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Detection of Metastatic Insulinoma by Positron Emission Tomography with [(68)Ga]Exendin-4 -: a case report
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
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2014 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 5, 1519-1524 p.Article in journal (Refereed) Published
Abstract [en]

Context:

Insulinomas are the most common cause of endogenous hyperinsulinaemic hypoglycaemia in non-diabetic adult patients. They are usually benign and curative surgery is the "gold standard" treatment if they can be localized. Malignant insulinomas are seen in less than 10% and their prognosis is poor. The Glucagon Like Peptide-1 receptor (GLP-1R) is markedly upregulated in insulinomas - especially benign lesions which are difficult to localize with current imaging techniques.

Objective:

To assess the possibility of the detection of primary and metastatic insulinoma by PET using [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 ([(68)Ga]Exendin-4) in a patient with severe hypoglycemia.

Design:

Dynamic and static PET/CT examination of a patient using [68Ga]Exendin-4.

Setting:

Uppsala University Hospital, Uppsala, Sweden.

Patients:

A patient presented with hypoglycemia requiring continuous intravenous glucose infusions. A pancreatic 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 was performed. Histopathology showed a WHO grade II insulinoma. Postoperatively hypoglycemia persisted but a PET/CT examination using the neuroendocrine marker [(11)C]-5-hydroxy-L-tryptophan was negative.

Interventions:

The patient was administered with [(68)Ga]Exendin-4 and examined by dynamic PET over the liver and pancreas.

Main Outcome Measures:

N/A

Results:

The stable GLP-1 analogue Exendin-4 was labeled with (68)Ga for PET imaging of GLP-1R expressing tumors. The patient was examined by [(68)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 [(68)Ga]Exendin-4-PET/CT examination provided the basis for continued systemic treatment.

Conclusion:

The results of the [(68)Ga]Exendin-4-PET/CT examination governed the treatment strategy of this particular patient and demonstrated the potential of this technique for future management of patients with this rare, but potentially fatal disease.

Place, publisher, year, edition, pages
2014. Vol. 99, no 5, 1519-1524 p.
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:uu:diva-218879DOI: 10.1210/jc.2013-3541ISI: 000342339800030PubMedID: 24512490OAI: oai:DiVA.org:uu-218879DiVA: diva2:697702
Available from: 2014-02-19 Created: 2014-02-19 Last updated: 2017-12-06Bibliographically approved
In thesis
1. [68Ga]Exendin-4: Bench-to-Bedside: PET molecular imaging of the GLP-1 receptor for diabetes and cancer
Open this publication in new window or tab >>[68Ga]Exendin-4: Bench-to-Bedside: PET molecular imaging of the GLP-1 receptor for diabetes and cancer
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes epidemic is underway. Beta cell dysfunction (BCF) and loss of beta cell mass (BCM) are known to be key events in its progression. Currently, there are no reliable techniques to estimate or follow the loss of BCM, in vivo. Non-invasive imaging and quantification of the whole BCM in the pancreas, therefore, has a great potential for understanding the progression of diabetes and the scope for early diagnosis for Type 2 diabetes.

Glucagon-like peptide-1 receptor (GLP-1R) is known to be selectively expressed on the pancreatic beta cells and overexpressed on the insulinoma, a pancreatic neuroendocrine tumor (PNET). Therefore, this receptor is considered to be a selective imaging biomarker for the beta cells and the insulinoma. Exendin-4 is a naturally occurring analog of GLP-1 peptide. It binds and activates GLP-1R with same the potency and engages in the insulin synthesis, with a longer biological half-life. In this thesis, Exendin-4 precursor, DO3A-VS-Cys40-Exendin-4 labeled with [68Ga], [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 ([68Ga]Exendin-4), was evaluated in different species models, namely, immune deficient nude mice, rats, pigs, non-human primate (NHP), and clinically in one insulinoma patient by positron emission tomography (PET), for its potential in beta cell imaging and its quantification as well as for visualizing the insulinoma. From internal dosimetry, the possible number of repetitive [68Ga]Exendin-4-PET/CT scans was estimated.

Pancreatic uptake and insulinoma tumor uptake of [68Ga]Exendin-4 were confirmed to be mediated by the specific binding to the GLP-1R. Pancreatic GLP-1R could be visualized and semi-quantified, for diabetic studies, except in rats. Nonetheless, we found conflicting results regarding the GLP-1R being a selective imaging biomarker for the beta cells. PET/CT scan of the patient with [68Ga]Exendin-4 has proven to be more sensitive than the clinical neuroendocrine tracer, [11C]5-HTP, as  it could reveal small metastatic tumors in liver. The kidney was the dose-limiting organ in the entire species model, from absorbed dose estimation. Before reaching a yearly kidney limiting dose of 150 mGy and a whole body effective dose of 10 mSv, 2–4 [68Ga]Exendin-4 PET/CT scans be performed in an adult human, which enables longitudinal clinical PET imaging studies of the GLP-1R in the pancreas, transplanted islets, or insulinoma, as well as in healthy volunteers enrolled in the early phase of anti-diabetic drug development studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 202
Keyword
PET, [68Ga]Exendin-4, beta cell imaging, insulinoma, dosimetry
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-261629 (URN)978-91-554-9323-3 (ISBN)
Public defence
2015-10-23, Fåhraeussalen, Rudbecklaboratoriet (hus C5), Dag Hammarskjölds väg 20, 751 85, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-10-06 Created: 2015-09-02 Last updated: 2015-10-12

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Eriksson, OlofVelikyan, IrinaSelvaraju, Ram KJohansson, LarsAntoni, GunnarEriksson, BarbroSörensen, JensKorsgren, Olle

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