A pilot study of 4′-[methyl-11C]-thiothymidine PET/CT for detection of regional lymph node metastasis in non-small cell lung cancer
11 A pilot study of 4′-[methyl- C]-thiothymidine PET/CT for detection of regional lymph node metastasis in non-small cell lung cancer
Ryogo Minamimoto 0
Jun Toyohara 2
Hideyuki Ito 1
Ayako Seike 1
Yoko Miyata 0
Miyako Morooka 0
Momoko Okasaki 0
Kazuhiko Nakajima 0
Kimiteru Ito 2
Kiichi Ishiwata 2
Kazuo Kubota 0
0 Division of Nuclear Medicine, Department of Radiology, National Center for Global Health and Medicine , 1-21-1, Toyama, Shinjyuku-ku, Tokyo 162-8655 , Japan
1 Department of Thoracic Surgery, National Center for Global Health and Medicine , Tokyo , Japan
2 Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology , Tokyo , Japan
Background: 4′-[methyl-11C]-thiothymidine (4DST) is a novel positron emission tomography (PET) tracer to assess proliferation of malignancy. The diagnostic abilities of 4DST and 2-deoxy-2-18 F-fluoro-D-glucose (FDG) for detecting regional lymph node (LN) metastases of non-small cell lung cancer (NSCLC) were prospectively compared. In addition, the relationship between the PET result and the patient's prognosis was evaluated. Methods: A total of 31 patients with NSCLC underwent 4DST PET/computed tomography (CT) and FDG PET/CT. The PET/CT images were evaluated qualitatively and quantitatively for focal uptake of each PET tracer, according to the staging system of the American Joint Committee on Cancer. Surgical and histological results provided the reference standards. Patients were followed for up to two years to assess disease-free survival. Results: On a per-lesion basis, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for LN staging were 82%, 72%, 32%, 96%, and 73%, respectively, for 4DST, and 29%, 86%, 25%, 88%, and 78%, respectively, for FDG. The sensitivity of 4DST was significantly higher than that of FDG (P < 0.001). The disease-free survival rate with positive 4DST uptake in nodal lesions was 0.35, which was considerably lower than the rate of 0.83 with negative findings (P = 0.04). Among the factors tested, nodal staging by 4DST was the most influential prognostic factor (P = 0.05) in predicting the presence of a previously existing spread lesion or of a recurrence over the course of 2 years. Conclusion: 4DST PET/CT is sensitive for detecting mediastinal lymph node metastasis in NSCLC, but its low specificity is a limitation. However, it may be helpful in predicting the prognosis of NSCLC.
4DST; FDG-PET/CT; Lymph node metastasis; Non-small cell lung cancer (NSCLC); Cell proliferation
Lymph node (LN) involvement and distant metastasis of
non-small cell lung cancer (NSCLC) are indicators of a
poor prognosis [
]. The 5-year survival has been shown
to decrease with the extent of LN involvement in cases
with any T designation (any T) and without extra-nodal
metastatic disease (M0) [
]. Clinical staging can sometimes
indicate the appropriate direction for therapy. Pathologic
staging is still the reference standard, and the overall level
of agreement between clinical staging based on thoracic
computed tomography (CT) and pathological staging was
only from 35% to 55% [
]. Therefore, a sensitive diagnostic
tool for clinical staging has been needed to improve
treatment selection in NSCLC.
] and endobronchial
ultrasonographytransbronchial needle aspiration (EBUS-TBNA) [
high sensitivity and specificity for LN staging, but they are
invasive tests, and their ability to obtain a sample is
dependent on the location of the lesion. Noninvasive
imaging, such as CT and magnetic resonance imaging
(MRI), has been used for NSCLC staging.
