Ann Nucl Med (2013) 27:808–821
DOI 10.1007/s12149-013-0750-4

ORIGINAL ARTICLE

Diagnostic usefulness of an amino acid tracer,a-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeAIB),in the PET diagnosis of chest malignancies
Ryuichi Nishii • Tatsuya Higashi • Shinya Kagawa • Yoshihiko Kishibe • Masaaki Takahashi • Hiroshi Yamauchi •Hideki Motoyama • Kenzo Kawakami • Takashi Nakaoku • Jun Nohara • Misato Okamura • Toshiki Watanabe •Koichi Nakatani • Shigeki Nagamachi • Shozo Tamura • Keiichi Kawai • Masato Kobayashi

Received: 27 May 2013 / Accepted: 17 June 2013 / Published online: 4 July 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com

Abstract
Objectives Although positron emission tomography(PET) using [18F]-fluoro-2-deoxy-D-glucose (18F-FDG) isestablished as one of the first-choice imaging modalities inthe diagnosis of chest malignancies, there are several
problems to solve in clinical practice, such as false positive
uptake in inflammatory diseases. The aim of this study wasto evaluate the clinical usefulness of an amino acid tracer,a-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeAIB), in the diagnosis of chest malignancies, in combination
with 18F-FDG.

R. Nishii  T. Higashi (&)  S. Kagawa  Y. Kishibe 
M. Takahashi  H. Yamauchi
Shiga Medical Center Research Institute, 5-4-30 Moriyama,Moriyama, Shiga 524-8524, Japane-mail: higashi@res.med.shiga-pref.jp
R. Nishii  S. Nagamachi  S. Tamura
Department of Radiology, Faculty of Medicine, Miyazaki
University, 5200 Kihara, Kiyotake-cho,Miyazaki, Miyazaki 889-1692, Japan
H. Motoyama  K. Kawakami
Department of Thoracic Surgery, Shiga Medical Center, 5-4-30
Moriyama, Moriyama, Shiga 524-8524, Japan
T. Nakaoku  J. Nohara  M. Okamura  T. Watanabe 
K. Nakatani
Department of Respiratory Medicine, Shiga Medical Center,
5-4-30 Moriyama, Moriyama, Shiga 524-8524, JapanK. Kawai  M. Kobayashi
Division of Health Sciences, Graduate School of Medical
Science, Kanazawa University, 5-10-80 Kodachino, Kanazawa,
Ishikawa 920-0942, Japan

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Setting Fifty-nine cases (57 patients, 66 ± 12 years old)
who consulted to our institution for the wish to receive
differential diagnosis of chest diseases were included.
Purpose of the studies were as follows: differential diagnosis of newly developed lung nodules, n = 22; newly
developed mediastinal lesions, n = 20; and both, n = 17
(including lung cancer: n = 19, lymphoma: n = 1, othercancers: n = 2, sarcoidosis: n = 15, non-specific inflammation: n = 18, other inflammatory: n = 4, respectively).
Whole-body static PET or PET/CT scan was performed 20
and 50 min after the IV injection of 11C-MeAIB and 18FFDG, respectively.
Results 11C-MeAIB uptake of malignant and benign
lesions was statistically different both in pulmonary nodules (p \ 0.005) and in mediastinal lesions (p \ 0.0005).
In visual differential diagnosis, 11C-MeAIB showed higher
results (specificity: 73 %, accuracy: 81 %), compared tothose in 18F-FDG (60, 73 %, respectively). In cases ofsarcoidosis, 11C-MeAIB showed higher specificity (80 %)with lower uptake (1.8 ± 0.7) in contrast to the lower
specificity (60 %) with higher uptake of 18F-FDG(7.3 ± 4.5).
Conclusions 11C-MeAIB PET/CT was useful in the differential diagnosis of pulmonary and mediastinal masslesions found on CT. 11C-MeAIB PET or PET/CT showed
higher specificity than that of 18F-FDG PET/CT in differentiating between benign and malignant disease. Our datasuggest that the combination of 18F-FDG and 11C-MeAIB
may improve the evaluation of chest lesions, when CT and
18
F-FDG PET/CT are equivocal.
Keywords Amino acid tracer  Methylaminoisobutyricacid  Fluorodeoxyglucose  Lung cancer 
Lymphadenopathy  Positron emission tomography Sarcoidosis

