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(Radiology. 2001;220:54-62.)
© RSNA, 2001

Nuclear Medicine

Detection of Malignant Tumors: Whole-Body PET with Fluorine 18 {alpha}-Methyl Tyrosine versus FDG—Preliminary Study1

Tomio Inoue, MD, Keiko Koyama, MD, Noboru Oriuchi, MD, Saleh Alyafei, PhD, Zhibin Yuan, PhD, Hideki Suzuki, MD, Kazuo Takeuchi, MD, Yumi Tomaru, MD, Katsumi Tomiyoshi, PhD, MD, Jun Aoki, MD and Keigo Endo, MD

1 From the Departments of Nuclear Medicine (T.I., K.K., N.O., S.A., Z.Y., Y.T., K. Tomiyoshi, K.E.) and Diagnostic Radiology (J.A.), Gunma University School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma 371-8511 Japan; and the Departments of Medical Information (H.S.) and Nursing (K. Takeuchi), Gunma Prefectural College of Health Sciences, Japan. Received August 19, 1999; revision requested October 7; final revision received December 28, 2000; accepted January 16, 2001. Address correspondence to T.I. (e-mail: tomioi@med.gunma-u.ac.jp).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To compare the diagnostic potential of whole-body positron emission tomography (PET) with fluorine 18 {alpha}-methyl tyrosine (FMT) with that of whole-body PET with 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG).

MATERIALS AND METHODS: Nineteen patients with or suspected of having malignant tumors and five healthy volunteers underwent whole-body PET with FMT and FDG.

RESULTS: In comparison with FDG uptake, FMT uptake was significantly less in the brain, heart, lung, liver, and spine. On a lesion-by-lesion basis, the sensitivity of whole-body FMT PET for depicting malignant tumors was inferior to that of whole-body FDG PET, but this difference was not statistically significant (74% [26 of 35 lesions] vs 91% [32 of 35 lesions], P > .05). The positive predictive value of FMT PET was superior to that of FDG PET (87% [26 of 30 lesions] vs 63% [32 of 51 lesions], P < .001). The difference in uptake between benign and malignant lesions was significant with FMT PET (mean ± SD, 1.64 ± 0.96 vs 0.79 ± 0.23; P < .001) but not with FDG PET (5.02 ± 3.56 vs 4.02 ± 2.90, P > .05).

CONCLUSION: Whole-body FMT PET is clinically useful in the diagnosis of malignant tumors and may be effective in the depiction of primary and metastatic lesions in the cardiac region or in the brain.

Index terms: Fluorine, radioactive • Metabolism • Neoplasms, PET, **.121632, **.12166 • Positron emission tomography (PET), comparative studies, **.12163, **.12166, 10.12173 • Positron emission tomography (PET), technology, **.12163, **.12166, 10.12173


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Given that malignant tumors represent a hypermetabolic state, radiolabeled glucose or an amino acid analog with positron emitters can be used to detect viable cancer cells at positron emission tomography (PET). A glucose analog, 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG), and an amino acid, carbon 11 methionine, are commonly used radiopharmaceuticals for PET in the detection of malignant tumors (1). Recent PET technology makes it possible to obtain a whole-body tomographic image for the staging and screening of malignant tumors (2,3). However, only FDG is available for this purpose, since the physical half-life of 18F (109 minutes) is more suitable for the acquisition of a whole-body image than that of 11C (20 minutes). Tumor imaging with amino acid tracers likely allows assessment of more specific uptake in tumors, since FDG PET is known to show nonspecific uptake in inflammatory cells and granulation tissue (4).

18F-labeled amino acids, such as 18F phenylalanine (5) and 18F tyrosine (6), have been developed, but their clinical applicability is limited due to a low chemical yield. To our knowledge, clinically valid whole-body PET images showing the activity of amino acid metabolism have not been reported. On the other hand, iodine 123–labeled {alpha}-methyl tyrosine (IMT), an artificial amino acid for single photon emission computed tomography (SPECT), has been proved effective for the detection of brain tumors (7). Recently, whole-body planar images obtained with IMT that show the activity of amino acid transport in healthy volunteers and patients with cancer have been reported (8,9). However, whole-body planar images obtained with single photon emitters have the inherent limitation of poor spatial resolution. From this viewpoint, clinically available whole-body tomographic images obtained by using 18F-labeled amino acids are needed.