2-Deoxy-2-18F-fluoro-D-glucose (FDG) positron
emission tomography (PET) has contributed to more accurate
mediastinal staging of lung cancer with median sensitivity
and specificity of 61% and 79%, respectively [
]. In recent
studies, FDG PET/CT has been highly specific in
mediastinal nodal staging (specificity 84% to 100%), but it has
been sensitive in a different range (sensitivity 45.2% to
]. Even though integrated PET/CT helps
improving the accuracy of mediastinal nodal staging, it
is still insufficient for detection of microscopic lymph
node metastases [
A biologic factor intimately related to malignancy is
tumor cell proliferation. Such proliferation has a
prognostic relevance in various malignancies, including NSCLC
]. Recently, a thymidine analog, carbon-11-labeled
4′thiothymidine ([11C] 4DST, originally designated as [11C]
S-dThd), was introduced as a cell proliferation imaging
agent based on its mechanism of incorporation into DNA
]. In our previous report, we demonstrated the great
potential of 4DST-PET/CT for proliferation imaging in
lung cancer itself [
]. Moreover, we showed a case which
indicated the potential of 4DST for the detection of LN
metastasis in NSCLC [
]. The background 4DST uptake
in mediastinum was lower than that of FDG; therefore, we
hypothesize that 4DST might have an advantage for
detecting mediastinal lymph node metastasis. In this study,
the characteristics of 4DST PET/CT for LN staging were
evaluated, especially in comparison to those of FDG PET/
CT. In addition, patients' prognoses according to several
factors evaluated in the pre-surgical state were surveyed.
This prospective study was approved by the National
Center for Global Health and Medicine institutional
review board, and written informed consent was obtained
from all patients. The inclusion criteria of this study were
first histologic diagnosis of NSCLC based on
bronchoscopic biopsy or cytology, clinical stage I to IIIA based on
contrast-enhanced (CE) CT examination, and scheduled
to complete resection of primary lung tumor without any
neoadjuvant therapy. Exclusion criteria for this study were
patients with age 20 years or younger, uncontrolled
diabetes, pregnancy, and suggested extrathoracic metastasis
by whole-body FDG-PET/CT scan; however, no patients
met these exclusion criteria. A total of 31 patients (21
men and 10 women; mean (±SD) age 67.6 ± 11.7 years;
range 36 to 88 years) was included consecutively (Table 1).
All included patients were referred to our hospital for
further testing of detected lung lesion. Most of the patients
were asymptomatic and detected lung lesions by annual
medical examination based on chest X-ray and/or chest
CT. As a result, the high rate of early stage NSCLC was
included in this study.
A part of data from 18 of these patients was used in the
previous study [
]. All patients underwent CECT before
4DST-PET/CT and FDG-PET/CT. All imaging was
performed before surgical resection of the lung lesion and
systematic resection of LNs. The mean interval between
CE chest CT and surgery was 28 days.
4DST PET/CT examination
The 4DST was synthesized as previously described [
All subjects fasted for 5 h before receiving an
intravenous injection of 4DST with a median of 716 MBq (range
283 to 777 MBq). According to our previous report [
PET/CT images were obtained 40 min after intravenous
injection of 4DST, and used either of two PET/CT
systems (Biograph 16; Siemens Medical Solutions, Munich,
Germany and Discovery PET/CT 600; GE Healthcare,
Pewaukee, WI, USA). These systems consist of a PET
scanner and a multi-detector-row CT scanner (16 detectors).
Imaging covered from the vertex to the mid-thigh.
Lowdose CT with shallow breathing was performed first and
used for attenuation correction and image fusion.
Lowdose CT data for Biograph 16 was acquired at 120 kVp
using an auto exposure control system, beam pitch of
0.833, slice thickness of 5 mm, and that data for Discovery
PET/CT 600 was acquired at 120 kVp using an auto
exposure control system, beam pitch of 0.938, slice thickness
of 3.75 mm. Emission images were acquired in
threedimensional mode for 2.5 min per bed position. PET data
were reconstructed using a Gaussian filter with an
ordered-subset expectation maximization algorithm (three
iterations, eight subsets for the Biograph 16, and three
iterations, 16 subsets for the Discovery PET/CT 600). The
mean intervals between CE chest CT and 4DST-PET/CT,
between 4DST-PET/CT and FDG-PET/CT, and
between 4DST-PET/CT and surgery were 16, 5, and 12 days,
FDG PET/CT examination
An in-house cyclotron and automated synthesis system
(F100 or F200; Sumitomo Heavy Industries, Shinagawa,
Tokyo, Japan) was used in accordance with the authorized
procedure to synthesize FDG.
All subjects fasted for 5 h before blood glucose levels
were measured, and the blood glucose level had to be
under 120 mg/dL at the time of FDG injection. FDG
was intravenously injected, and the activity was fixed at
370 MBq for 22 patients and administered at 5.0 MBq/kg
of body weight (range 283 to 388 MBq) for nine patients.
