Carbidopa pretreatment improves image interpretation and visualisation of carcinoid tumours with 11C-5-hydroxytryptophan positron emission tomography.

PURPOSE: Positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) as tracer is a promising imaging instrument in the management of patients with neuroendocrine tumours (NETs). However, high radioactivity concentrations in the urinary collecting system sometimes produce image reconstruction artefacts that can make detection of small NETs difficult. As a means to decrease urinary excretion of radioactivity and thereby improve image quality, we examined the effect of pretreatment with carbidopa (CD), a peripheral inhibitor of aromatic amino acid decarboxylase (AADC), which converts 5-HTP to serotonin (5-hydroxytryptamine, 5-HT). METHODS: Six patients with midgut carcinoid metastases were examined with 11C-5-HTP PET before and 1 h after oral administration of 100 or 200 mg of CD. RESULTS: There was a fourfold significant reduction of tracer uptake in the urinary collecting system after CD administration (p=0.0277, n=6), with a mean standard uptake value (SUV) of 155+/-195 before CD and 39+/-14 after CD. In tumour lesions there was a significant increase in SUV after CD administration (p<0. 0001, n=18), with a mean SUV of 11+/-3 before CD and 14+/-3 after CD. There was no difference between the doses (100 and 200 mg) of CD in this respect. In all patients, image interpretation and tumour detection were markedly improved after CD administration. CONCLUSION: We conclude that CD premedication improves 11C-5-HTP PET image quality and facilitates detection of NET lesions. Because of the similarity of metabolic pathways, this method could probably be applied to improve PET imaging using other tracers like 18F-DOPA and 11C-DOPA.

Whole-body (11)C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography.

Neuroendocrine tumors (NETs) can be small and situated almost anywhere throughout the body. Our objective was to investigate whether whole-body (WB) positron emission tomography (PET) with (11)C-5-hydroxytryptophan (5-HTP) can be used as a universal imaging technique for NETs and to compare this technique with established imaging methods. Forty-two consecutive patients with evidence of NET and a detected lesion on any conventional imaging (six bronchial, two foregut, 16 midgut, and two thymic carcinoids; one ectopic Cushing's syndrome; four gastrinomas; one insulinoma; six nonfunctioning endocrine pancreatic tumors; one gastric carcinoid, one paraganglioma; and two endocrine-differentiated pancreatic carcinomas) were studied. The WB-(11)C-5-HTP-PET examinations were compared with WB-computed tomography (CT) and somatostatin receptor scintigraphy (SRS). Tumor lesions were imaged with PET in 95% of the patients. In 58% of the patients, PET could detect more lesions than SRS and CT and equal numbers in 34%, whereas in three cases, SRS or CT showed more lesions. In 84% (16 of 19 patients), PET could visualize the primary tumor compared with 47 and 42% for SRS and CT, respectively. The surgically removed PET-positive primary tumor sizes were 6-30 mm. To conclude, this study indicates that WB-(11)C-5-HTP-PET can be used as a universal imaging method for detection of NETs. This study also shows that WB-(11)C-HTP-PET is sensitive in imaging small NET lesions, such as primary tumors, and can in a majority of cases image significantly more tumor lesions than SRS and CT.

Developments in PET for the detection of endocrine tumours.

Positron emission tomography (PET) supplies a range of labelled compounds to be used for the characterization of tumour biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow-up, and clinical research. (18)F-fluorodeoxyglucose PET scanning is now a widely accepted imaging approach in clinical oncology, reflecting increased expression of glucose transporters in cancerous tissue. This tracer, however, does not show sufficient uptake in well-differentiated tumours such as neuroendocrine tumours. Endocrine tumours have the unique characteristics of taking up and decarboxylating amine precursors. These so-called APUD characteristics offer highly specific targets for PET tracers. Using this approach, radiopharmaceuticals such as [(11)C]-5-hydroxytryptophan and [(11)C]-L-dihydroxyphenylalanine for localization of carcinoid and endocrine pancreatic tumours, 6-[(18)F]-fluorodopamine and [(11)C]-hydroxyephedrine for phaeochromocytomas, and [(11)C]-metomidate for adrenal cortical tumours have been developed. Functional imaging with PET using these compounds is now being employed to complement rather than replace other imaging modalities. Development of new PET radiopharmaceuticals may in the future allow in vivo detection of tumour biological properties, such as malignant potential and responsiveness to treatment.

Demonstration of high monoaminoxidase-A levels in neuroendocrine gastroenteropancreatic tumors in vitro and in vivo-tumor visualization using positron emission tomography with 11C-harmine.