Radiosynthesis of 18F {alpha}-methyl tyrosine (FMT), an amino acid analog with a relatively high chemical yield, was developed at our institute (10), and FMT PET was proved to be useful in depicting brain tumors (11). To our knowledge, there have been no previous clinical trials of tomographic whole-body imaging with PET and 18F-labeled amino acids.

The aim of this study was to investigate the normal biodistribution of FMT and to assess the diagnostic potential of whole-body PET with FMT compared with that of whole-body PET with FDG.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Preparation of Radiopharmaceuticals and the PET Scanner
FMT and FDG, respectively, were produced at our cyclotron facility by using the method developed by Tomiyoshi et al (10) and Inoue et al (11) and a modified method based on that of Hamacher et al (12).

PET images were obtained by using a machine (SET 2400W; Shimadzu, Kyoto, Japan) with 59.5- and 20.0-cm transverse fields of view, which produced 63 image planes with a 3.125-mm interval between images. Transverse resolution at the center of the field of view was 4.2 and 5.0 mm full width half maximum.

Dosimetry and Normal Distribution of FMT
Three healthy male volunteers (mean age, 20 years; age range, 19–22 years) were enrolled as subjects for dosimetry in the FMT PET study, and another five healthy male volunteers (mean age, 36 years; age range, 20–49 years) were enrolled as subjects for the assessment of normal biodistribution of FMT and FDG. In the FMT PET studies, volunteers were not required to fast before the test, whereas in the FDG PET studies, volunteers were required to fast for at least 4 hours.

For dosimetry of FMT, transmission scans of the thoracic and abdominal sections were obtained by using a rotating external source (370 MBq of germanium 68–gallium 68 at installation) prior to the administration of 200 MBq of FMT. Dynamic emission scans of the thoracic and abdominal sections were alternately obtained every 5 minutes until 2 hours after the intravenous injection of FMT. After the intravenous injection of FMT, 2 mL of venous blood was sampled every 15 seconds in the 1st minute and then at 2, 5, 20, 40, 60, 90, 120, and 240 minutes after the injection. Urine was collected at 2 and 4 hours after the injection. Radioactivity of blood and urine samples was measured by using a scintillation counter against which the PET scanner was cross-calibrated by using a cylindrical phantom filled with the 18F solution. Injected radioactivity of FMT was measured by using a calibrated curie meter.

Attenuation-corrected dynamic transverse images obtained with FMT were reconstructed into 128 x 128 matrices with pixel dimensions of 4.0 mm in plane and 3.125 mm axially. Regions of interest were manually drawn for the right and left kidneys, liver, heart, spleen, and bone marrow of the thoracic spine (K. Tomiyoshi, S.A.). By using the measurements of radioactivity excreted in urine, data on blood clearance, and PET counts in each organ, absorbed doses to various organs from the intravenous administration of FMT were estimated by using computer software (Fukushi K, National Institute of Radiation Sciences, Chiba, Japan) designed to calculate the absorbed dose of radiotracer on the basis of the Medical Internal Radiation Dose, or MIRD, phantom (13,14).

For the comparative study of the normal biodistributions of FMT and FDG, a whole-body image created by using a simultaneous emission-transmission method with a rotating external source (370 MBq of 68Ge-68Ga at installation) (15) was initiated 40 minutes after the injection of 185–370 MBq of FMT or FDG by using the multiple–bed position technique. The timing of imaging for each body section was identical with FMT and FDG imaging. The software was set to provide four to 10 bed increments (8-minute acquisition per bed position). Five sections that included the head to the thigh were imaged in four healthy volunteers. Ten sections that included the entire body were imaged in one healthy volunteer.

Attenuation-corrected transverse images obtained with FMT and FDG were reconstructed with the ordered-subsets expectation maximization algorithm into 128 x 128 matrices with pixel dimensions of 4.0 mm in plane and 3.125 mm axially. Coronal images with a 9.8-mm section thickness were also reconstructed from attenuation-corrected transverse images for visual interpretation. Regions of interest in the brain, heart, and lung were determined in the entire area of each organ by using the transmission images, and those of kidneys and liver were determined on the attenuation-corrected transverse images. In healthy volunteers, FDG and FMT uptake values for each organ were expressed as a percentage of injected dose per organ.

By using attenuation-corrected transverse images, injected doses of FMT and FDG, body weight, and cross-calibration factors between the PET scanner and the dose calibrator, functional images of the standardized uptake value (SUV) were also produced. SUV was defined as follows: SUV = conc/dose/wt, where conc is the radioactive concentration in tissue or lesion in megabecquerels per gram, dose is the injected dose in megabecquerels, and wt is the patient’s body weight in grams.