PET/CT images were obtained 60 min after injection with
the same PET/CT machine and method as for the 4DST
PET/CT examination. The mean intervals between CE
chest CT and FDG PET/CT, and between surgery and
FDG PET/CT were 14 and 28 days, respectively.
PET/CT data analysis
All 4DST and FDG-PET/CT scans were evaluated in
consensus of two board-certified nuclear medicine physicians
blind to clinical and pathological information. Regions of
Table 1 Clinical data and PET/CT findings in 31 patients with NSCLC
Patient Age Sex Pathology Tumor TNM
no. diameter classification
interest (ROI) were placed over the lung lesion according
to the CT images obtained from PET/CT and with
reference to the CE chest CT image. The maximum
standardized uptake value (SUVmax) was determined for 4DST
and FDG PET/CT images. The size of the lung lesion was
determined from the CE chest CT image.
Nodal stage was classified according to the American
Joint Committee on Cancer (AJCC) staging system for the
classification of lung cancer [
] in order to compare the
results of PET/CT and histopathological analysis. The
reference standard for the diagnosis of mediastinal
metastases was surgical exploration of the mediastinum
and histopathological examination of mediastinal LN
compartments. Patients' TNM stages were determined
according to the 7th Edition of the Lung Cancer TNM
Classification; four patients who were inoperable were
assessed by a combination of clinical and pathological
TNM staging. Pathological diagnosis was performed by
an experienced pathologist based on hematoxylin and
eosin-stained tissue Sections.A positive PET scan for
an N2 lesion was defined as a visually focal PET uptake
that was matched to any small nodal lesions identified
on the CT image of the PET/CT and with reference to
the CECT image. The exact location of an N1 lesion
was difficult to assess on PET/CT; thus, a PET scan was
defined as positive for the N1 area if any focal uptake was
confirmed in an N1 area. Any LN that existed in an N1
area was combined with that region and, by definition,
generated one region named an N1 group (N1G). The
SUVmax values of these visually focal uptakes were
measured for both 4DST and FDG. To survey the mediastinal
background uptake, an ROI was also placed on the
ascending aorta as guided by the CT image from the
PET/CT. With each agent, a lesion-to-background (L/B)
ratio was calculated from the value of the visually focal
PET uptake and the value of the background uptake.
After resection of the primary tumor and regional LNs,
any patient with a pathology-confirmed nodal metastasis
received cisplatin-based or oral uracil-tegafur-based
chemotherapy. Among the 27 patients who had surgical
resection of the lung lesion and LN(s), 19 patients could
be followed for at least 2 years for the recurrence of
cancer. Of the other eight patients, two patients dropped
out from this study 4 months after surgery, and the
other six patients were followed-up for less than 2 years
without evidence of recurrence.
The presence of a recurrent lesion was determined
clinically based on the results of follow-up CE chest and
abdominal CT, contrast-enhanced brain MRI, and bone
scintigraphy. These tests were performed with duration
between tests of 6 months or less. In the present study,
disease-free survival (DFS) was defined as the absence of
evidence of a previously existing spread lesion or of the
recurrence of cancer over the course of 2 years after
Data are expressed as mean ± SD. Mann-Whitney's U test
was used to compare both the SUVmax and the L/B ratio
between 4DST and FDG. Sensitivity, specificity, positive
predictive value (PPV), negative predictive value (NPV),
and accuracy values for N staging on a per-node and a
per-patient basis were calculated for 4DST and FDG.
The values are expressed as means with 95% confidence
intervals (CI). The Mc Nemar chi-square test was
performed to compare the sensitivity and specificity between
4DST and FDG, and the chi-square test for independence
was performed to compare spread lesion or the recurrence
rate between 4DST and FDG.
Univariate and multivariate logistic regression analyses
were used to identify potential prognostic factors for
DFS from among the following: nodal staging by 4DST,
nodal staging by FDG, 4DST uptake in the lung tumor,
FDG uptake in the lung tumor, lung tumor diameter,
and patient age. To obtain suitable cutoff points for
4DST uptake, FDG uptake (SUVmax), and tumor
diameter for primary lung cancer, receiver-operating
characteristic curves were used. Two-tailed P values < 0.05 were
PET imaging and histopathological results for primary lung cancer
The first patient was enrolled on July 2010, and the last
on September 2012. All primary lung tumors with
histologically proven malignancy were identified by
4DSTThe numbers in parentheses represent 95% confidence interval; NSCLC, non-small cell lung cancer; PPV, positive predictive value; and NPV, negative
PET/CT and FDG-PET/CT by their positive uptake. The
mean SUVmax of 4DST in primary lung tumors was
significantly lower than that of FDG (3.3 ± 1.3 vs. 7.2 ± 5.3;
P < 0.002).
