionine measures amino acid uptake/protein synthesis (tumor cells require an external supply of methionine). Methionine is needed for protein synthesis as a precursor of S-adenosylmethionine which is required for polyamine synthesis [55]. Increased uptake of methionine reflects increased carrier mediated transport, transmethylation rate, and protein synthesis in malignant tissue [55,130]. The agent has primarily been used for imaging of CNS neoplasms [18]. There is normally low uptake in the brain (gray matter) due to low amino acid metabolism in normal brain tissue, and somewhat higher uptake in the salivary glands, lacrimal glands, bone marrow, and occasionally the myocardium [18,243]. Abdominal uptake in the liver and pancreas (usually high uptake) is frequently seen, and there is variable intestinal uptake of the agent [18]. Moderate activity is seen in the renal cortex [18]. Pituitary uptake is high [18]. See also CNS tumor imaging.

¹¹C-thymidine:

¹¹C-thymidine is used in the evaluation of tumor DNA replication and cell division rates. ⁶⁸Ga-EDTA has been used in the evaluation of disruption of the blood brain barrier.

¹¹C-choline:

¹¹C-choline (¹¹C-CHOL) is an agent that is incorporated into tumor cells by conversion (a phosphorylation reaction that is catalyzed by choline kinase [261]) into ¹¹C-phosphorlycholine which is trapped inside the cell. This is followed by synthesis of ¹¹C-phosphatidylcholine which constitutes a main component of cell membranes [26]. Because tumor cells duplicate very quickly, the biosynthesis of cell membranes is also very fast and there is increased uptake of choline and upregulation/overexpression of the enzyme choline kinase [26,261]. Essentially, the uptake of ¹¹C-CHOL in tumors represents the rate of tumor cell proliferation [5]. ¹¹C-CHOL is very rapidly cleared from the blood, and optimal tumor-to-background contrast is reached within 5 minutes [26,59]. The initial high uptake remains at a nearly constant level afterward [59]. There are two mechanisms of tracer uptake: energy dependent choline-specific transport and simple diffusion [59].

Prominent tracer uptake is seen in the liver, renal cortex, and salivary glands (the liver and kidney are major sites for choline oxidation) [26]. Less intense uniform tracer uptake can be seen in then lungs, spleen, skeletal muscles, bone marrow, choroid plexus, and pituitary gland [26]. High to variable pancreatic and duodenal uptake can be seen due to secretion of phospholipid-rich pancreatic juice [26,59]. Variable uptake is seen in the small bowel and urinary bladder [26]. Generally, there is only minimal activity in the urinary tract and bladder of fasting individuals which may aid in the evaluation of pelvic malignancies [59]. No uptake is generally observed in the mediastinum or myocardium [26]. Since normal brain cells are in a non-dividing state, the uptake of ¹¹C-CHOL is very low, while brain tumors and metastases have increased cell membrane synthesis and increased tracer uptake [59]. The agent is superior to FDG-PET imaging for the detection of brain metastases from lung cancer [26]. Tracer uptake can occur in inflammatory processes such as pelvic inflammatory disease [59].

¹¹C-acetate:

¹¹C-acetate is another PET tumor imaging agent. Acetate can be metabolized as a substrate for beta-oxidation through the tricarboxylic acid cycle (Krebs cycle) or it can be used as a substrate for fatty acid synthesis and the production of phospholipids in cellular membranes [179,191,261]. In the myocardial mitochondria, ¹¹C-acetate is converted into acetyl-coenzyme A which is followed by rapid metabolism via the citric acid cycle and clearance as CO₂. However, as previously mentions- acetate is not only a metabolic substrate of beta-oxidation, but also a precursor of amino acids, fatty acids, and sterol [58]. The mechanism of tumor uptake is uncertain, but may be multifactoral [57] and related to low oxygen consumption and enhanced lipid synthesis in tumor cells [88]. The agent appears to be incorporated into cell membrane lipids [160] (it may be involved with active basal lipid metabolism in the cell membrane in cancer tissue with low oxidative metabolism and high lipid synthesis [57,58]). Preliminary studies have indicated that certain prostate tumors prefer ¹¹C-acetate to FDG as a substrate for cellular metabolism [88]. Malignancy induced upregulation of fatty acid synthase (FAS) may play a role in ¹¹C-acetate uptake in prostate cancers [15,261]. FAS is a multifuncational enzymatic protein that catalyzes fatty acid biosynthesis- it is overexpressed in prostate cancers (as well as other tumors), but levels are low or absent in most normal tissues [15]. ¹¹C-acetate also shows high uptake in other tumors such as renal cell carcinomas and hepatomas [160]. In the brain, acetate is preferentially metabolized by astrocytes with low uptake in normal brain tissue [225]. The agent is taken up by all meningiomas [225].

Normal biodistribution: ¹¹C-acetate accumulates in the pancreas (high accumulation), there is variable uptake in the liver and bowel, heart, kidneys, spleen, stomach, and bone marrow [88,241]. Although there is some renal uptake, urinary excretion is not seen, although mild bladder activity may be observed [57]. The lack of urinary activity is useful for imaging prostate cancer [241]. There is relatively rapid clearance of the agent from most other tissues because of its oxidative metabolism to ¹¹C-CO₂.

Tumor hypoxia agents:

Tumor cell growth outstrips vascular development so that oxygen delivery is decreased beyond its diffusion distance [194]. Hypoxemia promotes neovascularization through a variety of molecular signals [194]. FDG uptake in tumors reflects tumor hypoxia because glucose transporter expression (GLUT-1) is up-regulated in hypoxia [282]. Tumors that demonstrate low perfusion, but high glucose metabolism (a dissociation between metabolism and flow) show an adaptation to hypoxia and reflects tumor aggressiveness and may reflect a poorer response to treatment [266]. However, tumor hypoxia and glucose metabolism do not always correlate [282]. The intracellular partial pressure of oxygen in normally perfused cells is in the range of 30-50 mm Hg; while in hypoxic tumors it can be as low as 3-15 mmHg [188].

