Krenning, E.P.

Peptide receptor radionuclide therapy (PRRT) for GEP-NETs (Article)

2012-12-01T00:00:00Z

Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues plays an increasing role in the treatment of patients with inoperable or metastasised gatroenteropancreatic neuroendocrine tumours (GEP-NETs).90Y-DOTATOC and177Lu-DOTATATE are the most used radiopeptides for PRRT with comparable tumour response rates (about 15-35%). The side effects of this therapy are few and mild. However, amino acids should be used for kidney protection, especially during infusion of90Y-DOTATOC. Options to improve PRRT may include combinations of radioactive labelled somatostatin analogues and the use of radiosensitising drugs combined with PRRT. Other therapeutic applications of PRRT may include intra-arterial administration, neo-adjuvant treatment and additional PRRT cycles in patients with progressive disease, who have benefited from initial therapy. Considering the mild side-effects, PRRT may well become the first-line therapy in patients with metastasised or inoperable GEP-NETs if more widespread use of PRRT can be accomplished.

Tumor response assessment to treatment with [ 177Lu-DOTA 0,Tyr 3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors: Differential response of bone versus soft-tissue lesions (Article)

2012-09-01T00:00:00Z

We have noted that bone lesions on CT respond differently from soft-tissue lesions to treatment with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). We therefore compared the response of bone lesions with that of soft-tissue lesions to treatment with177Luoctreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors (NETs). Methods: Forty-two patients with well-differentiated NETs who had bone metastases that were positive on [111In-DTPA0]octreotide somatostatin receptor scintigraphy (SRS) before treatment, and who had soft-tissue lesions, were studied. All patients had had a minimum of 1 follow-up CT scan. Lesions were scored on CT and bone lesions also on SRS before and after treatment. Tumor markers (chromogranin A and 5-hydroxyindoleacetic acid) before and after treatment were compared. Results: Because bone lesions were not visible on CT before treatment in 11 of 42 patients (26%), bone and softtissue lesions were evaluated in 31 patients. Whereas bone lesions increased in size, soft-tissue lesions decreased in size. The percentage change in bone and soft-tissue lesions was significantly different at all time points up to 12 mo of follow-up (P < 0.001). The intensity or number of bone lesions on SRS decreased after treatment in 19 of 23 patients (83%) in whom SRS after treatment was available. The tumor markers also decreased significantly after treatment. In 1 patient, bone lesions became visible on CT after treatment, mimicking progressive disease with "new" bone lesions, although there was an overall treatment response. Conclusion: In patients with NETs, the apparent increase in size of bone lesions or the appearance of new bone lesions on CT after treatment with177Lu-octreotate should be interpreted cautiously, as this finding may be therapy-related rather than indicative of tumor progression. Copyright

Treatment of Gastroenteropancreatic Neuroendocrine Tumors with Peptide Receptor Radionuclide Therapy (Article)

2012-01-10T00:00:00Z

The primary treatment of gastroenteropancreatic neuroendocrine tumors (GEPNETs) is surgery with curative intent or debulking of the tumor mass. In case of metastatic disease, cytoreductive options are limited. A relatively new therapeutic modality, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs, is currently available in a number of mostly European centers. Complete and partial responses obtained after treatment with [90Y-DOTA0,Tyr3]octreotide are in the same range as after treatment with [177Lu-DOTA0,Tyr3]octreotate (i.e. 10-30%). However, significant nephrotoxicity has been observed after treatment with [90Y-DOTA0,Tyr3]octreotide. Options to improve PRRT may include combinations of radioactive labeled somatostatin analogs, intra-arterial administration, and the use of radiosensitizing drugs combined with PRRT. Other therapeutic applications of PRRT may include additional therapy cycles in patients with progressive disease after benefit from initial therapy, PRRT in adjuvant or neoadjuvant setting, or PRRT combined with new targeted therapies, such as sunitinib or everolimus. Randomized clinical trials comparing PRRT with other treatment modalities, or comparing various radioactive labeled somatostatin analogs should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs. Copyright

Improved control of severe hypoglycemia in patients with malignant insulinomas by peptide receptor radionuclide therapy (Article)

