S P E C I A L F E A T U R E

C l i n i c a l C a s e S e m i n a r

Detection of Metastatic Insulinoma by Positron

Emission Tomography With [68Ga]Exendin-4—A Case
Report

Olof Eriksson,* Irina Velikyan,* Ram K. Selvaraju, Fouad Kandeel, Lars Johansson,
Gunnar Antoni, Barbro Eriksson, Jens Sörensen, and Olle Korsgren
Preclinical PET Platform (O.E., I.V., R.K.S.), Department of Medicinal Chemistry, Uppsala University, SE-

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751 83 Uppsala, Sweden; Department of Radiology, Oncology, and Radiation Sciences (I.V., L.J., G.A.,
J.S.), Uppsala University, SE-751 83 Uppsala, Sweden; PET Centre (I.V., G.A., J.S.), Centre for Medical
Imaging, Uppsala University Hospital, Uppsala, SE-751 83 Sweden; Beckman Research Institute of the
City of Hope (F.K.), Duarte, California 91010; AstraZeneca R&D (L.J.), SE-431 50 Mölndal, Sweden;
Department of Medical Sciences (B.E.), Uppsala University, SE-751 83 Uppsala, Sweden; and Department
of Immunology, Genetics, and Pathology (O.K.), Uppsala University SE-751 83, Uppsala, Sweden

Context: Insulinomas are the most common cause of endogenous hyperinsulinemic hypoglycemia in
nondiabetic adult patients. They are usually benign, and curative surgery is the “gold standard” treat-
ment if they can be localized. Malignant insulinomas are seen in less than 10% of patients, and their
prognosis is poor. The glucagon like peptide-1 receptor (GLP-1R) is markedly up-regulated in insuli-
nomas— especially benign lesions, which are difficult to localize with current imaging techniques.

Objective: The aim of the study was to assess the possibility of the detection of primary and
metastatic insulinoma by positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Ex-
endin-4 ([68Ga]Exendin-4) in a patient with severe hypoglycemia.

Design and Setting: Dynamic and static PET/computed tomography (CT) examination of a patient
was performed using [68Ga]Exendin-4 at Uppsala University Hospital, Uppsala, Sweden.

Patients: A patient presented with hypoglycemia requiring continuous iv glucose infusions. A pan-
creatic insulinoma was suspected, and an exploratory laparotomy was urgently performed. At surgery,
a tumor in the pancreatic tail with an adjacent metastasis was found, and a distal pancreatic resection
(plus splenectomy) and removal of lymph node were performed. Histopathology showed a World
Health Organization classification grade II insulinoma. Postoperatively, hypoglycemia persisted, but a
PET/CT examination using the neuroendocrine marker [11C]-5-hydroxy-L-tryptophan was negative.

Interventions: The patient was administered [68Ga]Exendin-4 and was examined by dynamic PET
over the liver and pancreas.
68
Results: The stable GLP-1 analog Exendin-4 was labeled with Ga for PET imaging of GLP-1R-
68
expressing tumors. The patient was examined by [ Ga]Exendin-4-PET/CT, which confirmed several
small GLP-1R-positive lesions in the liver and a lymph node that could not be conclusively identified
by other imaging techniques. The results obtained from the [68Ga]Exendin-4-PET/CT examination
provided the basis for continued systemic treatment.

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2014 by the Endocrine Society
Received September 19, 2013. Accepted January 27, 2014.
First Published Online February 10, 2014
* O.E. and I.V. contributed equally to this work.
Abbreviations: CT, computed tomography; [18F]L-DOPA, [18F]-L-dihydroxyphenylalanine;
DOTATATE, (DOTA0-D-Phe1-Tyr3)octreotate; DOTATOC, (DOTA0-D-Phe1-Tyr3)octreotide;
[68Ga]Exendin-4, [68Ga]Ga-DO3A-VS-Cys40-Exendin-4; [18F]FDG, [18F]fluorodeoxyglucose;
GLP-1R, glucagon like peptide-1 receptor; [11C]5-HTP, [11C]5-hydroxy-L-tryptophan; MEN 1,
multiple endocrine neoplasia type 1; NET, neuroendocrine tumor; PET, positron emission to-
mography; p-glucose, plasma glucose; SPECT, single photon emission CT; SRS, somatostatin
receptor scintigraphy; US, ultrasound.