Tumor hypoxia has been shown to correlate with a worse prognosis in certain malignancies [178,307]. Hypoxic cells are more resistant to radiation and chemotherapy and therefore require dose escalation radiation treatment or additional chemo- or hypoxia directed therapy to achieve adequate cytotoxicity [74,76,134,178,262,307]. Hypoxia causes radiotherapy resistance primarily by limiting oxygen fixation, the crucial step for radiation to effect DNA damage [331]. The presence of hypoxia is associated with more aggressive tumor phenotypes, resulting in local tissue invasion and an increased metastatic potential [192]. Hypoxia has also been shown to be associated with increased multidrug resistance type 1 protein (MDR1) [204]. In general, patients with tumors that have significant hypoxia have a worse prognosis and shorter disease free survival when compared to better oxygenated tumors [134,154]. One point to remember is that hypoxia is a dynamic process in constant change in in the relative contribution of acute and chronic hypoxia to the total hypoxic tumor volume [284]. Definition of the hypoxic volume can aid in choosing the appropriate target for radiation dose escalation [17].

Interestingly, the agent metformin may have radiosensitizing properties and may affect tumor response and growth either directly or indirectly [331]. The direct effect is attributed to the inhibition of the mitochondrial complex I and its downstream pathways, resulting in activation of the cellular energy sensor adenosine monophosphate-activated kinase [331]. This activation in turn increases cellular catabolism and reduced anabolism [331]. The indirect effect is caused by metformin's lowering effects on blood glucose and insulin levels, two major factors that stimulate cancer growth [331].

¹⁸F-fluoromisonodazole (FMISO): Radiolabeled nitroimidazoles can be used for the evaluation of tumor hypoxia [134]. ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) is a PET tracer used for the evaluation of tissue hypoxia [134,154]. ¹⁸F-FMISO acts as a bioreceptor molecule and is incorporated into cell constituents under hypoxic conditions [74]. The agent is lipophilic and freely diffuses across the cell membrane and is metabolized by intracellular nitroreductases into a radical anion (in the presence of oxygen the agent readily diffuses back out of the cell) [194,210,304]. Oxygen acts as an electron acceptor for the ¹⁸F-FMISO radical anion [194]. Under normoxic conditions the reduced form of fluoromisonodazole is rapidly oxidized back to it's diffusible form, with tissue levels rapidly declining as blood borne fluoromisonodazole is cleared [304]. In the absence of oxygen, the unstable ¹⁸F-FMISO radical anion is further reduced (by nitroreductase) and covalently binds to intracellular macromolecules and becomes trapped within the hypoxic, yet metabolically active cells, leading to progressive accumulation of the agent [134,188,194,246,304]. Nitroimidazoles bind to cells at a rate that is maximal under conditions of severe hypoxia (less than 0.05% oxygen) and are inhibited as a function of increasing oxygen concentration [134,194]. The uptake of the agent is increased only when tissue hypoxia of pO₂  < 10 mm Hg is present [154] (and significant retention can be seen at oxygen levels below 3 mm Hg [194]). The metabolism of the agent requires active electron transport and therefore the agent is not incorporated into necrotic tissue [134].  Unfortunately, there is slow clearance from the blood compartment, slow cellular uptake (the agent traverses tissue by passive diffusion), and slow washout from non-hypoxic tissues which limit image quality and the effectiveness of this agent [74,204,262]. Because blood pool clearance of the agent is slow, a 2.5 hour wait after injection is required to allow for adequate contrast between hypoxic and non-hypoxic tissue [210,269]. A longer delay of up to 4 hours has also been used [269]. Contrast between normal and pathologic tissue can be low [246]. A FMISO tumor-to-blood activity ratio of greater than 1.2-1.4 has been used for defining the presence of hypoxia [242,304]. This low contrast is also in part related to the heterogeneous distribution of hypoxic regions within tumors- often only 5-30% of a tumor is hypoxic [262]. Note that a combination of severely hypoxic and necrotic tissues supplied by structurally and functionally abnormal vasculature may lead to low total uptake of the agent, even at late time points [304]. Additionally, tissue may be misidentified as hypoxic as a consequence of slow clearance of the agent from regions of high tumor perfusion [320]. This variable uptake and slow clearance means that it is not always possible to unambiguously differentiate the impact on uptake of hypoxia and perfusion by static PET imaging alone [320].

¹⁸F-fluoroazomycin arabinoside (¹⁸F-FAZA) is also used to study hypoxia [316]. FAZA undergoes electron reduction as it enters the cell [307]. Under normoxic conditions the tracer is reoxygenated and transported out of the cell [307]. Under hypoxic conditions the tracer is retained in the cell [307]. The agent undergoes rapid renal clearance and clears from the blood more rapidly than FMISO resulting in a more favorable tumor-to-background ratio in most anatomic regions [282,284,307]. The agent also exhibits good in vivo stability against enzymatic activity [282].

 ⁶²Cu-ATSM (diacetyl-bis (N⁴-mthylthiosemicarbazone) is another tumor hypoxia agent which diffuses into cells where it is selectively bioreduced and trapped within viable cells under hypoxic conditions (the agent undergoes rapid clearance from non-hypoxic tissue) [74,76,178,209]. ⁶²Cu has a half-life of 9.7 minutes and can be produced from a ⁶²Zn/⁶²Cu generator [178].

 ⁶⁴Cu-ATSM and  ⁶⁴Cu-PTSM are two other PET agents used for hypoxia imaging [204].  ⁶⁴Cu-PTSM is a PET perfusion tracer with distribution proportional to blood flow, but the agent lacks hypoxia selectivity [204].  ⁶⁴Cu-ATSM is highly lipophilic and differs from PTSM in only one methyl group, but it possesses a lower redox potential- consequently it is more readily reduced and trapped in hypoxic tissues [204].   ⁶⁴Cu-ATSM shows rapid tumor delineation and high tumor-to-blood ratios [204]. The mechanism underlying its retention are incompletely understood [204]. A drawback of ⁶⁴Cu imaging is the emission of beta particles (38.5%) which results in less favorable dosimetry [316].