2011-11-01T00:00:00Z

Context: Insulinomas are relatively rare neuroendocrine tumors of the pancreas. Only 10% are considered malignant. Control of insulin hypersecretion and hypoglycemia in patients with malignant insulinomas may be extremely difficult. Different medications and chemotherapy schedules have been used. Patients: Five patients with metastatic insulinomas and severe, poorly controllable, hypoglycemia are described. These patients required continuous glucose infusion to control severe hypoglycemia, which were induced by the high levels of insulin secretion. Conventional medications, such as diazoxide, or streptozotocin-based chemotherapies had been used to control hypoglycemia but were ineffective and/or produced adverse effects. All patients were treated with sc octreotide. Intervention: Peptide receptor radionuclide therapy with radiolabeled-somatostatin analogs was used. Results: After the start of radiolabeled somatostatin analog therapy, the five patients with metastatic insulinomas had stable disease for a mean period of 27 months. During these months, the patients were without any hypoglycemic episodes. Finally, three of five patients died because of progressive disease. Conclusions: Radiolabeled somatostatin analog therapy can stabilize tumor growth and can be very successful in further controlling severe hypoglycemia in malignant insulinomas. In our series, this eventually resulted in improved survival outside the hospital setting. Copyright

Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours (Article)

2011-10-01T00:00:00Z

Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy (SRS) with [111In-DTPA0]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic NETs (GEP-NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Most of these analogues can also be labelled with positron-emitting radionuclides that are being used in positron emission tomography imaging. The latter imaging modality, especially in the combination with computed tomography, is of interest because of encouraging results in terms of improved imaging quality and detection capabilities. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localisation of the primary and metastatic disease remains the ultimate goal of research. This review provides an overview of the currently used imaging modalities and ongoing developments in the imaging of NETs, with the emphasis on nuclear medicine and puts them in perspective of clinical practice. The advantage of SRS over other imaging modalities in GEP-NETs is that it can be used to select patients with sufficient uptake for treatment with radiolabelled somatostatin analogues. Peptide receptor radionuclide therapy (PRRT) is a promising new tool in the management of patients with inoperable or metastasised NETs as it can induce symptomatic improvement with all Indium-111, Yttrium-90 or Lutetium-177-labelled somatostatin analogues. The results that were obtained with [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3] octreotate are even more encouraging in terms of objective tumour responses with tumour regression and documented prolonged time to progression. In the largest group of patients receiving PRRT, treated with [177Lu-DOTA0,Tyr3]octreotate, a survival benefit of several years compared with historical controls has been reported.

Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [ 177Lu-DOTA 0,Tyr 3]octreotate (Article)

2011-09-01T00:00:00Z

Quality of life (QOL) is an important outcome in cancer therapy. In this study, we investigated the QOL and symptoms after [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) therapy in patients with inoperable or metastasized gastroenteropancreatic or bronchial neuroendocrine tumors (NETs). Methods: Two hundred sixty-five Dutch patients completed the QOL questionnaire of the European Organization for the Research and Treatment of Cancer after being treated for NETs. ANOVA was used for statistical analyses, with a P value of 0.05 or less being considered significant. Differences of at least 10 points in global health status (GHS)/QOL scores, symptom scores, and Karnofsky performance scores (KPS) before and after therapy were regarded as indicating an improvement. Results: Regardless of the treatment outcome, GHS/QOL, insomnia, appetite loss, and diarrhea improved significantly in the total group. These improvements were also seen in patients with bone metastases or a decrease of 50% or more in chromogranin A. Improvement in the scores by at least 10 points was also analyzed in a subgroup of patients with decreased GHS/QOL or symptoms at the start of therapy: in 36% of these patients, GHS/QOL improved after therapy; in 49%, fatigue; in 70%, nausea plus vomiting; in 53%, pain; in 44%, dyspnea; in 59%, insomnia; in 63%, appetite loss; in 60%, constipation; and in 67%, diarrhea. Additionally, we did not see a statistically significant deterioration in patients who had GHS/QOL 100, KPS 100, or no symptoms at the start. In patients with initial stable disease or remission after treatment, GHS/QOL and KPS decreased significantly when re-growth of the tumors occurred. Conclusion: GHS/QOL, KPS, and symptoms improved significantly after177Lu-octreotate therapy, and there was no significant decrease in QOL in patients who had no symptoms before therapy. In patients who had suboptimal scores for GHS/QOL or symptoms before therapy, a clinically significant improvement was demonstrated. Our results indicate that177Lu-octreotate therapy not only reduces tumors and prolongs overall survival but also improves the patients' self-assessed QOL. Copyright

Gastrin-releasing peptide receptor-based targeting using bombesin analogues is superior to metabolism-based targeting using choline for in vivo imaging of human prostate cancer xenografts (Article)

