(dtpa-phe(1))-octreotide and Pancreatic-Neoplasms

Peptide receptor radionuclide therapy is a new treatment modality for patients with inoperable or metastasised neuroendocrine gastroenteropancreatic tumours. After the successful implementation of somatostatin receptor scintigraphy in daily clinical practice, the next logical step was to increase the radiation dose of the administered radiolabelled somatostatin analogue in an attempt to induce tumour shrinkage. Since then, an increasing number of patients has been successfully treated with this approach, resulting in a substantial numbers of patient with objective tumour shrinkage. Serious side-effects have been rare. This article reviews the effectiveness of the different radiolabelled somatostatin analogues used, the currently known side-effects and the survival data available. Furthermore, clinical issues, including indication and timing of therapy, are discussed. Finally, important directions for future research are briefly mentioned to illustrate that, although the currently available results already suggest a favourable outcome compared with other systemic therapies, new strategies are being developed to increase efficacy.

Topics: Animals; Carcinoma, Neuroendocrine; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Lutetium; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Patient Selection; Pentetic Acid; Peptides, Cyclic; Quality of Life; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Peptide; Receptors, Somatostatin; Somatostatin; Treatment Outcome; Yttrium Radioisotopes

In preclinical studies in rats we evaluated biodistribution and therapeutic effects of different somatostatin analogs, [(111)In-DTPA]octreotide, [(90)Y-DOTA,Tyr(3)]octreotide and [(177)Lu-DOTA,Tyr(3)]octreotate, currently also being applied in clinical radionuclide therapy studies. [Tyr(3)]octreotide and [Tyr(3)]octreotate, chelated with DTPA or DOTA, both showed high affinity binding to somatostatin receptor subtype 2 (sst(2)) in vitro. The radiolabelled compounds all showed high tumor uptake in sst(2)-positive tumors in vivo in rats, the highest uptake being reached with [(177)Lu-DOTA,Tyr(3)]octreotate. In preclinical therapy studies in vivo in rats, excellent, dose dependent, tumor size responses were found, responses appeared to be dependent on tumor size at therapy start. These preclinical data showed the great promise of radionuclide therapy with radiolabelled somatostatin analogues. They emphasised the concept that especially the combination of somatostatin analogs radiolabeled with different radionuclides, like (90)Y and (177)Lu, is most promising to reach a wider tumor size region of high curability. Furthermore, different phase I clinical studies, using [(111)In-DTPA]octreotide, [(90)Y-DOTA,Tyr(3)]octreotide or [(177)Lu-DOTA, Tyr(3)]octreotate are described. Fifty patients with somatostatin receptor-positive tumors were treated with multiple doses of [(111)In-DTPA(0)]octreotide. Forty patients were evaluable after cumulative doses of at least 20 GBq up to 160 GBq. Therapeutic effects were seen in 21 patients: partial remission in 1 patient, minor remissions in 6 patients, and stabilization of previously progressive tumors in 14 patients. The toxicity was generally mild bone marrow toxicity, but 3 of the 6 patients who received more than 100 GBq developed a myelodysplastic syndrome or leukemia. Radionuclide therapy with [(90)Y-DOTA,Tyr(3)]octreotide started in 3 different phase I trials. Overall, antimitotic effects have been observed: about 20% partial response and 60% stable disease (N = 92) along with complete symptomatic cure of several malignant insulinoma and gastrinoma patients. Maximum cumulative [(90)Y-DOTA,Tyr(3)]octreotide dose was about 26 GBq, without reaching the maximum tolerable dose. New is the use of [(177)Lu-DOTA,Tyr(3)]octreotate, which shows the highest tumor uptake of all tested octreotide analogs so far, with excellent tumor-to-kidney ratios. Radionuclide therapy with this analog in a phase 1 trial started recently in our c

Topics: Animals; Humans; Indium Radioisotopes; Liver Neoplasms; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Pentetic Acid; Radiopharmaceuticals; Rats; Receptors, Somatostatin; Tumor Cells, Cultured; Yttrium Radioisotopes

Topics: Algorithms; Animals; Binding, Competitive; Biomarkers, Tumor; Clinical Trials, Phase I as Topic; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Staging; Neuroendocrine Tumors; Neuropeptides; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radiology, Interventional; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Sensitivity and Specificity; Somatostatin

In patients with gastro-enteropancreatic neuroendocrine tumours the localization of all the neoplastic lesions and an accurate staging of the diseases have important therapeutic implications. Somatostatin receptor scintigraphy with In-111 pentatreotide has proved to be useful in detecting gastro-enteropancreatic tumours; however, the role of abdominal single photon emission computed tomography has not yet been definitively established. In a series of 52 patients with gastro-enteropancreatic tumours (9 non-functioning islet cell carcinomas, 4 insulinomas, 3 somatostatinomas, 2 VIPomas, 1 glucagonoma and 33 carcinoids) we compared somatostatin receptor scintigraphy with the results of computed tomography and magnetic resonance imaging performed within one month. Four and 24-hour total body planar images and 4-hour abdominal single photon emission computed tomography were acquired after the i.v. injection of approximately 250 MBq of In-111 pentatreotide. Only abdominal localizations were considered: planar scans detected 16 extrahepatic lesions in 13 patients and 54 liver sites in 21 patients; single photon emission computed tomography visualized 31 extrahepatic lesions and 89 liver metastases in 27 and 28 patients, respectively; computed tomography and magnetic resonance imaging detected 11 extrahepatic lesions in 10 patients and 73 liver sites in 21 patients. In-111 pentatreotide single photon emission computed tomography was the only imaging method able to localize tumoural lesions in 13 patients; all these localizations were then histologically verified. The scintigraphic positivity did not depend on the site or on the presence of hormonal hypersecretions. In conclusion, our results indicate that single photon emission computed tomography is more sensitive than planar images and computed tomography/magnetic resonance imaging in detecting abdominal gastro-enteropancreatic tumours and their metastases; it is able to increase both the number of visualized lesions and that of patients with positive findings. Single photon emission computed tomography is particularly useful in patients in whom tumoural lesions have not been already localized; it should be the first imaging modality in patients with gastro-enteropancreatic tumours: its initial use will result in more information and proper management.

Topics: Female; Gastrointestinal Neoplasms; Humans; Male; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Receptors, Somatostatin; Sensitivity and Specificity; Tomography, Emission-Computed, Single-Photon

Neuroendocrine tumors of the gastrointestinal tract are rare tumors that can be classified as APU-Domas (amine precursor uptake and decarboxylation). They can be subdivided into the carcinoid tumors of the gastrointestinal submucosa and the islet cell endocrine tumors of the pancreas. Although the majority of tumors that become clinically apparent are malignant, they are frequently slow growing. Despite this, neuroendocrine tumors may generate disabling hormonal syndromes requiring aggressive treatment to achieve palliation. Recent advances in understanding the pathophysiology of these tumors has led to better radiographic imaging and more accurate localization techniques. Medical therapies with somatostatin analogues, omeprazole, and locoregional tumor ablation have made a positive impact on curative and palliative therapy. This review updates the recent efforts made in the radiographic imaging and therapeutics of the gastrointestinal neuroendocrine tumors.

Topics: Adenoma, Islet Cell; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biogenic Amines; Carcinoid Tumor; Clinical Trials as Topic; Diagnostic Imaging; Embolization, Therapeutic; Gastrointestinal Neoplasms; Hepatic Artery; Humans; Indium Radioisotopes; Ligation; Liver Neoplasms; Octreotide; Palliative Care; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Pentetic Acid; Receptors, Somatostatin

To evaluate the effectiveness of indium In 111 pentetate (diethylenetriaminepentaacetic acid [DTPA]-D-Phe-labeled octreotide scintigraphy in the localization of gastroenteropancreatic neuroendocrine lesions, and to identify covert lesions, determine multicentricity, define the distribution of metastases, confirm complete removal of tumor postoperatively, and evaluate the efficacy of therapeutic embolization.. Unmasked comparison.. Tertiary care referral center.. We studied 28 patients over a 12-month period. Biochemical evidence of a gastroenteropancreatic tumor was present in 13 patients. Octreoscan 111 was employed in four patients with an ambiguous biochemical diagnosis of gastroenteropancreatic tumor. Postoperative examination to document complete tumor removal was undertaken in seven patients. In one patient, Octreoscan 111 was used to evaluate the efficacy of therapeutic embolization.. [111In]DTPA-D-Phe-octreotide scintigraphy.. Identification of somatostatin receptor-bearing neuroendocrine tumors.. Intravenous administration of [111In]DTPA-D-Phe-octreotide followed by whole-body gamma camera scintigraphy resulted in the localization of gastroenteropancreatic neuroendocrine tumors with 75% sensitivity, 100% specificity, 100% positive predictive value, 63% negative predictive value, and 82% overall accuracy.. While Octreoscan 111 has been shown to localize the majority of amine precursor uptake and decarboxylation system (APUD) cell tumors as well as various other somatostatin-positive tumors, this technique may also be useful in a number of other circumstances. These include prediction of tumors that will respond to octreotide therapy, identification of covert metastases, intraoperative identification of tumors, and postoperative surveillance. Use of an alternative isotope may provide a vehicle for the administration of local therapeutic radiation to tumor cells. The precise efficacy of Octreoscan 111 in the identification of lesions smaller than 3 cm with low-density somatostatin-2 receptor expression remains to be determined.