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(146) J Nucl Med 2006; Rosen RS, et al. Increased ¹⁸F-FDG uptake in degenerative disease of the spine: characterization with ¹⁸F-FDG-PET/CT. 47: 1274-1280

(147) J Nucl Med 2006; Jhanwar Y, Straus DJ. The role of PET in lymphoma. 47: 1326-1334

(148) J Nucl Med 2006; Montravers F, et al. Can fluorodihydroxyphenylalanine PET replace somoatostatin receptor scintigraphy in patients with digestive endocrine tumors? 47: 1455-1462

(149) AJR 2006; Iagaru A, Henderson R. PET/CT followup in nonossifying fibroma. 187: 830-832

(150) AJR 2006; Goodin GS, et al. PET/CT characterization of fibroosseous defects in children: 18F-FDG uptake can mimic metastatic disease. 187: 1124-1128

(151) J Nucl Med 2006; Agool A, et al. ¹⁸F-FLT PET in hematologic disorders: a novel technique to analyze the bone marrow compartment. 47: 1592-1598

(152) J Nucl Med 2006; Muzi M, et al. Kinetic analysis of 3'-deoxy-3'-¹⁸F-fluorothymidine in patients with gliomas. 47: 1612-1621

(153) J Nucl Med 2006; Kamel EM, et al. Forced diuresis improved the diagnostic accuracy of ¹⁸F-FDG-PET in abdominopelvic malignancies. 47: 1803-1807

(154) J Nucl Med 2006; Cherk MH, et al. Lack of correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in non-small cell lung cancer assessed by ¹⁸F-fluoromisonidazole and ¹⁸F-FDG-PET. 47: 1921-1926

(155) Radiographics 2006; Chong S, et al. Integrated PET-CT for the characterization of adrenal gland lesions in cancer patients: diagnosic efficacy and interpretation pitfalls. 26: 1811-1826

(156) Radiographics 2007; Prabhakar HB, et al. Bowel hot spots at PET-CT. 27: 145-159

(157) J Nucl Med 2007; Roh JL, et al. Clinical utility of ¹⁸F-FDG-PET for patients with salivary gland malignancies. 48: 240-246

(158) J Nucl Med 2007; Kasamon YL, et al. Integrating PET and PET/CT into risk-adapted therapy of lymphoma. 48: 19S-27S

(159) J Nucl Med 2007; Weber WA, Figlin R. Monitoring cancer treatment with PET/CT: does it make a difference? 48: 36S-44S

(160) J Nucl Med 2007; Ponde DE, et al. ¹⁸F-fluoroacetate: a potential acetate analog for prostate tumor imaging- in vivo evaluation of ¹⁸F-fluoroacetate versus ¹¹C-acetate. 48: 420-428

(161) J Nucl Med 2007; Gabriel M, et al. ⁶⁸Ga-DOTA-Tyr³-Octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. 48: 508-518

(162) J Nucl Med 2007; Schillaci O. Somatostatin receptor imaging in patients with neuroendocrine tumors: not only SPECT? 48: 498-500

(163) J Nucl Med 2007; Floeth FW, et al. Prognostic value of O-(2-¹⁸F-fluoroethyl)-L-tyrosine PET and MRI in low-grade glioma. 48: 519-527

(164) J Nucl Med 2007; Rutten I, et al. PET/CT of skull base meningiomas using 2-¹⁸F-fluoro-L-tyrosine: initial report, 48: 720-725

(165) Radiographics 2007; Elaini AB, et al. Improved detection and characterization of adrenal disease with PET-CT. 27: 755-767

(166) J Nucl Med 2007; Karatanis D, et al. Clinical significance of diffusely increased ¹⁸F-FDG uptake in the thyroid gland. 48: 896-901

(167) J Nucl Med 2007; Doot RK, et al. Dynamic and static approaches to quantifying ¹⁸F-FDG uptake for measuring cancer response to therapy, including the effect of granulocyte CSF. 48: 920-925

(168) J Nucl Med 2007; Baba S, et al. Effect of nicotine and ephedrine on the accumulation of ¹⁸F-FDG in brown adipose tissue. 48: 981-986

(169) AJR 2007; Smith CS, et al. Thymic extension in the superior mediastinum in patients with thymic hyperplasia: potential cause of false-positive findings on ¹⁸F-FDG PET/CT. 188: 1716-1721

(170) J Nucl Med 2007; Louis E, et al. Noninvasive assessment of Crohn's disease intestinal lesions with ¹⁸F-FDG PET/CT. 48: 1053-1059

(171) AJR 2007; Wittram C, Scott JA. ¹⁸F-FDG PET of pulmonary embolism. 189: 171-176

(172) J Nucl Med 2007; Nanni C, et al. ¹⁸F-DOPA PET and PET/CT. 48: 1577-1579

(173) J Nucl Med 2007; Timmers HJ, et al. The effects of crbiopa on uptakeof 6-¹⁸F-fluoro-L-DOPA in PET of pheochromocytoma and extraadrenal abdominal paraganglioma.48: 1599-1606

(174) J Nucl Med 2007; Baba S, et al. Comparison of uptake of multiple clinical radiotracers into brown adipose tissue under cold-stimulated and nonstimulated conditions. 48: 1715-1723

(175) J Nucl Med 2007; Zhernosekov KP, et al. Processing of generator-produced ⁶⁸Ga for medical application. 48: 1741-1748

(176) Radiographics 2006; Blake MA, et al. Pearls and pitfalls in interpretation of abdominal and pelvic PET-CT: 26: 1335-1353

(177) J Nucl Med 2008; Grant FD, et al. Skeletal PET with ¹⁸F-fluoride: applying new technology to an old tracer. 49: 68-78

(178) AJR 2008; Wong TZ, et al. PET of hypoxia and perfusion with ⁶²Cu-ATSM and ⁶²Cu-PTSM using a ⁶²Zn/⁶²Cu generator. 190: 427-432

