Search

Knowledge about body composition is important in metabolic and nutritional studies. In this cross-sectional study the body composition of 403 healthy white Dutch children and adolescents was evaluated by using dual-energy X-ray absorptiometry (DXA), Possible determinants of body composition were analyzed. In 85 subjects the results of bioelectrical impedance analysis (BIA) were compared with DXA. Fat mass, lean tissue mass, and bone mineral content were greater in older boys and girls. Percentage body fat was greater in older girls but not in boys and it was higher in girls than in boys at all ages. From die age of 14 y boys had higher lean tissue mass and bone mineral content than girls. Tanner stage had a significant relation with body composition in both sexes. Percentage body fat was lower in boys in stage 4 than in stage 3 and was higher in consecutive Tanner stages in girls. After adjustment for age, Tanner stage was significantly positively related to lean tissue mass and bone mineral content in boys and girts and to percentage body fat and fat mass in girls. The profession of the parents and the education of the father had a significant negative correlation with percentage body fat and fat mass in girls (P [is less than] 0.01). Physical activity was related to lean tissue mass (P = 0.001) but not to fat mass in boys after adjustment for age. A high correlation and a small difference was found between lean body mass by BIA and lean tissue mass by DXA. Body composition in healthy Dutch children and adolescents is related to age, sex, Tanner stage, socioeconomic status, and physical activity. Am J Clin Nutr 1997;66:232-8.

PURPOSE: To assess the feasibility of somatostatin receptor scintigraphy for patients with Cushing's syndrome caused by tumors secreting ectopic corticotropin or corticotropin-releasing hormone (CRH). PATIENTS AND METHODS: Ten patients with Cushing's syndrome, nine with ectopic corticotropin-secreting tumors and one with a CRH-secreting tumor, were consecutively studied. For comparison purposes, eight patients with corticotropin-secreting pituitary tumors and one patient with an autonomous adrenal adenoma were investigated. In vivo tumor localization was performed for all patients using a radionuclide-coupled somatostatin analog. The results obtained with this technique were compared with those obtained with conventional imaging techniques. For some patients, the clinical effects of octreotide therapy were evaluated. RESULTS: Somatostatin analog scintigraphy successfully identified the primary ectopic corticotropin-secreting and CRH-secreting tumors or their metastases, or both, in 8 of 10 patients; in 2 patients with corticotropin-secreting bronchial carcinoids, the tumors could not be visualized. Normal scans were obtained for the 8 patients with corticotropin-secreting pituitary tumors and the one patient with an adrenal adenoma. CONCLUSION: Somatostatin analog scintigraphy can be included as a diagnostic step in the workup of Cushing's syndrome patients with a suspected ectopic corticotropin-secreting tumor or a CRH-secreting tumor.

Objectives: Cardiovascular disease is the leading cause of morbidity and mortality in the elderly. The evaluation of coronary artery disease by exercise stress testing is frequently limited by the patient's [...]

The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n= 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

Peptide receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors patients. Most studies report objective response rates in 15% to 35% of patients. Progression-free (PFS) and overall survival (OS) compare favorably with that for somatostatin analogues, chemotherapy, or newer, “targeted” therapies. Prospective, randomized data regarding the potential PFS and OS benefit of PRRT compared with standard therapies is anticipated.

Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs is a novel method of treatment in patients with metastatic neuroendocrine tumors (NETs). For the first time in the United States, we present preliminary results of the treatment with Lutetium 177 (177Lu) DOTATATE in patients with progressive NETs.

When assessing neuroendocrine tumours (NETs), which comprise a wide variety of tumours with different imaging characteristics, morphological imaging (mostly CT or MRI) and nuclear medicine techniques are complementaryCT and MRI are typically used to evaluate a patient's response to therapy; however, a role for nuclear medicine techniques, aside from establishing progressive disease by visualizing new lesions, has yet to be definedSomatostatin receptor imaging with radiolabelled somatostatin analogues is mandatory to determine whether patients are eligible for peptide receptor radionuclide therapy111In-pentetreotide scintigraphy is currently the most widely used method to assess somatostatin receptor expression, but 68Ga-DOTA-somatostatin analogue PET–CT could become the nuclear medicine test of choice for staging of patients with well-differentiated NETsPET–CT with 18F-dihydroxy-L-phenylalanine and 11C-hydroxy-L-tryptophan might potentially be used in the future for therapy response evaluation18F-FDG-PET is only recommended in patients with grade 3 neuroendocrine cancers but shows potential for other indications, for example, to predict prognosis and determine treatment schedule

AbstractObjective:The associations between peak bone mineral density (BMD) and body composition with 25 hydroxyvitamin D (25OHD) levels in healthy young adults were evaluated.Methods:The number of participants was 464; 347 women and 117 men. The mean age was 24.3 years (range 17–31 years). BMD of the lumbar spine, total body and femoral neck (FN) and body composition were measured by dual energy X-ray absorptiometry. Volumetric BMD, bone mineral apparent density (BMAD), of the lumbar spine and FN was calculated.Results:In females, 25OHD level was positively associated with FN BMD and BMAD (both p<0.01) and negatively with percentage body fat (p<0.001). In males, 25OHD levels had a positive association with total body BMD and lean body mass (p=0.03 and p=0.01).Conclusions:25OHD level is a determinant of peak BMD in both sexes. Vitamin D status was associated with body fat in females and with lean body mass in males.

Neuroendocrine tumors (NETs) of the thorax, including bronchial and thymic neuroendocrine NETs, are often referred to as NETs of the foregut. The incidence and prevalence of NETs are increasing in the United States as demonstrated in the Surveillance, Epidemiology, and End Results from 1973 to 2004 (J Clin Oncol. 2008;26183063-3072). Although the majority of bronchial and thymic NETs are sporadic, approximately 5% to 10% can be associated with hereditary syndrome, multiple endocrine neoplasms type 1 (Nat Rev Cancer. 2005;55367-375). Diagnosis is made by tissue pathology, allowing for characterization and classification of the NET. Radiologic evaluation is performed to determine the extent of disease involvement. Clinical symptoms from hormonal overproduction or from paraneoplastic processes are medically managed to improve patients' quality of life. Locoregional disease can be curative with surgery; however, distant or metastatic disease is rarely curable. Therapeutic options for metastatic/advanced NETs of the thorax are mainly to palliate symptoms. Final treatment recommendations for patients with either bronchial or thymic NETs should be individualized, weighing the risks and benefits of therapy.

Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs, such as octreotide, is a promising option for the treatment of somatostatin-receptor-positive endocrine tumors. Here, van Essenet al. evaluate data from preliminary studies of PRRT, and discuss the pros and cons of this approach. The authors propose that PRRT might soon become the treatment of choice for patients with metastatic or inoperable endocrine tumors.

