PET Oncologic Imaging:

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 (such as Glut-1 and Glut-3) and increased intracellular enzyme levels of hexokinase and phosphofructokinase which promote glycolysis [4,16,20]. This enhanced glycolytic rate of malignant cells facilitates their detection utilizing PET FDG imaging.

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]. 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].

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, the study should be delayed until the glucose level is under 200 mg/dL [3,76]. 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]. If possible, diabetic patients should test their ability to maintain reasonable glucose levels after fasting prior to the PET exam [143].

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 two dimensional (2D) acquisition is acquired from the base of the brain to the mid thighs [3]. The exam usually requires 45 minutes to 1 hour to acquire when performing attenuation corrected exams using a conventional BGO scanner [15].  LSO PET cameras can perform a similar 3D acquisition in a shorter period of time. Imaging times are also shortened when CT is used for attenuation correction.

In addition to whole 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:

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]. 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].

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]. 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]. 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 1-2 weeks after completion of chemotherapy is recommended to avoid transient fluctuations in FDG metabolism [53]. 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 ratio (SUR), also known as a standardized uptake value (SUV), is used to determine if a lesion has increased ¹⁸FDG activity. The SUR normalizes the amount of FDG accumulation in a region of interest (ROI) to the total injected dose and the patient?s body weight [60]. It provides a means of comparison of FDG uptake between patients [14]. The SUR is calculated by dividing the mean activity within a selected region of interest (in mCi/ml) by the injected dose (in mCi/kg). Modifications of the SUR 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].

SUR= Mean selected region activity (mCi/ml)/[injected dose (mCi)/body weight (kg)]

It is important to remember that SUR 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 SUR 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 SUR determination is more difficult for nodules smaller than 1.5 cm due to partial volume effects [85].

An SUR 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]. 

Changes in SUV have been used to monitor tumor response to therapy [126]. 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]. The European Organization for Research and Treatment of Cancer recommends that an increase in SUV measurement of 25% from the baseline scan 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]. Complete metabolic response is defined as complete resolution of FDG uptake in the tumor [147].

Factors affecting 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].
4. Body weight or body surface area
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
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].

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, patient motion, image resolution, and window display level [82].

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].

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]. 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.

2- Myocardium- in the post-prandial state, there is marked cardiac activity. Little myocardial activity is generally noted in the fasting state as the myocardium preferentially utilizes fatty acids for energy generation. 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]. 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 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].

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].

 

 

Prominent tracer uptake has also been described within the supraclavicular fat on PET/CT in about 2% to 4% 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]. Brown fat is most prominent in newborns and diminishes with age [67]. Brown fat (unlike white adipose tissue fat) has the capacity to generate heat [67]. Brown fat is stimulated by several factors, including exposure to cold which causes over-expression of glucose transporter 4 in brown fat [62]. The incidence of uptake in brown fat has been shown to be increased during periods of cooler temperatures [62]. The incidence of tracer uptake in brown fat is also increased in women [62,91] 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]. 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]. Brown fat is known to increase glucose uptake when the sympathetic nervous system is activated by cold stimulation and other causes [86]. Because brown fat is stimulated by the sympathetic nervous system, pretreatment with propranolol has been shown to reduce FDG uptake in an animal model [86].

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 [39]. 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 can minimize this finding [51]. 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]. 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]. 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]. 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].

 

 

 

 

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 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].

 

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) [98]. 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].

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% of children and in 5% to 16% of adults [4,7,8,19,98]. Thymic enlargement can persist for up to 6 months following completion of chemotherapy [7].

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]. On anatomic imaging studies, the thymus should also have a normal appearance [98]. Lack of uptake on the pre-therapy scan should 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]. 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- incidental uptake of FDG in the thyroid can be seen in about 2% to 4.3% of scans [31,120,140]. Diffuse thyroid uptake can occur in association with thyroiditis or Graves' disease and is generally felt to be a benign finding [140]. Focal thyroid uptake can occur with autonomously functioning thyroid nodules and thyroid malignancies. Patients with focal uptake should be further evaluated due to a higher risk of the finding being associated with thyroid malignancy (27-57% risk for malignancy) [31,112,120,140].

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. Faint uterine activity is common. In premenopausal patients, greater endometrial accumulation can be seen in the uterus during menstruation and ovulation (mid-cycle) [20,77]. 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]. Mild endometrial activity can 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]. Increased ovarian uptake can be normal in premenopausal patients and is associated with ovulation [77]. Ovarian uptake in post-menopausal women is associated with malignancy and should always prompt further evaluation [77].