Ann Nucl Med (2013) 27:808–821

Introduction
The positron emission tomography (PET) radiopharmaceutical 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) iscurrently used for diagnostic imaging of a variety of tumors[1]. However, 18F-FDG is known to accumulate in normal
structures and in sites of inflammation, reducing its specificity [2–5]. Several investigators have reported that
18
F-FDG PET performed to assess for malignancy showed
20–50 % false positive results, with the higher false positive
rates found in geographical areas of endemic granulomatous diseases, such as histoplasmosis or tuberculosis [5–8].
A variety of new tracers has been introduced in order toovercome these limitations [9–11]. Amino acid tracers are
one promising category. 11C-methionine (11C-MET) has
been extensively investigated, though with several drawbacks being revealed [12]. 11C-MET is not stable in vivo,
becoming trans-methylated, and losing its 11C moiety as
it is metabolized [13]. Several studies have shown that
11
C-MET is not tumor-specific, and accumulates in someinflammatory diseases, such as sarcoidosis [14, 15].
[N-methyl-11C]a-methylaminoisobutyric acid (11C-MeAIB)
is an artificial amino acid PET tracer, which, unlike 11C-MET,
is metabolically stable in vivo [16, 17]. It has been shownthat 11C-MeAIB is a useful tracer for measurement ofamino acid uptake by skeletal muscle, and in the diagnosis
of malignant lymphoma and head and neck cancers [16, 18,19]. The utility of 11C-MeAIB PET in the diagnosis ofchest malignancies has not yet been evaluated.
The purpose of this study is to investigate the efficacy of
11
C-MeAIB PET or PET/CT as a diagnostic tool for distinguishing between malignancies and inflammatory diseases, when CT or 18F-FDG PET or PET/CT shows
equivocal findings.

Materials and methods
Patients
From March 2009 to September 2012, 59 cases (57patients; male: 35, female: 22; ranging from 28 to 88 years;
mean age: 65.5 ± 12.3) (Table 1, left) of new chest lesions
detected by CT scan (21 patients had lung lesions only, 20
patients had mediastinal lesions only, and 18 patients had
both lesions) were selected. Two patients received thisstudy protocol twice with 1 year interval or more. Eachpatient gave written informed consent. The tracer study
was approved by our institutional review boards, the
Human Study Committee (approval number: #36-04, Mar.
25, 2009) and the Committee for the Clinical Use of ShortHalf Life Radioactive Materials (approval number: #200801, Nov. 28, 2008).

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Inclusion criteria were: (1) a new chest lesion detectedon CT scan, suspicious for malignancy, (2) CT (and18
F-FDG PET or PET/CT) showing equivocal findings,
with further evaluation requested by referring pulmonologists, and (3) disease confirmed by pathology, or clinicalfollow-up for more than 12 months after PET studies.
Exclusion criteria were: (1) malignant or inflammatory
lesions which received treatment within 6 months before
18
F-FDG PET or PET/CT, (2) apparent direct invasion ofneighboring organs, (3) apparent extra-pulmonary metastatic lesions, and (4) patients who refused to undergo
11
C-MeAIB PET or PET/CT. Baseline diseases or detailed
background of clinical conditions are shown in Table 1(left).
The CT scans had been performed as routine clinicalstudies with a multi-detector row CT scanner, Aquilion 16(Toshiba, Tokyo, Japan). All patients subsequently underwent both 18F-FDG and 11C-MeAIB PET or PET/CT
within 2 weeks of the CT.
PET studies
18

F was produced by 18O(p, n) 18F reaction. 18F-FDG wassynthesized by the nucleophilic substitution method using
an 18F-FDG-synthesizing instrument F-100 (SHI, Tokyo,
Japan) and a cyclotron, CYPRIS-325R (SHI, Tokyo,
Japan). Otherwise, 18F-FDG was purchased commerciallyfrom Nihon-Medi-Physics (Tokyo, Japan).
Production of 11C-MeAIB was based on the method
proposed by Någren et al. [20]. The patients fasted formore than 5 h before the injection of 18F-FDG or 11CMeAIB. Blood glucose levels were measured before theinjection of 18F-FDG, and all the patients showed levels of
B150 mg/dL (95.2 ± 13.1 mg/dL). All subjects underwent
two separate scans, one following an intravenous injectionof 18FDG (298 ± 68 MBq), and another after the intravenous injection of 11C-MeAIB (512 ± 50 MBq). Wholebody PET image acquisition commenced 50 min after 18FFDG and 20 min after 11C-MeAIB injection. PET scans
were performed either by a whole-body PET scanner, GE
Advance (GE Healthcare, Waukesha WI, USA), or by awhole-body PET/CT scanner, Siemens True Point Biograph 16 (Siemens/CTI, Erlangen, Germany).
Image analysis
Visual analysis of each lesion on the two PET scans was
performed by two experienced nuclear medicine physicians(RN, TH) provided with clinical information including CT
scans and tumor markers. All lesions were graded as
positive or negative by consensus of two readers. If a
nodule showed similar or lower uptake than that in theupper to middle normal mediastinal tissues, uptake was

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Table 1 Characteristics of Total 57 Patients [59 PET studies (2 patients received 2 series of PET studies with [5 months interval)] and 80
lesions
Age (years)

Final diagnosis (lesion-based), n (%)

Mean ± SD

65.5 ± 12.3

Range

28–88

Pulmonary nodules in the lung fields: (n = 42)

Gender, n (%)

Lung cancer

18 (43 %)Male

35 (61 %)Adenocarcinoma

12 (29 %)Female22 (39 %)Squamous cell carcinoma

3 (7 %)