Topics: Adult; Aged; Carcinoid Tumor; Duodenal Neoplasms; Female; Gastrinoma; Humans; Indium Radioisotopes; Insulinoma; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Sensitivity and Specificity; Stomach Neoplasms

Topics: Europe; Humans; Indium Radioisotopes; Neoplasm Metastasis; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Receptors, Somatostatin; Stomach Neoplasms; Tomography, Emission-Computed, Single-Photon

In this review, we evaluate radiological techniques currently used to localize gastroenteropancreatic (GEP) endocrine tumors. We also describe the visualization, using intravenous administration of two isotope-labelled somatostatin analogs (123-I-Tyr3-octreotide and 111In-DTPA-octreotide), of islet cell tumors in 25 patients and carcinoids in 39 patients. The primary tumor as well as previously unrecognized distant metastases were visualized in 20 of the 25 patients (80%) and in 37 of the 39 (95%). Parallel in vitro detection of somatostatin receptors on those tumors also visualized in vivo showed that ligand binding to the tumor in vivo represents binding to specific somatostatin receptors. The detection of somatostatin receptors on tumors in vivo predicted a good suppressive effect of octreotide on hormonal hypersecretion by these tumors. It is an easy, quick and harmless procedure, valuable in the localization of primary endocrine pancreatic tumors and their often radiologically and clinically unrecognized metastases. Future prospective controlled studies comparing this procedure with other radiological investigative techniques should demonstrate its sensitivity and specificity and determine the place of somatostatin receptor imaging in the localization of GEP endocrine tumors.

Topics: Adenoma, Islet Cell; Carcinoid Tumor; Diagnostic Imaging; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Iodine Radioisotopes; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Receptors, Somatostatin

To evaluate the diagnostic sensitivity and accuracy and the cost-effectiveness of this technique in the detection of gastroenteropancreatic carcinoid tumors and their metastases in comparison with conventional imaging methods.. Somatostatin receptor scintigraphy (SRS) was performed in 24 patients with confirmed carcinoids and 7 under investigation. The results were compared with those of conventional imaging methods (chest X-ray, upper abdominal ultrasound, chest CT, upper and lower abdominal CT). Also a cost-effectiveness analysis was performed comparing the cost in Euro of several combinations of SRS with conventional imaging modalities.. SRS visualized primary or metastatic sites in 71.0% of cases and 61.3% of conventional imagings. The diagnostic sensitivity of the method was higher in patients with suspected lesions (85.7% vs 57.1%). SRS was less sensitive in the detection of metastatic sites (78.9% vs 84.2%). The undetectable lesions by SRS metastatic sites were all in the liver. Between several imaging combinations, the combinations of chest X-ray/upper abdominal CT/SRS and chest CT/upper abdominal CT/SRS showed the highest sensitivity (88.75%) in terms of the number of detected lesions. The combinations of chest X-ray/upper abdominal US/SRS and chest CT/upper abdominal ultrasound /SRS yielded also a quite similar sensitivity (82%). Compared to the cost of the four sensitive combinations the combination of chest X-ray/upper abdominal ultrasound/SRS presented the lower cost, 1183.99 Euro vs 1251.75 Euro for chest CT/upper abdominal ultrasound/SRS, 1294.93 Euro for chest X/ray/upper abdominal CT/SRS and 1362.75 Euro for chest CT/upper abdominal CT/SRS.. SRS imaging is a very sensitive method for the detection of gastroenteropancreatic carcinoids but is less sensitive than ultrasound and CT in the detection of liver metastases. Between several imaging combinations, the combination of chest X-ray/upper abdominal CT/SRS shows the highest sensitivity with a cost of 1294.93 Euro.

Topics: Adult; Aged; Carcinoid Tumor; Cost-Benefit Analysis; Female; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Sensitivity and Specificity

After injection of 111In-labelled DTPA-D-Phe1-octreotide, intraoperative tumour localisation was performed using a scintillation detector in 23 patients with neuroendocrine tumours. Count rates from suspect tumour lesions and adjacent normal tissue were expressed as a ratio before (Rin situ) and after (Rex vivo) excision. 111In activity concentration ratios of tumour tissue to blood (T/B) were determined in a gamma counter. In patients with midgut carcinoids, (all scintigraphy positive), false Rin situ recordings were found in 4/29 macroscopically identified tumours. T/B ratios were all high (27-650). In patients with medullary thyroid carcinomas (eight out of ten scintigraphy positive), misleading Rin situ results were found in 4/37 macroscopically identified tumours. T/B ratios were lower (3-39) than those seen in midgut carcinoids. Two out of four patients with endocrine pancreatic tumours had positive scintigraphy, reliable intraoperative measurements and very high T/B ratios (910-1500). One patient with a gastric carcinoid had correct measurements in situ and ex vivo with high T/B ratios (71-210). In situ measurements added little information to preoperative scintigraphy and surgical findings using the present detection system. Rex vivo measurements were more reliable. The very high T/B ratios seen in midgut carcinoids and some endocrine pancreatic tumours would be favourable for future radiation therapy via somatostatin receptors.

Topics: Carcinoid Tumor; Female; Humans; Indium Radioisotopes; Intraoperative Care; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Stomach Neoplasms; Thyroid Neoplasms; Uterine Cervical Neoplasms

Peptide receptor scintigraphy is more sensitive at the biological than anatomical level, in contrast to conventional imaging, which it complements. Neuroendocrine tumours have the most somatostatin receptors in vitro and their metastases are somatostatin receptor positive in vitro, so that [111In-DTPA-D-Phe1]octreotide (OCT) can be used to image them. OCT was compared with conventional imaging techniques (CON) in a European Multicentre Trial. In 350 evaluable patients, CON detected 88%, and OCT 80% (glucagonomas 100%, VIPomas 88%, carcinoids 87%, non-functioning islet cell tumours 82%, insulinomas 46%) of tumour sites but there was no systematic use of abdominal single-photon-emission computerised tomography. OCT demonstrated multiple tumour sites in 62 of 178 patients in whom CON had found only 1 lesion, with 60% confirmed. 12/16 lesions detected by OCT in 11 patients with no lesions according to CON were also confirmed. The impact of OCT on management was evaluated in 235 patients and affected 40%: it determined 29 surgical decisions, led to octreotide therapy in 47, and modified octreotide dose in 18. Six end-stage patients with neuroendocrine tumours were treated with OCT radionuclide therapy (up to a cumulative dose of 53 GBq per patient) in a phase I trial. There were no major side-effects after up to 2 years treatment, with impressive effects on hormone production and a likely anti-proliferative effect.

Topics: Humans; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Stomach Neoplasms

To evaluate the effectiveness of indium In 111 pentetate (diethylenetriaminepentaacetic acid [DTPA]-D-Phe-labeled octreotide scintigraphy in the localization of gastroenteropancreatic neuroendocrine lesions, and to identify covert lesions, determine multicentricity, define the distribution of metastases, confirm complete removal of tumor postoperatively, and evaluate the efficacy of therapeutic embolization.. Unmasked comparison.. Tertiary care referral center.. We studied 28 patients over a 12-month period. Biochemical evidence of a gastroenteropancreatic tumor was present in 13 patients. Octreoscan 111 was employed in four patients with an ambiguous biochemical diagnosis of gastroenteropancreatic tumor. Postoperative examination to document complete tumor removal was undertaken in seven patients. In one patient, Octreoscan 111 was used to evaluate the efficacy of therapeutic embolization.. [111In]DTPA-D-Phe-octreotide scintigraphy.. Identification of somatostatin receptor-bearing neuroendocrine tumors.. Intravenous administration of [111In]DTPA-D-Phe-octreotide followed by whole-body gamma camera scintigraphy resulted in the localization of gastroenteropancreatic neuroendocrine tumors with 75% sensitivity, 100% specificity, 100% positive predictive value, 63% negative predictive value, and 82% overall accuracy.. While Octreoscan 111 has been shown to localize the majority of amine precursor uptake and decarboxylation system (APUD) cell tumors as well as various other somatostatin-positive tumors, this technique may also be useful in a number of other circumstances. These include prediction of tumors that will respond to octreotide therapy, identification of covert metastases, intraoperative identification of tumors, and postoperative surveillance. Use of an alternative isotope may provide a vehicle for the administration of local therapeutic radiation to tumor cells. The precise efficacy of Octreoscan 111 in the identification of lesions smaller than 3 cm with low-density somatostatin-2 receptor expression remains to be determined.