doi: 10.1210/jc.2013-3541 J Clin Endocrinol Metab, May 2014, 99(5):1519 –1524 jcem.endojournals.org 1519
1520 Eriksson et al Insulinoma Imaging by Exendin-4 PET
Conclusion: The results of the [68Ga]Exendin-4-PET/CT examination governed the treatment strat-
egy of this particular patient and demonstrated the potential of this technique for future man-
agement of patients with this rare but potentially fatal disease. (J Clin Endocrinol Metab 99:
1519 –1524, 2014)
nsulinomas, with an incidence of 1–3 per million per
I year, are the most common cause of endogenous hy-
perinsulinemic hypoglycemia in nondiabetic adult pa-
tients. More than 90% are benign, curative surgery is the
“gold standard” of treatment, and accurate localization of
the tumors is of the utmost importance. This report pres-
ents the impact of diagnostic imaging using positron emis-
sion tomography (PET) targeting glucagon like peptide-1
receptor (GLP-1R) in an insulinoma patient with postop-
erative hypoglycemia.
Case Report
A female presented with an attack of unconsciousness due
to hypoglycemia (plasma glucose [p-glucose], 2.2
mmol/L) requiring continuous iv glucose infusions (10 –
30%) in July 2012. During the previous year, the patient
had changed eating habits and gained 40 kg in weight. The
patient was examined for suspected primary pancreatic
insulinoma with a fast that had to be stopped after 4 hours
(insulin, 88 mE/L [normal range, ⬍11]; C-peptide, 1.76
nmol/L [normal range, ⬍1.5]; and p-glucose, 1.8 mmol/L
[normal range, ⬎4]), where mE/L is mEquivalents/L. Pre-
operative imaging with contrast-enhanced computed to-
mography (CT) and ultrasound (US) was negative, but
endoscopic ultrasonography indicated a small lesion in the
body of the pancreas. Because of clinical urgency, an ex-
ploratory laparotomy with intraoperative ultrasonogra-
phy was performed in August 2012, and a 2-cm tumor in
the tail of the pancreas and an adjacent lymph node me-
tastasis were found. A distal pancreatic resection plus sple-
nectomy was performed. Histopathology verified a locally
invasive insulinoma (World Health Organization classi-
fication grade II), positive for cytokeratin, chromogranin,
synaptophysin, and insulin, with some cells positive for
calcitonin, and one lymph node metastasis with a cell pro-
liferation rate (Ki-67) of 5–10%. No positive immunos-
tainings for glucagon, pancreatic polypeptide, somatosta-
tin, or gastrin were detected. Multiple endocrine neoplasia
type 1 (MEN 1) was excluded by normal serum calcium,
PTH, and prolactin.
Severe hypoglycemia persisted postoperatively, indi-
cating remaining lesions. Ultrasonography indicated two
small lesions (⬍1 cm) in the liver, but biopsies showed
normal liver parenchyma. [11C]5-hydroxy-L-tryptophan
([11C]5-HTP)-PET/CT (1), which according to our expe-
J Clin Endocrinol Metab, May 2014, 99(5):1519 –1524
rience is more sensitive than conventional imaging and
somatostatin receptor imaging with [111In]-DTPA-oc-
treotide (Octreoscan) in localizing insulinomas (2), was
negative in both the pancreas and the liver. Based on our
clinical experience of prompt improvement of hypoglyce-
mia in insulinoma patients, treatment with everolimus at
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10 mg/d (3) was initiated in September 2012, which re-
duced iv glucose requirements from 6 L/d to 4 L/d after 1
week. Streptozocin and 5-fluorouracil (4), first-line treat-
ment in metastatic insulinomas, was subsequently started.
Three weeks later, the patient was normoglycemic, and
hormone levels had decreased. Systemic treatment had to
be withdrawn in October 2012, due to an infection with
septicemia and elevated creatinine at 280 ␮mol/L (normal
range, ⬍90). [18F]Fluorodeoxyglucose ([18F]FDG)-
PET/CT (without contrast due to elevated creatinine)
showed uptake in the operated area, confirming a post-
operative infection. Two small lesions in the liver were
seen with unspecific uptake of [18F]FDG. During the fol-
lowing weeks, hypoglycemia recurred (p-glucose, 2.8
mmol/L), hormone levels increased (insulin, 187 mE/L;
C-peptide, 2.8 nmol/L; proinsulin, 918 pmol/L), and iv
glucose infusions had to be reinitiated; renal function
slowly improved but was still impaired. Because of the
patient’s serious general condition, an intra-arterial cal-
cium stimulation test with venous sampling was consid-
ered to be contraindicated.
Because we had not been able to clearly visualize met-
astatic lesions, at this time surgery, radiofrequency abla-
tion, and liver embolization were not an option. Soma-
tostatin analogs were considered, but in our experience
could worsen hypoglycemia. Diazoxide was contraindi-
cated because of elevated creatinine and risk for fluid
retention, in particular because the patient weighed 120
kg. Peptide receptor radionuclide therapy using [177Lu]-
(DOTA0-D-Phe1-Tyr3)octreotate (DOTATATE) was
not a therapeutic option due to the elevated creatinine.
Pretherapeutic somatostatin receptor expression con-
firmation using either [111In]-DTPA-octreotide (Oc-
treoscan)/single photon emission CT (SPECT) or [68Ga]-
(DOTA0-D-Phe1-Tyr3)octreotide (DOTATOC)-PET/CT
was not considered. Additionally, the lesions were as-
sumed to be too small in size to be detected by Octreoscan/
[68Ga]-DOTATOC because they were not detected by
[11C]5-HTP-PET/CT.
In a further attempt to localize the insulinoma lesions,
the patient was examined with [68Ga]Ga-DO3A-VS-
doi: 10.1210/jc.2013-3541 jcem.endojournals.org 1521