Regions of interest delineating each organ were drawn by one author (T.I.) on the area corresponding to the thigh muscle, kidney, liver, lower lung field, heart, lower thoracic spine, gray matter of the centrum semiovale of the brain, and white matter in the same sections. Except for the heart and thoracic spine, the mean value of the average SUVs in the right and left organ was used as the SUV of each organ.

Patients
Patients with or suspected of having malignancies were recruited for this study from various clinical departments. Twenty consecutive patients undergoing whole-body FDG and FMT PET studies within 1 week were included in this study. One patient who received an injection of low-dose FMT (74 MBq) was excluded because of poor image quality at whole-body FMT PET. In the end, 19 patients (13 men, six women; age range, 20–84 years; mean age, 58 years) were enrolled in the study.

Pathologic diagnoses of the primary lesions were established in all patients. Ten patients had lung cancer, two had malignant melanoma, one had a bone tumor (chondrosarcoma), one had prostatic cancer, one had malignant lymphoma, one had a metastatic lesion of unknown origin, one had a soft-tissue tumor (schwannoma), and two had sarcoidosis (Table 1).


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  		TABLE 1. Absorbed Doses after Intravenous Administration of FMT

 
The final histopathologic diagnoses were established after the PET studies. Sixteen patients had no history of treatment when PET scans were obtained. Three patients suspected of having recurrent tumors had not undergone treatment for malignant tumors for 10 months prior to the PET studies. In 19 patients, 57 lesions that showed any abnormality that was characterized as a lesion at anatomic imaging, FMT imaging, or FDG imaging were evaluated. Of 35 malignant tumors that were diagnosed, 21 were diagnosed with pathologic findings, and 14 were diagnosed with the results of follow-up clinical observation, including tumor marker levels and radiographic evidence of disease progression or marked tumor volume reduction at computed tomography (CT) or magnetic resonance (MR) imaging after chemotherapy and/or irradiation. Twenty-two lesions in eight patients were nonmalignant tumors; 10 were diagnosed with pathologic findings, and the remaining 12 were diagnosed with the results of clinical follow-up. Radiologic examinations were performed more than 8 months after the PET studies.

Patients fasted for at least 4 hours before the FDG PET studies, but they were not required to do so before the FMT PET studies. The results of FDG PET performed within 1 week of the FMT PET examination were included in this study. None of the patients had diabetes mellitus. Blood glucose levels in the patients in the FDG PET studies ranged from 64 to 95 mg/dL (3.5–5.3 mmol/L).

Whole-Body PET for Clinical Study
For the evaluation of tumor depictability with both tracers in patients suspected of having malignant lesions, a whole-body image was obtained 40 minutes after the injection of 200–370 MBq of FMT or FDG by using the multiple–bed position technique. Four or five sections that included the head to the thigh were imaged in 18 patients, and 10 sections that included the entire body were imaged in a patient with malignant melanoma and tumor involvement in the foot. A filtered back-projection method, with a combined ramp filter with a critical frequency equal to the Nyquist rate (fNyq = 1.6 Hz/cm) and a Butterworth filter (cutoff frequency, 0.312 Hz/cm; order 4) were used to produce the whole-body PET images in the initial 11 patients who underwent PET as of December 1997.

Since the ordered-subsets expectation maximization algorithm was introduced to improve image quality, it was used to produce whole-body PET images in the final eight patients. Attenuation-corrected transverse images with FMT and FDG were reconstructed into 128 x 128 matrices with pixel dimensions of 4.0 mm in plane and 3.125 mm axially. Coronal images with a 9.8-mm section thickness were produced by using transverse images. Transverse and coronal images were used for the visual assessment. Functional images of the SUV were produced by using the method described previously.

The imaging protocols for the FMT and FDG PET studies were approved by the ethics committee of our institution, and all patients gave informed consent to undergo the examinations.