During surgery, four patients were deemed inoperable
due to dissemination of cancer into the pleura in three
patients and into the pericardium in the other. The
cancer dissemination consisted of small lesions less than
2 mm in size. These small lesions had not been detected
by either of the preoperative PET examinations, and they
could not be seen on postoperative retrospective review.
However, pleural dissemination was suspected in two of
the three cases on the CE chest CT image because of
slight pleural thickening and because the lung tumor was
located adjacent to the pleura. The other 27 patients had
surgical resection of the lung lesion with negative
surgical margins and of the regional LNs. Pathologic analysis
showed adenocarcinoma in 22 patients including two
cases of bronchioloalveolar cancer, squamous cell
carcinoma in six patients, and large cell carcinoma in three
patients (Table 1).
Detection of LN metastases
A total of 156 LNs (N2 area 97, N1 area 59) was
resected by surgery. Of these, 21 LNs (N2 area 10, N1
area 11) proved to be positive for malignancy in nine
of the 27 patients. Finally, 123 nodal groups (N2 area
97, N1G 26) were defined for 27 patients, with proven
malignancy in 17 nodal groups (N2 area 10, N1G 7) of
nine patients. Sensitivity, specificity, PPV, NPV, and
accuracy values for N staging on a per-nodal basis and on
a per-patient basis are shown in Table 2. The sensitivity
on a per-node basis was significantly higher with 4DST
than with FDG (82.4% vs. 29.4%; P < 0.002), and it was
higher on a per-patient basis (66.7% vs. 22.2%), but not
significantly (P = 0.06). In contrast, the specificity on a
per-node basis was significantly lower with 4DST than
with FDG (71.7% vs. 85.8%; P < 0.02) and also lower on
a per-patient basis (33.3% vs. 61.1%), but not significantly
(P = 0.09). 4DST PET/CT showed positive uptake for all the
true positive lesions (n = 5) on FDG-PET/CT. However, no
significant differences between 4DST and FDG were
observed for PPV, NPV, or accuracy. Figures 1, 2, and 3
show the 4DST and FDG PET/CT images of patients
with LN metastasis.
The average SUVmax for visually positive regions was
3.0 ± 1.2 with 4DST and 3.1 ± 0.9 with FDG, with no
significant difference (P = 0.40). There also was no significant
difference between the SUVmax for true positives and that
for false positives with 4DST (2.6 ± 0.9 vs. 3.2 ± 1.3; P =
0.12) and with FDG (3.5 ± 0.8 vs. 2.9 ± 1.0; P = 0.18). The
ascending aorta SUVmax was lower with 4DST (0.7 ± 0.2)
than with FDG (1.9 ± 0.3; P < 0.001). The L/B ratio was
significantly higher with 4DST (5.0 ± 2.9) than with FDG
(1.7 ± 0.5; P < 0.001). No significant difference was
observed between true positives and false positives with
4DST (4.1 ± 2.2 vs. 5.4 ± 3.2; P = 0.16), but there was a
significant difference between them with FDG (2.1 ± 0.6
vs. 1.5 ± 0.4; P = 0.03).
The results for staging are shown in Table 3. The nodal
stage based on 4DST-PET/CT imaging was overstaged in
16 patients (59.3%), with no understaged cases, whereas
the stage based on FDG-PET/CT imaging was overstaged
in nine patients (33.3%) and understaged in five patients
(18.5%). Both CECT and FDG imaging showed no
evidence of distant metastatic lesions in all patients included
in the study. For two false positives by all three imaging
modalities (4DST, FDG, and CECT), one was
histopathologically proven to be reactivation of sarcoidosis, and the
other was proven to be chronic inflammation.