ably liver metastases, in both liver

lobes (the largest, 1 cm) and a para-
aortal lymph node (Figure 1, A, D,
and G). Neither of the lesions had
been conclusively detected by mor-
phological imaging with CT and US
or molecular imaging with [11C]5-
HTP-PET/CT (Figure 1, B, E, and H)
or [18F]FDG-PET/CT (Figure 1, C, F,
and I). Native pancreas, containing a
large number of cells positive for
GLP-1R, exhibited marked uptake

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of [68Ga]Exendin-4 (Figure 1G).
Maximum intensity projections of
the abdomen showed the GLP-1R-
positive lesions in liver and lymph
nodes as well as native pancreas (Fig-
ure 2, A–C).
Figure 1. [68Ga]Exendin-4 PET (left panels) confirmed several GLP-1R-positive lesions (white Because this was the first exami-
arrows) in the liver (A, D) and a para-aortal lymph node (G). No pancreatic or hepatic lesions nation with this PET tracer, the up-
could be conclusively detected by PET/CT using established tumor markers [11C]5-HTP (middle
take in the native pancreas is not
panels) and [18F]FDG (right panels). Each row shows the same transaxial abdominal sections for
[68Ga]Exendin-4, [11C]5-HTP, and [18F]FDG, clearly demonstrating focal GLP-1R-positive lesions known. However, because MEN 1
that could not be localized by established PET techniques. ␤-Cells in normal pancreas (red arrow) had been excluded in this patient, the
have significant expression of GLP-1R and can also be visualized by this technique (G). All images high uptake in the pancreas most
are normalized to a standardized uptake value of 1 with no background subtracted.
likely represents the presence of a
Cys40-Exendin-4 ([68Ga]Exendin-4)-PET/CT targeting large number of GLP-1R-expressing
GLP-1R. Previously, Exendin-4 has been proposed as an normal cells.
imaging biomarker for native ␤-cells in the context of The results obtained from the [68Ga]Exendin-4-
quantifying changes in ␤-cell mass in response to disease PET/CT examination provided the basis for continued
progression for both type 1 and type 2 diabetes, as well as systemic treatment. Because the patient had initially
for evaluation of cellular replacement therapy (5, 6). responded to everolimus and chemotherapy with normal-
GLP-1R is overexpressed by up to five times in insulinoma ization of glucose levels and reduction in hormone levels,
compared to normal human ␤-cells. Even so, the presence both therapies were reinitiated when creatinine normal-
of a background of receptor-specific uptake in the pan- ized in late November 2012. After two courses of chemo-
creas may potentially cause difficulties in the diagnosis of therapy, the patient was normoglycemic again with p-glu-
pancreatic insulinoma. For example, focal concentrations cose levels at 6.9 mmol/L, insulin of 36 mE/L, C-peptide of
of normal pancreatic cells with high GLP-1R expression 1.39 nmol/L, and proinsulin of 104 pmol/L. Unfortu-
may present as a false-positive insulinoma. This is also nately, in April 2013 she had to stop everolimus because
characteristic for [11C]5-HTP and [18F]-L-dihydroxyphe- of pneumonitis, a known side effect of this drug. Chemo-
nylalanine ([18F]L-DOPA) because the decarboxylation therapy alone did not control hyperinsulinemia, and a CT
uptake mechanism is present and highly utilized also in with contrast of the abdomen in May 2013 showed pro-
normal islet cells (7). gression in both liver lobes, with some lesions now mea-
Whole-body [68Ga]Exendin-4-PET/CT examinations suring 1.5 cm. In June 2013, a bland embolization with
showed accumulation in multiple small nodes, presum- embospheres of the right hepatic artery supplying most of