Image Interpretation
All FDG and FMT whole-body PET images obtained in the same patient were prospectively interpreted at different times in routine hard-copy consensus review by three experienced nuclear radiologists (T.I., N.O., K.K.). Compared with the surrounding background radioactivity, uptake scores of the lesions were defined as no uptake, faint uptake, moderate uptake, or clearly abnormal intense uptake. Moderate uptake and clearly abnormal intense uptake were defined as positive results for the depiction of malignant tumors, and no uptake and faint uptake were defined as negative results. Preliminary diagnoses were made prior to PET, but the radiologists conducted the image interpretations without knowledge of the preliminary diagnoses. All PET findings were compared with the final diagnosis regarding the presence of malignant tumors. The diagnostic performance of whole-body PET with FMT and FDG for depicting malignant tumors was assessed on a lesion-by-lesion basis.

For the analysis of tumor uptake of FMT and FDG, regions of interest 1 cm in diameter were manually placed over lesions on the functional images of SUV, which included the site of maximal FMT or FDG uptake. The assessment of SUV could not be conducted in a patient with lung cancer (patient 1) because of the inaccurate calibration of data between the PET camera and the dose calibrator.

Region-of-interest analysis for tumor uptake was conducted by a radiologist (H.S.) with knowledge of the clinical data. The location of the region of interest in the lesion corresponded to the CT and/or MR imaging findings.

Statistical Analysis
The relationship between FMT and FDG SUVs in the lesions was assessed by using linear regression analysis. Differences in mean SUV and percentage of injected dose of FMT and FDG in normal tissues and lesions were evaluated for statistical significance by using a Wilcoxon signed rank test. Differences in mean SUV between benign and malignant lesions were also evaluated for statistical significance by using a nonparametric Mann-Whitney U test. Differences in sensitivity were estimated by using a McNemar paired test, and differences in the positive predictive value were statistically analyzed by using the method proposed by Leisenring et al (16). A P value of less than .05 was considered to indicate a significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Dosimetry and Normal Distribution of FMT
The mean absorbed doses for each target organ are presented in Table 1. Target organs showing relatively higher absorbed doses were the bladder wall, kidneys, uterus, ovaries, lower large intestinal wall, and testes, in this order. The mean effective doses in the three volunteers were 0.024 mSv/MBq for men and 0.025 mSv/MBq for women. Mean accumulated urinary excretion values at 2 and 4 hours after the injection were 28.6% and 35.7%, respectively.

The whole-body FMT PET images in healthy volunteers revealed a high concentration of radioactivity in the kidneys and urinary bladder. Faint FMT uptake was observed in the brain, liver, cardiac blood pool, and soft tissue (Fig 1). On the FDG PET images in the same volunteer, a greater intensity of uptake was observed in the brain and heart. In comparison with FDG, significantly less FMT uptake was observed in the brain, heart, lung, liver, and spine in healthy volunteers. Mean muscular FMT uptake was also lower than that of FDG, but the difference was not statistically significant. Only renal FMT uptake was significantly higher than that of FDG (Tables 2, 3).



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  		Figure 1a. Whole-body PET images in a 49-year-old healthy male volunteer. The more posterior images are on the left; the more anterior images are on the right. (a) FMT images reveal high radioactivity in the kidneys (arrows) and urinary bladder (arrowheads) and faint uptake in the brain, heart, liver, and soft tissue. (b) FDG image shows intense physiologic uptake in the brain (open arrows) and heart (solid arrow).

 


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  		Figure 1b. Whole-body PET images in a 49-year-old healthy male volunteer. The more posterior images are on the left; the more anterior images are on the right. (a) FMT images reveal high radioactivity in the kidneys (arrows) and urinary bladder (arrowheads) and faint uptake in the brain, heart, liver, and soft tissue. (b) FDG image shows intense physiologic uptake in the brain (open arrows) and heart (solid arrow).

 

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  		TABLE 2. Injected Doses per Organ

 

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  		TABLE 3. SUVs per Organ

 
Comparative Clinical Study of Whole-Body PET
Thirty-two (56%) of 57 lesions showed agreement in the PET results obtained at visual interpretation of FDG and FMT images. Twenty-five of the 32 lesions had true-positive results for the depiction of malignant tumors with both FMT and FDG PET (Figs 2, 3); two were true-negative, two were false-negative, and three were false-positive. Thus, 27 lesions (25 true-positive and two true-negative results in the diagnosis of malignant tumors) were evaluated accurately with both FMT and FDG PET.