2011-07-01T00:00:00Z

Purpose: Prostate cancer (PC) is a major health problem. Overexpression of the gastrin-releasing peptide receptor (GRPR) in PC, but not in the hyperplastic prostate, provides a promising target for staging and monitoring of PC. Based on the assumption that cancer cells have increased metabolic activity, metabolism-based tracers are also being used for PC imaging. We compared GRPR-based targeting using the68Ga-labelled bombesin analogue AMBA with metabolism-based targeting using18F-methylcholine (18F-FCH) in nude mice bearing human prostate VCaP xenografts. Methods: PET and biodistribution studies were performed with both68Ga-AMBA and18F-FCH in all VCaP tumour-bearing mice, with PC-3 tumour-bearing mice as reference. Scanning started immediately after injection. Dynamic PET scans were reconstructed and analysed quantitatively. Biodistribution of tracers and tissue uptake was expressed as percent of injected dose per gram tissue (%ID/g). Results: All tumours were clearly visualized using68Ga-AMBA.18F-FCH showed significantly less contrast due to poor tumour-to-background ratios. Quantitative PET analyses showed fast tumour uptake and high retention for both tracers. VCaP tumour uptake values determined from PET at steady-state were 6.7±1.4%ID/g (20-30 min after injection, N=8) for68Ga-AMBA and 1.6±0.5%ID/g (10-20 min after injection, N=8) for18F-FCH, which were significantly different (p<0.001). The results in PC-3 tumour-bearing mice were comparable. Biodistribution data were in accordance with the PET results showing VCaP tumour uptake values of 9.5±4.8%ID/g (N=8) for68Ga-AMBA and 2.1±0.4%ID/g (N=8) for18F-FCH. Apart from the GRPR-expressing organs, uptake in all organs was lower for68Ga-AMBA than for18F-FCH. Conclusion: Tumour uptake of68Ga-AMBA was higher while overall background activity was lower than observed for18F-FCH in the same PC-bearing mice. These results suggest that peptide receptor-based targeting using the bombesin analogue AMBA is superior to metabolism-based targeting using choline for scintigraphy of PC.

68Ga-labeled DOTA-peptides and 68Ga-labeled radiopharmaceuticals for positron emission tomography: Current status of research, clinical applications, and future Perspectives (Article)

2011-07-01T00:00:00Z

In this review we give an overview of current knowledge of68Ga-labeled pharmaceuticals, with focus on imaging receptor-mediated processes. A major advantage of a68Ge/68Ga generator is its continuous source of68Ga, independently from an on-site cyclotron. The increase in knowledge of purification and concentration of the eluate and the complex ligand chemistry has led to68Ga-labeled pharmaceuticals with major clinical impact.68Ga-labeled pharmaceuticals have the potential to cover all today's clinical options with99mTc, with the concordant higher resolution of positron emission tomography (PET) in comparison with single photon emission computed tomography.68Ga-labeled analogs of octreotide, such as DOTATOC, DOTANOC, and DOTA-TATE, are in clinical application in nuclear medicine, and these analogs are now the most frequently applied of all68Ga-labeled pharmaceuticals. All the above-mentioned items in favor of successful application of68Ga-labeled radiopharmaceuticals for imaging in patients are strong arguments for the development of a68Ge/68Ga generator with Marketing Authorization and thus to provide pharmaceutical grade eluate. Moreover, now not one United States Food and Drug Administration-approved or European Medicines Agency-approved68Ga-radiopharmaceutical is available. As soon as these are achieved, a whole new radiopharmacy providing PET radiopharmaceuticals might develop.

The relation between 25-hydroxyvitamin D with peak bone mineral density and body composition in healthy young adults (Article)

2011-06-01T00:00:00Z

Objective: 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.

Dosimetry of yttrium-labelled radiopharmaceuticals for internal therapy: 86Y or 90Y imaging? (Article)

2011-05-01T00:00:00Z

This paper reviews issues concerning86Y positron emission tomography (PET),90Y PET and90Y bremsstrahlung imaging. Specific methods and corrections developed for quantitative imaging, for application in preclinical and clinical studies, and to assess90Y dosimetry are discussed. The potential imaging capabilities with the radioisotopes87Y and88Y are also considered. Additional studies required to assess specific unaddressed issues are also identified.

Reduction of 68Ge activity containing liquid waste from 68Ga PET chemistry in nuclear medicine and radiopharmacy by solidification (Article)

2011-04-01T00:00:00Z

PET with68Ga from the TiO2- or SnO2- based68Ge/68Ga generators is of increasing interest for PET imaging in nuclear medicine. In general, radionuclidic purity (68Ge vs.68Ga activity) of the eluate of these generators varies between 0.01 and 0.001%. Liquid waste containing low amounts of68Ge activity is produced by eluting the68Ge/68Ga generators and residues from PET chemistry. Since clearance level of68Ge activity in waste may not exceed 10 Bq/g, as stated by European Directive 96/29/EURATOM, our purpose was to reduce68Ge activity in solution from >10 kBq/g to <10 Bq/g; which implies the solution can be discarded as regular waste. Most efficient method to reduce the68Ge activity is by sorption of TiO2or Fe2O3and subsequent centrifugation. The required 10 Bq per mL level of68Ge activity in waste was reached by Fe2O3logarithmically, whereas with TiO2asymptotically. The procedure with Fe2O3eliminates â‰¥ 90% of the68Ge activity per treatment. Eventually, to simplify the processing a recirculation system was used to investigate68Ge activity sorption on TiO2, Fe2O3or Zeolite. Zeolite was introduced for its high sorption at low pH, therefore68Ge activity containing waste could directly be used without further interventions.68Ge activity containing liquid waste at different HCl concentrations (0.05-1.0 M HCl), was recirculated at 1 mL/min. With Zeolite in the recirculation system,68Ge activity showed highest sorption.