Topics: Adult; Aged; Carcinoid Tumor; Duodenal Neoplasms; Female; Gastrinoma; Humans; Indium Radioisotopes; Insulinoma; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Sensitivity and Specificity; Stomach Neoplasms

The advantage of intraoperative gamma probe detection with (111)In-DPTA-octreotide radiotracer has previously been demonstrated in functional neuroendocrine tumors. We report the only known case of a recurrent nonfunctional pancreatic neuroendocrine neoplasm localized intraoperatively using this radiotracer and a hand held gamma probe.. A 51-year-old woman was found to have a recurrence 23 months after laparoscopic distal pancreatectomy, splenectomy and wedge resection of a liver metastasis for a non-functional neuroendocirne neoplasm of the pancreas. CT scan and (111)In-DPTA-octreotide scan displayed two lesions in the right lobe of the liver and a third area of increased isotope uptake adjacent to kidney and pancreas. A single liver lesion was seen on CT. There were concerns regarding the ability to localize the lesion in the upper abdomen. In order to facilitate identification the patient was injected with (111)In-DPTA-octreotide preoperatively and intraoperatively a gamma probe was used to identify two lymph node posterior to the pancreas, only one of which could be palpated.. In this case the technique of preoperative injection with octreotide radiotracer and intraoperative hand held gamma probe successfully localized a nonfunctional neuroendocrine tumor that CT scan and intraoperative exploration failed to identify.

Topics: Carcinoma, Neuroendocrine; Female; Gamma Rays; Humans; Liver Neoplasms; Lymphatic Metastasis; Middle Aged; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radiometry; Recurrence; Reoperation; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

111In-DTPA octreotide (DTPAOC) has been used for detecting somatostatin receptor positive tumor for years. In-111 DOTA-Tyr3-octreotide (DOTATOC) is newly developed for diagnostic and therapeutic purposes. In this study, we compared the biodistribution and tumor uptake ratio after injection of In-111 DTPAOC and In-111 DOTATOC in rats. Twelve rats bearing pancreatic tumors were divided into two groups: six rats were sacrificed at 4 hr after injection of 3.7 MBq of In-111 DTPAOC and another 6 rats were sacrificed at the same time after injection of 3.7 MBq of In-111 DOTATOC. Samples of various organs were obtained and counted to calculate the tissue concentration. In addition, 12 rats bearing pancreatic tumors were scanned at 4, 24, and 48 hr after injection of 37 MBq of In-111 DTPAOC or In-111 DOTATOC. The tumor uptake ratios (T/N ratio) were calculated. The biodistribution data showed that the activity in the tumor as well as in the kidney was significantly higher in the In-111 DOTATOC group than in the In-111 DTPAOC group, although both radiopharmaceuticals had the expected high affinity to the tumor. The T/N ratios in the In-111 DOTATOC group were also significantly higher than those in the In-111 DTPAOC group at 24 hr after injection. We conclude that In-111 DOTATOC showed lower clearance than In-111 DTPAOC in the rats bearing pancreatic tumors, although both of these radiopharmaceuticals showed expected high tumor uptake.

Topics: Animals; Indium Radioisotopes; Male; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radiopharmaceuticals; Rats; Rats, Inbred Lew; Tissue Distribution

Insulinomas are rare endocrine tumors that are mostly sporadic, benign, and small. Preoperative radiography diagnosis may be difficult. Intraoperative palpation and ultrasound remain the gold standard for detection and planned resection. Recent studies find intraoperative gamma-probe localization as a good technique for identifying primary neuroendocrine tumors. We report a case of a 75-year-old woman with functioning lymph node recurrence of a malignant insulinoma. Spleno-pancreatectomy was performed in order to treat the malignant insulinoma. Clinical, biochemical, and radiological examination confirmed the total excision of the primary lesion. However, clinical symptoms appeared 9 months later. Octreo-scan, abdominal CT, and biochemical study showed lymph node recurrence and four hepatic metastases. Surgery was performed after two [111In-DTPA] octreotide scans. Intraoperative gamma probe detection was planned in order to localize a small latero-aortic lymph node recurrence. Intraoperative count rates were high in para-aortic tissue. Para-aortic lymphadenectomy and metastasectomy were carried out. Ex-situ count rates and histological examination confirmed the recurrence. Six months later clinical and biochemical studies and scans remain negative for recurrence. Intraoperative [111In-DTPA] octreotide gamma probe examination may be a useful tool in the surgical approach to insulinoma recurrence.

Topics: Aged; Female; Humans; Insulinoma; Intraoperative Care; Lymph Node Excision; Lymphatic Metastasis; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Recurrence

Radiolabeled somatostatin analogs are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin receptor-positive tumors. The aim of this study was to compare 3 somatostatin analogs designed for the labeling with (99m)Tc (where HYNIC is 6-hydrazinopyridine-3-carboxylic acid): 6-hydrazinopyridine-3-carboxylic acid(0)-octreotide (HYNIC-OC/(99m)Tc-(1)), [HYNIC(0),Tyr(3)]octreotide (HYNIC-TOC/(99m)Tc-(2)), and [HYNIC(0),Tyr(3),Thr(8)]octreotide (HYNIC-TATE/(99m)Tc-(3)), using ethylenediamine-N,N'-diacetic acid (EDDA) as a coligand. In addition, we compared the (99m)Tc-labeled peptides [(111)In-diethylenetriaminepentaacetic acid(0)]octreotide ([(111)In-DTPA]-OC) and [(111)In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid(0),Tyr(3),Thr(8)]octreotide ([(111)In-DOTA]-TATE) with regard to the rate of internalization and the biodistribution in AR4-2J (expressing the somatostatin receptor subtype 2) tumor-bearing rats. The main attention was directed toward a potential correlation between the rate of internalization and the tumor or pancreas uptake.. Synthesis was performed on solid phase using a standard Fmoc strategy. Internalization was studied in cell culture (AR4-2J) and biodistribution was studied using a Lewis rat tumor model (AR4-2J).. The 5 radiopeptides showed a specific internalization into AR4-2J cells in culture (as shown by blocking experiments). The rate of internalization of the 5 radiopeptides differed significantly according to the following order: (99m)Tc-(1) approximately = [(111)In-DTPA]-OC < (99m)Tc-(2) < (99m)Tc-(3) approximately = [(111)In-DOTA]-TATE. All radiopeptides displayed a rapid blood clearance and a fast clearance from all somatostatin receptor-negative tissues predominantly via the kidneys. A receptor-specific uptake of radioactivity was observed for all compounds in somatostatin receptor-positive organs such as the pancreas, the adrenals, and the stomach. After 4 h, the uptake in the AR4-2J tumor was comparable for (99m)Tc-(2) (3.85 +/- 1.0 injected dose per gram tissue (%ID/g)), (99m)Tc-(3) (3.99 +/- 0.58%ID/g), and [(111)In-DOTA]-TATE (4.12 +/- 0.74%ID/g) but much lower for [(111)In-DTPA]-OC (0.99 +/- 0.08%ID/g) and (99m)Tc-(1) (0.70 +/- 0.13%ID/g). The specificity was determined by blocking experiments using a large excess of [Tyr(3)]octreotide. (99m)Tc-(3) displayed the highest tumor-to-kidney ratio (2.5:1), followed by (99m)Tc(2) (1.9:1) and [(111)In-DOTA]-TATE (1.7:1).. These data show that the 5 radiopeptides are specific radioligands for the somatostatin receptor subtype 2. The rate of internalization correlates with the uptake in the tumor (R(2) = 0.75; P = 0.026) and pancreas (R(2) = 0.98; P = 7.4.10(-5)). [Tyr(3),Thr(8)]octreotide derivatives show superiority over the corresponding octreotide and [Tyr(3)]octreotide derivatives, indicating that [(111)In-DOTA]-TATE and [(99m)Tc/EDDA/HYNIC]-TATE are suitable candidates for clinical studies.