Spread lesion and recurrence after PET studies
At the time of analysis, all patients were alive, but eight
patients had cancer recurrences as LN metastasis (n = 2),
pleural dissemination (n = 2), brain metastasis (n = 2),
pulmonary metastasis (n = 1), or as a bone metastasis
(n = 1). Table 4 shows the results for spread lesion (n = 4)
or recurrence (n = 19) for 23 patients according to the
nodal staging based on 4DST and FDG imaging. Cases
with 4DST uptake in the nodal lesion showed a high
frequency of spread lesion or recurrence, compared to the
results of FDG. The DFS rate with positive 4DST uptake
in nodal lesions was 0.35 (95% CI 0.13 to 0.58), which
was lower than the 0.83 rate (95% CI 0.54 to 1.13) with
negative findings (P = 0.04), whereas the DFS rate with
positive FDG uptake in nodal lesions was 0.56 (95% CI
0.23 to 0.88), which was higher than the 0.50 (95% CI
0.24 to 0.76) with negative findings (P = 0.79). The
recurrence-free rate for 2 years with positive 4DST
uptake in nodal lesions was 0.46 (95% CI 0.19 to 0.73),
which was lower than the 0.83 rate (95% CI 0.53 to
1.13) with negative findings (P = 0.12). The
recurrencefree rate with positive FDG uptake in nodal lesions was
0.43(95% CI 0.06 to 0.80), which was only slightly
lower than the 0.59 rate (95% CI 0.30 to 0.86) with
negative findings (P = 0.96).
Logistic regression analysis of potential prognostic
factors for the presence of spread lesion or recurrence
over 2 years showed that 4DST was the most
influential factor (odds ratio 29.08), but it was not significant
(P = 0.05). Lung lesion 4DST was the second most
influential factor (odds ratio 8.39; Table 5).
The numbers in parentheses represent the case with spread lesion or recurrence
within two years.
The present study demonstrated that 4DST has a better
sensitivity for N staging than FDG in NSCLC, both on a
per-patient basis and on a per-node basis. In addition,
4DST uptake in a nodal lesion may predict the spread
lesion and recurrence more sensitively than other factors.
The biggest difference between 4DST and FDG imaging
was the background uptake in the mediastinum. Since
positive uptake was not different between 4DST and FDG,
4DST could show accumulation in LNs more easily
because of greater contrast to the ‘background’. The same
facts are also reflected in the difference in the L/B ratio
between 4DST and FDG. However, it was difficult to set a
cutoff value for 4DST uptake to distinguish true positives
from false positives because the true- and false-positive
4DST uptakes overlapped. That was a limitation of 4DST
for evaluating nodal staging.
As mentioned previously, FDG PET has shown higher
sensitivity and specificity than CT in detecting LN
metastasis in lung cancer [
]. For small LNs with a diameter
less than 1 cm, FDG PET also has higher sensitivity than
CT for detecting regional LN metastasis . FDG-PET/
CT showed variable sensitivity, but consistently high
]. However, the sensitivity of FDG-PET/
CT decreased to 42% in stage T1 NSCLS [
]. Stiles et al.
reported that lymph node metastasis was pathologically
detected in 11.7% of patients with clinical stage IA lung
]. These facts indicate a limitation of FDG PET/
CT. The present study showed lower sensitivity and
specificity for FDG PET/CT than has been reported previously
]. The likely causes are (1) the evaluation of small LN
groups that would be treated as negative by CT imaging
but could be detected as positive by the surgical procedure
in the present study, (2) the inclusion of many T1-stage
cases (41% of all cases included in the present study), and
(3) the inclusion of many cases with micrometastases in
lymph nodes. In fact, when the diameter of lymph node
with 10 mm or greater in short axis was regarded as
positive, the diagnostic result from CECT by two
boardcertified radiologists was lower (sensitivity 29.4% [5/17],
specificity 89.6% [95/106] per nodal station) than
previously reported [
The use of 3′-deoxy-3′-18F-fluorothymidine (FLT) for
cellular proliferation imaging has yielded good clinical
]. In contrast, the diagnostic performance of
FLT for staging and restaging of thoracic tumors has
been reported to be inadequate [
]. Several reports
have shown that FLT has better specificity and PPV than
FDG, but lower sensitivity [
]. FLT has also shown a
limited ability in discriminating reactive and metastatic
LNs in head and neck cancers [
]; this is caused by the
FLT uptake to reactive B-lymphocyte proliferation [
Chronic inflammatory granulomatous lesions include more
than a small Ki-67-positive lymphocyte fraction [
therefore, increased FLT uptake was confirmed in granulomas
that arose after radiation and chemotherapy [
]. FLT is
not incorporated into DNA because of the lack of a
3′hydroxyl, unlike thymidine [
]. On the other hand,
considering that 4DST is incorporated into DNA [
4DST is expected to discriminate metastatic LNs from
others, but it also has a possibility of accumulating with
reactive proliferation. According to an animal study, very
low levels of 4DST uptake were observed in subacute
inflammatory areas, which reflects the cell proliferation
status of inflammatory tissues . In fact, the present
results showed no significant difference in 4DST uptake
between true positives and false positives. Although 4DST
is a proliferation marker, it accumulated not only in
malignant lesions, but it also reacted to chronic inflammatory
lesions; these facts were also reflected by 4DST uptake in
sarcoid lesions. Furthermore, the low PPV and overstaging
of 4DST for LN lesions might be partially due to reactive
LNs. Low specificity is one of the limitations of 4DST for
nodal staging in lung cancer.