Small cell carcinoma

2 (5 %)

Large cell carcinoma

1 (2 %)

Purpose of total 57 PET study, n (%)
Evaluation of lung nodule(s)22 (37 %)Other malignancies (post-treated)

4 (10 %)

Evaluation of mediastinal nodule(s)20 (34 %)Mesothelioma

2 (5 %)

Evaluation of both

17 (29 %)Colorectal cancer
Lymphoma1 (2 %)
1 (2 %)

Non-malignant diseases

20 (48 %)Baseline diseases, n (%)
None, newly developed lung nodule

30 (51 %)Non-specific inflammatory changes

13 (31 %)None, newly developed mediastinal lesion(s)20 (34 %)Sarcoid nodule

5 (12 %)

Abscess

2 (5 %)

Newly developed chest lesion(s)in the follow-up of other malignancies (post operated)

9 (15 %)

Gastric malignant lymphoma

2 (3 %)

Hilar and mediastinal nodules: (n = 38)

Colorectal cancer

3 (5 %)

Malignant diseases

10 (26 %)Gastric cancer

2 (3 %)

Adenocarcinoma

4 (11 %)

Esophageal cancer

1 (2 %)Squamous cell carcinoma

3 (8 %)Urinary bladder cancer

1 (2 %)

Small cell carcinoma

1 (3 %)

Mesothelioma

1 (3 %)

Final confirmation of 57 PET diagnosis

Lymphoma1 (3 %)

Pathological confirmation

35 (59 %)Non-malignant diseases

28 (74 %)Surgical resection (including VATS**)17 (29 %)Sarcoidosis

15 (39 %)Biopsy at bronchoscopy
Biopsy at thoracoscopy

6 (10 %)
3 (5 %)

Non-specific inflammatory changes
IgG4 related disease

9 (24 %)
2 (5 %)

CT-guided biopsy

1 (2 %)Squamous cell papilloma

1 (3 %)

Resection or biopsy of superficial lymph node

7 (12 %)

Tubercular nodule

1 (3 %)

Sputum culture

1 (2 %)

Clinical follow-up ([12 months)

24 (42/1 %)defined as negative. If a nodule showed higher uptake thanthat of the normal mediastinal tissues, its uptake wasdefined as positive. However, high 18F-FDG uptake wassometimes defined as negative in cases of sarcoidosis andother benign entities with a characteristic pattern by consensus of two readers.
Semi-quantitative analysis of 18F-FDG and 11C-MeAIB
uptake was also performed. Regions of interest (ROIs) were
defined on the target lesions in the transaxial tomograms of
PET-only images. PET-to-CT co-registration was performed using automatic rigid/non-rigid body-deformablefusion software: Quantiva/BodyGuide (Tomographix IP
Ltd., Toronto, Canada). In PET/CT scans, ROIs were
defined and confirmed on the fused PET and CT images(hereafter all scans will be referred to as PET/CT scans,123

since PET images were always fused to CT images). The
standardized uptake value (SUV) was calculated as follows:
SUV ¼CðkBq=mlÞIDðkBqÞ=body weight ðgÞ

where C represents tissue activity concentration measured
by PET and ID represents the injected dose. The mean
SUV of the normal tissue (lung field and mediastinum) was
defined as the SUVmean. The highest SUV of the lesion
was defined as the SUVmax.
Statistics
All values are expressed as mean ± SD. All the statisticalanalyses were performed using statistical software, JMP 8J

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C

D

A

B

Fig. 1 A case of lung cancer. Fifty-nine-year-old asymptomatic malepatient. Screening chest X-ray showed abnormal density in the left
upper lung zone. The patient underwent a contrast-enhanced chest CT
scan, which revealed a nodule in the left apex (a) with probably lymph
node (ln) metastasis in the left hilum (b). Bronchoscopic biopsy
revealed squamous cell carcinoma (SCC). Both 18F-FDG PET and
11
C-MeAIB PET (c, d: MIP image) showed high accumulation in theleft upper lobe lesion (SUVmax = 13.2 for 18FDG, 6.3 for 11CMeAIB, arrows) and left hilar ln (SUVmax = 21.9 for 18F-FDG, 11.5
for 11C-MeAIB, arrowheads). It should be noted that 18F-FDG uptake
was relatively greater in the periphery than that of 11C-MeAIB. It was
confirmed as concomitant inflammatory changes in the tissue
surrounding the lesion. A small bone metastasis was also suspectedin the right scapula (not pathologically confirmed)

version (SAS Institute, Cary NC, USA), in which p values\0.05 were considered statistically significant. A comparison between each group was analyzed by the Wilcoxon
score for unpaired data. Receiver operating characteristic
curve (ROC) analyses for the diagnostic accuracy in 11CMeAIB PET/CT and 18F-FDG PET/CT were generatedusing GraphPad Prism ver. 5.0 (GraphPad software, San
Diego CA, USA). A comparison of SUVmax between 11CMeAIB and 18F-FDG in each lesion was analyzed by the
Logistic regression.