Topics: Animals; Male; Metabolic Clearance Rate; Octreotide; Organ Specificity; Organometallic Compounds; Organotechnetium Compounds; Pancreas; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Rats; Rats, Inbred Lew; Receptors, Somatostatin; Statistics as Topic; Tissue Distribution

Malignant carcinoid tumors express high numbers of somatostatin receptors. Radiation therapy using labeled somatostatin analogs is a novel treatment modality for these tumors. We have analyzed the biokinetics and therapeutic effect of radiolabeled somatostatin analog on a human midgut carcinoid grafted to nude mice. A transplantable human midgut carcinoid (GOT1) was grafted to the back of nude mice. Tumor-bearing mice were injected with (111)In-DTPA-D-Phe(1)-octreotide, followed by measurement of (111)In activity concentration ratios in tumor tissues. Tumor-bearing mice were also injected with (177)Lu-DOTA-Tyr(3)-octreotate and followed for 7 days. The concentration of (111)In-DTPA-D-Phe(1)-octreotide in tumor tissues was very high 4 hours postinjection with 0.4-13% of injected activity per gram. Injection of 30-120 MBq (177)Lu-DOTA-Tyr(3)-octreotate reduced tumor volume to 7-14% of the original tumor volume 7 days postinjection. Microscopic analysis of treated tumors revealed widespread areas of tumor cell necrosis and fibrosis. It was found that grafted GOT1 cells to nude mice represent an authentic model for studying human midgut carcinoids. Radiolabeled somatostatin analogs have a high selectivity for tumor tissue and can induce tumor cell necrosis. Radiotherapy of carcinoid tumors with (177)Lu-DOTA-Tyr(3)-octreotate appears to be a promising treatment modality for either palliative treatment or completion therapy after attempted surgical cure.

Topics: Animals; Carcinoid Tumor; Disease Models, Animal; Indium Radioisotopes; Mice; Mice, Nude; Neoplasm Transplantation; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Pentetic Acid; Radiopharmaceuticals; Receptors, Somatostatin; Xenograft Model Antitumor Assays

Peptide receptor radionuclide therapy (PRRT) using [(111)In-DTPA(0)]octreotide (where DTPA is diethylenetriaminepentaacetic acid) is feasible because, besides gamma-radiation, (111)In emits both therapeutic Auger and internal conversion electrons having a tissue penetration of 0.02-10 and 200-500 micro m, respectively. The aim of this study was to investigate the therapeutic effects of [(111)In-DTPA(0)]octreotide in a single-cell model including the effects of incubation time, radiation dose, and specific activity of [(111)In-DTPA(0)]octreotide. Finally, we discriminated between the effects of the Auger electrons and internal conversion electrons in PRRT.. An in vitro, colony-forming assay to study cell survival after PRRT using the sst subtype 2-positive rat pancreatic tumor cell line CA20948 was developed.. In this in vitro system [(111)In-DTPA(0)]octreotide can control tumor growth to 0% survival, and the effects were dependent on incubation time, radiation dose, and specific activity used. Similar concentrations of (111)In-DTPA, which is not internalized into sst-positive tumor cells like [(111)In-DTPA(0)]octreotide, did not influence tumor survival. Excess unlabeled octreotide (10(-6) mol/L) could decrease tumor cell survival to 60% of control; the addition of radiolabeled peptide ([(111)In-DTPA(0)]octreotide [10(-9) mol/L] + 10(-6) mol/L octreotide) did not further decrease survival.. These in vitro studies show that the therapeutic effect of (111)In is dependent on internalization, enabling the Auger electrons with their very short particle range to reach the nucleus. Our results also indicate that the PRRT effects were receptor mediated.

Topics: Animals; Apoptosis; Dose-Response Relationship, Radiation; Electrons; Indium Radioisotopes; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radiopharmaceuticals; Rats; Receptors, Peptide; Reproducibility of Results; Sensitivity and Specificity; Tumor Cells, Cultured

Insulinoma is a rare endocrine tumour in the elderly. We report the case of an 81-year-old woman suffering from grand mal seizures. Insulinoma was suspected because plasma glucose and insulin levels were 1.5 mmol/l and 80.4 pmol/l, respectively. A pancreatic computerized tomography (CT) scan, magnetic resonance imaging (MRI) and arteriography were normal but (111)In-DTPA-octreotide scintigraphy detected a hotspot in the pancreatic tail. Intraoperative pancreatic ultrasonography and palpation were non-contributory due to multiple pancreatic cysts and nodular lesions. However, a gamma-detecting probe localized a small tumour, labelled preoperatively with (111)In-DTPA-octreotide. Intraoperative insulin measurements in portal venous blood confirmed the successful removal of an insulinoma that was 6 mm in diameter histologically. Pancreatic cystic lesions increase with age and make the intraoperative localization of the insulinoma difficult. Intraoperative gamma probe detection of the tumour labelled with (111)In-DTPA-octreotide might therefore constitute a useful surgical tool.

Topics: Aged; Aged, 80 and over; Female; Humans; Indium Radioisotopes; Insulinoma; Intraoperative Period; Octreotide; Pancreatic Cyst; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals

64Cu (half-life, 12.7 h; beta+, 0.653 MeV [17.4%]; beta-, 0.579 MeV [39%]) has shown potential as a radioisotope for PET imaging and radiotherapy. (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide (OC) was developed for imaging somatostatin-receptor-positive tumors using conventional scintigraphy. With the advantages of PET over conventional scintigraphy, an agent for PET imaging of these tumors is desirable. Here, we show that 64Cu-TETA-OC (where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid) and PET can be used to detect somatostatin-receptor-positive tumors in humans.. Eight patients with a history of neuroendocrine tumors (five patients with carcinoid tumors and three patients with islet cell tumors) were imaged by conventional scintigraphy with (111)In-DTPA-OC (204-233 MBq [5.5-6.3 mCi]) and by PET imaging with 64Cu-TETA-OC (111 MBq [3 mCi]). Blood and urine samples were collected for pharmacokinetic analysis. PET images were collected at times ranging from 0 to 36 h after injection, and the absorbed doses to normal organs were determined.. In six of the eight patients, cancerous lesions were visible by both (111)In-DTPA-OC SPECT and 64Cu-TETA-OC PET. In one patient, (111)In-DTPA-OC showed mild uptake in a lung lesion that was not detected by 64Cu-TETA-OC PET. In one patient, no tumors were detected by either agent; however, pathologic follow-up indicated that the patient had no tumors. In two patients whose tumors were visualized with (111)In-DTPA-OC and 64Cu-TETA-OC, 64Cu-TETA-OC and PET showed more lesions than (111)In-DTPA-OC. Pharmacokinetic studies showed that 64Cu-TETA-OC was rapidly cleared from the blood and that 59.2% +/- 17.6% of the injected dose was excreted in the urine. Absorbed dose measurements indicated that the bladder wall was the dose-limiting organ.. The high rate of lesion detection, sensitivity, and favorable dosimetry and pharmacokinetics of 64Cu-TETA-OC indicate that it is a promising radiopharmaceutical for PET imaging of patients with neuroendocrine tumors.

Topics: Adenoma, Islet Cell; Aged; Animals; Carcinoid Tumor; Female; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Papio; Pentetic Acid; Radiation Dosage; Radiopharmaceuticals; Receptors, Somatostatin; Sensitivity and Specificity; Tomography, Emission-Computed

Glucagonomas, like other neuroendocrine tumors, express somatostatin receptors in more than 80% of cases. Unfortunately, because of the rarity of these tumors, the sensitivity and specificity of somatostatin analog (octreotide) imaging have not been established. Nonetheless, there have been limited reports in the literature supporting the use of indium In-111 DTPA N-terminal D-phenylalanine (D-PHE1) octreotide for glucagonoma imaging and may be most beneficial as an adjuvant to conventional imaging for tumor staging and therapeutic decision making. Current therapeutic applications of octreotide focus on stabilization of disease in tumors expressing somatostatin receptors, and tumor destruction, using beta-emitting isotopes. In this report, imaging of a glucagonoma with In-111 DTPA-D-PHE1 octreotide scintigraphy is described in a 51-year-old woman examined for a large palpable abdominal mass.