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  		Figure 2a. Transverse images in a 61-year-old man with lung cancer. (a) Brain FMT PET image more clearly demonstrates the metastatic lesions (arrowheads) than does (b) the FDG PET image. (c) CT scan demonstrates the lesions (arrows). (d) FMT and (e) FDG PET images depict the mediastinal lesions (arrow) in the same way. (f) On this CT scan, the lesion corresponds to a paratracheal lesion. (g-i) A metastatic lesion (arrow) in the right adrenal gland was also confirmed on both (g) FMT and (h) FDG PET images, which corresponded to the adrenal mass on the (i) CT image.

 


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  		Figure 2b. Transverse images in a 61-year-old man with lung cancer. (a) Brain FMT PET image more clearly demonstrates the metastatic lesions (arrowheads) than does (b) the FDG PET image. (c) CT scan demonstrates the lesions (arrows). (d) FMT and (e) FDG PET images depict the mediastinal lesions (arrow) in the same way. (f) On this CT scan, the lesion corresponds to a paratracheal lesion. (g-i) A metastatic lesion (arrow) in the right adrenal gland was also confirmed on both (g) FMT and (h) FDG PET images, which corresponded to the adrenal mass on the (i) CT image.

 


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  		Figure 2c. Transverse images in a 61-year-old man with lung cancer. (a) Brain FMT PET image more clearly demonstrates the metastatic lesions (arrowheads) than does (b) the FDG PET image. (c) CT scan demonstrates the lesions (arrows). (d) FMT and (e) FDG PET images depict the mediastinal lesions (arrow) in the same way. (f) On this CT scan, the lesion corresponds to a paratracheal lesion. (g-i) A metastatic lesion (arrow) in the right adrenal gland was also confirmed on both (g) FMT and (h) FDG PET images, which corresponded to the adrenal mass on the (i) CT image.

 


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  		Figure 2d. Transverse images in a 61-year-old man with lung cancer. (a) Brain FMT PET image more clearly demonstrates the metastatic lesions (arrowheads) than does (b) the FDG PET image. (c) CT scan demonstrates the lesions (arrows). (d) FMT and (e) FDG PET images depict the mediastinal lesions (arrow) in the same way. (f) On this CT scan, the lesion corresponds to a paratracheal lesion. (g-i) A metastatic lesion (arrow) in the right adrenal gland was also confirmed on both (g) FMT and (h) FDG PET images, which corresponded to the adrenal mass on the (i) CT image.

 


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  		Figure 2e. Transverse images in a 61-year-old man with lung cancer. (a) Brain FMT PET image more clearly demonstrates the metastatic lesions (arrowheads) than does (b) the FDG PET image. (c) CT scan demonstrates the lesions (arrows). (d) FMT and (e) FDG PET images depict the mediastinal lesions (arrow) in the same way. (f) On this CT scan, the lesion corresponds to a paratracheal lesion. (g-i) A metastatic lesion (arrow) in the right adrenal gland was also confirmed on both (g) FMT and (h) FDG PET images, which corresponded to the adrenal mass on the (i) CT image.

 


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  		Figure 2f. Transverse images in a 61-year-old man with lung cancer. (a) Brain FMT PET image more clearly demonstrates the metastatic lesions (arrowheads) than does (b) the FDG PET image. (c) CT scan demonstrates the lesions (arrows). (d) FMT and (e) FDG PET images depict the mediastinal lesions (arrow) in the same way. (f) On this CT scan, the lesion corresponds to a paratracheal lesion. (g-i) A metastatic lesion (arrow) in the right adrenal gland was also confirmed on both (g) FMT and (h) FDG PET images, which corresponded to the adrenal mass on the (i) CT image.

 


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  		Figure 2g. Transverse images in a 61-year-old man with lung cancer. (a) Brain FMT PET image more clearly demonstrates the metastatic lesions (arrowheads) than does (b) the FDG PET image. (c) CT scan demonstrates the lesions (arrows). (d) FMT and (e) FDG PET images depict the mediastinal lesions (arrow) in the same way. (f) On this CT scan, the lesion corresponds to a paratracheal lesion. (g-i) A metastatic lesion (arrow) in the right adrenal gland was also confirmed on both (g) FMT and (h) FDG PET images, which corresponded to the adrenal mass on the (i) CT image.

 


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  		Figure 2h. Transverse images in a 61-year-old man with lung cancer. (a) Brain FMT PET image more clearly demonstrates the metastatic lesions (arrowheads) than does (b) the FDG PET image. (c) CT scan demonstrates the lesions (arrows). (d) FMT and (e) FDG PET images depict the mediastinal lesions (arrow) in the same way. (f) On this CT scan, the lesion corresponds to a paratracheal lesion. (g-i) A metastatic lesion (arrow) in the right adrenal gland was also confirmed on both (g) FMT and (h) FDG PET images, which corresponded to the adrenal mass on the (i) CT image.