Somatostatin Receptor-Targeted Radionuclide Therapy in Patients with Gastroenteropancreatic Neuroendocrine Tumors (Article)

2011-03-01T00:00:00Z

Treatment with radiolabeled somatostatin analogs is a promising tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all 111Indium-, 90Yttrium-, or 177Lutetium-labeled somatostatin analogs used for peptide receptor radionuclide therapy. If kidney protective agents are used, the side-effects are few and mild, and the median duration of the therapy response is 30 and 40 months, respectively. Overall survival is several years from diagnosis. These data compare favorably with the limited number of alternative treatments. If more widespread use of PRRT can be guaranteed, such therapy may become the therapy of first choice.

Somatostatin analogs for the treatment of neuroendocrine tumors (Article)

2011-03-01T00:00:00Z

Somatostatin is an important regulator of endocrine and exocrine secretion, affecting the release of many hormones. The effects of somatostatin are mediated through its interaction with one of five somatostatin receptors. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express multiple somatostatin receptors, making them excellent potential therapeutic targets. Many trials have shown that treatment with somatostatin analogs is associated with disease stabilization and prolonged survival. More recently, somatostatin analogs have been shown to have antiproliferative effects, thus broadening the scope of their uses. In this review, we update the current data on the treatment of GEP-NETs with somatostatin analogs, with particular emphasis on the results of the PROMID study. In addition, we discuss the current state of knowledge of novel therapies against GEP-NETs, including the use of somatostatin analogs with broader receptor binding profiles, chimeric somatostatin-dopamine molecules, combinations of somatostatin analogs with other active chemotherapy agents, and peptide receptor-targeted radionuclide therapy.

Characteristics of SnO2-based 68Ge/68Ga generator and aspects of radiolabelling DOTA-peptides (Article)

2011-02-01T00:00:00Z

Objectives: PET scintigraphy with68Ga-labelled analogs is of increasing interest in Nuclear Medicine and performed all over the world. Here we report the characteristics of the eluate of SnO2-based68Ge/68Ga generators prepared by iThemba LABS (Somerset West, South Africa). Three purification and concentration techniques of the eluate for labelling DOTA-TATE and concordant SPE purifications were investigated. Methods: Characteristics of 4 SnO2-based generators (range 0.4-1GBq68Ga in the eluate) and several concentration techniques of the eluate (HCl) were evaluated. The elution profiles of SnO2-based68Ge/68Ga generators were monitored, while [HCl] of the eluens was varied from 0.3-1.0M. Metal ions and sterility of the eluate were determined by ICP. Fractionated elution and concentration of the68Ga eluate were performed using anion and cation exchange. Concentrated68Ga eluate, using all three concentration techniques, was used for labelling of DOTA-TATE.68Ga-DOTA-TATE-containing solution was purified and RNP increased by SPE, therefore also 11 commercially available SPE columns were investigated. Results: The amount of elutable68Ga activity varies when the concentration of the eluens, HCl, was varied, while68Ge activity remains virtually constant. SnO2-based68Ge/68Ga generator elutes at 0.6M HCl >100% of the68Ga activity at calibration time and ±75% after 300 days. Eluate at discharge was sterile and Endotoxins were <0.5EU/mL, RNP was always <0.01%. Metal ions in the eluate were <10ppm (in total). Highest desorption for anion purification was obtained with the 30mg Oasis WAX column (>80%). Highest desorption for cation purification was obtained using a solution containing 90% acetone at increasing molarity of HCl, resulted in a68Ga desorption of 68±8%. With all68Ge/68Ga generators and for all 3 purification methods a SA up to 50MBq/nmol with >95% incorporation (ITLC) and RCP (radiochemical purity) by HPLC ±90% could be achieved. Purification and concentration of the eluate with anion exchange has the benefit of more elutable68Ga with 1M HCl as eluens. The additional washing step of the anion column with NaCl and ethanol, resulted in a lower and less variable [H+] in the eluate, and, as a result the pH in the reaction vial is better controlled, more constant, and less addition of buffer is required and concordant smaller reaction volumes. Desorption of68Ga-DOTA-TATE of SPE columns varied, highest desorption was obtained with Baker C18100mg (84%). Purification of68Ga-DOTA-TATE by SPE resulted in an RNP of <10-4%. Conclusions: Eluate of SnO2-based68Ge/68Ga generator, either by fractionated elution as by ion exchange can be used for labelling DOTA-peptides with68Ga at a SA of 50MBq/nmol at >95% incorporation and a RCP of ±90%. SPE columns are very effective to increase RNP.