Topics: Female; Glucagonoma; Humans; Indium Radioisotopes; Middle Aged; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals

Somatostatin receptor-positive lesions can be visualized by scintigraphy using [111In-DTPA0]octreotide. Recently, there have been reports of differences in receptor binding between somatostatin receptor subtypes and between somatostatin analogues, such as RC-160 and octreotide, as well as of differences in internalization between the somatostatin receptor subtypes. The possibility that certain somatostatin receptor-positive tissues and tumours which do not bind octreotide may bind and internalize RC-160 would open new scintigraphic or radiotherapeutic applications of radiolabelled RC-160. We investigated the metabolism and tissue distribution of [111In-DTPA0]RC-160 in comparison with [111In-DTPA0]octreotide in four patients after injection of 250 MBq (10 microgram) of these radiopharmaceuticals. Patient 1 had a metastatic follicular thyroid carcinoma, patient 2 a metastatic medullary thyroid carcinoma, patient 3 tuberculosis and patient 4 an insulinoma. The plasma clearance of the [111In-DTPA0]RC-160 was slower than that of [111In-DTPA0]octreotide, with 5% and 2%, respectively, of the initial plasma radioactivity remaining at 10 h p.i. The urinary excretion of [111In-DTPA0]RC-160 was initially also slower than that of [111In-DTPA0]octreotide, but the cumulative excretion of radioactivity was not significantly different at 48 h p.i. Approximately 80% of injected radioactivity was cleared in the urine, while in one patient 20% of the injected dose was recovered in the faeces. The slower clearance of [111In-DTPA0]RC-160 resulted in a higher background in all organs studied i.e. liver, spleen, kidneys and lungs, at 24 h p.i. Although the target to background ratio with [111In-DTPA0]octreotide was higher, no differences were found between the two analogues with regard to their sensitivity in detecting lesions in these four patients. We conclude that although only four subjects were studied, [111In-DTPA0]RC-160 does not appear to have additional value for scintigraphy and is associated with higher background activity.

Topics: Adenocarcinoma, Follicular; Adult; Carcinoma, Medullary; Female; Humans; Indium Radioisotopes; Insulinoma; Male; Middle Aged; Octreotide; Oligopeptides; Organ Specificity; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Thyroid Neoplasms; Tuberculosis

A wide variety of neuroendocrine tumours express somatostatin receptors, and can be visualized by radiolabelled somatostatin analogue scintigraphy. To investigate the value of [111In]-octreotide scintigraphy (Octreoscan), 48 patients (37 with proven carcinoid, pancreatic endocrine and medullary carcinoma of thyroid tumours, 11 with neuroendocrine syndromes multiple endocrine neoplasia (MEN-I) and Zollinger-Ellison syndrome (ZES) were examined with 111In-DTPA-D-Phe1-octreotide. Scintigrams were obtained at 24 and 48 h, and the results were compared with CT and magnetic resonance imaging (MRI). Thirty-five of 48 patients had positive [111In]-octreotide scintigraphy (23/25 (92%) carcinoids, 8/9 (89%) PETs, 4/11 (36%) MEN-I & ZES). Of the 42 lesions located by conventional imaging techniques, 37 (88%) were also identified by Octreoscan. Unexpected lesions (40 sites), not detected by CT or MR imaging were found in 24/48 (50%) patients. [111In]-octreotide scintigraphy has a higher sensitivity for tumour detection, and is superior to MR imaging and CT scanning in the identification of previously unsuspected extraliver and lymph node metastases. It may also be helpful for the localization of clinically suspected tumours in patients with MEN-I and ZES.

Topics: Adolescent; Adult; Aged; Carcinoid Tumor; Carcinoma, Medullary; Child; Female; Humans; Indium Radioisotopes; Magnetic Resonance Imaging; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Sensitivity and Specificity; Thyroid Neoplasms; Tomography, X-Ray Computed

Somatostatin receptor scintigraphy (SRS) and octreotide therapy have both changed the management of gastroenteropancreatic endocrine tumours, but very few data are available on the use of SRS and octreotide to visualise and treat somatostatinomas.. The results of SRS and octreotide treatment in three somatostatinoma patients were examined.. SRS was able to detect extensive hepatic involvement in patient 1, one hepatic and one pancreatic lesion in patient 2, and one hepatic lesion in patient 3. Octreotide therapy (0.5 mg/day subcutaneously) was effective in decreasing plasma levels of somatostatin in all three patients. Symptoms (diabetes and diarrhoea) were greatly improved in the two patients with "somatostatinoma syndrome".. The study shows that somatostatinoma, like most other gastroenteropancreatic endocrine tumours, possesses functioning somatostatin receptors.

Topics: Aged; Antineoplastic Agents, Hormonal; Female; Humans; Liver Neoplasms; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Somatostatinoma

To compare somatostatin-receptor scintigraphy and conventional imaging modalities in the differentiation of small hepatic hemangiomas from small liver metastases in Zollinger-Ellison syndrome.. Twenty-nine patients had hypervascular liver lesions smaller than 2 cm that could have been either metastases or hemangiomas. Fourteen patients had metastases, 14 had hemangiomas, and one had both. Scintigraphy was compared with computed tomography (CT), magnetic resonance (MR) imaging, and angiography for the correct identification of the lesions.. The hemangiomas and liver metastases both had a mean size of 1.3 cm. In the patients with hepatic hemangiomas, scintigraphy showed no lesions. CT, angiography, or MR imaging showed a lesion in 40%-93%. With metastases present, any liver lesion was detected in 93% with scintigraphy versus 20%-60% with another modality. Scintigraphy depicted liver metastases in 93% of patients, which was higher than the sensitivities of other modalities. The accuracy (96%) and positive (100%) and negative (93%) predictive values of scintigraphy for detecting liver metastases were superior to those of other modalities. There were 45 liver metastases and 31 hemangiomas; a per lesion analysis gave results similar to the per patient analysis results.. In Zollinger-Ellison syndrome, somatostatin-receptor scintigraphy provides an excellent diagnostic tool to differentiate small hepatic hemangiomas from small liver metastases.

Topics: Adult; Aged; Diagnosis, Differential; Female; Gastrinoma; Hemangioma; Humans; Indium Radioisotopes; Liver Neoplasms; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Predictive Value of Tests; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Sensitivity and Specificity

This article describes the visualization of a pancreatic somatostatinoma and liver metastases using 111In-pentetreotide imaging in a patient with somatostatinoma syndrome. A 61-yr-old woman with gallbladder stones, diabetes, weight loss, diarrhea and steatorrhea, immunohistochemical diagnosis of somatostatinoma (liver biopsy) and high plasma values of somatostatin was studied by somatostatin receptor scintigraphy. Six sites of focal abnormal 111In-pentetreotide hyperfixation were found: three in the liver and three in the pancreatic area. This case report demonstrates that in vivo detection of somatostatinoma with somatostatin receptor imaging is possible in the presence of high levels of circulating somatostatin, suggesting that receptor downregulation has not occurred.

Topics: Female; Humans; Indium Radioisotopes; Liver Neoplasms; Middle Aged; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatinoma; Tomography, Emission-Computed, Single-Photon

Ten dogs with hypoglycemia due to insulinomas were studied to assess the expression of somatostatin receptors (SSTRs) in canine insulinomas and its potential diagnostic value.. The response of circulating glucose and insulin concentrations to the subcutaneous administration of a somatostatin analog, octreotide, was measured. SSTRs were visualized in vitro by autoradiography. [Iodine-125-Tyr3]-octreotide and [125I-Tyr11]-somatostatin-14 (SRIF-14) were used as radioligands. SPECT was performed 6 hr after the injection of [111In-DTPA-D-Phe1]-octreotide.. After subcutaneous injection of 50 micrograms octreotide, plasma glucose concentration rose from 2.3 +/- 0.2 mmol/liter to 3.2 +/- 0.3 mmol/liter at 3.5 hr (p < 0.05) and plasma insulin concentration decreased from 451 +/- 135 pmol/liter to a nadir of 249 +/- 115 pmol/liter at 30 min (p < 0.05). In vitro autoradiography revealed that all primary insulinomas and their metastases had specific SSTRs for both [125I-Tyr3]-octreotide and [126I-Tyr11]-SRIF-14. Scatchard analysis of SSTR binding in the tumor tissue of one dog revealed high-affinity binding sites for [125I-Tyr3]-octreotide (dissociation constant (Kd) 1.7 nM, maximum binding capacity (Bmax) 499 fmol/mg membrane protein). The primary tumor and/or metastases in five of six dogs could be visualized and localized by SPECT with [111In-DTPA-D-Phe1]-octreotide. In the remaining dog, multiple metastases (< 3 mm) were found in the liver at necropsy, apparently too small to be visualized by SPECT.. The in vitro autoradiography and ligand binding studies indicate that canine insulinomas express one type of SSTR. This is in contrast with findings in humans where, on the basis of ligand binding studies, different subtypes of SSTRs have been identified. The uniformity of SSTRs, their high frequency of expression and the high incidence of metastatic disease make canine insulinomas very suitable for investigation of the value of SRIF analogs in the diagnosis and treatment of metastasized endocrine pancreatic tumors.