BACKGROUND AND AIMS: A majority of neuroendocrine gastroenteropancreatic (GEP) tumors can be detected by conventional radiological methods and scintigraphic techniques. Still there are problems to visualize small tumor lesions and non-functioning tumors. The aim of this study was to investigate some of the monoamine processing pathways of neuroendocrine GEP-tumors and try to find a new tracer substance for in vivo characterization and visualization by Positron Emission Tomography (PET). SUBJECTS AND METHODS: Autoradiography of tumor sections from 8 midgut carcinoids (MGC) and 8 endocrine pancreatic tumors (EPT) was performed with (11)C-labeled tracers for serotonin and dopamine transporters, serotonin HT2A-, dopamine D1- and muscarinic receptors and for monoamine oxidase A (MAO-A). The in vitro results initiated PET studies with (11)C-Harmine in 4 patients with MGC and 7 patients with EPT (one insulinoma, two glucagonomas and four non-functioning EPT). RESULTS: The MAO-A-ligand Harmine expressed specific in vitro binding of 87 +/-21% for MGC and 125 +/- 50% for EPT, compared to reference tissue (rat brain, 100%). All other substances showed relatively low specific binding. (11)C-harmine-PET could visualize tumors in all patients. The mean standardized uptake value (SUV) for MGC was 7.5 +/- 3.9 and for EPT 12.9 +/- 2.7, whereas the SUV of normal liver, intestine and pancreas were 3.1 +/- 0.5, 3.4 +/- 1.2 and 8.9 +/- 3.0 respectively. CONCLUSIONS: This study demonstrates in vitro and in vivo that neuroendocrine GEP-tumors are characterized by a high MAO-A-expression, thereby adding to the similarities of neuronal and neuroendocrine tissue. It also indicates a possible application for (11)C-harmine as a new PET-tracer for neuroendocrine GEP-tumors with the potential to visualize also non-functioning EPT's.

Use of PET in neuroendocrine tumors. In vivo applications and in vitro studies.

Positron emission tomography (PET) performed with various radiolabelled compounds facilitates the study of tumor biochemistry. If the tumor uptake of an administered tracer is greater than that of surrounding normal tissue, it is also possible to localize the tumor. In initial studies, 18F-labeled deoxyglucose (FDG) was attempted to visualize the tumors, since this tracer had been successfully used in oncology, reflecting increased glucose metabolism in cancerous tissue. However, this tracer was not to any significant degree taken up by the neuroendocrine tumors. Instead, the serotonin precursor 5-hydroxytryptophan (5-HTP) labeled with 11C was used and showed an increased uptake and irreversible trapping of this tracer in carcinoid tumors. The uptake was selective and the resolution so high that we could detect more liver and lymph node metastases with PET than with CT or octreotide scintigraphy. One problem was, however, the high renal excretion of the tracer producing streaky artifacts in the area of interest. Using the decarboxylase inhibitor carbidopa, given as peroral premedication, the renal excretion decreased 6-fold and at the same time the tumor uptake increased 3-fold, hence improving the visualization of the tumors. When patients were followed during treatment with PET using 5-HTP as a tracer, a > 95% correlation between changes in urinary 5-hydroxyindoleacetic acid (U-5-HIAA) and changes in the transport rate constant for 5-HTP was observed. Thus, PET can be used to monitor treatment effects. Elevation of U-5-HIAA is considered to be uncommon in endocrine pancreatic tumors (EPTs). Initially, 11C-labeled L-DOPA was attempted as another amine important in the APUD system. With L-DOPA about half of the EPTs, mainly functioning tumors, could be detected. Recently, 5-HTP was explored as a universal tracer also for EPT and foregut carcinoids, extending the PET-examination to both thorax and abdomen (whole-body PET-examination). With this method we were able to visualize small lesions in the pancreas and thorax (e.g. ACTH-producing bronchial carcinoids) not detectable by any other method including octreotide scintigraphy, MRI and CT. Several other tracers have been investigated, e.g. the monoamineoxidase (MAO-A) inhibitor harmine with promising results in non-functioning EPTs. We are currently exploring a wide range of biochemical systems, including enzymes and receptors, both for neurotransmitters and for peptides and proteins in in vitro assays with the potential to use some of the developed tracers for in vivo visualization and tumor biological studies. In conclusion, PET is a valuable tool in the diagnosis of neuroendocrine tumors. It can detect small lesions in the thorax and abdomen not detected by other methods, which has been of great value preoperatively in several cases. It detects more lesions in the liver and lymph nodes than other methods and furthermore, it can be used to monitor treatment effects.

Uptake of 14C- and 11C-labeled glutamate, glutamine and aspartate in vitro and in vivo.

To explore their potential use as in vivo tracers, the uptake of the amino acids glutamine, glutamate and aspartate, labeled with 11C or 14C, was evaluated in tumor cell aggregates, in vivo in rats and a few pilot studies with positron emission tomography (PET) in patients. The uptake in aggregates increased linearly with time, and was competitively inhibited by the same amino acids. The uptake of 14C-glutamate in carcinoid cells (BON) was inhibited by cystine but not by aspartate, contrary to the result in neuroblastoma (LAN). 6-Diazo-oxy-L-norleucine (a glutamine analogue) and Substance P had different effect on the uptake of glutamate in different cells. The metabolic fate of 14C-glutamate was evaluated with protein separation and with HPLC. The in vivo distribution in rats showed the highest uptake of 11C-glutamine and 11C-glutamate in pancreas and kidney, and of 11C-aspartate in the lung. In the human studies with PET, pancreas had the highest uptake followed by kidney with 11C-glutamate, and followed by spleen with 11C-aspartate. A primary pancreas tumour and metastases in liver were difficult to identify except in one case.