Dynamic and static small-animal SPECT in rats for monitoring renal function after177Lu-labeled Tyr3-octreotate radionuclide therapy (Article)

2010-12-01T00:00:00Z

High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with β-particle-emitting radio-labeled somatostatin analogs will lead to renal failure several months after treatment, urging the coinfusion of the cationic amino acids lysine and arginine to reduce the renal radiation dose. In rat PRRT studies, renal protection by the coadministration of lysine was confirmed by histologic examination of kidney specimens indicating nephrotoxicity. In the current study, we investigated dedicated small-animal SPECT/CT renal imaging in rats to monitor renal function in vivo during follow-up of PRRT, with and without lysine. Methods: The following 3 groups of rats were imaged using a multipinhole SPECT/CT camera: controls (group 1) and rats at more than 90 d after therapy with 460 MBq (15 μg) of 177Lu-DOTA-Tyr3-octreotate without (group 2) or with (group 3) a 400-mg/kg lysine coinjection as kidney protection (n ≥ 6 per group). At 90 and 140 d after therapy, static kidney scintigraphy was performed at 2 h after injection of 25 MBq of 99mTc-dimercaptosuccinic acid (99mTc-DMSA). In addition, dynamic dual-isotope renography was performed using 50 MBq of 111In-diethylenetriaminepentaacetic acid (111In-DTPA) and 50 MBq of 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) at 100-120 d after therapy. Results: 111In-DTPA and 99mTc-MAG3 studies revealed a time-activity pattern comparable to those in patients, with a peak at 2-6 min followed by a decline of renal radioactivity. Reduced 111In-DTPA, 99mTc-MAG3, and 99mTc-DMSA uptake indicated renal damage in group 2, whereas group 3 showed only a decrease of 99mTc-MAG3 peak activity. These results indicating nephrotoxicity in group 2 and renal protection in group 3 correlated with levels of urinary protein and serum creatinine and urea and were confirmed by renal histology. Conclusion: Quantitative dynamic dual-isotope imaging using both 111In-DTPA and 99mTc-MAG3 and static 99mTc-DMSA imaging in rats is feasible using small-animal SPECT, enabling longitudinal monitoring of renal function. 99mTc-MAG3 renography, especially, appears to be a more sensitive marker of tubular function after PRRT than serum chemistry or 99mTc-DMSA scintigraphy.

Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy (Article)

2010-09-01T00:00:00Z

The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have increased in the past 20 years. GEP-NETs are heterogeneous tumors, in terms of clinical and biological features, that originate from the pancreas or the intestinal tract. Some GEP-NETs grow very slowly, some grow rapidly and do not cause symptoms, and others cause hormone hypersecretion and associated symptoms. Most GEP-NETs overexpress receptors for somatostatins. Somatostatins inhibit the release of many hormones and other secretory proteins; their effects are mediated by G proteincoupled receptors that are expressed in a tissue-specific manner. Most GEP-NETs overexpress the somatostatin receptor SSTR2; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone-related symptoms and also have antitumor effects. Long-acting formulations of somatostatin analogues stabilize tumor growth over long periods. The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP-NETs. Peptide receptor radiotherapy has significant antitumor effects, increasing overall survival times of patients with tumors that express a high density of SSTRs, particularly SSTR2 and SSTR5. The multi-receptor somatostatin analogue SOM230 (pasireotide) and chimeric molecules that bind SSTR2 and the dopamine receptor D2 are also being developed to treat patients with GEP-NETs. Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways, such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor, might be the most effective therapeutics for GEP-NETs.

NANETS Consensus Guideline for the Diagnosis and Management of Neuroendocrine Tumors: Well-Differentiated Neuroendocrine Tumors of the Thorax (Includes Lung and Thymus) (Article)

2010-08-01T00:00:00Z

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;26[18]:3063-3072). 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;5[5]:367-375). 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. Copyright

A standardised study to compare prostate cancer targeting efficacy of five radiolabelled bombesin analogues (Article)