AbstractBackground/Aims:The aim of the present study was to evaluate bone mineral density (BMD) and body composition of patients with childhood-onset growth hormone (GH) deficiency (GHD) treated with GH during the transition period. Methods:BMD and body composition, measured by dual-energy X-ray absorptiometry, were evaluated at final height and yearly thereafter during 2 years. Twenty-nine of the 40 patients had also been measured before start and during GH therapy. Results:Mean lumbar spine BMD and bone mineral apparent density (BMAD) as well as total body BMD and lean body mass (LBM) SD score (SDS) were significantly lower than normal at final height and during the 2 years thereafter for all patients. Final-height SDS was related to the change in height SDS as well as in LBM SDS during the first year of GH treatment. LBM SDS decreased significantly in the group of patients with GHD without GH treatment (p < 0.01, n = 19). Fat mass SDS increased in all patients. Conclusion:Mean BMD, BMAD and LBM SDS were significantly lower than normal in adolescents with childhood-onset GHD at and 2 years after the attainment of final height.Copyright © 2009 S. Karger AG, Basel

We estimated the absorbed doses for 111In-DTPA-D-Phe1-octreotide and 90Y-DOTA-D-Phe1-Tyr3-octreotide in the same patients in order to compare the potential effectiveness (tumour dose) and safety (kidney and red marrow dose) of these drugs for peptide-targeted radiotherapy of somatostatin receptor positive tumours.

Objective: Clinically non-functioning pituitary adenomas (NFPAs) can express functional dopamine D2 receptors. Therapy with dopamine (DA) agonists may result in a NFPA size reduction. However, DA agonist-sensitive and -resistant NFPAs are clinically indistinguishable. We have studied the correlation between in vivoimaging of D2 receptors using 123I-epidepride and the radiological response of NFPA to DA in 18 patients.Methods: Patients were treated with either cabergoline (1–2 mg/week) or quinagolide (150–300 μg/day) for a mean period of 89.7 months (range, 34–187 months).Results: Pituitary uptake of 123I-epidepride varied from slight uptake classified as grade 0 to very high classified as grade 3. Grade 0 uptake was found in four patients; grade 1 in three; grade 2 in ten, and grade 3 in one. NFPA stabilization or shrinkage with DA agonist therapy showed no significant difference between grade 0, 1, and 2 tumors (mean tumor stabilization or shrinkage: 31, 30, and 36% respectively). However, when we considered a decrease in tumor size ranging from 0 to 20% as tumor stabilization and >20% decrease in tumor size as true shrinkage, one out of four NFPAs with grade 1 uptake, two out of three with grade 1 uptake, and eight out of ten with grade 2 uptake showed tumor shrinkage.Conclusion: In conclusion, there is limited clinical usefulness of dopamine D2 receptor imaging for predicting the clinical efficacy of DA agonist in selected patients with NFPAs. DA agonist therapy in NFPAs can result in tumor stabilization and shrinkage.

Infusion of amino acids (AAs) can reduce renal uptake of radiolabelled somatostatin analogues resulting in a lower kidney exposure during peptide radiotherapy of patients with neuroendocrine tumours. In this study, we investigated the metabolic effects related to the infusion of large amounts of amino acids in patients undergoing positron emission tomography (PET) studies with [(86)Y]DOTA(0)-D-Phe(1)-Tyr(3)-octreotide.

Somatostatin analogues have been shown to inhibit smooth muscle cell proliferation after local administration in vivo in animal models and in vitro using human coronary smooth muscle cell cultures. However, the optimal dosage for attaining effective site-specific administration remains undefined. This study was performed to determine the required theoretical dose of the somatostatin analogue, octreotide, to be delivered site specifically, for prevention of restenosis after coronary angioplasty in humans using a previously described methodology to determine regional pharmacokinetics of site-specific intracoronary administrated compounds. In 7 patients, 111In-octreotide, a -labeled somatostatin analogue, was infused post angioplasty at the site of dilatation via a coil-balloon and quantified using a radio-isotopic technique. Efficiency of delivery ranged from 0.1 to 2.7 of the total infused dose of 0.18 g, corresponding to a mean peak delivered amount of 1.8 ± 1.9 ng. Total locally bioavailable 111In-octreotide reached 2.28 ± 2.15 ng h. Based on current in vitro bioavailability and peak concentration data to inhibit proliferation and thymidine incorporation in human coronary smooth muscle cells, a 4000× higher averaged dose (∼700 g) should be infused site specifically to obtain a biologic efficacy in 50 of the treated patients (ED50). Quantification of regional pharmacokinetics enables the determination of a theoretical site-specific dose for achieving appropriate bioavailablility above the therapeutic threshold concentration for smooth muscle cell inhibition. This approach is proposed for the determination of the appropriate site-specific coronary infusion dose for the inhibition of restenosis after balloon angioplasty.

Abstract: With the in vivo demonstration of somatostatin-receptor-positive tumors in patients using a radiolabeled somatostatin analog, peptide receptor scintigraphy became available some 15 yr ago. Octreoscan® is a radiopharmaceutical with proven clinical importance in the visualization of somatostatin-receptor-positive tumors, and the overall sensitivity of somatostatin receptor imaging is high. In a number of neuroendocrine tumor types, as well as in Hodgkin’s disease, inclusion of somatostatin receptor imaging in the localization or staging procedure may be very rewarding. The value of somatostatin receptor imaging in patients with other tumors, like breast cancer, or in patients with granulomatous diseases, has to be established.

Background: Percutaneous transendomyocardial injection with an injection catheter is a new drug delivery method for e.g. therapeutic angiogenesis. Little is known about the efficacy of this drug delivery technique. We studied efficiency and retention of transendomyocardial injections with a NOGA guided injection catheter system by using scintigraphy with radio-labeled model drugs. Methods: Ten non-ischemic landrace pigs were used. In each animal 2-3 transendomyocardial injections were performed using a 3-D mapping based catheter system called NOGA. As a model for proteins like angiogenic growth factors we used 99mTc labeled albumin and as a model for small particles like microspheres or adenovirus we used 99mTc labeled colloid albumin. Efficiency of the injections and retention of the transendomyocardial deposited substance were evaluated by a gamma camera during and after injection of 0.1 or 0.2 ml. Results: All 29 injections showed scintigraphic proof of intramyocardial deposition. The average injection efficiency of all 29 injections was 26 ± 23%. The average injection efficiency of 0.1 and 0.2 ml injections were 33 ± 30% (n= 8) and 24 ± 20% (n= 21), respectively (p= 0.33). Intramyocardial retention curves of albumin showed a rapid wash-out within the first 2 hours of the injection, whereas the retention of colloid albumin showed no decrease. In conclusion, transendomyocardial delivery of proteins or particles with an injection catheter show favorable efficiency rates, however the retention time of intramyocardial deposited small proteins like albumin is short. This may indicate the need for sustained release systems of angiogenic growth factors for intramyocardal injection in therapeutic angiogenesis.