Topics: Animals; Autoradiography; Blood Glucose; Dogs; Female; Indium Radioisotopes; Insulin; Insulinoma; Iodine Radioisotopes; Liver Neoplasms; Male; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin

We analyzed the results of conventional imaging and somatostatin receptor scintigraphy in 150 patients with neuroendocrine tumors.. The outcomes of combinations of imaging modalities were compared in terms of tumor localization, effect on patient management and financial costs.. In patients with carcinoids, a combination of somatostatin receptor scintigraphy, chest radiograph and ultrasound of the upper abdomen had a high sensitivity for tumor localization, and detected lesions in patients in whom no tumor was found with conventional imaging, justifying the greater cost. In patients with medullary thyroid carcinoma, somatostatin receptor scintigraphy adds little to the information obtained with conventional imaging and therefore should not be used as a screening method. In patients with paraganglioma, CT scanning of the region where a paraganglioma is suspected, followed by somatostatin receptor scintigraphy to detect multicentricity has the best cost effectiveness ratio. In patients with gastrinomas, the combination of somatostatin receptor scintigraphy and CT scanning of the upper abdomen had the highest sensitivity. The relatively high cost of this process is outweighed by its demonstrating a resectable tumor. In patients with insulinomas, the highest yield against the lowest cost is obtained if somatostatin receptor scintigraphy is only performed if CT scanning fails to demonstrate the tumor.. Somatostatin receptor scintigraphy should be performed in patients with small-cell lung carcinoma because it can lead to a change of stage and may demonstrate otherwise undetected brain metastases. The cost increase is outweighed by the omission of unnecessary treatment for some of the patients and by the possibility of irradiating brain metastases at an early stage, which may lead to a better quality of life.

Topics: Carcinoid Tumor; Carcinoma, Medullary; Carcinoma, Small Cell; Cost-Benefit Analysis; Costs and Cost Analysis; Humans; Indium Radioisotopes; Lung Neoplasms; Netherlands; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Paraganglioma; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Sensitivity and Specificity; Thyroid Neoplasms; Tomography, X-Ray Computed

The synthesis of peptides which possess a high affinity for the somatostatin receptor and contain a chelator for the radionuclide technetium-99m is described. The target compounds were designed such that they would form stable, oxotechnetium(V) chelate complexes in which the Oxorhenium(V) chelate complexes of these peptides were prepared as nonradioactive surrogates for the technetium complexes. Peptide oxorhenium complexes and Tc-99m complexes eluted closely upon HPLC analysis. The receptor-binding affinities of both the free and rhenium-coordinated species were measured in vitro. The binding affinities of the free peptides (Ki's in the 0.25 - 10 nM range) compared favorably with [DTPA]octreotide (Ki = 1.6 nM), which, as the indium-111 complex, is already approved for somatostatin receptor (SSTR)-expressing tumor imaging in the United States and Europe. Furthermore, the rhenium-coordinated peptides had binding affinities which, in many cases, were higher than those of the corresponding free peptides, with several complexes having a Ki's of 0.1 nM. Some of the more potent SSTR-binding peptides were labeled with technetium-99m and assessed in an in vivo study with tumor-bearing rats. The 99m Tc-labeled peptides prepared in this study should be useful as SSTR-expressing tumor-imaging agents due to their high SSTR-binding affinities, ease of preparation, and, because they are low molecular weight peptides, expected pharmacokinetics characterized by rapid tracer excretion from the body resulting in high-contrast images.

Topics: Amino Acid Sequence; Animals; Chelating Agents; Humans; Mass Spectrometry; Molecular Sequence Data; Molecular Structure; Octreotide; Oligopeptides; Pancreatic Neoplasms; Pentetic Acid; Peptides, Cyclic; Protein Binding; Rats; Receptors, Somatostatin; Rhenium; Somatostatin; Technetium Compounds; Tumor Cells, Cultured

A 51-year-old woman with metastatic gastrinomas in the liver was intravenously injected with 80.3 MBq of 111In-DTPA-D-Phe-octreotide (111In-pentetreotide). Planar images were obtained at 4 hr, 24 hr and 48 hr after the injection. SPECT was also performed at 24 hr after the injection. Two metastatic lesions in the liver were visualized on each imaging occasion. 111In-pentetreotide imaging is useful to visualize gastrinomas.

Topics: Female; Gastrinoma; Humans; Indium Radioisotopes; Liver Neoplasms; Middle Aged; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging

We evaluated a hand-held scintillation detector for intra-operative localisation of somatostatin-receptor-positive tumours in situ, and after excision, as an addition to preoperative scintigraphy with [111In-DTPA-Phe1]octreotide. Using the hand-held detector, the suspect tumour/normal tissue ratio R(in situ) between measurements was calculated for 23 patients with neuroendocrine tumours. The count rates of excised tumour and normal tissue were also measured ex vivo and their ratio R(ex vivo) was calculated. In midgut carcinoid (MC) patients (all scintigraphy positive), 4/29 macroscopically identified tumours gave false R(in situ). Tumour/blood 111In activity (T/B) ratios measured in a gamma counter were all high (27-650). In patients with medullary thyroid carcinoma (8/10 scintigraphy positive), misleading R(in situ) were found in 4/37 macroscopically identified tumours. T/B ratios were lower (3-39) than those seen in MC patients. 2/4 patients with endocrine pancreatic tumours (EPTs) had positive scintigraphy, reliable intra-operative measurements, and very high T/B ratios (910-1,500). 1 patient with a gastric carcinoid had correct R(in situ) and R(ex vivo), with high T/B ratios (71-210). 1 patient with sporadic insulinoma had negative scintigraphy and 1 patient with neuroendocrine carcinoma of the uterus also had low T/B ratios. In most cases, in situ measurements added little information to preoperative scintigraphy and surgical findings. The very high T/B ratios seen in MC tumours and some EPTs seem promising for future radiotherapy via somatostatin receptors.

Topics: Carcinoid Tumor; Carcinoma, Medullary; Humans; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging

The characteristics of terbium-161 diethylene triamine penta-acetic acid (DTPA) labelled octreotide with respect to specific binding to somatostatin (octreotide) receptors on rat brain cortex membranes, biological activity, uptake and excretion by isolated perfused rat livers and metabolism in vivo in normal and tumour-bearing rats were determined and compared to those of indium-111 DTPA-octreotide. The results of the binding studies demonstrate that 161Tb-DTPA-octreotide is a high-affinity radioligand for somatostatin receptors, with an affinity comparable to that of 111In-DTPA-octreotide. Rat growth hormone secretion inhibition experiments showed that 161Tb-DTPA-octreotide has a similar potency to 111In-DTPA-octreotide. 161Tb-DTPA-octreotide appeared to be taken up even less by the isolated perfused rat liver than 111In-DTPA-octreotide, as almost no tracer disappeared from the perfusion medium. Furthermore, hardly any radioactivity was found in the liver, and excretion into the bile was negligible. The biodistribution studies showed that for octreotide receptor-positive organs, such as pancreas and adrenals, uptake of 161Tb-DTPA-octreotide is lower then that of 111In-DTPA-octreotide. However, as the clearance from the blood of the former compound is faster than that of the latter, the tissue/blood ratio is higher in the case of 161Tb-DTPA-octreotide than with 111In-DTPA-octreotide. Furthermore, these studies demonstrated that the uptake of 161Tb-DTPA-octreotide by the renal tubular cells after glomerular filtration can be reduced by administration of lysine or sodium maleate. Increase in urine production before and during the experiment had no effect on the kidney uptake of 161Tb-DTPA-octreotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Kidney; Liver; Male; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radioisotopes; Rats; Rats, Inbred Lew; Rats, Wistar; Terbium; Tissue Distribution

For this study, 24 patients with medullary thyroid cancer (MTC) and 10 with carcinoid-/GEP-tumours underwent scintigraphy with 123I-Tyr3-octreotide or 111In-DTPA-D-Phe1-octreotide (Octreoscan) or 99mTc-V-DMSA. Calcitonin and CEA were elevated in MTC patients, the other had tumour lesions on CT. Octreoscan-scintigraphy was positive in 68% of all suspicious cases. On the other hand, 123I-Tyr3-octreotide showed only rarely positive results. 99mTc-V-DMSA-scans in MTC patients were positive in 23%. Liver metastases could be seen only with Octreoscan in the non-MTC-group. These results showed better sensitivity of 111In-labelled octreotide.