12 months in 24 cases. Of the 59 cases in the present study,
there were 22 malignant and 20 benign pulmonary nodules
in the lungs and 10 malignant and 28 benign mediastinal
lesions.
Figure 1 shows a typical malignant case, while Fig. 2
shows a typical benign case; in this instance, sarcoidosis. In
Fig. 3, a 18F-FDG-strongly positive lung nodule wasdiagnosed as sarcoidosis. Equivocal findings of metastaticcolon cancer are shown in Fig. 4.
Semi-quantitative analysis of 18FDG uptake
and 11C-MeAIB uptake

Results
Table 1 summarizes the patient characteristics. The final
diagnosis was confirmed pathologically by surgical resection in 17 cases, while biopsy at bronchoscopy, thoracoscopy, and CT-guided biopsy confirmed diagnosis in 10
cases. Resection or biopsy of lymph nodes at neck or supraclavicular area was performed in seven cases. Clinicaldiagnosis was determined by follow-up for at least

The average SUVmax and SUVmean for 18F-FDG and
C-MeAIB uptake in normal lung and mediastinum areshown in Table 2. The average SUVmax of 18F-FDG in
malignant lesions was significantly higher than that inbenign lesions for 42 pulmonary nodules, while not significantly different for 38 benign and malignant mediastinal lesions. There was a wide overlap in 18F-FDG uptake
between malignant and benign chest diseases, resulting in
11

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A

B

C

D

E

Fig. 2 A case of sarcoidosis. Forty-four-year-old asymptomatic
female patient. She had been followed as an outpatient after complete
remission (more than 1 year previously) of malignant abdominal
lymphoma (post-chemotherapy). She had no history of sarcoidosis oruveitis. The patient underwent chest CT scan (a), which revealed
multiple nodules (arrows) in the middle mediastinum. 18F-FDG PET(b: MIP image) showed high accumulation in these lesions (SUVmax = 6.0 for the highest uptake in right hilar lesion), but there wasno other lesions in the body. 11C-MeAIB PET (c: MIP image) showedno accumulation in these lesions (SUVmax = 1.8, with the highest
uptake in the mediastinum). Thoracoscopic biopsy revealed sarcoidosis (d: low magnification, e: high magnification)

many false positive cases on 18F-FDG PET/CT, especiallyin mediastinal lesions.
The average SUVmax of malignant lesions with
11
C-MeAIB PET/CT was significantly lower than that for
18
F-FDG PET/CT. On the other hand, 11C-MeAIB uptake
by malignant and benign lesions showed greater statisticaldifferences both among pulmonary nodules and mediastinal lesions.
Figure 5 shows the result of ROC analyses for 18F-FDG
and 11C-MeAIB, in which the diagnostic accuracies wereobtained from the SUVmax values of each tumor in both
PET/CT studies. An SUVmax = 3.0 was used as thethreshold for 18F-FDG diagnosis. Other thresholds (SUVmax = 2.0, 2.5, 3.5, 4.0) gave similar or worse diagnostic
results. In 11C-MeAIB PET/CT studies, an SUVmax = 2.0

was used as the optimum threshold. 11C-MeAIB scans
showed a higher value than 18F-FDG scans both in patientbased (Fig. 5) and lesion-based diagnoses (not shown).

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Patient-based diagnostic results
Visual diagnosis of 18FDG and 11C-MeAIB on a perpatient basis in 59 cases is shown in Table 3 (top). The
accuracy of 18FDG was 72.9 %, which was better than thatfrom semi-quantitative analysis. Although 18FDG uptake
was often equivocally positive, the final diagnosis was
judged as true negative in many benign or inflammatory
cases because of the analysis of pattern and location of the18
F-FDG uptake. Fifteen false positive cases with 18F-FDG
were as follows: granulomatous inflammatory lung nodules

Ann Nucl Med (2013) 27:808–821

813

A

B

D

C

E

F

Fig. 3 A case of sarcoidosis with lung nodule and mediastinal
lesions. Sixty-three-year-old asymptomatic male patient. He had been
followed as an outpatient for mediastinal sarcoidosis in anotherhospital. A new lung nodule was detected on CT scan and he wasreferred to our hospital. Both 18F-FDG PET/CT and 11C-MeAIB PET/CT were performed (a, d: MIP image). There was high 18F-FDG
accumulation (SUVmax = 12.3) in the right lower lobe lesion (b: CT,
c: PET/CT image), multiple mediastinal lesions, including right hilar

lymph nodes (SUVmax = 7.6, arrowheads) and also in the upper
abdominal lymph nodes (cardiac involvement was also indicated andconfirmed later). 11C-MeAIB PET/CT showed very low accumulation(SUVmax = 1.7) in the right lower lobe lesion (e: CT, f: PET/CT
image) (SUVmax = 1.7), multiple mediastinal lesions, including left
hilar lymph nodes (SUVmax = 1.7, arrowheads), and also in theupper abdominal lymph nodes. Follow-up CT scan revealed shrinkage
of lung nodule, and the diagnosis of sarcoidosis was confirmed