Objective:To evaluate fracture rate and bone mineral density (BMD) and body composition in children with acute lymphoblastic leukemia (ALL) treated with dexamethasone-based chemotherapy. Study design:Children with ALL (n = 61) participated. At diagnosis, during therapy, and one year after cessation of therapy, BMD and body composition were measured using dual energy X-ray absorptiometry of lumbar spine (LS) and total body (TB). Serum markers of bone turnover were assessed. Results:BMDLSwas significantly reduced at diagnosis, and remained low during therapy. BMDTBwas normal at diagnosis, with a fast decrease in the first 32 weeks, in which chemotherapy was relatively intensive. Apparent ("volumetric") BMDLSwas also reduced, but this did not reach significance at diagnosis and follow-up. Bone formation markers were reduced at diagnosis; formation as well as resorption markers increased during treatment. Fracture rate was 6 times higher in ALL patients compared with healthy controls. Lean body mass was decreased at baseline. Percentage of body fat increased significantly during therapy. After ALL treatment was completed, BMD and body composition tended to improve. Conclusions:Children with ALL are at risk for osteopenia because of the disease itself and the intensive chemotherapy. Fracture rate increases substantially, not only during but also shortly after treatment. (J Pediatr 2002;141:204-10)

Aim:To study the effects of growth hormone (GH) deficiency (GHD) and GH replacement therapy (GHRx) on bone mineral density (BMD) and body composition. Methods:59 GHD children participated (age range 0.4–16.9 years); the follow-up period was 6 years. Lumbar spine BMD (BMDLS), total-body BMD (BMDTB), and body composition were measured prospectively using dual-energy X-ray absorptiometry. Results:Mean BMDLS and BMDTB were significantly reduced at the time of the diagnosis. The bone mineral apparent density of the lumbar spine (BMADLS) was reduced to a lesser degree. The BMADLS increased to normal values after 1 year; BMDLS and BMDTB normalized 1 year later. At the time of the diagnosis, the lean body mass was reduced and steadily increased during GHRx. Percentage of body fat was increased at baseline and normalized within 6 months. The severity of GHD was not associated with the BMD at diagnosis or the response to GHRx. Conclusion:Areal BMDLS and BMDTB and, to a lesser extent, BMADLS are decreased in GHD children, but normalize within 1–2 years.

The somatostatin analogue [DOTA0,Tyr3]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA0,Tyr3]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) with [111In-DTPA0]octreotide (111In-octreotide) in six patients with somatostatin receptor-positive tumours. Plasma radioactivity after 177Lu-octreotate expressed as a percentage of the injected dose was comparable with that after 111In-octreotide. Urinary excretion of radioactivity was significantly lower than after 111In-octreotide, averaging 64% after 24 h. The uptake after 24 h, expressed as a percentage of the injected dose of 177Lu-octreotate, was comparable to that after 111In-octreotide for kidneys, spleen and liver, but was three- to fourfold higher for four of five tumours. The spleen and kidneys received the highest absorbed doses. The doses to the kidneys were reduced by a mean of 47% after co-infusion of amino acids. It is concluded that in comparison with the radionuclide-coupled somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, 177Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of 177Lu as compared with 90Y may be especially important for small tumours.

In vivo somatostatin receptor-mediated scintigraphy has proven to be a valuable method for the visualisation of neuroendocrine tumours and their metastases. A new application is the use of radiolabelled analogues for somatostatin receptor-mediated therapy. This paper presents a review on the basic science, historical background and current knowledge of somatostatin receptor subtypes and their expression in neuroendocrine tumours. New somatostatin analogues, new chelators, "new" radionuclides and combinations thereof are also discussed. Due attention is given to limitations and future perspectives of somatostatin receptor-mediated imaging and therapy.

Childhood leukemia has increasing numbers of survivors, so more emphasis is being placed on long-term effects. The ALL-6 protocol of the Dutch Childhood Leukemia Study Group involved high-dose dexamethasone and methotrexate and no cranial irradiation. Therefore, we studied the long-term effects on bone mineral density (BMD), body composition, and growth in survivors of nonhigh-risk ALL treated with the ALL-6 protocol. Twenty-three subjects (12.2–25.4 years) participated in this cross-sectional study. Mean follow-up was 9.6 years (range 7.9–11.4 years). BMD of lumbar spine (LS) and total body (TB) and body composition were measured by dual energy X-ray absorptiometry; results are expressed as standard deviation scores (SDS). Bone mineral apparent density (BMADLS) was calculated to correct for bone size. A question-naire was administered to determine physical activity, calcium intake, and medical history. Mean SDS for BMDLS, BMDTB, and BMADLS were normal. None of the subjects had BMD below −2 SDS; one subject had BMADLS below −2 SDS. Mean SDS for lean body mass, percentage fat, and height were not significantly different from zero. Calcium intake correlated positively with BMD. Nine subjects reported traumatic fractures (eight during or shortly after therapy). Ten years after ALL-6 treatment, no long-term side effects on height, BMD, or body composition were found in this small group of patients, despite high-dose dexamethasone and methotrexate. This study suggests that ALL treatment without cranial irradiation might not be associated with long-term side effects on growth and BMD. Med. Pediatr. Oncol. 35:415–420, 2000. © 2000 Wiley-Liss, Inc.

Cholecystokinin (CCK)-B receptors have been demonstrated on a high percentage of medullary thyroid carcinomas (MTC) in vitro. After encouraging results both in vitro and in animal studies, we studied the efficacy of an octapeptide [111In-DTPA]-CCK analogue in seven patients with MTC. In four of five patients in whom serum calcitonin levels were monitored, a significant rise was found following the injection, indicating retained biological activity of the radiopeptide. In all patients there was visualization of the CCK-B receptor-positive stomach. In one of two patients with known MTC lesions, some of the lesions were visualized; in addition some lesions were visualized in one of the five other patients who had elevated serum tumour markers but negative localizing studies. Radioactivity in the presumed tumour sites was still present at 48 h p.i. The uptake in the presumed tumour sites and stomach was low. Background radioactivity dropped rapidly owing to urinary excretion. After 1 h, breakdown products of the labelled analogue predominated both in urine and in serum, and virtually no intact peptide was present. In conclusion: (1) the CCK-B receptor-positive gastric mucosa and presumed MTC lesions could be visualized in patients using an octapeptide [111In-DTPA]-CCK analogue that is probably internalized, proving the feasibility of CCK-B receptor imaging in vivo; (2) there was a relatively low uptake of the CCK analogue in the strongly CCK receptor-positive stomach, and rapid degradation of the peptide in serum.