Topics: Adult; Aged; Calcitonin; Carcinoembryonic Antigen; Carcinoid Tumor; Carcinoma, Medullary; False Positive Reactions; Female; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Iodine Radioisotopes; Liver Neoplasms; Male; Middle Aged; Octreotide; Organotechnetium Compounds; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Sensitivity and Specificity; Succimer; Technetium Tc 99m Dimercaptosuccinic Acid; Thyroid Neoplasms

Indium-111 activity concentrations in human tumor and normal tissue samples were determined at 24, 48 and 120 hr after i.v. injection of 111In-DTPA-D-Phe-1-octreotide. Fourteen patients were included in the study. Seven patients had medullary thyroid carcinoma, four had midgut carcinoid tumors, two had endocrine pancreatic tumors and one had chronic pancreatitis.. For midgut carcinoids, the tumor-to-blood ratio was 51:220, for medullary thyroid carcinoma 4:39, and for two endocrine pancreatic tumors 6 and 1500. Tumor-to-muscle ratios varied between 1 and 1200 and tumor-to-fat between 2 and 1500 depending on tumor type.. The sometimes extremely high tumor-to-normal tissue ratios present the possibility for use of radiolabeled octreotide for radiation therapy of somatostatin receptor positive tumors.

Topics: Abdominal Neoplasms; Adult; Aged; Carcinoid Tumor; Chronic Disease; Female; Humans; Indium Radioisotopes; Injections, Intravenous; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pancreatitis; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Reference Values; Thyroid Neoplasms

Copper-64 (T1/2 = 12.8 hr) is a reactor-produced radionuclide that has applications in both nuclear medicine imaging by PET and radiotherapy. Octreotide, a somatostatin receptor ligand, has been conjugated with TETA and CPTA, labeled with 64Cu, evaluated both in vitro and in vivo and compared to 111In-DTPA-D-Phe1-octreotide.. The carboxylic acid moieties on the T bifunctional chelates were conjugated to the N-terminal amine of D-Phe using the linking agents hydroxybenzotriazol (HOBT) and diisopropylcarbodiimide (DIC). Receptor binding assays on all three radiolabeled octreotide conjugates were accomplished in AtT20 mouse pituitary carcinoma cell membranes. In vivo biodistribution was performed using normal Sprague-Dawley rats and Lewis rats carrying a somatostatin receptor-positive rat pancreatic tumor.. The binding affinities of 64Cu-CPTA-D-Phe1-octreotide and 64Cu-TETA-D-Phe1-octreotide in AtT20 cell membranes were both greater than 111In-DTPA-D-Phe1-octreotide (Kd, 78.5 pM, 314 pM and 3.28 nM, respectively). In normal rats, 64Cu-CPTA-D-Phe1-octreotide was localized primarily in the liver. Copper-64-TETA-D-Phe1-octreotide, similar to 111In-DTPA-D-Phe1-octreotide, had moderate uptake in the kidneys; the hepatobiliary uptake was negligible. In rats bearing CA 20948 pancreatic tumors, both 64Cu-CPTA-D-Phe1-octreotide and 64Cu-TETA-D-Phe1-octreotide had uptake in tumors comparable to better than 111In-DTPA-D-Phe1-octreotide.. Of the two 64Cu-labeled octreotide conjugates evaluated, 64Cu-CPTA-D-Phe1-octreotide has the highest affinity for the somatostatin receptor; however, the clearance was hepatobiliary with slow excretion. Copper-64-TETA-D-Phe1-octreotide binds to the somatostatin receptor with five times the affinity of 111In-octreotide, has desirable clearance properties (renal clearance with rapid excretion) and is a potential agent for PET imaging of somatostatin receptors.

Topics: Adrenal Glands; Animals; Copper Radioisotopes; Female; Indium Radioisotopes; Male; Mice; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Pituitary Neoplasms; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors, Somatostatin; Tissue Distribution; Tomography, Emission-Computed; Tumor Cells, Cultured

High numbers of high-affinity somatostatin binding sites have been found on carcinoid tumors, gastrinomas, small cell lung cancers and the majority of medullary thyroid cancers, enabling in vivo visualization of these tumors with octreotide scintigraphy. A comparison of the results obtained at our institution and another 15 centers in Europe show a few remarkable similarities and differences. The overall sensitivity of octreotide receptor scintigraphy to detect the primary GEP tumor and its metastases is high, e.g. 80-90%. The main difference was found in gastrinomas and to a lesser extent in insulinomas. These differences might be attributed to different scanning protocols. Furthermore, octreotide scintigraphy also has a high sensitivity to localize the primary tumor and its metastases causing Cushing's syndrome by ectopic production of ACTH or CRH. Octreotide scintigraphy is a new, sensitive and noninvasive technique to localize somatostatin receptor expressing endocrine tumors and their metastases.

Topics: Carcinoid Tumor; Cushing Syndrome; Gastrinoma; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Lung Neoplasms; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Receptors, Somatostatin; Sensitivity and Specificity; Tomography, Emission-Computed, Single-Photon

To determine the value of somatostatin-receptor scintigraphy in the localization of various endocrine gastrointestinal tumors, we compared the results obtained with this new technique with the results obtained with computed tomography and sonography. We could not find an overall advantage of somatostatin-receptor scintigraphy as compared to computed tomography or sonography in the localization of intestinal carcinoids (n = 13), gastrinomas (n = 12), functionally non-active endocrine pancreatic tumors (n = 8) and various other endocrine pancreatic tumors (n = 4). In 2 patients with endocrine pancreatic tumors however, the tumors were localized preoperatively only by somatostatin-receptor scintigraphy. Somatostatin-receptor scintigraphy may occasionally be helpful in the localization of gastrointestinal endocrine tumors if these tumors are not localized by conventional imaging studies. Somatostatin-receptor scintigraphy does not solve the problem to localize small endocrine tumors.

Topics: Biomarkers, Tumor; Carcinoid Tumor; Gastrinoma; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Insulinoma; Multiple Endocrine Neoplasia Type 1; Octreotide; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Pentetic Acid; Receptors, Somatostatin; Tomography, Emission-Computed, Single-Photon; Zollinger-Ellison Syndrome

In patients with the Zollinger-Ellison syndrome, which is either sporadic or integrated into multiple endocrine neoplasia type 1, accurate localization of all the tumours is difficult and may have therapeutic implications. In an attempt to improve this localization, somatostatin receptor scintigraphy using [111In-DTPA-D-Phe1]-octreotide was performed prospectively in 48 consecutive patients with the Zollinger-Ellison syndrome. Thirty of them had the sporadic type of this disease. Scintigraphic data were compared with data obtained by conventional imaging methods, and also, in 32 selected patients, with those obtained by endoscopic ultrasonography. Somatostatin receptor scintigraphy showed abnormal tracer uptake in 39 patients (81%), in whom it correctly identified 50 of the 60 tumoral sites (83%) previously localized by the other imaging methods. In 17 patients (35%) somatostatin receptor scintigraphy disclosed abnormal tracer uptake at 18 different tumoral sites: 14 were located in the abdomen, including four in the liver and eight in the duodenopancreatic area, and four outside the abdomen, including two in the mediastinum. Six of the ten tumoral sites which were not correctly identified by somatostatin receptor scintigraphy were located in the duodenopancreatic area. However, in the 20 patients for whom conventional techniques failed to visualize any tumour in the duodenopancreatic area, somatostatin receptor scintigraphy was positive in ten (50%) whereas endoscopic ultrasonography was only positive in five (25%). In our patients with the Zollinger-Ellison syndrome, somatostatin receptor scintigraphy appeared to be a useful new addition to the battery of tests used for tumour detection.