 


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  		Figure 2i. Transverse images in a 61-year-old man with lung cancer. (a) Brain FMT PET image more clearly demonstrates the metastatic lesions (arrowheads) than does (b) the FDG PET image. (c) CT scan demonstrates the lesions (arrows). (d) FMT and (e) FDG PET images depict the mediastinal lesions (arrow) in the same way. (f) On this CT scan, the lesion corresponds to a paratracheal lesion. (g-i) A metastatic lesion (arrow) in the right adrenal gland was also confirmed on both (g) FMT and (h) FDG PET images, which corresponded to the adrenal mass on the (i) CT image.

 


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  		Figure 3a. Coronal (a) FMT and (b) FDG PET images in a 41-year-old woman with anaplastic large cell lymphoma. Both images reveal lesions in the lung (long arrow), liver (short arrows), and spleen (arrowheads). The more posterior images are on the left; the more anterior images are on the right.

 


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  		Figure 3b. Coronal (a) FMT and (b) FDG PET images in a 41-year-old woman with anaplastic large cell lymphoma. Both images reveal lesions in the lung (long arrow), liver (short arrows), and spleen (arrowheads). The more posterior images are on the left; the more anterior images are on the right.

 
The visual interpretations of the whole-body FMT PET images of 25 lesions (44%) were inconsistent with the interpretations of the whole-body FDG PET images. Seven lesions had false-negative results with FMT PET and true-positive results with FDG PET in the diagnosis of malignant tumors: one metastatic bone lesion, two metastatic lesions in regional lymph nodes from lung cancer, one metastatic adrenal gland lesion from lung cancer, one pleural recurrent lung cancer, and two primary lesions from lung cancer. Sixteen lesions showed true-negative results with FMT PET and false-positive results with FDG PET in the diagnosis of malignant tumors: 12 sarcoid lesions in two patients, one suspected colon lesion (which was not detectable at colorectal endoscopy, ultrasonography [US], and CT), one suspected bone lesion, one suspected recurrent lung lesion (histologically proved to be benign), and one anthracosis in the mediastinal lymph node. One lesion in the foot of a patient with malignant melanoma had a true-positive result on the FMT PET image and a false-negative result on the FDG PET image. One lesion in the upper arm in a patient with schwannoma had a false-positive result on the FMT PET image and a true-negative result on the FDG PET image (Table 4).


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  		TABLE 4. Patient Characteristics and Results with FMT and FDG PET

 
In terms of the diagnostic performance on a lesion-by-lesion basis, the sensitivity of whole-body FMT PET for depicting malignant tumors was inferior to that of whole-body FDG PET, but this difference was not statistically significant. However, the positive predictive value of whole-body FMT PET was superior to that of whole-body FDG PET (Table 5).


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  		TABLE 5. Summary of PET Results

 
FMT uptake in the malignant lesions was significantly less than FDG uptake (1.64 ± 0.96 vs 5.02 ± 3.56; P < .001), and a weak linear correlation between the two was observed (Fig 4). However, the diagnostic performance in differentiating malignant lesions from benign lesions with FMT PET seemed to be superior to that of FDG PET, because there was a significant difference in SUVs of FMT between malignant and benign lesions (1.64 ± 0.96 vs 0.79 ± 0.23; P < .001), while no significant difference in the SUVs of FDG was observed (5.02 ± 3.56 vs 4.02 ± 2.90; P > .05) (Fig 5).



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  		Figure 4. Plot shows the relationship between the SUVs of FMT and FDG in malignant lesions. A weak linear correlation is observed.

 


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  		Figure 5a. Plots show the SUVs in malignant and benign lesions with (a) FMT and (b) FDG. A significant difference in SUVs between the lesions is observed with FMT PET, while there was no significant difference in SUVs with FDG PET. The mean SUV in the malignant lesions with FMT was smaller than that with FDG (1.64 ± 0.96 vs 5.02 ± 3.56, P < .001).