Background: This study assessed the accuracy of exercise methoxy isobutyl isonitrile (MIBI) single photon emission computed tomography (SPECT) in the evaluation of the extent of coronary artery disease (CAD) in patients with an earlier myocardial infarction. Methods and Results: We studied 135 patients (mean age, 57 ± 10 years; 115 men) at a mean of 4.1 years (median, 1 year) after myocardial infarction with symptom-limited bicycle exercise stress and rest MIBI SPECT imaging. Coronary angiography was performed within 3 months. Significant CAD was defined as a stenosis of 50% or larger in luminal diameter in 1 or more major coronary arteries. Conclusions: Exercise MIBI SPECT imaging is an accurate method for the diagnosis and localization of CAD in patients with an earlier myocardial infarction. The technique provides a high specificity and moderate sensitivity for the diagnosis of multivessel CAD on the basis of myocardial perfusion abnormalities in more than 1 vascular region.

Most neuroendocrine tumours and several other tumours, such as breast carcinoma and malignant lymphoma, express somatostatin receptors (SS-Rs). Lesions expressing these receptors can be visualised by receptor scintigraphy using a low radioactive dose of the radiolabelled SS analogue [¹¹¹In-DTPA⁰]octreotide. This radioligand is internalised and transported to the lysosomes with a long residence time of ¹¹¹In. The aim of this experimental study in rats was to investigate whether the same agent, given in a high radioactive dose, can be used for therapy of hepatic metastases of different tumour cell lines. The development of hepatic metastases was determined 21 days after direct injection of SS-R-positive or -negative tumour cells into the vena porta in rats. On day 1 and/or 8, animals were treated with 370 MBq (0.5 μg) [¹¹¹In-DTPA⁰]octreotide. In one experiment, using SS-R-positive tumour cells, animals were pre-treated with a high dose of cold octreotide to block the SS-R by saturation. The number of SS-R-positive liver metastases was significantly decreased after treatment with [¹¹¹In-DTPA⁰]octreotide. Blocking the SS-R by octreotide substantially decreased the efficacy of treatment with [¹¹¹In-DTPA⁰]octreotide, suggesting that the presence of SS-R is mandatory. This was confirmed by the finding that the number of SS-R-negative liver metastases was not affected by treatment with [¹¹¹In-DTPA⁰]octreotide. Therefore, we conclude that (i) high radioactive doses of [¹¹¹In-DTPA⁰]octreotide for PRRT (peptide receptor radionuclide therapy) can inhibit the growth of SS-R-positive liver metastases in an animal model, (ii) PRRT is effective only if SS-Rs are present on the tumours, (iii) the effect of PRRT with [¹¹¹In-DTPA⁰]octreotide can be reduced by pre-treatment with cold octreotide, which indicates that receptor binding is essential for PRRT. Our data suggest that PRRT with radiolabelled octreotide might be a new promising treatment modality for SS-R-positive tumours. Int. J. Cancer 81:767–771, 1999. © 1999 Wiley-Liss, Inc.

Thyroid hormone action and metabolism are intracellular events that require transport of the hormone across the plasma membrane. We tested the possible involvement of the Na+/taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide (oatp1) in the hepatic uptake of the prohormone T4, the active hormone T3, and the metabolites rT3 and 3,3′-T2.Xenopus laevisoocytes were injected with 2.3 ng Ntcp or oatp1 cRNA and, after 2–3 days, incubated for 1 h at 25°C with usually 0.1 μM125I-labeled ligand. Uninjected oocytes showed marked uptake of iodothyronines and this was further increased by Ntcp and oatp1 cRNA, i.e., 1.9- and 2.8-fold for T4, 1.7- and 1.7-fold for T3, 1.8- and 6.0-fold for rT3, and 1.3- and 1.4-fold for 3,3′-T2, respectively. Mostly due to much lower uptake by uninjected oocytes, Ntcp and oatp1 cRNA induced larger, 12- to 76-fold increases in uptake of iodothyronine sulfates. The Ntcp cRNA-induced iodothyronine uptake was completely inhibited in Na+-deplete medium, whereas the oatp1 cRNA-induced uptake was not affected. These results suggest that hepatic uptake of thyroid hormones and their metabolites is mediated at least in part by Ntcp and oatp1.

We compared internalization of three radioiodinated octreotide (OCT) somatostatin (SS) analogs—[125I-Tyr3]OCT, [DTPA°,125I-Tyr3]OCT, and [DOTA°,125I-Tyr3]OCT—by somatostatin receptor (SSR)-positive mouse AtT20 pituitary tumor cells and human insulinoma cells. The three SS analogs were internalized in a specific, time-dependent manner. Internalization was significantly inhibited by pertussis toxin (100 μg/l) by 38%, 43%, and 31%, and by an inhibitor of receptor-mediated endocytosis (phenyl arsine oxide; 10 μM) by 98%, 94%, and 92%, respectively. Binding affinities of the three radioligands were comparable (0.2, 0.2, and 0.3 nM, respectively). However, [DOTA°,125I-Tyr3]OCT was internalized in a five-fold higher amount in comparison with the two other radioligands. A comparably high uptake of [DOTA°,125I-Tyr3]OCT was found in SSR-positive organs (pituitary, pancreas, and adrenals) in vivo in rats (a ten-fold, five-fold, and eight-fold higher uptake 4 hr post injection, respectively, compared with the two other radioligands). This resulted in very high target-background ratios for [DOTA°,125I-Tyr3]OCT 4 hr post injection amounting to 274, 566, and 623 in the pituitary, adrenals, and pancreas, respectively. Both in vivo and in vitro there was a rapid dissociation of radioactivity from the SSR-positive cells. Main conclusions are that: 1) coupling of chelating groups like DTPA or DOTA to the SS analog [Tyr3]OCT does not prevent the internalization of OCT after binding to SSRs; 2) [DOTA°,125I-Tyr3]OCT is internalized in a significantly higher amount by AtT20 and human insulinoma cells and in vivo in rats in SSR-positive organs, in comparison with [DTPA°,125I-Tyr3]OCT and [125I-Tyr3]OCT; and 3) the very high target-background ratios in vivo make radioiodinated [DOTA°,Tyr3]OCT a very suitable ligand for SSR-targeted radioguided surgery of SSR-positive human neuroendocrine tumors.