and mediastinal lymphadenopathy confirmed by surgicalresection (n = 6), mediastinal sarcoid lymphadenopathy
by lymph node biopsy (n = 5), mediastinal IgG4-related
lymphadenopathy by lymph node biopsy (n = 1), and nonspecific inflammatory change followed for more than
12 months (n = 3). The accuracy of 11C-MeAIB was
81.4 %. Ten false positive cases with 11C-MeAIB were as
follows: granulomatous inflammatory lung nodules andmediastinal lymphadenopathy confirmed by surgicalresection (n = 4), mediastinal sarcoid lymphadenopathy
by lymph node biopsy (n = 3), mediastinal IgG4-related
lymphadenopathy by lymph node biopsy (n = 1), and nonspecific inflammatory change followed for more than
12 months (n = 2). Nine of these 11C-MeAIB false positive cases were also false positive with 18F-FDG. One false
negative case was of metastatic colon cancer, which was
also false negative in 18F-FDG PET images (Fig. 4).
In the semi-quantitative diagnoses (59 cases) with
SUVmax = 3.0 cut-off value, the accuracy of 18F-FDG

PET/CT was 47.5 %, in which there were many false
positive results as compared with those at visual diagnosis(Table 3 bottom). There were two false negative cases with
18
F-FDG PET/CT; both were papillary adenocarcinomas
with ground-glass opacity (n = 2, diameter: 25 and25 mm, SUVmax: 1.89 and 2.00). The accuracy of 11CMeAIB PET/CT with SUVmax = 2.0 cut-off value was
74.6 %. There were 13 false positive cases and 2 false
negative cases. The false positive cases were as follows:
granulomatous inflammatory mediastinal lymphadenopathy confirmed by surgical resection (n = 4), mediastinal
sarcoid lymphadenopathy by lymph node biopsy (n = 3),
IgG4-related syndrome (n = 1), and non-specific inflammatory change followed for more than 12 months (n = 5).
The two false negative cases were papillary adenocarcinomas with ground-glass opacity (n = 2, diameter: 25 and30 mm, SUVmax: 1.74 and 1.93). The former one was also
false negative case with 18FDG, but the latter one was true
positive with 18FDG.

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A

B

C

D

E

Fig. 4 A case of metastatic colon cancer. Sixty-two year-old
asymptomatic female patient and without elevated tumor markers.
She had been followed as an outpatient after the resection of primaryadvanced colon adenocarcinoma with mucin secretion. In the followup period (1 year after surgery), the patient underwent a contrastenhanced chest CT scan (a), which revealed a small lung nodule in theleft apex. Both 18FDG and 11C-MeAIB PET showed faintaccumulation in the left upper lobe lesion (SUVmax = 3.12 for 18FFDG, 2.06 for 11C-MeAIB). Both 18F-FDG and 11C-MeAIB PET
diagnoses were ‘‘equivocal’’ (visual diagnosis: negative, quantitative
diagnosis: positive) (b, c). After close follow-up by CT scan andtumor markers, she underwent left upper lobe resection, and thislesion was confirmed as metastatic colon cancer with mucin secretionby pathology (d: low magnification, e: high magnification)

Lesion-based semi-quantitative diagnostic results

Discussion

In the differential diagnosis of pulmonary nodules with
SUVmax = 3.0 cut-off value, the accuracy of 18F-FDG
PET/CT was 65.0 % (Table 4 top). The accuracy of 18FFDG PET/CT for the diagnosis of mediastinal nodules(Table 4 bottom) was only 31.6 %. There were 26 cases offalse positive results with 18F-FDG PET/CT, and thepositive predictive value was only 27.8 %. 11C-MeAIB
PET/CT showed better accuracy. The accuracy of
11
C-MeAIB with SUVmax = 2.0 cut-off value for pulmonary nodules and mediastinal nodules was 76.2 and76.3 %, respectively. In mediastinal nodules, there were
only nine cases of false positive results, for a positive
predictive value of 52.6 %.

Several amino acid compounds have been suggested as
feasible candidates for oncologic PET tracers which canovercome the drawbacks of 18F-FDG. 11C-MeAIB is considered to be one of the most promising amino acid radiotracers in clinical oncology. To our knowledge, thepresent study is the first to evaluate the clinical applicationof 11C-MeAIB PET-to-chest lesion diagnosis.
Our principal finding is that the diagnostic results of
11
C-MeAIB PET/CT were better than those of 18F-FDG
PET/CT, especially for the identification of non-malignant
lesions. Table 3 clearly reveals the higher specificity of
11
C-MeAIB PET/CT in these cases. In the evaluation ofmediastinal lesions, 11C-MeAIB PET/CT showed 67.9 %123

