Topics of nuclear medicine research in Europe
Ann Nucl Med
Topics of nuclear medicine research in Europe
Masayuki Inubushi 0 1 2 3 4 5 6
Tomohiro Kaneta 0 1 2 3 4 5 6
Takayoshi Ishimori 0 1 2 3 4 5 6
Etsuko Imabayashi 0 1 2 3 4 5 6
Atsutaka Okizaki 0 1 2 3 4 5 6
Naohiko Oku 0 1 2 3 4 5 6
0 Department of Radiology, Yokohama City University , 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004 , Japan
1 Division of Nuclear Medicine, Department of Radiology, Kawasaki Medical School , 577 Matsushima, Kurashiki 701-0192 , Japan
2 & Masayuki Inubushi
3 HIMEDIC Clinic WEST , 3-3-17 Minami Senba, Chuo-ku, Osaka 542-0081 , Japan
4 Department of Radiology, Asahikawa Medical University , 2- 1-1-1 Midorigaoka-higashi, Asahikawa 078-8510 , Japan
5 Integrative Brain Imaging Center, National Center of Neurology and Psychiatry , 4-1-1 Ogawahigashi, Kodaira 187-8551 , Japan
6 Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine , 54 Kawaharacho, Shogoin, Sakyoku, Kyoto 606-8507 , Japan
Last year in the European Journal of Nuclear Medicine and Molecular Imaging, we introduced some recent nuclear medicine research conducted in Japan. This was favorably received by European readers in the main. This year we wish to focus on the Annals of Nuclear Medicine on some of the fine nuclear medicine research work executed in Europe recently. In the current review article, we take up five topics: prostate-specific membrane antigen imaging, recent advances in radionuclide therapy, [18F]fluorodeoxyglucose positron-emission tomography (PET) for dementia, quantitative PET assessment of myocardial perfusion, and iodine-124 (124I). Just at the most recent annual meeting of the European Association of Nuclear Medicine 2016, Kyoto was selected as the host city for the 2022 Congress of the World Federation of Nuclear Medicine and Biology. We hope that our continuous efforts to strengthen scientific cooperation between Europe and Japan will bring many European friends and a great success to the Kyoto meeting.
Prostate-specific membrane antigen (PSMA); Radionuclide therapy; Dementia; Quantitative myocardial perfusion PET; Iodine-124 (124I)
At the last annual meeting of the European Society of
Nuclear Medicine 2016, prostate-specific membrane
antigen (PSMA) imaging for prostate cancer (PCA) and
somatostatin receptor imaging for neuroendocrine tumors
(NET) attracted the most attention in their early clinical
results and linkage to radionuclide therapy. Thus, we start
the current review article by discussing recent oncological
studies on PSMA imaging and radionuclide therapy.
Then, from two outstanding articles in neurology, we
would like to reaffirm the fundamental and crucial roles of
[18F]fluoro-deoxyglucose (FDG) positron-emission
tomography (PET) not only for the clinical diagnosis and
determination of prognosis of dementia, but also for
measuring synaptic activity to investigate pathological changes.
As the next topic from cardiology, we take up
quantitative PET assessment of myocardial perfusion. Although
quantitative or semi-quantitative analysis is commonly
used in neurological and oncological nuclear medicines,
qualitative analysis has been a mainstay of diagnosis for
ischemic heart disease or cardiomyopathy, because there
are some difficulties specific in cardiac nuclear medicine
imaging, such as relatively lower spatial resolution related
to the size of the myocardium, and effects of artifacts
derived from heartbeat, respiration, and physiological
adjacent uptake. Nevertheless, the number of reports on
quantitative PET assessment of myocardial perfusion has
increased in recent years.
Finally, we focus on a relatively new radionuclide
iodine-124 (124I). As a PET isotope, 124I is somewhat
inferior to the traditional ones (e.g., 18F and 11C) in
physical properties, but superior in biological and chemical
characteristics. Giving a few recent instances of research
application of 124I, we briefly discuss its potential future.