Abstract.: Dobutamine stress echocardiography and thallium-201 myocardial perfusion scintigraphy are clinically useful methods for the evaluation of coronary artery disease (CAD). However, the relative merits of these imaging modalities in the evaluation of the extent of CAD after myocardial infarction have not been well studied. The aim of this study was to compare the accuracy of dobutamine stress echocardiography and simultaneous 201Tl single-photon emission tomography (SPET) imaging for the diagnosis and localization of CAD late after acute myocardial infarction. Dobutamine (up to 40 µg kg–1 min–1)-atropine (up to 1 mg) stress echocardiography in conjunction with stress-reinjection 201Tl SPET was performed for the evaluation of myocardial ischaemia in 90 patients with previous myocardial infarction who underwent coronary angiography. Significant CAD was predicted on bases of myocardial ischemia (new or worsening wall motion abnormalities on echocardiography and reversible perfusion defects on 201Tl SPET). Significant CAD (≥ 50% luminal diameter stenosis) was detected in 73 (81%) patients. The sensitivity, specificity and accuracy of echocardiography in detecting remote ischaemia for the diagnosis of remote CAD (present in 53 patients) were, respectively, 79% (CI 70%–88%), 85% (CI 77%–93%) and 81% (CI 73%–90%), while the corresponding figures for 201Tl SPET were 75% (CI 66%–85%), 78% (CI 69%–87%) and 76% (CI 67%–86%) respectively (P = NS vs echocardiography). The sensitivity, specificity and accuracy of echocardiography in detecting peri-infarction ischaemia for the diagnosis of infarct-related artery stenosis (present in 70 patients) were, rspectively, 77% (CI 68%–86%), 85% (CI 78%–92%) and 79% (CI 70%–87%) while the corresponding figures for 201Tl SPET were 73% (CI 64%–82%), 85% (CI 78%–92%) and 76% (CI 67%–84%) respectively (P = NS vs echocardiography). The agreement between the two methods for the diagnosis of peri-infarction and remote ischaemia was 70% (kappa = 0.37) and 80% (kappa = 0.59) respectively. It is concluded that dobutamine stress echocardiography and 201Tl SPET have comparable accuracy for the diagnosis of infarct related and remote CAD in patients with previous myocardial infarction. The agreement between the methods is higher for the diagnosis of remote CAD than for that of peri-infarction ischaemia.

Abstract.: Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin analogue [Tyr3]octreotide (d-Phe-c(Cys-Tyr-d-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelator DOTA (tetra-azacyclododecane-tetra-acetic acid), enabling stable radiolabelling with both the high-energy beta particle-emitter yttrium-90 and the Auger electron-emitter indium-111. The thus produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in vitro and in vivo (rat) experiments with these radiolabelled compounds showed favourable binding and biodistribution characteristics with high uptake and retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization of radiolabelled [DOTA0,Tyr3]octreotide in somatostatin receptor subtype 2 (sst2)-positive rat pancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of injected peptide on tissue distribution of 111In-labelled [DOTA0,Tyr3]octreotide in normal, i.e. non-tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find the amount of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide therapy while simultaneously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled [DOTA0,Tyr3]octreotide in sst2-positive organs showed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals), 0.05–0.1 (pituitary and stomach) and 0.25 (pancreas) µg. Uptake in the tumour was highest at 0.5 µg injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for [111In-DTPA0]octreotide ((d-Phe-c(Cys-Phe-d-Trp-Lys-Thr-Cys)-Thr(ol), DTPA = diethylene-triamine-penta-acetic acid), consistent with the higher receptor affinity of the first compound. Our observations of mass-dependent differences in uptake of radiolabelled [DOTA0, Tyr3]octreotide, being the resultant of a positive effect of increasing amounts of peptide on, for example, receptor clustering and a negative effect of receptor saturation, are of consequence for rat radionuclide therapy studies with radiolabelled peptides and may also be of consequence for human radionuclide therapy studies with this compound.

This study investigated the prognostic value of dobutamine-atropine technetium-99m (Tc-99m) sestamibi singlephoton emission computed tomographic (SPECT) myocardial perfusion imaging.

Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radionuclide-labeled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 32/37 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, and 5/7 small cell lung cancers. Somatostatin receptor imaging is an easy, harmless and painless diagnostic method. It localizes multiple and/or metastatic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems to be of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers.

Abstract. In vitro octreotide receptor binding of [¹¹¹In-DOTA⁰,d-Phe¹,Tyr³]octreotide (¹¹¹In-DOTATOC) and the in vivo metabolism of ⁹⁰Y- or ¹¹¹In-labelled DOTATOC were investigated in rats in comparison with [¹¹¹In-DTPA⁰]octreotide [¹¹¹In-DTPAOC). ¹¹¹In-DOTATOC was found to have an affinity similar to octreotide itself for the octreotide receptor in rat cerebral cortex microsomes. Twenty-four hours after injection of ⁹⁰Y- or ¹¹¹In-labelled DOTATOC, uptake of radioactivity in the octreotide receptor-expressing tissues pancreas, pituitary, adrenals and tumour was a factor of 2-6 that after injection of ¹¹¹In-DTPAOC. Uptake of labelled DOTATOC in pituitary, pancreas, adrenals and tumour was almost completely blocked by pretreatment with 0.5 mg unlabelled octreotide, indicating specific binding to the octreotide receptors. These findings strongly indicate that ⁹⁰Y-DOTATOC is a promising radiopharmaceutical for radiotherapy and that ¹¹¹In-DOTATOC is of potential value for diagnosis of patients with octreotide receptor-positive lesions, such as most neuroendocrine tumours.

In 80% to 90% of patients with carcinoids, tumor sites can be detected with [111In-DTPA-d-Phe1]-octreotide scintigraphy. Unexpected, additional localizations are reported in one-third to two-thirds of patients. In a group of 52 patients, we analyzed the results of various combinations of octreotide scintigraphy and conventional imaging. Octreotide scintigraphy, alone or in combination with other imaging modalities, led to the detection of more tumor sites than any combination of conventional imaging techniques. The combination of octreotide scintigraphy, chest radiography, and ultrasonography of the upper abdomen led to the detection of lesions in all patients in whom they could be demonstrated by any imaging means, with a sensitivity of 87% in terms of the number of detected lesions. The calculated cost for this imaging regimen was higher than for the combination of conventional imaging as applied in our group. However, the benefit was the detection of at least one lesion in 11% of patients in whom with conventional imaging no abnormalities were found. Moreover, if the results from our patient group were extrapolated to a group of 100 patients, the advantage in terms of the number of extra lesions detected would be 65 extra lesions per 100 patients. The detection of more tumor sites in patients who are known to have one tumor localization with conventional imaging may be essential when deciding whether to perform surgery. Octreotide scintigraphy can be used to localize tumors, direct the choice of medical therapy, and (expected in the near future) select patients for radiotherapy. The impact on patient management is fourfold: Octreotide scintigraphy may detect resectable tumors that would be unrecognized with conventional imaging techniques; it may prevent surgery in patients whose tumors have metastasized to a greater extent than can be detected with conventional imaging; it may direct the choice of therapy in patients with inoperable tumors; and in the future it may be used to select patients for radionuclide therapy.