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Table 2 Quantitative analysis of total 42 pulmonary lesions and 38 mediastinal lesions

n.s. not significant* p \ 0.05, § p \ 0.005, §§ p \ 0.0005

specificity in lesion-based semi-quantitative diagnosis,
while 18F-FDG PET/CT’s specificity was only 7.1 %(Table 4). The low positive predictive value (27.8 %) of
18
F-FDG PET/CT confirms that positive uptake of18
F-FDG is not reliably diagnostic of malignancy. We
believe that 11C-MeAIB PET/CT would make a great
contribution in the diagnosis of patients with pulmonary
nodules or mediastinal lesions, when CT and 18F-FDG
PET/CT shows equivocal findings.
It should be noted that 11C-MeAIB PET/CT displayedhigh diagnostic accuracy in the evaluation of sarcoidosis.
There were 20 sarcoid lesions in 14 patients and the averagelesion 18F-FDG SUVmax was 7.3 ± 4.5, while that of 11CMeAIB was 1.8 ± 0.7 (Table 5). Visual diagnosis with 18FFDG PET/CT showed false positives in six patients, while
those with 11C-MeAIB PET/CT showed false positives inthree patients. Although 18F-FDG PET/CT can diagnose
sarcoidosis by the specific uptake pattern of hilar andmediastinal lesions, sarcoidosis can form pulmonary nodules as well, and those lesions can be difficult to distinguishfrom malignancies. In addition, malignancy is often
observed synchronously or metachronously in patients withsarcoidosis. In the present study, there were five pulmonary

Fig. 5 Receiver operating characteristic curve (ROC) analyses forthe diagnostic accuracy of 11C-MeAIB and 18F-FDG using semiquantitative analysis. The area under the curve (AUC) value for 11CMeAIB PET/CT was 0.85 with standard error: 0.039, 95 % CI:
0.77–0.92 and p \ 0.0001. AUC for 18F-FDG PET/CT was 0.70 withstandard error: 0.056, 95 % CI: 0.60–0.82 and p \ 0.001. These
analyses indicated the better diagnostic accuracy of 11C-MeAIB forchest diseases (p \ 0.05)

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59.5
Specificity (%)

95.5

Sensitivity (%)

21.6
Specificity (%)

90.9

Sensitivity (%)

40.8

NPV
(%)

PPV
(%)

NPV (%)PPV (%)

Accuracy
(%)

72.9

95.7

58.3

Accuracy (%)

47.5

80.0

PPV positive predictive value, NPV negative predictive value

8

2

29

20

FDG: negative

Patients withbenign lesions,n = 37

FDG: positive

Patients withmalignantlesions, n = 22

FDG (SUVmax = 3.0 as threshold)

Diagnosis using semi-quantitative analysis

22

1

FDG:
negative

15

21

Patients with benign
lesions, n = 37

FDG:
positive

Patients with malignant
lesions, n = 22

FDG (visual diagnosis)

Visual diagnosis

Table 3 Patient-based diagnostic results of FDG- and MeAIB-PET (PET/CT)

Sensitivity (%)

95.5

1

21

MeAIB: negative

MeAIB: positive

Sensitivity (%)

90.9

2

20

Patients withmalignant lesions,n = 22MeAIB (SUVmax = 2.0 as threshold)

MeAIB:
negative

MeAIB:
positive

Patients with malignant
lesions, n = 22

MeAIB (visual diagnosis)

Specificity (%)

64.9

24

13

Patients withbenign lesions,n = 37

Specificity (%)

73.0

27

10

Accuracy
(%)

81.4

96.4

67.7

Accuracy (%)

74.6

92.3

60.6

Patients with benign
lesions, n = 37

NPV (%)PPV (%)

NPV
(%)

PPV
(%)

816
Ann Nucl Med (2013) 27:808–821

33.3
Specificity (%)

90.9

Sensitivity (%)

7.1
Specificity (%)

100.0

Sensitivity (%)

NPV** (%)

MeAIB: negative

MeAIB: positive

Sensitivity (%)

90.9

2

20

Malignant lesions,(n = 22)

MeAIB (SUVmax-2.0 as threshold)

MeAIB: negative

MeAIB: positive

Sensitivity (%)

100.0

0

10

Malignant lesions,(n = 10)MeAIB (SUVmax-2.0 as threshold)

NPV** (%)

PPV* (%)

PPV* (%)

Accuracy (%)

65.0

75.0

62.5

Accuracy (%)

31.6

100.0

27.8

* PPV positive predictive value, ** NPV negative predictive value

2

0

26

10

FDG: negative

Benign lesions,(n = 28)

FDG: positive

Malignantlesions,(n = 10)

FDG (SUVmax = 3.0 as threshold)Hilar and mediastinal nodules: (n = 38)

6

2

12

20

FDG: negative

Benign lesions, (n = 20)

FDG: positive

Malignant lesions,(n = 22)

FDG (SUVmax = 3.0 as threshold)Pulmonary nodules in the lung fields: (n = 42)

Table 4 Lesion-based diagnostic results of FDG- and MeAIB-PET (PET/CT) using semi-quantitative analysis

Specificity (%)

67.9

19

9

Benign lesions,(n = 28)

Specificity (%)

60.0

12

8

Benign lesions,(n = 20)
71.4

Accuracy (%)

76.3

100.0

52.6

Accuracy (%)

76.2

85.7

PPV* (%)

NPV** (%)

PPV* (%)

NPV** (%)

Ann Nucl Med (2013) 27:808–821
817

123

123

50/M

70/F

10

65/Fa

9

64/F

6

71/M

36/M

5

8

63/M
(Fig. 3)

4

34/F

M

61/F

3

7

M

58/M

2

M

M

M

M

P&M

P&M

P&M

P&M

P&M

48/F

1

Purposeof PET

Age/sexPatientno.