(179) J Nucl Med 2008; Vavere AL, et al. 1-¹¹C-acetate as a PET radiopharmaceutical for imaging fatty acid synthase expression in prostate cancer. 49: 327-334

(180) J Nucl Med 2008; Hsu WK, et al. Characterization of osteolytic, osteoblastic, and mixed lesions in a prostate cancer mouse model using ¹⁸F-FDG and ¹⁸F-fluoride PET/CT. 49: 414-421

(181) AJR 2008; Smith CS, et al. False-positive findings on ¹⁸F-FDG PET/CT: differentiation of hibernoma and malignant fatty tumor on the basis of fluctuating standardized uptake values. 190: 1091-1096

(182) J Nucl Med 2008; Jager PL, et al. 6-L-¹⁸F-fluorodihydroxyphenylalanine PET in neuroendocrine tumors: basic aspects and emerging clinical applications. 49: 573-586

(183) AJR 2008; Williams G, Kolodny GM. Method for decreasing uptake of ¹⁸F-FDG by hypermetabolic brown adipose tissue on PET. 190: 1406-1409

(184) AJR 2008; Roedl JB, et al. Visual PET/CT scoring for nonspecific ¹⁸F-FDG uptake in the differentiation of early malignant and benign esophageal lesions. 191: 515-521

(185) AJR 2008; Kwak JY, et al. Thyroid incidentalomas identified by ¹⁸F-FDG PET: sonographic correlation. 191: 598-603

(186) J Nucl Med 2008; Lee SJ, et al. Reversal of vascular ¹⁸F-FDG uptake with plasma high-density lipoprotein elevation by atherogenic risk reduction. 49: 1277-1282

(187) J Nucl Med 2008; Karam M, et al. Bilateral hilar foci of ¹⁸F-FDG PET scan in patients without lung cancer: variables associated with benign and malignant etiology. 49: 1429-1436

(188) J Nucl Cardiol 2008; Jain D, He ZX. Direct imaging of myocardial ischemia: a potential new paradigm in nuclear cardiovascular imaging. 15: 617-630

(189) J Nucl Med 2008; High ¹⁸F-FDG uptake in synthetic aortic vascular grafts on PET/CT in symptomatic and asymptomatic patients. 49: 1601-1605

(190) AJR 2008; Vikram R, et al. Utility of PET/CT in differentiating benign from malignant adrenal nodules in patients with cancer. 191: 1545-1551

(191)  J Nucl Med 2008; Park JW, et al. A prospective evaluation of ¹⁸F-FDG and ¹¹C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma. 49: 1912-1921

(192) J Nucl Med 2008; Komar G, et al. ¹⁸F-EF5: a new PET tracer for imaging hypoxia in head and neck cancer. 49: 1944-1951

(193) AJR 2009; Iyer RB, et al. Adrenal pheochromocytoma with surronding brown fat stimulation. 192: 300-301

(194) J Nucl Med 2009; Swanson KR, et al. Complementary but distinct roles for MRI and ¹⁸F-fluoromisonidazole PET in the assessment of human glioblastomas. 50: 36-44

(195) J Nucl med 2009; Roy FN, et al. Impact of intravenous insulin on ¹⁸F-FDG PET in diabetic cancer patients. 50: 178-183

(196) J Nucl Med 2009; Zhao B, et al. Imaging surrogates of tumor response to therapy: anatomic and functional biomarkers. 50: 239-249

(197) AJR 2009; Nakajo M, et al. Effect of clinicopathologic factors on visibility of colorectal polyps with FDG PET. 192: 754-760

(198) AJR 2009; Boland GW, et al. PET/CT for the characterization of adrenal masses in patients with cancer: qualitative versus quantitative accuracy in 150 consecutive patients. 192: 956-962

(199) J Nucl Med 2009; Fox JJ, Strauss HW. Onestep closer to imaging vulnerable plaque in the coronary arteries. 50: 497-500

(200) J Nucl Med 2009; Iagaru A, et al. Novel strategy for a cocktail ¹⁸F-fluoride and ¹⁸F-FDG PET/CT scan for evaluation of malignancy: results of the pilot phase study. 50: 501-505

(201) J Nucl Med 2009; Groves AM, et al. Idiopathic pulmonary fibrosis and diffuse parenchymal lung disease: implications from initial experience with ¹⁸F-FDG PET/CT. 50: 538-545

(202) J Nucl Med 2009; Wykrzykowska J, et al. Imaging of inflammed and vulnerable plaque in coronary arteries with ¹⁸F-FDG PET/CT in patients with suppression of myocardial uptake using a low-carbohydrate, high-fat preparation. 50: 563-568

(203) J Nucl Med 2009; Jerushalmi J, et al. Physiologic thymic uptake of ¹⁸F-FDG in children and young adults: a PET/CT evaluation of incidence, patterns, and relationship to treatment. 50: 849-853

(204) J Nucl Med 2009; Liu J, et al. Retention of the radiotracers  ⁶⁴Cu-ATSM and  ⁶⁴Cu-PTSM in human and murine tumors is influenced by MDR1 protein expression. 50: 1332-1339

(205) AJR 2009; Paidisetty S, Blodgett TM. Brown fat: atypical locations and appearances encountered in PET/CT. 193: 359-366

(206) J Nucl Med 2009; Jacene HA, et al. Assessment of interobserver reproducibility in quantitative ¹⁸F-FDG PET and CT measurements of tumor response to therapy. 50: 1760-1769

(207) J Nucl Med 2009; Jadvar H, et al. ¹⁸F-FDG uptake in lung, breast, and colon cancers: molecular biology correlates and disease characterization. 50: 1820-1827

(208) J Nucl Med 2009; Kayani I, et al. A comparison of ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT in pulmonary neuroendocrine tumors. 50: 1927-1932

(209) J Nucl Med 2009; Lohith TG, et al. Pathophysiologic correlation between ⁶²Cu-ATSM and ¹⁸F-FDG in lung cancer. 50: 1948-1953