We investigated 3,3′,5-tri-iodo-l-thyronine transport by human erythrocytes and by ‘ghosts’ prepared from these cells. Uptake of tri-iodothyronine by erythrocytes at 37°C was time-dependent with a maximum reached after 60min. Tracer analysis after incubation for 1min revealed only one saturable binding site, with Km 128±19nm (mean±s.e.m.; n=7) and Vmax. 4.6±0.7pmol of tri-iodothyronine/min per 6×107 cells. After 10min incubation Km 100±16nm (n=10) was found with Vmax. 7.7±1.2pmol of tri-iodothyronine/10min per 6×107 cells. At 0°C the uptake system is still active, with Km 132±26nm and Vmax. 1.8±0.3pmol of tri-iodothyronine/10min per 6×107 cells. The Vmax. with intact cells is 5-fold greater than the Vmax. with membranes derived from the same amount of cells when uptake studies are performed in media with similar free tri-iodothyronine concentrations. This indicates that at least 80% of tri-iodothyronine taken up by the intact erythrocytes enters the cell. This saturable uptake system can be inhibited by X-ray-contrast agents in a dose-dependent fashion. (±)-Propranolol, but not atenolol, has the same effect, indicating that the membrane-stabilizing properties of (±)-propranolol are involved. Furthermore, there is no inhibition by ouabain or vanadate, which indicates that tri-iodothyronine uptake is not dependent on the activity of Na++K+-dependent adenosine triphosphatase. We have prepared erythrocyte ‘ghosts‘, resealed after 2.5min with 0mm-, 2mm- or 4mm-ATP inside. Inclusion of ATP and integrity of the membrane of the erythrocyte ‘ghosts’ were verified on the basis of an ATP-concentration-dependent functioning of the Ca2+ pump. No difference was found in the uptake of tri-iodothyronine by erythrocyte ‘ghosts’ with or without ATP included, indicating that uptake of tri-iodothyronine is not ATP-dependent. The following conclusions are drawn. (1) Tri-iodothyronine enters human erythrocytes. (2) There is only one saturable uptake system present for tri-iodothyronine, which is neither energy (i.e. ATP)-dependent nor influenced by the absence of an Na+ gradient across the plasma membrane. This mode of uptake of tri-iodothyronine by human erythrocytes is in sharp contrast with that of rat hepatocytes, which uptake system is energy-dependent and ouabain-sensitive [Krenning, Docter, Bernard, Visser & Hennemann (1978) FEBS Lett.91, 113–116; Krenning, Docter, Bernard, Visser & Hennemann (1980) FEBS Lett.119, 279–282]. (3) X-ray-contrast agents inhibit tri-iodothyronine uptake by erythrocytes in a similar fashion to that by which they inhibit the uptake of tri-iodothyronine by rat hepatocytes [Krenning, Docter, Bernard, Visser & Hennemann (1982) FEBS Lett.140, 229–233].

Abstract.: Stress echocardiography has been considered an accurate method for the diagnosis of coronary artery disease in hypertensive patients and in patients with left ventricular hypertrophy. In contrast, the specificity of myocardial perfusion scintigraphy in these patients has been questioned. The aim of this study was to compare the accuracy of these two imaging modalities in conjunction with dobutamine stress test for the diagnosis of coronary artery disease in hypertensive patients with and without left ventricular hypertrophy. Dobutamine (up to 40 μg kg–1min–1) stress echocardiography in conjunction with sestamibi (MIBI) single-photon emission tomography (SPET) was performed in 84 patients with the diagnosis of systemic hypertension who had been referred for evaluation of myocardial ischaemia. Ischaemia was defined as new or worsened wall motion abnormalities at echocardiography and reversible perfusion defects at SPET. Significant coronary artery disease (≥50% luminal diameter stenosis) was detected in 66 patients (79%). The sensitivity, specificity and accuracy of the ischaemic pattern at echocardiography for the diagnosis of coronary artery disease were 73% (CI 63%–82%), 83% (CI 75%–91%) and 75% (CI 66%–84%), those for MIBI were 67% (CI 57%–77%), 83% (CI 75%–91%) and 70% (CI 60%–80%) respectively (P = NS vs echocardiography). Significant stenosis was detected in 123 (49%) of the 252 analysed coronary arteries. The sensitivity, specificity and accuracy of echocardiography for the regional diagnosis of coronary artery disease were 63% (CI 56%–69%), 90% (CI 86%–94%) and 77% (CI 72%–82%). Those for MIBI were 58% (CI 51%–64%), 91% (CI 87%–94%) and 75% (CI 69%–80) respectively (P = NS vs echocardiography). Left ventricular hypertrophy was detected in 59 patients (70%) by echocardiography and did not influence the overall or regional specificity of echocardiography or MIBI SPET. It is concluded that in hypertensive patients, dobutamine stress echocardiography and MIBI SPET have a comparable accuracy for the overall and regional diagnosis of coronary artery disease. Hypertensive patients with or without left ventricular hypertrophy should not be considered unsuitable candidates for stress myocardial perfusion scintigraphy.

Abstract.: Granulomatous diseases can be visualized in vivo after the injection of indium-111-DTPA-octreotide (111In-pentetreotide), a radiolabelled somatostatin analogue. We evaluated whether somatostatin receptor imaging reflects disease activity, whether certain scintigraphic characteristics can predict the disease prognosis and whether repeat scintigraphy correlates with the clinical course in patients with sarcoidosis. 111In-pentetreotide was injected in 46 patients and images were obtained 24 h later. Known mediastinal, hilar and interstitial disease was recognized in 36 of 37 patients. Also, such pathology was found in seven other patients who had normal chest X-rays. In five of these, somatostatin receptor imaging pointed to interstitial disease. Frequently, accumulation of radioactivity in parotid glands and supraclavicular lymph nodes was found. Neither the degree of radioactive accumulation in the thorax nor a specific pattern of pathological uptake was correlated with disease severity or clinical course. The degree of uptake of radioactivity in the parotid glands was correlated with significantly higher serum angiotensin-converting enzyme (ACE) levels. Somatostatin receptor imaging was repeated in 13 patients. In five of six patients in whom chest X-ray monitored improvement of disease activity, the pentetreotide scintigram also showed a decrease in pathological uptake. In two of five patients in whom the chest X-ray was unchanged, but serum ACE concentrations had decreased and lung function improved, normalization on pentetreotide scintigrams was found. It is concluded that: (1) somatostatin receptor imaging can demonstrate active granulomatous disease in patients with sarcoidosis; (2) pathological uptake of radioactivity in the parotid glands during somatostatin receptor imaging is correlated with higher serum ACE concentrations; (3) the value of somatostatin receptor imaging in the follow-up of patients with sarcoidosis will have to be determined in a prospective longitudinal study.