Anginapectoris

None

Colon polyps

None

Gastric
malignantlymphoma

Gastric
malignantlymphoma

None

Diabetes(controlled)

None

Ulcerative
colitis

None

Other
diseases

Table 5 Patient characteristics (sarcoidosis)

11.1

16.9

24.6

19.6

23.9

19.1

13.4

31.9

13.3

7.0

21.3

ACEb
IU/L

None

None

None

Superficial
lymph nodes

None

None

Superficial
lymph nodesHeart(diagnosed by
PET)

Eye

None

None

Extrapulmonary
involvement ofsarcoidosis

Not
treatedNot
treatedNot
treatedNot
treatedNot
treatedNot
treatedNot
treatedNot
treatedSteroid
eye drop

Not
treatedNot
treatedTreatmentforsarcoidosis

Follow-up
more than
1 yearBiopsy atthoracoscopy

Follow-up
more than
1 yearBiopsy atsuperficial
lymph node

Follow-up
more than
1 yearFollow-up
more than
1 yearBiopsy atsuperficial
lymph node

Biopsy atthoracoscopy

Biopsy atthoracoscopy

Follow-up
more than
1 yearFollow-up
more than
1 yearPathological
Confirmation

Mediastinal
lesions

Mediastinal
lesions

Mediastinal
lesions

Mediastinal
lesions

Mediastinal
lesions

TN

TN

TN

FP

TN

TN

FP

PulmonarylesionMediastinal
lesions

FP

FP

PulmonarylesionMediastinal
lesionsFP

TN

PulmonarylesionMediastinal
lesionsFP

TN

PulmonarylesionMediastinal
lesionsTN

TN

PulmonarylesionMediastinal
lesions

TN

2.8

16.1

5.7

17.9

6.1

4.1

10.9

8.1

12.3

7.6

1.3

6.4

0.8

6.8

1.3

6.8

SUVmaxF-FDG diagnosis

Visualdiagnosis

18

Mediastinal
lesions

Target lesion
at PET

TN

FP

FP

FP

FP

FP

FP

FP

FP

FP

TN

FP

TN

FP

TN

FP

Quantitative
diagnosisc

TN

TN

TN

FP

TN

TN

FP

FP

TN

TN

TN

TN

TN

TN

TN

TN

Visualdiagnosis

1.7

1.7

1.9

3.6

2.0

1.8

2.1

3.2

1.7

1.7

0.7

1.8

0.7

1.5

0.6

2.4

SUVmaxC-MeAIB diagnosis

11

TN

TN

TN

FP

TN

TN

FP

FP

TN

TN

TN

TN

TN

TN

TN

FP

Quantitative
diagnosisd

818
Ann Nucl Med (2013) 27:808–821

64/F

77/F

71/F

44/F
(Fig. 2)

11

12

13

14

M

M

M

M

Purposeof PET

Gastric
malignantlymphoma

None

None

None

Other
diseases

None

12.0

ACE: angiotensin-converting enzyme (normal range: 8.3 to 21.4 IU/L)

Threshold: SUVmax = 3.0

Threshold: SUVmax = 2.0

b

c

d

Same patient diagnosed 1 year later (with post-treated lymphoma)

None

Eye

None

Extrapulmonary
involvement ofsarcoidosis

16.9

23.7

13.4

ACEb
IU/L

a

FP false positive, TN true negative

Age/sexPatient
no.

Table 5 continued

Not
treatedNot
treatedSteroid
eye drop

Not
treatedTreatmentforsarcoidosis

Biopsy atthoracoscopy

Follow-up
more than
1 yearBiopsy atthoracoscopy

Follow-up
more than
1 yearPathological
Confirmation

7%

FP: 1460 %FP: 6Specificity:

TN: 1

TN: 9

Patient-based
diagnosis

FP: 16
8%

60 %

FP: 8
Specificity:

TN: 4

7.3 ± 4.5
TN: 12Average ± SD

FP

FP

FP

FP

Quantitative
diagnosisc

Lesion-based
diagnosis

6.0

8.0

7.3

9.7

SUVmax

FP

TN

FP

TN

Visualdiagnosis

F-FDG diagnosis

18

Mediastinal
lesions

Mediastinal
lesions

Mediastinal
lesions

Mediastinal
lesions

Target lesion
at PET

80 %

FP: 3

TN: 12

80 %

FP: 4

TN: 161.8 ± 0.7

TN

TN

FP

TN

Visualdiagnosis

1.8

1.9

2.0

1.8

SUVmaxC-MeAIB diagnosis

11

73 %

FP: 4

TN: 11

75 %

FP: 5

TN: 15

TN

TN

FP

TN

Quantitative
diagnosisd

Ann Nucl Med (2013) 27:808–821
819

123

820

Fig. 6 Relationship between SUVmax of 11C-MeAIB and that of
18
F-FDG of each lesion in both PET study using Logistic regression.
In malignant lesions, SUVmax of 11C-MeAIB shows a significant
linear relationship with that of 18F-FDG (p \ 0.0001, R2 = 0.406).
On the other hand, that of 11C-MeAIB also shows a linear correlation
with that of 18F-FDG but not significant in benign lesions (p = 0.055,
R2 = 0.078)

lesions (all of them finally confirmed as benign) in fivepatients with sarcoidosis. In these cases, 11C-MeAIB PET/CT played a useful diagnostic role (Fig. 3). Since 11C-MET
accumulates in sarcoidosis [14, 15], it is suggested that 11CMeAIB may be superior to 11C-MET in the differentiationof sarcoidosis from malignancy. Our result is compatible
with previous studies using other amino acid PET tracers,
such as [18F]-methyltyrosine (18F-FMT) [21]. Kaira et al.
suggested in their report that the use of 18F-FMT PET in
combination with 18F-FDG PET may be effective for thispurpose. In terms of biological mechanism, it is not fully
understood why 11C-MET and the other amino acid PET
tracers (11C-MeAIB and 18F-FMT) show different uptake
patterns in sarcoidosis. One of the conceivable mechanisms
for the low uptake in sarcoidosis lesions of 11C-MeAIB and18
FMT is that these PET tracers, as artificial amino acids,
are not metabolized in vivo [16, 22]. Concerning in vivo
instability of 11C-MET, inflammatory lesion can be misdiagnosed by 11C-MET PET because of its non-specific123

Ann Nucl Med (2013) 27:808–821

accumulation of free 11C in blood when an inflammatory
lesion shows hypervascularity. Comparative study of theseamino acid PET tracers should be further evaluated.
In the diagnosis of malignancy, the sensitivity of18
F-FDG and 11C-MeAIB based on semi-quantitative
patient-based diagnosis showed the same values (90.9 %)(Table 4). In addition, the uptake of 11C-MeAIB correlated
well with 18F-FDG uptake and there were basically no
discrepant cases (Fig. 6). 18F-FDG SUVs in malignant
cases was usually two to three times higher than those of
11
C. In previous studies using 11C-MET and 18F-FMT,
11
C-MET and 18F-FMT SUVs were also two to three times
lower than those of 18FDG [21, 23–25]. This may be acommon drawback of amino acid PET tracers. Although
our group included several different types of lung cancers,
such as adenocarcinoma, squamous cell carcinoma, andsmall cell carcinoma, there was no significant difference inthe uptake intensity of 11C-MeAIB among the different
histological types. It is not what we anticipated for
11
C-MeAIB PET/CT’s use as a predictor of therapeutic
effect, because amino acid transporters are known to workas carriers of chemotherapeutic agents, such as cisplatin,
methotrexate, taxol, and melphalan [26–28]. The role of
11
C-MeAIB PET/CT as an imaging modality for patienttailored medicine is unknown. Further study of pre- andpost-chemotherapeutic 11C-MeAIB PET or PET/CT isneeded.
Another drawback of 11C-MeAIB is its high physiological uptake by liver. It means that 11C-MeAIB PET/CT
cannot be performed as a first-choice diagnostic modality
in the evaluation of chest malignancies, because liver
metastasis is common in lung cancer. Therefore,
11
C-MeAIB PET or PET/CT cannot be performed as astudy for staging of advanced lung cancer. This is why wefocused our study only on the differential diagnosis in chest
diseases, and excluded cases with apparent distant metastasis and direct invasion of neighboring organs.

Conclusions
11

C-MeAIB PET/CT was useful in the differential diagnosis of pulmonary and mediastinal mass lesions found on
CT. 11C-MeAIB PET or PET/CT showed higher specificity
than that of 18F-FDG PET/CT in differentiating between
benign and malignant disease. Our data suggest that the
combination of 18F-FDG and 11C-MeAIB may improve theevaluation of chest lesions, when CT and 18F-FDG PET/CT
are equivocal.
Acknowledgments This study was supported by two categories of
the Grants-in-Aid for Scientific Research programmed by the Japan
Society for the Promotion of Science (JSPS), Challenging Exploratory

Ann Nucl Med (2013) 27:808–821
Research (Grant #50324629, 2009–2010), and Scientific Research(B) (Grant #23300360, 2011–2013).
Conflict of interest

The authors report no conflict of interest.

Open Access This article is distributed under the terms of theCreative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original
author(s) and the source are credited.

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