 

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 severeity 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 acitivity can be seen in association with severe atherosclerotic disease or aneurysms [39]. Vascular uptake may reflect active atherosclerosis [68] and is probably related to the presence of macrophages [89,97,119]. Vascular uptake is also seen in association with thrombophlebitis (which can be very intense) [39] and vasculitis [97,115]. Vascular grafts also demonstrate mild tracer accumulation as do sites of endarterectomy [39]. 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- Any focal area of increased tracer accumulation in the breast should prompt further evaluation to exclude an underlying malignancy [144]. 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, although the average SUV is typically less than 0.50 [61]. 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]. 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]. Although it is not necessary to stop breast feeding following an FDG exam, close contact with the infant should be avoided [21].

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

16- Benign adrenal lesions: Benign adrenal adenomas and adrenal myelolipomas can have uptake of FDG equal to or greater than the liver resulting in a false positive exam in (about 5% of adrenal adenomas demonstrate false positive findings) [135,137,155]. A cutoff SUV of 3.1 has been shown to have a sensitivity of 98.5% and a specificity of 92% for characterization of malignant adrenal lesions [136]. However- false negative exams can occur with neuroendocrine metastases, small lesions, and necrotic/hemorrhagic lesions [135,155]. 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]. 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].

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].

Other agents used for oncologic imaging:

¹⁸F-Fluoride:

¹⁸F-Fluoride is a bone imaging agent used for PET [78]. 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 deposits on the bone surface [78,122]. 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]. The spatial resolution of ¹⁸F-fluoride is also superior to standard bone scanning [78].

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]. Improved specificity is seen when the ¹⁸F-fluoride scan is interpreted with a fused CT exam [78,133].

Scanning is performed 45 minutes after the injection of 8-12 mCi of ¹⁸F-fluoride [78].

Somatostatin receptor imaging agents:

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:

Amino acid transport and protein synthesis are generally increased in malignant cells and amino acid imaging is less influenced by inflammation [18,56]. The replacement of a carbon atom by ¹¹C does not chemically change the molecule [18]. Amino acid agents typically have low CNS uptake which provides good contrast with tumor uptake (compared to FDG which has significant CNS activity) [18]. 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]. 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) [35,69,151]. 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 (less than 1%) because the agent lacks a 3'-hydroxyl group which is essential for chain propagation [100,102,152]. FLT anabolism occurs primarily in the liver to produce a glucuronide conjugate that is exported to the blood and cleared by the kidneys [152].

Imaging is started approximately 60 minutes following tracer administration [138]. 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 or myocardium [69,94]. Therefore, FLT may be more favorable than FDG for imaging brain metastases [109]. 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 [63,138]. 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]. 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 two factors: 1) Proliferation of lymphocytes; and 2) Nonspecific increased accumulation due to increased perfusion and vascular permeability [138].

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].

¹⁸F-fluorodihydroxyphenylalanine (DOPA):

¹⁸F-FDOPA is an agent being explored for imaging of neuroendocrine tumors [87]. The agents use is based on the capacity of endocrine tumor cells to take up, decarboxylate, and store amino acids such as dihydroxyphenylalanine [148]. 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, digestive, and urinary tracts [148]. 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].

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), and somewhat higher uptake in the salivary glands, lacrimal glands, bone marrow, and occasionally the myocardium [18]. 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].

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 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 of the enzyme choline kinase [26]. 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. The mechanism of uptake is uncertain, but may be multifactoral [57] and related to low oxygen consumption and enhanced lipid synthesis in tumor cells [88]. Acetate is not only a metabolic substrate of beta-oxidation, but also a precursor of amino acids, fatty acids, and sterol [58]. The agent 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].

The agent accumulates in the heart, kidneys, liver, pancreas, spleen, stomach, bowel, and bone marrow [88]. Urinary excretion is not seen, although mild bladder activity may be observed [57].