• BACKGROUND.— Trabecular carcinomas of the skin, or Merkel cell tumors, are aggressive neoplasms that tend to occur in sun-exposed skin. These tumors frequently metastasize and, despite therapy, the number of disease-related deaths is high. Ultrastructurally and immunocytochemically, the majority of these tumors have neuroendocrine characteristics. Recently, we described the in vivo visualization of various neuroendocrine tumors after injection of a radiolabeled somatostatin analogue (octreotide). In this study, we report the results of scintigraphy with radioactive-labeled somatostatin analogues in five patients with Merkel cell tumors. OBSERVATIONS.— In all four patients in whom tumor was detected using computed tomographic scanning and ultrasound, the tumor sites were also demonstrated on octreotide scintigrams. In one patient, a tumor with a diameter that was smaller than 0.5 cm could not be detected with octreotide scintigraphy, computed tomography, or ultrasound. Using octreotide scintigraphy we found presumed tumor spots in two patients that were not evident when other techniques were used. CONCLUSIONS.— Octreotide scintigraphy has an equal or even greater sensitivity than computed tomography and ultrasound for detecting Merkel cell tumors and their metastases. Establishing the spread of the disease in this way may ensure an optimal choice of treatment in patients with this type of tumor.(Arch Dermatol. 1992;128:818-821)

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 that161Tb-DTPA-octreotide is a high-affinity radioligand for somatostatin receptors, with an affinity comparable to that of111In-DTPA-octreotide. Rat growth hormone secretion inhibition experiments showed that161Tb-DTPA-octreotide has a similar potency to111In-DTPA-octreotide.161Tb-DTPA-octreotide appeared to be taken up even less by the isolated perfused rat liver than111In-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 of161Tb-DTPA-octreotide is lower then that of111In-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 of161Tb-DTPA-octreotide than with111In-DTPA-octreotide. Furthermore, these studies demonstrated that the uptake of161Tb-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 of161Tb-DTPA-octreotide. Finally, it appeared that a maximal labelling efficiency of161Tb-DTPA-octreotide is essential, as with decreasing efficiency the uptake in the octreotide receptor-positive organs decreased, whereas non-specific uptake in the other organs was increased. It is concluded that, on the basis of the favourable physical characteristics of161Tb combined with the in vitro and in vivo studies performed with161Tb-DTPA-octreotide, the latter is a promising radiopharmaceutical for both intraoperative scanning and radiotherapy. Studies in patients need to be performed now to see whether161Tb-DTPA-octreotide can indeed open new therapeutic applications for patients bearing octreotide receptor-positive tumours.

Technetium-99m hexakis-2-methoxyisobutylisonitrile (MIBI),99mTc-tetrofosmin and99mTc-Q12 were all introduced for myocardial imaging but found additional applications as they are taken up by different tumours, enabling imaging of these lesions in patients. The aim of this study was to compare the uptake characteristics of these compounds in vitro in the human adenocarcinoma breast cell lines MCF-7 and ZR-75. It was shown that99mTc-MIBI had the highest cellular uptake (15.9%±0.5% dose/mg protein after 60 min in MCF-7, and 14.2%±0.4% dose/mg protein in ZR-75), followed by99mTc-tetrofosmin (6.8%±0.6% dose/mg protein in MCF-7, and 8.2%±0.2% dose/mg protein in ZR-75) and99mTc-Q12 (3,2%±0. I% dose/mg protein in MCF-7, and 3.5%±0.3% dose/mg protein in ZR-75 cells). For all three compounds tenfold differences in specific activity did not influence total cell-associated radioactivity. Uptake of99mTc-MIBI and99mTc-tetrofosmin was obviously lower at 4° C than at 37° C, whereas99mTc-Q12 uptake showed only slight temperature dependence. When uptake was compared in cells grown to different cell densities (1 mg/ml cellular protein versus 0.3 mg/ml), no differences in uptake were detected when uptake was corrected for the amount of cellular protein present in the dishes. Furthermore, for all compounds it was shown that cellular radioactivity decreased rapidly after washing. Apart from the differences in cellular uptake of the three compounds after 60 min, no differences in residual cellular radioactivity after washing were found between the different compounds when expressed as a percentage of their 60-min uptake, suggesting that the efflux process of the radiolabelled compounds was similar. The differences in cell-associated activity after 60 min were thus presumably caused by differences in uptake. It was concluded that of the Tc-labelled compounds tested,99mTc-MIBI had the highest cellular retention in both human breast tumour cell lines. However, for imaging in vivo not only radioactivity in the target organ is important, but also the ratio of radioactivity in the target versus that in the background. Therefore, further studies in vivo need to be performed to investigate which compound is the optimal imaging agent

Gamma-emitting radiopeptides are useful for scintigraphy of tumours on the basis of receptor binding. Likewise, ß-emitting radiopeptides may be used in radionuclide therapy of such tumours. As iodine-131 suggested to be suitable for this purpose, experiments were performed using three somatostatin analogues, in which the effects of coupling of a therapeutic dose of131I to such peptides were investigated. This study deals with the radioiodination of very small amounts of peptide on a therapeutic scale, the required purification procedures after radioiodination, and the influence of high beta fluxes from131I on a peptide during radioiodination and purification. Based on the regularly used therapeutic doses of131I in cancer treatment and our previous experience with [111In-DTPA-d-Phe1]-octreotide, it was assumed that a minimal effective therapeutic dose of 3.7 GBq131I has to be coupled to a maximum of ˜ 100 µg peptide, representing only a slight excess of peptide over131I. This contrasts with non-peptide radiopharmaceuticals in which high compound to radionuclide ratios are usually used. Labelling at low peptide to radionuclide ratios (low labelling yields) results in the formation of di-iodinated compounds, whereas at high peptide to radionuclide ratios (high labelling yields) mono-iodinated products of low specific activity are formed. Thus, after radioiodination the desired mono-iodinated peptide has to be separated from unreacted iodide, and from di-iodinaled and unreacted peptide, as both compounds compete for the receptors. Possible radiolysis of the peptide during labelling and separation steps were investigated by irradiating 30 µg unlabelled peptide with 370 MBq131I in a small volume. The peptide composition of the incubation mixtures was investigated by high-performance liquid chromatography after irradiation for 30 min to 24 h. The results showed that the peptide was degraded with a half-life of less than 1 h. During the preparation of a real therapeutic dose (at much higher ß-flux) the peptide will be degraded even faster during the various steps required. In conclusion, intact mono-iodinated131I-labelled somatostatin analogues for peptide receptor therapy will be difficult to obtain.