Figure 2. Three-dimensional maximum intensity projections of [68Ga]Exendin-4 PET (A), CT (B), and PET/CT fusion (C), which show the full tumor
burden in liver and lymph nodes (white arrows) in addition to normal ␤-cells in pancreas (red arrow).
1522 Eriksson et al Insulinoma Imaging by Exendin-4 PET
the liver metastases was performed. A few weeks later,
everolimus was reinitiated at a lower dose (10 mg three
times a week and 5 mg four times a week); the patient then
managed without glucose infusions, and a CT of the ab-
domen in August 2013 showed regression of some of the
metastases. Recently, pneumonitis recurred, and everoli-
mus was again withdrawn. Unfortunately, hormone levels
are increasing, and a pretherapeutic diagnosis with Oc-
treoscan or [68Ga]-DOTATATE for the determination of
somatostatin receptor expression is scheduled. If positive,
peptide receptor radionuclide therapy with [177Lu]-DOT-
ATATE may be considered.
Methods
Radiochemistry
Good manufacturing practice-compliant production
and quality control of the tracer were accomplished within
1 hour using the generator eluate fractionation method (8)
with purification of the final product (9). 68Ga (T[1/2] ⫽ 68
min) was obtained from a 68Ge/68Ga generator system
(1850 MBq; Eckert & Ziegler, Eurotope GmbH). The first
fraction of 1.5 mL was discarded, and the next 1.0 mL
containing over 70% of the total radioactivity was col-
lected and buffered with 200 ␮L acetate buffer and 10 ␮L
sodium hydroxide to provide a pH of 4.6 ⫾ 0.4. To sup-
press radiolysis, 100 ␮L of ethanol was added. Then the
mixture was transferred to a glass vial containing 10.5
nmol of good manufacturing practice grade DO3A-VS-
Cys40-Exendin-4 (C S Bio Company, Inc) and incubated at
75°C for 15 minutes. The product was purified using C-8
(Sep-Pak Light C8 cartridge; Waters) reversed solid-phase
extraction cartridge, eluted in 1.0 mL of 50% ethanol,
formulated in sterile phosphate buffer (pH 7.4), and
passed through a 0.22-␮m filter into a sterile injection vial.
A sample was taken for the determination of identity, ra-
diochemical and chemical purity, pH, estimation of the
peptide content, as well as control of sterility and
endotoxins.
PET/CT examination protocol
The subject was positioned to include the liver in the
center of the 15-cm axial field of view of a Discovery ST
PET/CT scanner (GE Healthcare) by assistance of a low-
dose CT scout view (140 kV, 10 mA). Attenuation cor-
rection was acquired by CT (140 kV, 10 – 80 mA) imme-
diately before the PET examination. Diagnostic CT with
contrast was not performed because of elevated creatinine.
The patient was then administered iv [68Ga]Exendin-4
(0.88 MBq/kg; 0.17 ␮g/kg; specific radioactivity, 56 MBq/
nmol) and examined by dynamic PET over the liver and
J Clin Endocrinol Metab, May 2014, 99(5):1519 –1524
pancreas for 45 minutes. This was followed by a whole-
body CT (for attenuation correction) and multibed whole-
body PET examinations (4-min acquisition per bed posi-
tion) 1.7 and 2 hours after tracer administration. Image
acquisition was performed in three-dimensional mode and
reconstructed using an iterative OSEM VUE Point algo-
rithm (two iterations/21 subsets, in a 128 ⫻ 128 matrix).
Reconstructed data were analyzed using Xeleris (GE
Healthcare).
Diagnosis of Insulinoma: A Review of the
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Literature