(210) J Nucl Med 2010; Wang W, et al. Pharmacokinetic analysis of hypoxia ¹⁸F-fluoromisonidazole dynamic PET in head and neck cancer. 51: 37-45

(211) J Nucl Med 2010; Visser EP, et al. SUV: silly useless value to smart uptake value. 51: 173-175

(212) J Nucl Med 2010; Rominger A, et al. In vivo imaging of macrophage activity in the coronary arteries using ⁶⁸Ga-DOTATATE PET/CT: correlation with coronary calcium burden and risk factors. 51: 193-197

(213) J Nucl Med 2010; Baba S, et al. CT hounsfield units of brown adipose tissue increase with activation: preclinical and clinical studies. 51: 246-250

(214)  AJR 2010; Iyer VR, Lee SI. MRI, CT, and PET/CT for ovarian cancer detection and adenexal lesion characterization. 194: 311-321

(215) J Nucl Med 2010; Mavi A, et al. The effect of age, menopausal state, and breast density on ¹⁸F-FDG uptake in normal glandular breast tissue. 51: 347-352

(216) J Nucl Med 2010; Campana D, et al. Standardized uptake values of ⁶⁸Ga-DOTANOC PET: a promising prognostic tool in enuroendocrine tumors. 51: 353-359

(217) J Nucl Med 2008; Qazi F, et al. Fatty liver: impact on metabolic activity as detected with 18F FDG-PET/CT. 49 (meeting abstract- supplement 1) 236P

(218) Radiology 2010; Abele JT, Fung CI. Effect of hepatic steatosis on liver FDG uptake measured in mean standard uptake values. 254: 917-924

(219) Radiology 2010; Drubach LA, et al. Skeletal trauma in child abuse: detection with ¹⁸F-NaF PET. 255: 173-181

(220) Radiology 2010; Davison JM, et al. Squamous cell carcinoma of the palatine tonsils: FDG standardized uptake value ratio as a biomarker to differentiate tonsillar carcinoma from physiologic uptake. 255: 578-585

(221) J Nucl Cardiol 2010; Cheng VY, et al. Impact of carbohydrate restriction with and without fatty acid loading on myocardial ¹⁸F-FDG uptake during PET: a randomized controlled trial. 17: 286-291

(222) AJR 2010; Kei PL, et al. Incidental finding of focal FDG uptake in the bowel during PET/CT: CT features and correlation with hsitopathologic results. 194: 1304

(223) J Nucl Med 2010; Yun M, et al. Physiologic ¹⁸F-FDG uptake in the fallopian tubes at mid cycle on PET/CT. 51: 682-685

(224) J Nucl Med 2010; Weber WA. Monitoring tumor response to therapy with ¹⁸F-FLT PET. 51: 841-844

(225) AJR 2010; Han YM, et al. Diagnostic value of CT density in patients with diffusely increased FDG uptake in the thyroid gland on PET/CT images. 195: 223-228

(226) AJR 2010; Adams MC, et al. A systemic review of the factors affecting accuracy of SUV measurements. 195: 310-320

(227) AJR 2010; Kitajima K, et al. Spectrum of FDG PET/CT findings of uterine tumors. 195: 737-743

(228) Radiographics 2010; Son H, et al. PET/CT evaluation of cervical cancer: spectrum of disease. 30: 1251-1268

(229) J Nucl Med 2010; De Saint-Hubert M, Mottaghy FM. Can evaluation of targeted therapy in oncology be improved by means of ¹⁸F-FLT? 51: 1499-1500

(230) J Nucl Med 2010; Lodge MA, et al. Characterization of a perirectal artifact in ¹⁸F-FDG PET/CT. 51: 1501-1506

(231) J Nucl Med 2010; Fueger BJ, et al. Correlation of 6-¹⁸F-fluoro-L-Dopa PET uptake with proliferation and tumor grade in newly diagnosed and recurrent gliomas. 51: 1532-1538

(232) J Nucl Med 2010; Segall G, et al. SNM practice guideline for sodium ¹⁸F-fluoride PET/CT bone scans 1.0. 51: 1813-1820

(233) Eur J Nucl Med Mol Imaging 2008; Gontier E, et al. High and typical 18F-FDG bowel uptake in patients treated with metformin. 35: 95-99

(234) Eur J Nucl Med Mol Imaging 2010; Ozulker T, et al. Clearance of the high intestinal (18)F-FDG uptake associated with metformin after stopping the drug. 37: 1011-1017

(235) AJR 2010; Osman MM, et al. ¹⁸F-FDG PET/CT of patients with cancer: comparison of whole-body and limited whole-body technique. 195: 1397-1403

(236) AJR 2010; Oh JR, et al. Impact of medication discontinuation on increased intestinal FDG accumulation in diabetic patients treated with metformin. 195: 1404-1410

(237) J Nucl Med 2010; Czernin J, et al. Molecular mechanisms of bone ¹⁸F-NaF deposition. 51: 1826-1829

(238) J Nucl Med 2010; Hofman MS, Hicks RJ. Restaging: should we PRECIST without pattern recognition? 1830-1831

(239) J Nucl Med 2010; Ambrosini V, et al. ⁶⁸Ga-DOTANOC PET/CT allows somatostatin receptor imaging in idiopathic pulmonary fibrosis: preliminary results. 51: 1950-1955

(240) AJR 2011; Abikhzer G, et al. Altered hepatic metabolic activity in patients with hepatic steatosis on FDG PET/CT. 196: 176-180

(241) J Nucl Med 2011; Jadvar H. Prostate cancer: PET with ¹⁸F-FDG, ¹⁸F- or ¹¹C-acetate, and ¹⁸F- or ¹¹C-choline. 52: 81-89

(242) J Nucl Med 2011; Chitneni SK, et al. Molecular imaging of hypoxia. 52: 165-168

(243) J Nucl Med 2011; Nagata T, et al. Examination of ¹¹C-methionine metabolism by the standardized uptake value in the normal brain of children. 52: 201-205