Tumor hypoxia agents:

Hypoxic cells are more resistant to radiation therapy and therefore require additional radiation to achieve adequate cytotoxicity [74,76,134]. 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]. Radiolabeled nitroimidazoles can be used for the evaluation of tumor hypoxia [134]. The agents are metabolized by intracellular nitroreductases and become trapped within hypoxic, yet metabolically active cells [134]. 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]. The metabolism of the agent requires active electron transport and therefore the agent is not incorportaed into necrotic tissue [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 uptake of the agent is increased only when tissue hypoxia of < 10 mm Hg is present [154]. Unfortunately, there is slow cellular uptake and slow washout from non-hypoxic tissues which limit the effectiveness of this agent [74]. ⁶²Cu-ATSM is another tumor hypoxia agent which accumulates in hypoxic tissues where it is reduced, and undergoes rapid clearance from non-hypoxic tissue [74,76]. [134]

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(112) Radiol Clin N Am 2004; Zhuang H, et al. Investigation of thyroid, head, and neck cancers with PET. 42: 1101-1111

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(118) J Nucl Med 2005; Weber WA. Use of PET for monitoring cancer therapy and predicting outcome. 46: 983-995

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(124) AJR 2005; Wandler E, et al. Diffuse FDG shoulder uptake on PET is associated with clinical findings of osteoarthritis. 185: 797-803

(125) Radiol Clin N Am 2005; Jadvar H, et al. PET in pediatric diseases. 43: 135-152

(126) Radiol Clin N Am 2005; Avril NE, Weber WA. Monitoring response to treatment in patients utilizing PET. 43: 189-204

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(128) J Nucl Med 2005; Kumar R, et al. Potential of dual-time-point imaging to improve breast cancer diagnosis with ¹⁸F-FDG PET. 46: 1819-1824

(129) J Nucl Med 2005; Pandit-Taskar N. Oncologic imaging in gynecologic malignancies. 46: 1842-1850

(130) J Nucl Med 2005; Jacobs AH, et al. ¹⁸F-fluoro-L-thymidine and ¹¹C-methylmethionine as markers of increased transport and proliferation in brain tumors. 46: 1948-1958

(131) AJR 2006; Mawlawi O, et al. Quantifying the effect of IV contrast media on integrated PET/CT: clinical evaluation. 186: 308-319

(132) J Nucl Med 2006; Pauleit D, et al. ¹⁸F-FET-PET compared with ¹⁸F-FDG-PET and CT in patients with head and neck cancer. 47: 256-261

(133) J Nucl Med 2006; Even-Sapir E, et al. The detection of bone metastases in patients with high-risk prostate cancer: ^99mTc-MDP planar bone scintigraphy, single- and multi-field-of-view SPECT, ¹⁸F-fluoride PET, and ¹⁸F-fluoride PET/CT. 47: 287-297

(134) J Nucl Med 2006; Cher LM, et al. Correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in gliomas using ¹⁸F-fluoromisonidazole, ¹⁸F-FDG PET, and immunohistochemical studies. 47: 410-418

(135) J Nucl Med 2001; Yun M, et al. 18F-FDG PET in characterizing adrenal lesions detected on CT or MRI. 42: 1795-1799

(136) J Nucl Med 2006; Metser U, et al. ¹⁸F-FDG PET/CT in the evaluation of adrenal masses. 47: 32-37

(137) Radiology 2006; Blake MA, et al. Adrenal lesions: characterization with fused PET/CT image in patients with proved or suspected malignancy- initial experience. 238: 970-977

(138) Chest 2006; Yap CS, et al. Evaluation of thoracic tumors with ¹⁸F-fluorothymidine and 18F-fluorodeoxyglucose-positron emission tomography. 129: 393-401

(139) J Nucl Med 2006; Meisetschlager G, et al. Gluc-Lys ([¹⁸F]FP)-TOCA PET in patients with SSTR-positive tumors: biodistribution and diagnostic evaluation compared with [¹¹¹In]DTPA-octreotide. 47: 566-573

(140) J Nucl Med 2006; Choi JY, et al. Focal thyroid lesions incidentally identified by integrated ¹⁸F-FDG PET/CT: clinical significance and improved characterization. 47: 609-615

(141) J Nucl Med 2006; Chen W, et al. ¹⁸F-FDOPA PET imaging of brain tumors: comparison study with ¹⁸F-FDG PET and evaluation of diagnostic accuracy. 47: 904-911

(142) J Nucl Med 2006; Jacene HA, et al. Effects of pegfilgrastim on normal biodistribution of ¹⁸F-FDG: preclinical and clinical studies. 47: 950-956

(143) J Nucl Med 2006; Shankar LK, et al. Consensus recommendations for the use of ¹⁸F-FDG PET as an indicator of therapeutic response in patients in national cancer institute trials. 47: 1059-1066

(144) AJR 2006; Korn RL, et al. Unexpected focal hypermetabolic activity in the breast: significance in patients undergoing ¹⁸F-FDG PET/CT. 187: 81-85

(145) J Nucl Med 2006; Avril N. ¹⁸F-FDG PET after radiofrequency ablation: is timing everything? 47: 1235-1237

(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