Molecular imaging in neuroendocrine tumors: Molecular uptake mechanisms and clinical results

Koopmans, Klaas Pieter; Neels, Oliver N.; Kema, Ido P.; Elsinga, Philip H.; Links, Thera P.; Vries, Elisabeth G.E. de; Jager, Pieter L.

doi:10.1016/j.critrevonc.2009.02.009

Cited by 138 publications

(112 citation statements)

References 90 publications

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“…The images also showed a high 11 C-hydroxytryptophan uptake in the kidney, which can be ascribed to renal excretion of the radiopharmaceutical. These results are in agreement with previous publications (10). Figure 4B shows a typical PET image of the abdomen in a clorgyline-treated rat.…”

Section: Petsupporting

confidence: 82%

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¹¹C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

et al. 2012

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Determination of the residual b-cell mass using noninvasive tools might help to follow up the efficacy of new treatments in both type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus, including islet transplantation. b-cells are neuroendocrine cells that can take up and metabolize the serotonin precursor 5-hydroxytryptophan. The serotonin pathway may therefore be an attractive target for the development of an imaging tracer for residual b-cell mass. The aim of this study was to evaluate the uptake mechanism and the retention of the PET tracer 11 C-hydroxytryptophan in endocrine and exocrine pancreas in vitro and in vivo. Methods: The exocrine human pancreas carcinoma cell line (PANC-1) and the endocrine human insulinoma cell line (CM) were applied for in vitro 11 Chydroxytryptophan accumulation/efflux experiments and blocking studies using inhibitors of key enzymes and transporters involved in the serotonin pathway. Animal experiments were performed on normal Wistar rats and on rats pretreated with the monoamine oxidase (MAO) inhibitor clorgyline. After intravenous injection of 11 C-hydroxytryptophan, a 60-min dynamic PET scan was acquired followed by an ex vivo biodistribution study. Autoradiography and hematoxylin-eosin staining were performed on the dissected pancreas to localize the radioactivity within the pancreatic tissue. Results: 11 C-hydroxytryptophan accumulated rapidly in both endocrine CM cells and exocrine PANC-1 cells. In the exocrine cells, a rapid efflux of radioactivity was observed, whereas most radioactivity remained trapped in the endocrine cells. PET images showed clear accumulation of 11 C-hydroxytryptophan in the pancreas in both animal groups, but with a significant 3-fold higher retention of the radiopharmaceutical in clorgyline-treated animals. Ex vivo biodistribution studies confirmed the results obtained by PET. Autoradiographs did not discriminate between the exocrine and endocrine pancreas in control animals, whereas autoradiographs showed intense radioactive spots colocalized with the islets of Langerhans in clorgyline-treated animals. The islets of Langerhans represent only 2%-3% of the total pancreas and consist of about 80% b-cells. In both type 1 and type 2 diabetes, dysregulation of glucose homeostasis and b-cell function and loss of b-cells are responsible of hyperglycemia (1). b-cells are neuroendocrine cells arising from precursor cells of the embryologic neural crest (2,3). Pancreatic b-cells regulate a large variety of body functions through paracrine and endocrine actions via dedicated amines and peptides, including the neurotransmitter serotonin. As a consequence, b-cells have an efficient mechanism for the uptake and metabolism of the amine precursors L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan through specific receptors (4,5).5-hydroxytryptophan and its precursor tryptophan are taken up in b-cells by the L-type amino acid transporter (LAT). Tryptophan is converted to 5-hydroxytryptophan by tryptophan hydroxylase (TPH). Subsequently,...

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Section: Petsupporting

confidence: 82%

“…11 C-hydroxytryptophan was synthesized as described by Neels et al in 15% 6 12% radiochemical yield (10). Radiochemical purity was greater than 99%, and average specific activity was 30 TBq/mmol.…”

Section: Chemicalsmentioning

confidence: 99%

¹¹C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

et al. 2012

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“…Different subtypes of NETs can develop in almost all organs and tissues, anywhere in the human body [1,2]. Carcinoid tumors are the subtype of NETs, accounting for less than 1% of all malignancies [2]. The majority of carcinoids arise in the gastroenteropancreatic and bronchopulmonary system [3].…”

Section: Introductionmentioning

confidence: 99%

The influence of Ki-67 proliferation index on Tc-99m-EDDA-HYNIC-TOC somatostatin receptor scintigraphy in patients with carcinoids

et al. 2014

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Abstract:The aim of this paper is to determine the influence of Ki-67 proliferation index on somatostatin receptor scintigraphy (SSRS) with Tc-99m-EDDA-HYNIC-TOC (Tc-99m-Tektrotyd) somatostatin analogue in patients with carcinoid tumors. Sixty-one patients (31 female, 30 male; age range: 33-76 years) were examined: 13 patients highly suspected of having a carcinoid, and 48 patients who had undergone the surgical removal of the tumor. Whole body SSRS at 4 h postinjection, spot scintigrams and SPECT of the selected regions were obtained for all patients. Tc-99m-Tektrotyd scintigraphy was classified as true positive in 26 out of 30 and true negative in 24 out of 28 patients. The sensitivity of Tc-99mTc-Tektrotyd scintigraphy was found to be as high as 94.74% in the group of patients with low mitotic index Ki67 (<2%), and it progressively decreased in patients with higher mitotic index (77.78% for Ki67 2-15% and 20% for Ki67% >20%). The likelihood of Tc-99m-Tektrotyd scan being positive when a carcinoid is present was found to be inversely proportional to the value of Ki67 proliferation index. The results showed that Tc-99m-Tektrotyd SSRS is a sensitive method for diagnosing and staging patients with well-differentiated carcinoid tumors. However, in poorly differentiated tumors with high Ki67 proliferation index, additional analyses are necessary for precise staging.

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“…Because the physical half-life of 18 F is 110 min, PET recordings show the total radioactivity concentration in living tissue, irrespective of any biotransformation of the tracer (9). In neuroendocrine tumors, the increased transport and AADC activity result in intracellular retention of metabolized 18 F-FDOPA and positive signals on PET images (10,11). In neuroblastic tumors, the neuroblastic cells also possess AADC activity (12) and, thus, theoretically can also be imaged by 18 F-FDOPA PET.…”

mentioning

confidence: 99%

Characterization of Neuroblastic Tumors Using ¹⁸F-FDOPA PET

Liu

Chang

et al. 2012

J Nucl Med

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Molecular imaging in neuroendocrine tumors: Molecular uptake mechanisms and clinical results

Cited by 138 publications

References 90 publications

¹¹C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

¹¹C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

The influence of Ki-67 proliferation index on Tc-99m-EDDA-HYNIC-TOC somatostatin receptor scintigraphy in patients with carcinoids

Characterization of Neuroblastic Tumors Using ¹⁸F-FDOPA PET

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Molecular imaging in neuroendocrine tumors: Molecular uptake mechanisms and clinical results

Cited by 138 publications

References 90 publications

11C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

11C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

The influence of Ki-67 proliferation index on Tc-99m-EDDA-HYNIC-TOC somatostatin receptor scintigraphy in patients with carcinoids

Characterization of Neuroblastic Tumors Using 18F-FDOPA PET

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¹¹C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

¹¹C-Hydroxytryptophan Uptake and Metabolism in Endocrine and Exocrine Pancreas

Characterization of Neuroblastic Tumors Using ¹⁸F-FDOPA PET