 


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  		Figure 5b. Plots show the SUVs in malignant and benign lesions with (a) FMT and (b) FDG. A significant difference in SUVs between the lesions is observed with FMT PET, while there was no significant difference in SUVs with FDG PET. The mean SUV in the malignant lesions with FMT was smaller than that with FDG (1.64 ± 0.96 vs 5.02 ± 3.56, P < .001).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Absorbed doses in the target organs—namely, the brain, lung, heart, and liver—in the FMT PET study were lower than those in the FDG PET study, as previously reported (17). The observed mean effective doses in this study of FMT PET, which were similar to those reported for FDG PET (17), demonstrate its safety in terms of radiation dose.

The biodistribution of FMT in humans appears to differ from that of FDG (Fig 1). Aside from renal uptake, the FMT PET images revealed relatively less uptake in the various organs than did the FDG PET images (Tables 2, 3). FMT uptake in the brain and heart, where physiologic accumulation of FDG occurs, was faint. Although a fast of 4 hours or longer prior to FDG administration may not be an ideal fasting period for the depiction of tumors, FDG uptake in the brain cortex after overnight fasting was reported to be 7.2 SUVs (18), which was close to the 7.77 SUVs obtained in this study (Table 3). SUVs of FDG in heart, liver, and muscle in this study were not significantly different from SUVs derived from FDG PET conducted after fasting of more than 6 hours (4.07 vs 3.6 in heart, 1.66 vs 2.1 in liver, 0.80 vs 0.80 in muscle [19]). Furthermore, no significant difference in myocardial FDG uptake after 6-hour and overnight fasting was reported (20). Even when patients fasted overnight, only moderate FDG uptake was observed in the heart, and this yielded apparent discrete foci, which could be misinterpreted as malignant lesions (21).

A brain tumor–to–normal cortex counts ratio of FMT was significantly higher than that of FDG in patients with brain tumors (11). This fact may suggest that whole-body PET images obtained with FMT are effective in depicting metastatic lesions in the cardiac region or in the brain (Fig 2a, 2b) The average brain SUV of FMT in this study was lower than that previously reported for eight healthy volunteers (11). This discrepancy may be due to the different dietary conditions in the PET study. The eight healthy volunteers in the previous report (11) fasted prior to FMT PET. In contrast, the five healthy volunteers in this study were not required to fast prior to FMT PET. Naturally present amino acids may compete in the brain uptake of {alpha}-methyl tyrosine and may reduce the brain SUV of FMT (22,23). Since it may also reduce the tumor uptake of FMT (23), further investigation may be needed to clarify the necessity of fasting prior to FMT PET. Initially, intense pancreatic uptake of FMT was expected on the basis of the reported (23) biodistribution in an animal experiment with mice. Since weak FMT uptake made it impossible to draw a region of interest on the pancreas, this area was excluded from region-of-interest analysis. This is consistent with the results of biodistribution of IMT in humans examined by using SPECT (9).

The subjects in this study had a heterogenous range of tumors with few benign neoplasms and with a tendency toward lung cancer in the malignant group. This is a limitation of this study in terms of our ability to assess the diagnostic accuracy of FMT PET in patients with malignant tumors. Another limitation of this study was the use of hard-copy images for interpretation, which was suboptimal compared with the use of images on the computer monitor with free manipulation of intensity and contrast.

The calculation of specificity and negative predictive value on a lesion-by-lesion basis is misleading when it is based on results in benign lesions rather than in disease-free sites. However, the number of disease-free sites could not be defined in the whole body. Only sensitivity and positive predictive value, as indirect indexes of specificity, were used for the analysis of diagnostic accuracy of the whole-body PET study. The sensitivity of whole-body FMT PET in depicting malignant tumors was lower than that of whole-body FDG PET in this study, but this difference was not significant (Table 5). On the other hand, the positive predictive value of whole-body FMT PET was superior to that of whole-body FDG PET (Table 5). FDG is known to accumulate in active inflammatory lesions (24,25) and granulomatous tissue, such as with sarcoidosis (26).

The large number of sarcoid lesions depicted in this study may account for the poor diagnostic performance of FDG PET in depicting malignant tumors. All 12 sarcoid lesions in this study had false-positive FDG PET results and true-negative FMT PET results. These lesions constituted 21% of the total number of lesions, and 75% of the FDG false-positive and FMT true-negative lesions (Tables 4, 5). In this study, false-positive FDG PET results were shown in five of six lesions with histologically proved inflammatory and granulomatous tissues. On the other hand, a false-positive result with FMT PET was observed in only one of six lesions (Table 4). One colon lesion was suspected on the basis of FDG PET (patient 4), but follow-up clinical examination with colon endoscopy, CT, and US did not depict any mass lesions corresponding to this FDG uptake, with no abnormal uptake of FMT in this area.