2010-07-01T00:00:00Z

Purpose: Prostate-specific antigen (PSA)-based screening for prostate cancer (PC) has dramatically increased early diagnosis. Current imaging techniques are not optimal to stage early PC adequately. A promising alternative to PC imaging is peptide-based scintigraphy using radiolabelled bombesin (BN) analogues that bind to gastrin-releasing peptide receptors (GRPR) being overexpressed in PC. When labelled to appropriate radionuclides BN targeting of GRPRs may also provide applications for peptide radionuclide receptor therapy (PRRT). Assessment studies under identical experimental conditions allowing a reliable comparison of the potential of such analogues are lacking. This study was performed to evaluate and directly compare five promising radiolabelled BN analogues for their targeting efficacy for PC under standardised conditions. Methods: The BN agonists [111In]DOTA-PESIN, [111In]AMBA, [111In]MP2346 and [111In]MP2653 and one antagonist [99mTc]Demobesin-1 were evaluated in GRPR-overexpressing human PC-3 tumour-bearing mice to determine peptide stability in vivo, biodistribution and GRPR targeting potential by animal SPECT/CT imaging and ex vivo autoradiography. Results: HPLC analysis of blood showed intact Demobesin-1 at 5 and 15 min after injection (64.1 ± 1.6% and 41.0 ± 01%, respectively) being much less for the other compounds. AMBA, the second most stable analogue, showed 36.1 ± 2.7% and 9.8 ± 1.1% intact peptide after 5 and 15 min. PC-3 tumour uptake at 1 h was comparable for Demobesin-1, AMBA, PESIN and MP2346 (3.0 ± 0.4, 2.7 ± 0.5, 2.3 ± 0.5 and 2.1 ± 0.9%ID/g, respectively), but very low for MP2653 (0.9 ± 0.2%ID/g). In addition, MP2346 showed undesirably high uptake in the kidneys (7.9 ± 1.9%ID/g) being significantly less for the other analogues. AMBA, MP2346 and PESIN revealed favourable increases in tumour to blood ratios over time while changes in tumour to kidney and pancreas ratios for Demobesin-1 from 1 to 24 h after injection were significantly better than for the other analogues. All analogues visualised PC-3 tumours by SPECT/CT and autoradiography. Conclusion: In the present study the BN antagonist Demobesin-1 was the best performing analogue showing superior in vivo stability, highest tumour uptake and retention while pancreatic and renal clearance were rapid. PESIN and AMBA were the best GRP agonists with sufficient in vivo stabilities as well as high tumour uptake and retention. Based on these results all three analogues deserve further evaluation for clinical use in PC patients.

Androgen-regulated gastrin-releasing peptide receptor expression in androgen-dependent human prostate tumor xenografts (Article)

2010-06-15T00:00:00Z

Human prostate cancer (PC) overexpresses the gastrin-releasing peptide receptor (GRPR). Radiolabeled GRPR-targeting analogs of bombesin (BN) have successfully been introduced as potential tracers for visualization and treatment of GRPR-overexpressing tumors. A previous study showed GRPR-mediated binding of radiolabeled BN analogs in androgen-dependent but not in androgen-independent xenografts representing the more advanced stages of PC. We have further investigated the effect of androgen modulation on GRPR-expression in three androgen-dependent human PC-bearing xenografts: PC295, PC310 and PC82 using the androgen-independent PC3-model as a reference. Effects of androgen regulation on GRPR expression were initially studied on tumors obtained from our biorepository of xenograft tissues performing reverse transcriptase polymerase chain reaction (RT-PCR) and autoradiography (125I-universal-BN). A prospective biodistribution study (111In-MP2653) and subsequent autoradiography (125I-GRP and111In-MP2248) was than performed in castrated and testosterone resupplemented tumor-bearing mice. For all androgen-dependent xenografts, tumor uptake and binding decreased drastically after 7 days of castration. Resupplementation of testosterone to castrated animals restored GRPR expression extensively. Similar findings were concluded from the initial autoradiography and RT-PCR studies. Results from RT-PCR, for which human specific primers are used, indicate that variations in GRPR expression can be ascribed to mRNA downregulation and not to castration-induced reduction in the epithelial fraction of the xenograft tumor tissue. In conclusion, expression of human GRPR in androgendependent PC xenografts is reduced by androgen ablation and is reversed by restoring the hormonal status of the animals. This knowledge suggests that hormonal therapy may affect GRPR expression in PC tissue making GRPR-based imaging and therapy especially suitable for non-hormonally treated PC patients.