(244) J Nucl Med 2011; Hyun SH, et al. Incidental focal  ¹⁸F-FDG uptake in the pituitary gland: clinical significance and differential diagnosis. 52: 547-550

(245) J Nucl Cardiol 2011; Minamimoto R, et al. Value of FDG-PET/CT using unfractionated heparin for managing primary cardiac lymphoma and several key findings. 18: 516-520

(246) J Nucl Med 2011; Hugonnet F, et al. Metastatic renal cell carcinoma: relationship between intial metastasis hypoxia, change after 1 month's Sunitinib, and therapeutic response: an ¹⁸F-fluoromisonidazole PET/CT study. 52: 1048-1055

(247) AJR 2011; Kang BJ, et al. Clinical significance of incidental finding of focal activity in the breast at ¹⁸F-FDG PET/CT. 197: 341-347

(248) J Nucl Cardiol 2011; Small GR, Ruddy TD. PET imaging of aortic atherosclerosis: is combined imaging of plaque and function an amaranthine quest or conceivable reality? 18: 717-728

(249) AJR 2011; Drubach LA, et al. Skeletal scintigraphy with ¹⁸F-NaF PET for the evaluation of bone pain in children. 197: 713-719

(250) Radiographics 2011; Stolzmann P, et al. Complementary value of cardiac FDG PET and CT for the characterization of atherosclerotic disease. 31: 1255-1269

(251) Radiographics 2011; Maurer AH, et al. How to differentiate benign versus malignant cardiac and paracardiac ¹⁸F FDG uptake at oncologic PET/CT. 31: 1287-1305

(252) J Nucl Med 2011; Benz MR, et al. ¹⁸F- FDG PET/CT for monitoring treatment responses to the epidermal growth factor inhibitor erlotinib. 52: 1684-1689

(253) J Nucl Med 2011; Hatt M, et al. Impact of tumor size and tracer uptake heterogeneity in ¹⁸F- FDG PET and CT non-small celll lung cancer tumor delineation. 52: 1690-1697

(254) J Nucl Med 2012; Boellaard R. Mutatis mutandis: harmonize the standard. 53: 1-3

(255) J Nucl med 2012; Vanderhoek M, et al. IMpact of the definition of peak standardized uptake value on quantification of treatment response. 53: 4-11

(256) J Nucl Med 2012; Chang KP, et al. Prognostic significance of ¹⁸F-FDG PET parameters and plasma Epstine-Barr virus DNA load in patients with nasopahryngeal carcinoma. 53: 21-28

(257) Radiology 2012; Gawande RS, et al. Differentiation of normal thymus from anterior mediastinal lymphoma and lymphoma recurrence at pediatric PET/CT. 262: 61

(258) J Nucl Med 2012; Dibble EH, et al. ¹⁸F-FDG metabolic tumor volume and total glycolytic activity of oral cavity and oropharyngeal squamous cell cancer: adding value of clinical staging. 53: 709-715

(259) Radiology 2012; Cronin CG, et al. Brown fat at PET/CT: correlation with patient characteristics. 263: 836-842

(260) J Nucl Med 2012; Lodge MA, et al. Noise considerations for PET quantification using maximum and peak standardized uptake value. 53: 1041-1047

(261) AJR 2012; Jadvar H. Molecular imaging of prostate cancer: PET radiotracers. 199: 278-291

(262) J Nucl Med 2012; Carlin S, Humm JL. PET of hypoxia: current and future perspectives. 53: 1171-1174

(263) J Nucl Med 2012; Kurdziel KA, et al. The kinetics and reproducibility of ¹⁸F-sodium fluoride for oncology using current PET camera technology. 53: 1175-1184

(264) J Nucl Med 2012; Vrieze A, et al. Fasting and postprandial activity of brown fat tissue in healthy men. 53: 1407-1410

(265) J Nucl Med 2012; Lim R, et al. ¹⁸F-FDG PET/CT metabolic tumor volume and total lesion glycolysis predict outcome in oropharyngeal squamous cell carcinoma. 53: 1506-1513

(266) AJR 2012; Goh V, et al. Integrated ¹⁸F-FDG PET/CT and perfusion of primary colorectal cancer: effect of inter and intraobserver agreement on metabolic-vascular parameters. 199: 1003-1009

(267) J Nucl Med 2013; Cook GJR. Combined ¹⁸F-Fluoride and ¹⁸F-FDG PET/CT scanning for evaluation of malignancy: results of an International multicenter trial. 54: 173-175

(268) J Nulc Med 2013; Iagaru A, et al. Combined ¹⁸F-Fluoride and ¹⁸F-FDG PET/CT scanning for evaluation of malignancy: results of an International multicenter trial. 54: 176-183

(269) J Nucl Med 2013; Okamoto S, et al High repreoducibility of tumor hypoxia evaluated by ¹⁸F-fluoromisonodazole PET for head and neck cancer. 54: 201-207

(270) J Nucl Med 2013; Metformin- an adjunct antineoplastic therapy- divergently modulates tumor metabolism and proliferation, interfering with early response prediction by ¹⁸F-FDG PET imaging. 54: 252-258

(271) J Nucl Med 2013; Massollo M, et al. Metformin temporal and localized effects on gut glucose metabolism assessed using ¹⁸F-FDG PET in mice. 54: 259-266

(272) J Nucl Med 2013; Menda Y, Buatti JM. PET imaging during radiotherapy of head and neck cancer. 54: 497-498

(273) J Nucl Med 2013; Muzik O, et al. ¹⁵O PET measurtement of blood flow and oxygen consumption in cold-activated human brown fat. 54: 523-531

(274) J Nucl Med 2013; Hoeben BAW, et al. ¹⁸F-FLT PET during radiotherapy or chemotherapy in head and neck squamous cell carcinoma is an ealry predictor of outcome. 54: 532-540

(275) J Nucl Med 2013; Wong KK, Piert M. Dynamic bone imaging with ^99mTc-labeled diphosphonates and ¹⁸F-NaF: mechanisms and applications. 54: 590-599