SUV analysis demonstrated that FMT PET has a superior ability to help differentiate malignant tumors from benign lesions compared with that of FDG PET (Fig 5). However, FMT and FDG PET are used to image different physiologic processes. FMT offers the opportunity to study different biologic activity and is not competitive with FDG.

There are several factors that influence the uptake and release of an amino acid by a cell. Delivery (concentration multiplied by blood flow), transport activity, and intracellular metabolism (synthesis and degradation) are some of these factors (27). Although the relationship between tumor blood flow and FMT tumor uptake was not investigated in this study, a marked positive correlation between IMT tumor uptake and tumor blood flow was reported in an animal experiment in which tumor-bearing rats and {alpha}-methyl tyrosine labeled with iodine 125 was used (28). FMT entered the tumor cells by means of the amino acid transport system, but most of the incorporated FMT was not metabolized (23). During its intracellular metabolism, tyrosine enters the pathways of protein synthesis, decarboxylation, and L-dopa and melanin synthesis. On the basis of the metabolic pathway of melanin synthesis derived from tyrosine, we expected FMT, as well as IMT (29), to be applicable for the depiction of melanoma . One of two melanomas was visualized with FMT PET even when FDG PET produced a negative result (Table 4). The other melanoma (in patient 12) was an unusual diffuse leptomeningeal dissemination of malignant melanoma. It was hard to differentiate FDG and FMT tumor uptake from ordinary physiologic uptake in the central nervous system.

Whole-body imaging is a powerful technique for use in nuclear medicine examinations in the assessment of malignant tumors, especially in the detection of distant metastatic lesions. Although IMT is already used in the detection of extracranial tumors with conventional gamma cameras (9), the advantage of FMT PET in depicting tumors is its potential to allow acquisition of whole-body tomographic images with a PET camera that has high spatial resolution. One drawback of whole-body FMT PET is that only a few institutes can perform this study because of the limited availability of cyclotron equipment and the cost involved. However, the satellite system may facilitate clinical use of not only FDG but also 18F-labeled amino acids such as FMT (30).

In conclusion, these preliminary findings indicate that whole-body FMT PET could be used clinically in the diagnosis of malignant tumors. The sensitivity of whole-body FMT PET in depicting malignant tumors was inferior to that of whole-body FDG PET, but this difference was not significant. The positive predictive value of whole-body FMT PET was superior to that of whole-body FDG PET. This could be partially due to the many lesions with sarcoid, which is well known to produce an inflammatory reaction and which would be expected to cause problems when an FDG PET study is performed. Because of its high positive predictive value, whole-body FMT PET may be useful for depicting biopsy sites in patients with malignant tumors who are suspected of having metastatic lesions. Whole-body FMT PET may also be effective in depicting metastatic lesions in the cardiac region or brain.


   ACKNOWLEDGMENTS
 
We thank Kunio Matsubara and Kazukuni Takahashi for technical assistance and Matsue Goto and Rumiko Hirai for preparing the manuscript. We express special thanks to Kiyoshi Fukushi, PhD, (National Institute of Radiation Sciences, Chiba, Japan) for his kind help in the calculation of absorbed dose by using a Medical Internal Radiation Dose, or MIRD, computer program.


   FOOTNOTES
 
2 **. Multiple body systems Back

Abbreviations: FDG = 2-[fluorine 18]fluoro-2-deoxy-D-glucose, FMT = fluorine 18 {alpha}-methyl tyrosine, IMT = iodine 123–labeled {alpha}-methyl tyrosine, SUV = standardized uptake value

Author contributions: Guarantor of integrity of entire study, T.I.; study concepts, T.I., K.K., N.O., K.E.; study design, T.I.; literature research, T.I., N.O., Z.Y., S.A.; clinical studies, T.I., K.K., N.O., H.S., Y.T., J.A.; data acquisition, T.I., N.O., K.K., K. Tomiyoshi, S.A., H.S.; data analysis, T.I., K.K., N.O., H.S.; statistical analysis, K. Takeuchi, T.O., K. Tomiyoshi; manuscript definition of intellectual content, T.I., J.A., K.E.; manuscript editing, T.I., K.E.; manuscript revision/review, T.I., J.A., K.E.; manuscript preparation and final version approval, T.I.


   REFERENCES
TOP
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 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
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