Insulinomas are most often localized to the pancreas, but
a small percentage (⬍2%) are extrapancreatic. Approxi-
mately 85% are solitary, 6 –13% are multiple, and 4 – 6%
are associated with MEN 1. Malignant insulinomas con-
stitute ⬍ 10% of all insulinomas, and the prognosis of
survival for patients with liver metastases has been esti-
mated to be less than 2 years (10).
The biochemical diagnosis of insulinomas is estab-
lished by measuring p-glucose, serum insulin, C-peptide,
and proinsulin during a 12- to 72-hour fast and showing
inappropriately high insulin/proinsulin levels for a glucose
level below 2.5 mmol/L. Eighty percent of patients with
insulinomas will present hypoglycemic symptoms and
positive fast after 24 hours, 90% after 48 hours, and
100% after 72 hours (11). The possibility of the insuli-
noma being a part of MEN 1 should also be excluded,
especially in young patients, in the presence of a family
history, or if there are multiple tumors in the pancreas. If
so, biochemical studies including serum PTH, ionized cal-
cium, and prolactin should be performed.
Once the biochemical diagnosis of an insulinoma has
been established, localization procedures should be un-
dertaken. Preoperative imaging is critical to optimize sur-
gical intervention. Due to the small size of the tumors
(82% ⬍ 2 cm, 47% ⬍ 1 cm), they are often difficult to
detect. US, CT, and magnetic resonance imaging are
widely available but are only conclusive in ⬍ 50% of cases.
Endoscopic US scans are positive in 70 –95% of all cases.
However, the technique often fails to detect tumors in the
tail of the pancreas. Because insulinomas are highly vas-
cularized, selective angiography can detect the lesion in
about 60% of subjects, and if combined with venous sam-
pling for insulin after intra-arterial calcium stimulation
administration, the accuracy increases to about 60 – 80%.
The procedure is, however, invasive and is accompanied
by risks for complications (12).
Functional imaging with somatostatin receptor scintig-
raphy (SRS) and SPECT/CT is positive in ⬍ 50% of benign
doi: 10.1210/jc.2013-3541
insulinomas because of low or absent expression of so-
matostatin receptor subtypes 2 and 5 that bind octreotide
with high affinity. Malignant insulinomas, in contrast,
may express these receptors and consequently show high
uptake at SRS (predicting benefit from treatment with un-
labeled or radiolabeled somatostatin analogs). Recently,
several studies have demonstrated that PET with 68Ga-
labeled somatostatin analogs, when combined with CT,
has a higher sensitivity for smaller lesions than SRS or
other modalities (13). Other PET tracers used for imaging
of NET, available in some centers, are [11C]5-HTP and
[18F]L-DOPA based on the amine-precursor uptake mech-
anisms of the tumors. PET using [11C]5-HTP has been
shown to be a highly sensitive modality for neuroendo-
crine tumor (NET) imaging that surpasses that of SRS and
CT. A comparison of [11C]5-HTP and [18F]L-DOPA
showed that the former more accurately visualized pan-
creatic NET (14). Still, in a recent study, where [11C]5-
HTP-PET imaging was correlated to surgical findings, it
failed to detect two of six insulinomas, although it had
higher sensitivity than other methods (2).
GLP-1R is expressed in human ␤-cells and highly over-
expressed in insulinomas (15). The endogenous peptide