Prostate-specific membrane antigen, also known as folate
hydrolase I or glutamate-carboxypeptidase II, is a type II
transmembrane protein with glutamate-carboxypeptidase
activity that shows a significant overexpression on PCA
cells, but a low expression in normal tissues. Thus, PSMA
can be considered as ideal as a target for radionuclide
imaging and therapy for PCA. 68Ga-labeled
PSMA-HBEDCC (PSMA-11) has been recently presented as a novel PET
tracer for the detection of PCA recurrence and/or
metastases. Unfortunately, PSMA-targeted PET imaging is not
available in Japan yet, but this technique seems to have
high clinical impact for the management of prostate cancer.
Sterzing et al. [
] evaluated the potential of 68Ga-PSMA-11
PET/CT for the radiotherapeutic management, and reported
that the TNM staging and therapy were changed in 50.8%
of cases. Verburg et al. [
] reported that 68Ga-labeled
PSMA-HBED-CC PET/CT identified PCA lesions even in
patients with very low PSA levels. Positive findings were
seen in 44, 79, and 89% of patients with PSA levels of B1,
1–2, and C2 ng/mL, respectively. Considering these
results, PSMA-targeted PET imaging is not only specific
for prostate cancer, but also extremely sensitive compared
with the conventional imaging techniques, such as MRI,
CT, bone scintigraphy, and FDG PET. The use of 68Ga
generators and kits for radiosynthesis will make the tracer
preparation easy and inexpensive. The cost-cutting of the
tracer will promote the spread of 68Ga-PSMA-HBED-CC
PET worldwide. PSMA-targeted radionuclide therapy
using b- or a-emitters is also expected [
Oncology—recent advances in radionuclide therapy
Radium-223 (223Ra) dichloride therapy is gaining
widespread use in patients with symptomatic bone metastases
from castration-resistant prostate cancer (mCRPC) in
Europe and Japan. Although a survival benefit has been
reported, it is not clear, where 223Ra should be placed in the
treatment algorithm for mCRPC patients in the clinical
setting. Etchebehere et al. [
] investigated the factors that
may predict outcome in patients undergoing 223Ra therapy.
In their study, the patients were able to tolerate
chemotherapy and secondary hormonal therapy
concomitant to 223Ra. Therefore, even in patients with visceral
metastases, 223Ra can perhaps be considered alongside with
chemotherapy, as there is a clear benefit in terms of overall
survival (OS), progression free survival (PFS), and bone
event-free survival (BeFS). In addition, abiraterone used
concurrently with 223Ra seemed to have a positive effect in
the patients, and the results of an ongoing randomized trial
evaluating the use of abiraterone and 223Ra are expected.
Since abiraterone is already approved in Japan, the results
may alter the therapeutic strategy in the near future.
Peptide receptor radionuclide therapy (PRRT) for the
treatment of NET has been studied for many years in
Europe, although it is yet to be introduced in Japan.
Mariniello et al. [
] investigated the long-term outcome of
PRRT in 114 patients with advanced bronchopulmonary
carcinoid (BPC). They compared the objective responses,
OS, and PFS among three different PRRT protocols
(90YDOTATOC vs. 177Lu-DOTATATE vs.
90YDOTATOC ? 177Lu-DOTATATE). The median OS was
58.8 months and the median PFS was 28.0 months.
177LuDOTATATE protocol resulted in the highest 5-year OS
(61.4%) and the 90Y-DOTATOC ? 177Lu-DOTATATE
protocol provided the highest response rate (38.1%). They
concluded 177Lu-DOTATATE monotherapy to be the best
option for PRRT, which proved to be promising in
prolonging survival and delaying disease progression with the
least toxicity. Since it is expected that PRRT using
177LuDOTATATE will be introduced in Japan in the near future,
sophisticated prospective trials of Japanese patients will be
Neurology—FDG PET for dementia
[18F]fluoro-deoxyglucose positron-emission tomography
imaging has been used to investigate Alzheimer’s disease
(AD), but few studies have attempted to discriminate
between AD and non-AD dementia, instead focusing on
patients with AD compared with control subjects. Perani
et al. [
] have provided valuable insight into this issue.