Nephrotoxicity in mice after repeated imaging using 111In- labeled peptides (Article)

2010-06-01T00:00:00Z

We determined the renal radiation dose of a series of111Inlabeled peptides using animal SPECT. Because the animals' health deteriorated, renal toxicity was assessed. Methods: Wild-type and megalin-deficient mice were imaged repeatedly at 3- to 6-wk intervals to quantify renal retention after injection of 40-50 MBq of111In- diethylenetriaminepentaacetic acid-labeled peptides (octreotide, exendin, octreotate, neurotensin, and minigastrin analogs), and the absorbed kidney radiation doses were estimated. Body weight, renal function parameters, and renal histology were determined at 16-20 wk after the first scan and compared with those in naive animals. Results: Because of high renal retention,111In-diethylenetriaminepentaacetic acid-exendin-4 scans resulted in a 70-Gy kidney radiation dose in wild-type mice. Megalin-deficient kidneys received 20-40 Gy. The other peptides resulted in much lower renal doses. Kidney function monitoring indicated renal damage in imaged animals. Conclusion: Micro-SPECT enables longitudinal studies in 1 animal. However, long-term nephrotoxic effects may be induced after high renal radiation doses, even with111In-labeled radiotracers. COPYRIGHT

Preclinical and Clinical Studies of Peptide Receptor Radionuclide Therapy (Article)

2010-05-01T00:00:00Z

In the 1980s, the111In-labeled somatostatin analog OctreoScan (Covidien, Hazelwood, MO) was developed for imaging of somatostatin receptor subtype 2 (sst2) overexpressing tumors. On the basis of this success, peptide receptor radionuclide therapy (PRRT) was developed using similar somatostatin analogs with different therapeutic radionuclides. Clinical application of PRRT demonstrated impressive results on tumor response, overall survival, and quality of life in patients with gastroenteropancreatic neuroendocrine tumors. The peptides 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), Tyr3-octreotate (DOTATATE) and DOTA, Tyr3-octreotide (DOTATOC) (brand name Onalta), predominantly targeting sst2, have been granted Orphan Drug status by the European Medicines Agency and the US Food and Drug Administration for application in PRRT. Besides somatostatin receptor-targeting peptides, multiple other radiopeptide analogs were developed targeting several other receptors overexpressed on various tumors. Some of these peptide analogs, including cholecystokinin, gastrin, gastrin-releasing peptide, arginine-glycine-aspartate (RGD)-peptides, and glucagon-like peptide 1 analogs appeared very promising in preclinical and clinical imaging and PRRT studies. Although the success of PRRT with radiolabeled somatostatin analogs has been established, there is still room for improvement. The therapeutic window of PRRT could be enlarged by the use of new and improved targeting compounds, of which new antagonists with excellent tumor to background ratios are very promising. Furthermore, locoregional administration, improved healthy tissue protection, and combination treatment can be applied to increase the effectiveness of PRRT. Combination treatment might include cocktails of different peptide analogs of different therapeutic radionuclides and of radiolabeled peptides with chemotherapeutic or radiosensitizing agents. This review summarizes results of PRRT and describes clinical and preclinical studies regarding PRRT optimizing strategies.

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues (Article)

2010-05-01T00:00:00Z

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower renal retention may be developed. Furthermore, knowledge on kidney protection from radiolabelled somatostatin analogues may be expanded to other peptides.

Somatostatin receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors (Article)

2010-03-01T00:00:00Z

Somatostatin receptor imaging (SRI) with [111In-DTPA 0]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors (GEPNETs). Newer radiolabeled somatostatin analogs which can be used in positron emission tomography (PET) imaging, and which have a higher affinity for the somatostatin receptor, especially receptor subtype-2, have been developed. It would be desirable, however, if one radiolabeled analog became the new standard for PET imaging, because the current application of a multitude of analogs implies a fragmented knowledge on the interpretation of the images that are obtained in clinical practice. In our view, the most likely candidates for such a universal PET tracer for SRI are [68Ga-DOTA0,Tyr3]octreotate or [68Ga-DOTA0,Tyr3]octreotide. Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all 111In-, 90Y-, or 177Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy (PRRT). The results that were obtained with [ 90Y-DOTA0,Tyr3]octreotide and [ 177Lu-DOTA0,Tyr3]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months respectively. The patients' self-assessed quality of life increases significantly after treatment with [177Lu-DOTA0,Tyr 3]octreotate. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with [177Lu-DOTA0,Tyr3]- octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable GEPNETs.

Peptide Receptor Radionuclide Therapy in Patients With Gastroenteropancreatic Neuroendocrine Tumors (Article)

2010-03-01T00:00:00Z

Somatostatin receptor imaging with [111In-DTPA0)octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors. Treatment with radiolabeled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized, well-differentiated neuroendocrine tumors. Symptomatic improvement may occur with all111In,90Y, or177Lu-labeled somatostatin analogues that have been used for peptide receptor radionuclide therapy. The results that were obtained with [90Y-DOTA0, Tyr3]octreotide and [177Lu-DOTA0, Tyr3]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months, respectively. The patients' self-assessed quality of life increases significantly after treatment with [177Lu-DOTA0, Tyr3]octreotate. Finally, compared with historical controls, there is a benefit in overall survival of several years from time of diagnosis in patients treated with [177Lu-DOTA0, Tyr3]octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of peptide receptor radionuclide therapy can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable gastroenteropancreatic neuroendocrine tumors.