Topics: Bone Neoplasms; Duodenal Neoplasms; Female; Humans; Indium Radioisotopes; Liver Neoplasms; Male; Mediastinal Neoplasms; Middle Aged; Multiple Endocrine Neoplasia Type 1; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Prospective Studies; Radionuclide Imaging; Receptors, Somatostatin; Ultrasonography; Zollinger-Ellison Syndrome

We have evaluated the potential usefulness of indium-111 labelled [DTPA-D-Phe1]RC-160, derived from the octapeptide somatostatin analogue RC-160, as a radiopharmaceutical for the in vivo detection of somatostatin receptor-positive tumours. For this purpose 111In-and 115In-labelled [DTPA-D-Phe1]RC-160 was tested for its biological activity, and applied for somatostatin receptor scintigraphy in vivo to rats bearing the transplantable rat pancreatic tumour CA20948, which expresses somatostatin receptors. We previously described the development of the 111In-labelled somatostatin analogue [DTPA-D-Phe1]octreotide and its use in the in vivo visualization of somatostatin receptor-positive tumours in rats and in humans. Like [111In-DTPA-D-Phe1]octreotide, [111In-DTPA-D-Phe1]RC-160 showed uptake in and specific binding in vivo to somatostatin receptor-positive organs and tumours, and the tumours were clearly visualized by gamma camera scintigraphy. However, as compared to [111In-DTPA-D-Phe1]octreotide, blood radioactivity (background) was higher, resulting in a lower tumour to blood (background) ratio. Using this animal model we therefore conclude that [111In-DTPA-D-Phe1]RC-160 has no advantage over [111In-DTPA-D-Phe1]octreotide as a radiopharmaceutical in the visualization of somatostatin receptors which bind both analogues. However, recent reports suggest the existence of different somatostatin receptor subtypes on some human cancers, which differentially bind RC-160 and not octreotide. These tumours include cancers of the breast, ovary, exocrine pancreas, prostate and colon. [111In-DTPA-D-Phe1]RC-160 might be of interest for future use in such cancer patients as a radiopharmaceutical for imaging somatostatin receptor-positive tumours, which do not bind octreotide.

Topics: Animals; Indium Radioisotopes; Male; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Rats; Rats, Inbred Lew; Receptors, Somatostatin; Somatostatin; Tissue Distribution

Topics: Female; Follow-Up Studies; Glucagonoma; Humans; Indium Radioisotopes; Liver Neoplasms; Middle Aged; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging

Topics: Diagnostic Imaging; Follow-Up Studies; Gastrointestinal Neoplasms; Humans; Image Enhancement; Indium Radioisotopes; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Prospective Studies; Receptors, Somatostatin; Tomography, Emission-Computed, Single-Photon

Topics: Carcinoid Tumor; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Sensitivity and Specificity

In-111 DTPA octreotide, a labeled somatostatin analog, was reported to be superior to I-123 octreotide for detection of somatostatin-receptor-bearing tumors because of longer half-life and better labeling characteristics. In addition, renal rather than hepatobiliary clearance decreases intestinal interference and greatly reduces accumulation of the tracer in the gallbladder. Using the In-111 labeled octreotide, the authors noted distinct gallbladder visualization in one patient with an insulinoma who was studied following an overnight fast. In two additional patients scanned in the fasting state gallbladder uptake was also demonstrated. In all 3 patients, this uptake disappeared following a meal. The authors conclude that when using this imaging modality, abdominal scans should not be performed in the fasting state. Furthermore, if significant uptake is demonstrated in the gallbladder area, imaging should be repeated several hours later, following a fatty meal. Both false-positive and false-negative findings of pathologic uptake in this area will thus be avoided.

Topics: False Negative Reactions; False Positive Reactions; Fasting; Female; Gallbladder; Humans; Indium Radioisotopes; Insulinoma; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Time Factors; Tomography, Emission-Computed, Single-Photon

The general features of the biodistribution of the labeled somatostatin analog 111In-pentetreotide are already known. We describe some details of 111In-pentetreotide accumulation in the thyroid gland, mammae, spleen and gastrointestinal tract with respect to endocrine parameters, kinetics and time of imaging. In addition, dose estimations were performed for liver, spleen and kidney in patients without neuroendocrine tumor load and in patients with large tumors positive for somatostatin receptors. The overall absorbed dose turned out to be within the range reported previously. However, in patients with extensive tumor burden the radiation dose in liver, spleen and kidney tended to be lower than in patients without such malignancy. The dependence of estimated organ doses on the presence of somatostatin receptor-expressing tumors will have to be considered if radiotherapy with suitable labeled somatostatin analogs becomes available.

Topics: Biomarkers, Tumor; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Recurrence; Thyroid Neoplasms; Tissue Distribution

Receptor scintigraphy with 111In-pentetreotide is a simple method with a sensitivity of 86% for the localization of the primary tumor and its metastases in patients presenting with the clinical and biochemical symptoms of an endocrine tumor of the gastrointestinal tract or the pancreas. As a whole-body scintigraphic technique it covers all body regions and is also able to reveal small tumors which either cannot be detected or can only be detected with difficulty by the usual imaging methods. In 85 patients with GEP tumors or after operative removal of such tumors, receptor scintigraphy proved to be superior to ultrasound and computed tomography in 34%, equal in 52%, and inferior in 14% of the cases.

Topics: Aged; Carcinoid Tumor; Gastrinoma; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Insulinoma; Metabolic Clearance Rate; Neoplasm Metastasis; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Tissue Distribution

The distribution and elimination characteristics of the 111In-labelled somatostatin analogue OctreoScan111 were studied in 23 patients with malignant tumours. The substance exhibited a rapid blood elimination following a bi-phasic pattern. The initial part of the elimination curves showed a t1/2a of between 0.27 and 3.6 h. The patients investigated had creatinine clearance rates ranging from 33 to 124 ml/min. However, within this range, no apparent correlation was found between the OctreoScan111 elimination rate and kidney function. Also no correlation was observed between the amount of administered activity and the elimination rate of OctreoScan111. The serum radioactivity of 6 patients was analyzed with respect to molecular size. These experiments showed that OctreoScan111 circulated unbound in serum. About 3% of the radioactivity, most probably representing 111In-chloride of DTPA-111In-chloride, circulated protein-bound. The elimination of OctreoScan111 radioactivity in urine displayed a bi-phasic pattern. Size separation of the radioactivity appearing in the urine after 24 h showed a higher molecular weight when compared with OctreoScan111, indicating the existence of a metabolite of the injected substance. The results obtained are discussed in the light of a potential role for the substance in systemic radiotherapy.

Topics: Adenoma, Islet Cell; Adult; Aged; Carcinoid Tumor; Chromatography, Gel; Endocrine Gland Neoplasms; Female; Half-Life; Humans; Indium Radioisotopes; Kidney; Male; Middle Aged; Molecular Weight; Neoplasms; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Thyroid Neoplasms

Somatostatin (SRIF) receptors are present in a variety of human tumors such as pituitary and endocrine pancreatic tumors, brain tumors, small cell lung cancers and malignant breast tumors. The 111In-labeled SRIF analog SDZ 215-811 (OctreoScan 111) binds with a high affinity to somatostatin receptors and exhibits SRIF-like biological properties, as demonstrated by the inhibition of growth hormone release from pituitary cells. We report here the in vitro characterization of SDZ 215-811 and the in vivo imaging of an islet cell tumor grown in rats using [111In]SDZ 215-811. In vitro autoradiographies revealed a high density of SRIF receptors on the pancreatic tumor tissue. As early as 5 min after intravenous injection of [111In]SDZ 215-811 into tumor-bearing rats, the tumors were clearly localized by gamma-camera scintigraphy. Even 24 h post injection, the islet cell tumor was still detectable. The radioligand was mainly cleared from the circulation via the kidneys, with a rapid alpha-phase (t1/2 = 5.6 min) and a slow elimination phase (t1/2 = 7.3 h). Biodistribution studies revealed a relatively high accumulation of radioactivity in the kidneys, but low uptake into the liver and the intestine. High uptake of [111In]SDZ 215-811 was observed for the tumor tissue (0.92 +/- 0.07% ID/g; 1 h post injection). Interestingly, a tumor load of 0.14 +/- 0.01% ID/g was still measured after 24 h. The tumor/blood ratio was 4.93 after 24 h, indicating specific accumulation of radioactivity in the islet cell tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenoma, Islet Cell; Animals; Indium Radioisotopes; Iodine Radioisotopes; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Rats; Receptors, Somatostatin; Tissue Distribution