Positron emission tomography in neuroendocrine tumours.

Positron emission tomography is an in vivo tracer and imaging technique that utilizes short-lived positron emitting radionuclides (11C, 15O, 13N, 18F) with half-lives ranging between 2 min and 2 hours. These radionuclides are interesting from the labelling viewpoint since they are natural constituents of most biologically active compounds. The short half-life is an advantage with regard to the irradiation dose to the patient but it is also a limitation since it requires the production of these radionuclides in close vicinity to the positron emission tomography camera.

[PET in neuroendocrine tumors]. / PET vid neuroendokrina tumörer.

With the radionuclide tracers available today, 50-90 per cent of neuroendocrine tumours of the gastro-intestinal tract can be visualised with PET (positron-emission tomography). PET also enables the effect of tumour treatment to be monitored in terms of biochemical and functional variables, which is not possible with other radiological techniques. Owing to the very good tumour resolution possible with PET, it serves as a complement to other routine methods such as computed tomography and ultrasonography, and can be used to screen the chest and abdomen for small primary tumours that can not be detected with other methods. In several pre-operative trials PET has been shown to demonstrate more changes in the pancreas and liver than was possible with other methods. In the near future it will be possible to demonstrate the presence of and quantify growth factor receptors, hormones, enzymes, DNA synthesis, mRNA synthesis and protein synthesis. Access to these tumour biological data will be of crucial importance to the individualisation of treatment.

Positron emission tomography with 5-hydroxytryprophan in neuroendocrine tumors.

PURPOSE: Carcinoid tumors, especially those of midgut origin, produce serotonin via the precursors tryptophan and 5-hydroxytryptophan (5-HTP). We have evaluated the usefulness of positron emission tomography (PET) with carbon-11-labeled 5-HTP in the diagnosis and treatment follow-up evaluation of patients with neuroendocrine tumors. PATIENTS AND METHODS: PET using 11C-labeled 5-HTP was compared with computed tomography (CT) in 18 patients (14 midgut, one foregut, one hindgut carcinoid, and two endocrine pancreatic tumors [EPT]). In addition, 10 of 18 patients were monitored with PET examinations during treatment. RESULTS: All 18 patients, including two with normal urinary 5-hydroxyindole acetic acid (U-5-HIAA), had increased uptake of 11C-labeled 5-HTP in tumorous tissue as compared with normal tissue. Liver metastases, as well as lymph node, pleural, and skeletal metastases, showed enhanced 5-HTP uptake and PET could detect more lesions than CT in 10 patients and equal numbers in the others. Tumor visibility was better for PET than for CT due to the high and selective uptake of 5-HTP with a high tumor-to-background ratio. Binding studies indicated an irreversible trapping of 5-HTP in the tumors. Linear regression analyses showed a clear correlation (r = .907) between changes in U-5-HIAA and changes in the transport rate constant for 5-HTP during treatment. CONCLUSION: PET with 11C-labeled 5-HTP demonstrated high uptake in neuroendocrine gastrointestinal tumors and thereby allowed improved visualization compared with CT. The in vivo data on regional tumor metabolism, as expressed in 11C-5-HTP uptake and transport rate, provided additional information over conventional radiologic techniques. The close correlation between the changes in 11C-5-HTP transport rate and U-HIAA during medical treatment indicates the potential of 11C-5-HTP-PET as a means to monitor therapy.

Effect of 6-diazo-5-oxo-L-norleucine (DON) on human carcinoid tumor cell aggregates.

The induction of glutamine starvation has been suggested as a potential target for antitumoral treatment using inhibitors of amidotransferase, an enzyme which mediates the conversion of glutamate to glutamine. Using multicellular aggregates from tumor cell lines, the effect of treatment with a suggested glutamine antagonist, 6-diazo-5-axo-L-norleucine (DON), was investigated. As indicators of treatment response, three different parameters were measured: aggregate size, uptake of 14C-methionine and secretion of Chromogranin A. Of six cell types evaluated (carcinoid, glioma, neuroblastoma pancreas and bladder cancer), the largest inhibition of 14Cmethionine uptake, amounting to 60%, was found in the carcinoid cell line BON. In this cell line the maximum effect was reached already at 10 microM concentration. DON induced marked growth inhibition in the BON aggregates which lasted 3-4 weeks after which regrowth started. During this period the secretion of chromogranin and methionine uptake was also inhibited. These studies suggest that the neuroendocrine cell line BON is especially vulnerable to treatment by DON and show that strong inhibitory effects are found at concentrations lower than that achieved in patient blood in previous clinical trials.