Cerebrospinal fluid (CSF) protein levels, structural
magnetic resonance imaging (MRI), and FDG PET were used
to examine patients with AD, frontotemporal lobar
degeneration (FTLD), dementia with Lewy bodies (DLB),
mild cognitive impairment (MCI) converters, and MCI
nonconverters. In the differentiation of AD and non-AD,
the CSF p-Tau/amyloid beta (Ab) ratio showed 83%
sensitivity and 64% specificity; FDG PET showed 94%
sensitivity and 86% specificity. Inclusion of AD-related
amyloid or tau pathology within the FTLD or DLB group
reduced specificity compared with FDG PET. Furthermore,
it is useful to discriminate FTLD or DLB, particularly with
analysis using statistical parametrical mapping (SPM)
t-maps. According to their statistical analysis of patients
with MCI, FDG PET was the only predictor of conversion
to AD in the final stepwise model.
Fluoro-deoxyglucose positron-emission tomography has
shown that posterior cingulate cortex (PCC)
hypometabolism is an indicator of the prodromal stages of AD [
however, the origin of this hypometabolism has not been
elucidated completely. Teipel et al. [
] investigated this
finding using cutting-edge image analysis. They measured
the volume, amyloid load, and glucose metabolism in the
hippocampus and PCC of subjects participating in the
Alzheimer’s Disease Neuroimaging Initiative. They found
that in cognitively normal individuals (CN) and those with
early MCI (EMCI), PCC hypometabolism was associated
only with hippocampus atrophy. In subjects with late MCI
(LMCI), it was associated with both local and remote
effects of atrophy as well as with local amyloid load. In
subjects with AD dementia, PCC hypometabolism was
related only to local atrophy. These findings suggest that
the effects of remote pathology on PCC hypometabolism
decrease and the effects of local pathology increase with
progression from the preclinical to clinical stages of AD.
Some functional MRI reports [
] described a link between
amyloid pathology and disrupted network connectivity,
suggesting that a decrease in the remote effect may have
resulted from the disconnect, due to the local amyloid load
in the PCC. Furthermore, in subjects with CN and EMCI,
whose global amyloid load was low, they found a positive
correlation between amyloid load and metabolism in the
PCC. This result was consistent with one demonstrating
that more synaptic activity led to higher levels of soluble
Ab species in ex vivo brain slices [
], because glucose
metabolism is known to be a surrogate marker of synaptic
Cardiology—quantitative PET assessment of myocardial perfusion
Berti et al. [
] investigated the accuracy of segmental
myocardial blood flow (MBF) and myocardial flow reserve
(MFR) measurements assessed by quantitative cardiac PET
imaging in the evaluation of coronary artery disease. The
diagnostic accuracy of absolute segmental MBF/MFR
values was assessed blinded to patients’ clinical data and to
visual analysis of PET images, using certain MBF/MFR
cut-off values. Inter-observer reproducibility of clinical
decisions and the objective performance of MBF/MFR
segmental values were also evaluated. 98 patients were
included in the final analysis, and they underwent cardiac
PET with H215O, 13NH3, or 82Rb. The gold standard was the
findings of invasive and/or CT coronary angiography. The
overall inter-observer agreements were 90% on a
per-patient basis and 88% on a per-vessel basis. Segmental PET
measurements correctly identified 85% of the patients. In
vessel-based analyses, quantitative perfusion parameters
had sensitivity, specificity, PPV and NPV of 92, 82, 42, and
99%, respectively. The authors concluded that the
assessment of absolute myocardial perfusion parameters
measured at a segment level leads to reliable and accurate
identification of patients with significant coronary stenosis.