Scintigraphy with iodine-123 or indium-111 labelled somatostatin analogue (octreotide) was performed in 52 patients diagnosed as, suspected of, or at risk of having carcinoid tumours. In 32 of 37 (86%) patients in whom histologically proven carcinoids were still present, known tumour sites were visualized. Using 123I-coupled octreotide, 24 of 40 (60%) known extrahepatic sites were visualized, whereas all of 12 (100%) extrahepatic lesions were visualized after injection of 111In-coupled octreotide. Known liver metastases were not distinctly visualized with octreotide scintigraphy in 12 of 24 patients. In all but two of these cases, an even distribution of radioactivity in the liver was observed. This is most probably due to the fact that these liver metastases accumulated about as much radioactivity as does normal liver tissue. Previously unsuspected localizations or sites not recognized with other imaging techniques were found in 20 of the 37 patients. In 3 of 11 patients who were thought to have been surgically cured, and in 4 of 4 patients who were suspected of having carcinoids, octreotide scintigraphy showed abnormal accumulation of radioactivity. Histological or radiological evidence that additional sites noticed on octreotide scintigrams indeed represented tumour tissue was obtained in ten patients. Visualization of the carcinoids did not depend on the site of the tumour or on the presence or absence of hormonal hypersecretion, as measured by urinary 5-hydroxyindoleacetic acid and serum α-subunit concentrations. Apart from its use for tumour localization, octreotide scintigraphy, in consequence of its ability to demonstrate somatostatin receptor positive tumours, could be used to select those patients with the carcinoid syndrome who are likely to respond favourably to octreotide treatment.

We evaluated octreotide scintigraphy in 81 untreated patients who were suspected of having bronchial carcinoma. Octreotide scintigraphy visualized the primary tumour in all of 40 patients with non-smallcell lung carcinoma (non-SCLC), and all of 26 patients with SCLC. In the remaining patients, other bronchial disease and metastases from extrapulmonary carcinomas were also visualized. Mediastinal lymph node involvement and distant metastases were recognized in 5 of 15 and 1 of 7 patients with non-SCLC, respectively. In vitro, none of the non-SCLCs were shown to bear somatostatin receptors. We postulate that the visualization of non-SCLC during octreotide scintigraphy is caused by binding of labelled octreotide to activated leucocytes or to proliferating neuroendocrine cells around the tumours. In patients with SCLC, radiologically suspected lymph node involvement was visualized for 21 of 25 sites. Distant metastases, especially to the liver and abdomen, were missed for 14 of 20 sites, most probably because no laxatives were administered and single photon emission tomography of the abdomen was not performed. The failure to recognize liver metastases is most probably due to a comparable uptake of radioactivity by the surrounding normal liver tissue. In 15 of 26 patients, previously unrecognized tumour sites were suggested during octreotide scintigraphy, leading to a downstaging of 5 of 14 patients with limited disease. Unexpected cerebral metastases were suggested in five patients with either limited or extensive disease. In all four of these for whom follow-up was available, cerebral metastases became manifest 5–8 months after octreotide scintigraphy. We conclude (1) that octreotide scintigraphy is of no use to differentiate SCLC from other lung disease, and (2) that octreotide scintigraphy should be included in the staging procedure of SCLC because it may allow early detection of metastases, especially to the brain.

The peptide somatostatin and its analog octreotide play an important role in neoplasia where their actions have been shown to be mediated by specific somatostatin receptors located in the tumor tissue. The identification of a high density of SS receptors in vitro in different types of human tumors has provided completely new and attractive possibilities for their diagnostic localization in vivo. This can be achieved by intravenous injection of 123I-[Tyr3]-octreotide or 111In-DTPA-D-Phe1-octreotide in patients suspected of having SS receptor-positive tumors and by subsequent localization of the tumors with gamma camera scintigraphy techniques. Hot spots representing radioligand binding on SS receptor-positive tumors are visualized with this method. This new SS receptor imaging method may help the clinicians for the localization of the primary tumor and its metastases, for the staging of certain tumors, to predict a successful SS therapy, and as a prognostic or differential diagnostic marker. It may also be of use in non-tumoral pathologies, to localize selected inflammatory processes and to monitor anti-inflammatory therapy. Somatostatin receptor imaging represents the first example of the clinical use of a small peptide as an efficient in vivo diagnostic tool and may be considered as a paradigm for further research on the role and the potential diagnostic use of other peptide receptors in pathological states.

Abstract.: 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 μg) 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.

Summary: Clinical introduction of octreotide, a long-acting somatostatin analog, has opened a new era in the medical therapy of patients with growth hormone (GH)- and thyroid-stimulating hormone (TSH)-secreting pituitary tumors. Good control of hormonal hypersecretion occurred in most patients, and tumor shrinkage has been observed in more than half of them. Octreotide therapy is of no value in most patients with Prolactin (PRL)- and adrenocorticotrophic (ACTH)-secreting pituitary tumors. However patients with Cushing's syndrome caused by ectopic ACTH secretion from a variety of endocrine tumors benefit from octreotide administration. In patients with visual disturbances related to chiasmal compression by nonfunctioning pituitary tumors, somatostatin analog administration has been reported to result in rapid improvement in visual acuity. This beneficial effect might not be related to a direct action of octreotide, but may reflect an effect on the retina and/or optic nerve. The presence of somatostatin receptors on a wide variety of pituitary tumors as well as on a number of parasellar tumors allows their in vivo visualization with radionucleotide-labelled somatostatin analogs. A positive scan in patients with GH- and TSH-secreting pituitary tumors is predictive of a good suppressive effect of octreotide on hormone release by these tumors. PRL- and ACTH-secreting pituitary adenomas cannot be visualized, but clinically nonfunctioning pituitary adenomas are visualized in 75% of cases with ¹¹¹In-DTPA-octreotide. At present it is unclear whether this has consequences with regard to the medical treatment of these last group of patients. Somatostatin receptor scintigraphy can be successfully used in the differential diagnosis between pituitary hypersecretion of GH and/or ACTH and the ectopic secretion of growth hormone-releasing hormone (GHRH) and ACTH by peripherally localized endocrine tumors. Again the visualization of such tumors also predicts successful control of hormonal hypersecretion by octreotide. Copyright 1993, 1999 Academic Press

Medical therapy of acromegaly with the somatostatin analog octreotide is very successful. Both clinical symptomatology and hormonal hypersecretion by the growth hormone-secreting pituitary adenomas are controlled, and peripheral IGF-I levels also return to near normal levels. Tumor shrinkage is observed in most patients. Somatostatin analogs can be used after noncurative surgery and for a limited period after radiotherapy, and octreotide pretreatment might improve the outcome of surgery.