One focal point of the present study was the
relationship between clinical nodal staging by PET and prognosis.
Cases with positive findings on 4DST in the nodal area
showed a high incidence of recurrence and lesion
extension compared to FDG. Except for the case with a
histologically proven sarcoid reaction, positive 4DST uptakes
were present along lymphatic channels from the primary
lesion so that they seemed to be valid for suspecting
metastatic LN lesions. They might be stimulated by the
primary lesion and indicate the spread of lesion, even
though no malignancy was proven.
The high sensitivity of 4DST for nodal metastasis
indicates that it may be detecting micro LN metastasis.
On the other hand, the low PPV was a disappointing
result with respect to providing accurate LN staging,
but positive 4DST uptake in LNs appeared to be a strong
factor for predicting the spread lesion or a high possibility
of early recurrence. If the false-negative 4DST uptake was
regarded as one of the reactive features from the
surroundings, it might be caused by inflammatory mediators
such as chemokines, cytokines, and prostaglandins
associated with cancer-related inflammation [
staging with 4DST and uptake in the primary lung tumor of
4DST were more influential prognostic factors than the
same features with FDG, but further evaluation is needed.
A limitation for M staging with 4DST was anticipated
due to physiological uptake in the liver, kidney, and bone
marrow. Since only a small number of patients was
examined, larger patient samples need to be examined to verify
the diagnostic accuracy of 4DST PET for N staging and its
potential for predicting prognosis.
4DST PET/CT is sensitive for detecting mediastinal
lymph node metastasis in NSCLC, but its low specificity
is a limitation. However, it may be helpful in predicting
the prognosis of NSCLC.
4DST: 4′-[methyl-11C]-thiothymidine; AJCC: American Joint Committee on
Cancer; CE: contrast-enhanced; CI: confidence intervals; CT: computed
tomography; DFS: disease-free survival; EBUS-TBNA: endobronchial
ultrasonography-transbronchial needle aspiration; FDG:
2-deoxy-2-18Ffluoro-D-glucose for detecting regional; FLT:
3′-deoxy-3′-18Ffluorothymidine; L/B: lesion-to-background; LN: lymph node;
MRI: magnetic resonance imaging; N1G: N1 group; NPV: negative
predictive value; NSCLC: Non-small cell lung cancer; PET: Positron
emission tomography; PPV: positive predictive value; ROI: regions of
interest; SUVmax: maximum standardized uptake value.
The authors declare that they have no competing interests.
RM and KK are guarantors of integrity of the entire study. RM, JT, KI, KK are
responsible for the study concepts and design. RM, JT, KI, KI, and KK
participated in the literature research. RM, HI, AS, KN, KK, and MO performed
the clinical studies. RM, YM, MM, MO, and KK performed the data analysis/
interpretation. RM, JT, KI, KI, and KK did the manuscript preparation. RM, JT,
KI, KI, and KK participated in the manuscript revision/review. All authors read
and approved the final manuscript.
We thank Takashi Sato, Shingo Kawaguchi, Takuya Mitsumoto, Fumio
Sunaoka, Yoshiaki Taguchi, Hiromi Suzuki, and Kahori Miyake for their
excellent technical support. This work was supported by a Grant from the
National Center for Global Health and Medicine No.21-126 (to Kazuo Kubota,
Jun Toyohara, and Kiichi Ishiwata), a Grant-in Aid for Scientific Research (B)
No. 22390241 from the Japan Society for the Promotion of Science (to Jun
Toyohara), and a Grant-in Aid for Young Scientists (B) No. 24791362 from the
Japan Society for the Promotion of Science (to Ryogo Minamimoto).
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