(276) J Nucl Med 2013; Jamar F, et al. EANM/SNMMI guideline for ¹⁸F FDG use in inflammation and infection. 54: 647-658

(277) J Nucl med 2013; Boktor RR, et al. Reference range for intrapatient variability in blood-pool and liver SUV for ¹⁸F-FDG PET. 54: 677-682

(278) J Nucl Med 2013; Walker RC, et al. Measured human dosimetry of ⁶⁸Ga-DOTATATE. 54: 855-860

(279) J Nucl Med 2013; Tehrani OS, Shields AF. PET imaging of proliferation with pyrimidines. 54: 903-912

(280) J Nucl Med 2013; Huang C, McConathy J. Radiolabeled amino acids for oncologic imaging. 54: 1007-1010

(281) AJR 2013; Rezai P, et al. A radiologist's guide to treatment response criteria in oncologic imaging: functional, molecular, and disease-specific imaging biomarkers. 201: 246-256

(282) J Nucl Med 2013; Bollineni VR, et al. PET imaging of tumor hypoxia using ¹⁸F-fluoroazomycin arabinoside in stage III-IV non-small cell lung caner patients. 54: 1175-1180

(283) J Nucl Med 2013; Fendler WP, et al. Validation of several SUV-based parameters derived from ¹⁸F-FDG PET for prediction of survival after SIRT of hepatic metastases from colorectal cancer. 54: 1202-1208

(284) Radiographics 2013; Bhatnagar P, et al. Functional imaging for radiation planning, response assessment, and adaptive therapy in head and neck cancer. 33: 1909-1929

(285) J NUcl Med 2013; Noh TS, et al. Relation of carotid artery ¹⁸F FDG uptake to c-reactive protein and Framingham risk score in a large cohort of asymptomatic adults. 54: 2070-2076

(286) J Nucl Med 2014; Keidar Z, et al. ¹⁸F FDG uptake in noninfected prosthetic vascular grafts: incidence, patterns, and changes over time. 55: 392-395

(287) J Nucl Med 2014; Orlhac F, et al. Tumor texture analysis in ¹⁸F FDG PET: relationships between texture parameters, histogram indices, standardized uptake values, metabolic volumes, and total lesion glycolysis. 55: 414-422

(288) J Nucl Med 2014; Segall GM. PET/CT with sodium ¹⁸F-fluoride for management of patients with prostate cancer. 55: 531-533

(289) J Nucl Med 2014; Mick CG, et al. Molecular imaging in oncology: ¹⁸F-sodium fluoride PET imaging of osseous metastatic disease. 203: 263-271

(290) J Nucl Med 2014; Heiss WD. Clinical impact of amino acid PET in gliomas. 55: 1219-1220

(291) J Nucl Med 2014; Tixier F, et al. Visual versus quantitative assessment of intratumor ¹⁸F-FDG PET uptake heterogeneity: prognostic value in non-small cell lung cancer. 55: 1235-1241

(292) AJR 2014; Keramida G, et al. Accumulation of ¹⁸F FDG in the liver in hepatic steatosis. 203: 643-648

(293) J Nucl Med 2014; Tahari AK, et al. Optimum lean body formulation for correction of standardized uptake value in PET imaging. 55: 1481-1484

(294) Radiographics 2014; Bastawrous S, et al. Nwere PET application with an old tracer: role of ¹⁸F-NaF skeletal PET/CT in oncologic practice. 34: 1295-1316

(295) Radiology 2014; Frings V, et al. Repeatability of metabolically active tumor volume measurements with FDG PET/CT in advanced gastrointestinal malignancies: a multicenter study. 273: 539-548

(296) AJR 2015; Tahari AK, et al. Two-time-point FDG PET/CT: liver SUL_mean repeatability. 204: 402-407

(297) J Nucl Med 2015; ¹⁸F-fluoride PET used for treatment monitoring of systemic cancer therapy: results from the National Oncologic PET registry. 56: 222-228

(298) J Nucl Cardiol 2015; Ahmed F, et al. Metal artefact reduction algorithms prevent false positive results when assessing patients for caediac implantable electronic deveice infection. 22: 219-220

(299) J Nucl Cardiol 2015; Ahmed FZ, et al. Metal artifact reduction algorithms prevent false positive rsults when assessing patients for cardiac implantable electronic device infection. 22: 219-220

(300) J Nucl Med 2015; GrahamMM, et al. Summary of the UPICT protocol for ¹⁸F-FDG PET/CT imaging in oncology clinical trials. 56: 955-961

(301) J Nucl Med 2015; Yan J, et al. Impact of image reconstruction setting on texture features in ¹⁸F-FDG PET. 56: 1667-1673

(302) J Nucl Med 2015; Sharma R, et al. Multicenter reproducibility of ¹⁸F-Fluciclatide PET imagign in subjects with solid tumors. 56: 1855-1861

(303) J Nucl Med 2015; Minamimoto R, et al. Prospective comparison of ^99mTc-MDP scintigraphy, combined ¹⁸F-NaF and ¹⁸F-FDG PET/CT, and whole-body MRI in patients with breast and prostate cancer. 56: 1862-1868

(304) J Nucl Med 2016; Grkovski M, et al. Feasibility of ¹⁸F-fluoromisonidazole kinetic modeling in head and neck cancer using shortened acquisition times. 57: 334-341

(305) J Nucl Med 2016; Bahler L, et al. Differences in sympathetic nervous stimulation of brown adipose tissue between young and old, and the lean and obese. 57: 372-377

(306) Radiographics 2016; Ziai P, et al. Role of optimal quantification of FDG PET imaging in the clinical practice of radiology. 36: 481-496

(307) J Nucl Med 2016; Iqbal R, et al. Multiparametric analysis of the relationship between tumor hypoxia and perfusion with
¹⁸F-fluoroazomycin arabinoside and ¹⁵O-H₂O PET. 57: 530-535

(308) J Nucl Med 2016; Burger IA, et al. ¹⁸F-FDG PET/CT of non-small cell lung carcinoma under neoadjuvant chemotherapy: background-based adaptive-volume metrics outperform TLG and MTV in predicting histopathologic response. 57: 849-854