GLP-1 has a very short biological half-life, and thus the
metabolically more stable synthetic peptide analog, Ex-
endin-4, has been developed and conjugated with a variety
of chelator moieties for subsequent radiolabeling with
111
In, 99Tc, or 68Ga. The resulting tracers have been eval-
uated preclinically for the targeting of insulinoma (16 –
18). Recently, [18F]-labeled Exendin-4 probes have also
been developed (19, 20). [Lys40(Ahx-DTPA-111In)NH2]
Exendin-4 has been used clinically for the detection of
occult insulinoma by SPECT/CT (21) and also for preop-
erative localization of insulinoma (22). GLP-1R has been
shown to have high sensitivity for localization of especially
benign insulinoma (21). Recently, a prospective, open-
label, multicenter phase II trial evaluated the insulinoma
detection rate of [Lys40(Ahx-DTPA-111In)NH2]Ex-
endin-4 SPECT/CT compared to CT or magnetic reso-
nance imaging. In 25 patients who underwent surgery
with histopathological verification, the sensitivities for the
two methods were 97 and 47%, respectively (23). Malig-
nant insulinomas have been described to have a lower
density of GLP-1Rs (15, 24). Positron-emitting 68Ga
(T[1/2] ⫽ 68 min; 89% ␤⫹) in combination with PET/CT
potentially provides advantages to SPECT, such as im-
proved sensitivity, higher resolution, faster acquisition
time, and accurate quantification. This may enable detec-
tion of smaller lesions resulting in accurate staging and
improved patient management. Moreover, the availability
of 68Ga from generator systems and the possibility for
jcem.endojournals.org 1523
labeling chemistry under radiopharmacy practice make
[68Ga]Exendin-4 affordable at any clinical center.
Conclusion
This is the first clinical experience using [68Ga]Exendin-
4-PET/CT for visualization of GLP-1R in insulinoma and
in native pancreas. Unfortunately, we were not able to
verify the lesions in the liver histopathologically by biop-
sies because they were too small (⬍1 cm), and represen-
tative tumor tissue could not be obtained. Even so, the
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results of the examination confirmed the presence of sus-
pected liver and lymph node metastases, which could
not be conclusively detected by other state-of-the-art
imaging techniques. The presented results demonstrate
the potential for this technique to become an important
diagnostic imaging choice for the detection and staging
of insulinomas.
Acknowledgments
Address all correspondence and requests for reprints to: Olof
Eriksson, PhD, MSc, Preclinical PET Platform, Department of
Medicinal Chemistry, Uppsala University, Dag Hammar-
skjölds väg 14C, 3tr, SE-751 83 Uppsala, Sweden. E-mail:
olof.eriksson@pet.medchem.uu.se.
This study was supported by grants from the Swedish Medical
Research Council (65X-12219-15-6), the VINNOVA Founda-
tion (2007-00069), the JDRF, ExoDiab, Barndiabetesfonden,
and Tore Nilssons Foundation for Medical Research. O.K.’s po-
sition is supported by the National Institutes of Health
(2U01AI065192-06). O.E.’s position is supported by ExoDiab.
Written informed consent was obtained from the patient for
publication of this case report and any accompanying images. A
copy of the written consent is available for review by the Editor
of this journal.
Disclosure Summary: The authors declare that they have no
conflicts of interests.
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