Castagnoli et al. [
] explored the role of quantitative
myocardial PET for risk stratification in patients with
hypertrophic cardiomyopathy (HCM). MBF \1.1 mL/
min/g following dipyridamole (Dip-MBF) assessed by
PET was previously identified as an important outcome
predictor in HCM, although such extreme Dip-MBF
impairment is only rarely observed recently. Therefore,
the authors tried to reassess the Dip-MBF threshold for
detecting high-risk HCM. Dip-MBF was measured using
13 N-ammonia in 100 patients with HCM. The endpoints
were cardiovascular death and unfavorable outcome. The
lowest tertile Dip-MBF was associated with a sevenfold
independent risk of unfavorable outcome compared to the
others. Dip-MBF 1.35 mL/min/g was identified as the best
threshold for outcome prediction using a
receiver-operating characteristics analysis. All cardiac deaths occurred in
patients who had Dip-MBF impairment in the lateral wall.
The authors concluded that Dip-MBF was a predictor of
outcome in HCM, with the threshold for prediction higher
than previously believed. Dip-MBF impairment in the
lateral wall might be associated with cardiac death in
Iodine-124 (124I) is a positron-emitting nuclide of cyclotron
product. As a PET isotope, 124I is somewhat inferior to the
traditional ones (e.g., 18F and 11C) in physical properties.
For 124I, positron decay ratio is low (only 23% of the time),
positron energies are high (1352 and 2135 keV), and
characteristic X-ray energies are also high (603 and
1691 keV). Low positron decay ratio results in the need for
longer acquisition times as compared to the initial dose,
and X-ray Compton scatters and wide positron range will
lower image contrast.
However, iodine has biologically and chemically
superior characteristics. First, iodine natively has high affinity
with thyroid tissue. Binse et al. [
] clearly visualized
metastatic lesions in patients with differentiated thyroid
cancer (DTC) using 124I and PET/CT or PET/MRI. PET
imaging using 124I will greatly contribute to the
management of patients with high-risk DTC.
Second, radio iodination techniques are established in
many substances including large molecules and proteins
]. In the past decade, development of radio-labeled
monoclonal antibodies (mAbs) has been accelerated by the
need for targeted imaging and therapies. Especially, the
relatively long half-life of 124I (4.2 days) tolerates a longer
synthetic time and slower behavior of molecules in vivo.
mAbs labeled with 124I will help visualize the
biodistribution of the targeted antigen. Accurate quantitative
information in high-resolution image can be obtained using
PET. The analysis of the image can be readily applied to
molecular diagnosis of diseases, dosimetry, and critical
organ analysis. These basic simulative analyses are
subsequently used in designing mAbs labeled with
betaemitting radionuclides such as 131I, 186Re, and 90Y.
These diagnostic and therapeutic techniques play
important roles in the tailored treatment strategy for
individual patients and in pharmaceutical development [
Last year in the European Journal of Nuclear Medicine and
Molecular Imaging (EJNMMI), we introduced some recent
nuclear medicine research conducted in Japan [
was favorably received by the European readers in the
main. This year we attempted to present in the Annals of
Nuclear Medicine (ANM) some of the fine research work
undertaken in Europe during the recent period. Just at the
last annual meeting of the European Association of Nuclear
Medicine (EANM) 2016, Kyoto was selected as the host
city for the 2022 Congress of the World Federation of
Nuclear Medicine and Biology (WFNMB). We hope that
our continuous effort to strengthen scientific cooperation
between Europe and Japan will bring many European
friends and a great success to the Kyoto meeting.
Acknowledgements This work was supported by a KAKENHI
Grant-in-Aid for Publication of Scientific Research Results
(Strengthening international dissemination of information (A); No.
251002) from the Japan Society for the Promotion of Science (JSPS).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
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