(309) J Nucl Med 2016; Apolo AB, et al. Prospective study evaluating Na¹⁸F PET/CT in predicting clinical outcomes and survival in advanced prostate cancer. 57: 886-892

(310) Radiology 2016; O JH, et al. Practical PERCIST: a simplified guide to PET response criteria in solid tumors 1.0. 280: 576-584

(311) J Nucl Med 2016; Takx RAP, et al. Supraclavicular brown adipose tissue ¹⁸F-FDG uptake and cardiovascular disease. 57: 1221-1225

(312) AJR 2016; Kendi ATK, et al. Is there a role for PET/CT parameters to characterize benign, malignant, and metastatic parotid tumors? 207: 635-640

(313) J Nucl Med 2016; Iagaru AH, et al. Bone-targeted imaging and radionuclide therapy in prostate cancer. 57: 19S-24S

(314) J Nucl Med 2016; Jadvar H. PET of glucose metabolism and cellular proliferation. 57: 25S-29S

(315) AJR 2016; Rydzak C, et al. Fat-containing hypermetabolic masses on FDG PET/CT: a spectrum of benign and malignant conditions. 207: 1095-1104

(316) AJR 2017; Paschali AN, et al. One coin, no need to flip: shared PET targets in cancer and coronary artery disease. 208: 434-445

(317) J Nucl Med 2017; Cottereau AS, et al. Baseline total metabolic tumor volume measured with fixed or different adaptive thresholding methods equally predicts outcome in peripheral T cell lymphoma. 58: 276-281

(318) Radiographics 2017; Lakhani A, et al. FDG PET/CT pitfalls in gynecoogic and genitourinary oncologic imaging. 37: 577-594

(319) J Nucl Med 2017; Lodge MA. Repeatability of SUV in oncologic ¹⁸F-FDG-PET. 58: 523-532

(320) J Nucl Med 2017; Schwartz J, et al. Pharamacokinetic analysis of dynamic ¹⁸F-fluoromisonidazole PET data in non-small cell lung cancer. 58: 911-919

(321) J Nucl Cardiol 2017; Moon SH, et al. Hepatic FDG uptake is associated with future cardiovascular events in asymptomatic individuals with non-alcoholic fatty liver disease. 24: 892-899

(322) J Nucl Med 2017; Ulaner GA, et al. Prospective clinical trial of ¹⁸F-fluciclovine PET/CT for determining the response to neoadjuvant therapy in invasive ductal and invasive lobular breast cancers. 58: 1037-1042

(323) J Nucl Med 2017; Gerngrob C, et al. Active brown fat during ¹⁸F-FDG-PET/CT imaging defines a patient group with characteristic traits and an increased probability of brown fat redection. 58: 1104-1110

(324) Radiographics 2017; Wallitt KL, et al. Clinical PET imaging in prostate cancer. 37: 1512-1536

(325) J Nucl Med 2017; Lofgren J, et al. A prospective study comparing ^99mTc-hydroxyethylene diphosphonate planar bone scintigraphy and whole body SPECT/CT with ¹⁸F-fluoride PET/CT and ¹⁸F-fluoride PET/MRI for the diagnosing bone metastases. 58: 1778-1785

(326) AJR 2018; Fan SKY, et al. Impact of interventional oncology therapies on tumor microenvironment and strategies to enhance their efficacy. 210: 648-656

(327) J Nucl Med 2018; Pattison DA, et al. ¹⁸F-FDG-avid thyroid incidentalomas: the importance of contextual interpretation. 59: 749-755

(328) J Nucl Med 2018; Bailey DL, et al. Accuracy of dose calibrators for 68Ga PET imaging: unexpected findings in a mutlicenter clinical pretrial assessment. 59: 636-638

(329) Radiology 2018; Viglianti BL, et al. Effects of tumor burden on reference tissue standardized uptake for PET imaging: modification of PERCIST criteria. 287: 993-1002

(330) Radiology 2018; Meformin discontinuation prior to FDG PET/CT: a randomized controlled study to compare 24- and 48-hour bowel activity. 289: 418-425

(331) J Nucl Med 2019; Bruycker SD, et al. ¹⁸F-flortanidazole hypoxia PET holds promise as a prognostic and predictive imaging biomarker in a lung cancer xenograft model treated with metformin and radiotherapy. 60: 34-40

(332) J Nucl Med 2019; Butof R, et al. Prognostic value of standard uptake ratio in patients with trimodality treatment of locally advanced esophageal carcinoma. 60: 192-198

(333) AJR 2019; Araki T, et al. Focal liver uptake on FDG PET/CT without CT correlate: utility of MRI in the evaluation of patients with known malignancy. 213: 175-181

(334) AJR 2019; Ulaner GA. PET/CT for patients with breast cancer: where is the clinical impact? 213: 254-265

(335) Radiographics 2019; Tappouni RR, et al. ACR TI-RADS: pitfalls, solutions, and future directions. 39: 2040-2052

(336) J Nucl Med 2020; Cook GJR, Goh V. Molecular imaging of bone metastases and their response to therapy. 61: 799-806

(337) J Nucl Med 2020; Iravani A, Hicks RJ. Imaging the cancer immune environment and its response to pharnacologic intervention, part 1: the role of ¹⁸F-FDG PET/CT. 61: 943-950

(338) AJR 2021; Calais J, Mona CE. Will FAPI PET/CT replace FDG PET/CT in the next decade? Point- an important diagnostic, phenotypic, and biomarker role. 216: 305-306

(339) AJR 2021; Moradi F, Iagaru A. Will FAPI PET/CT replace FDG PET/CT in the next decade? Counterpoint- no, not so fast! 216: 307-308

(340) J Nucl Med 2021; Altmann A, et al. The latest developments in imaging fibroblast activation protein. 62: 160-167

(341) J Nucl Med 2021; Hicks RJ, et al. FAPI PET/CT: will it end the hegemony of ¹⁸FDG in oncology? 62: 296-302