Salvage therapy with177Lu-octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumors (Article)

2010-03-01T00:00:00Z

Regular therapy with the radiolabeled somatostatin analog177Lu-octreotate (22.2-29.6 GBq) in patients with gastroenteropancreatic or bronchial neuroendocrine tumors results in tumor remission in 46% of patients, including minor response. We present the effects of additional therapy with177Lu-octreotate in patients in whom progressive disease developed after an initial benefit from regular therapy. Methods: Thirty-three patients with progressive disease after an initial radiologic or clinical response were treated with additional cycles of177Lu-octreotate. The intended cumulative dose of additional therapy was 14.8 GBq in 2 cycles. Responses were evaluated using Southwest Oncology Group criteria, including minor response (tumor size reduction of ≥25% and <50%). Results: Median time to progression (TTP) after regular therapy was 27 mo. In 4 patients, the intended cumulative dose was not achieved (2 had progressive disease, 2 had long-lasting thrombocytopenia). Hematologic toxicity grade 3 was observed in 4 patients, and grade 4, in 1. The median follow-up time was 16 mo (range, 1-40 mo). No kidney failure or myelodysplastic syndrome was observed. Renewed tumor regression was observed in 8 patients (2 partial remission, 6 minor response), and 8 patients had stable disease. Median TTP was 17 mo. Treatment outcome was less favorable in patients with a short TTP after regular cycles. Treatment effects in patients with pancreatic neuroendocrine tumors were similar to those in patients with other gastroenteropancreatic neuroendocrine tumors. Conclusion: Most patients tolerated additional cycles with177Lu-octreotate well. None developed serious delayed adverse events. Additional cycles with177Luoctreotate can have antitumor effects, but effects were less than for the regular cycles. This may be because of a worse clinical condition, more extensive tumor burden, or changed tumor characteristics. We conclude that this salvage therapy can be effective and is safe. Copyright

Dose-response effect of Gelofusine on renal uptake and retention of radiolabelled octreotate in rats with CA20948 tumours (Article)

2009-12-01T00:00:00Z

Purpose: Peptide receptor radionuclide therapy using β-emitting radiolabelled somatostatin analogues like DOTA,Tyr3-octreotate shows beneficial results in patients suffering from somatostatin receptor overexpressing tumours. However, after high-dose therapy partial renal reabsorption of radiopeptides may lead to nephrotoxicity. Co-infusion of lysine/arginine lowers renal retention of these radiopeptides without affecting tumour uptake. Recently co-administration of Gelofusine has been described to have a comparable kidney-protecting effect in rats. In the present study optimal dosing of Gelofusine co-administration was studied in tumour-bearing rats. Methods: Doses of 40, 80, 120 or 160 mg/kg Gelofusine were co-injected with 15 μg DOTA,Tyr3-octreotate, labelled with 3 MBq111In for biodistribution (24 h post-injection, n=4 per group) and with 60 MBq111In for microSPECT imaging experiments at 3, 24 and 48 h post-injection. An additional group of rats received 80 mg/kg Gelofusine plus 400 mg/kg lysine co-injection. Biodistribution studies were performed both in older (475 g) and younger (300 g) rats, the latter bearing CA20948 tumours. Results: Co-injection of 40 mg/kg Gelofusine resulted in 40-50% reduction of renal uptake and retention of111In-DOTA,Tyr3-octreotate, whereas higher doses further increased the reduction to 50-60% in both groups of rats. Combining Gelofusine and lysine caused 70% reduction of renal uptake. The uptake of radiolabelled octreotate both in somatostatin receptor-expressing normal tissues and tumours was not affected by Gelofusine co-injection. Conclusion: In rats co-injection of 80 mg/kg Gelofusine resulted in maximum reduction of renal retention of111In-DOTA,Tyr3- octreotate, which was further improved when combined with lysine. Tumour uptake of radiolabelled octreotate was not affected, resulting in an increased tumour to kidney ratio.

Imaging of activated macrophages in experimental osteoarthritis using folate targeted animal SPECT/CT (Article)

2009-09-09T00:00:00Z

Objective. Evaluation of macrophage activation may provide essential information about aetiology and progression rate of osteoarthritis. Activated macrophages abundantly express the folate-receptor-beta (FR-β), which can be targeted using radioactive labelled folic acid. The purpose of this study was to investigate if macrophage activation can be monitored in small animal OA models using a folate radiotracer and to test if macrophage activation differs in different models of OA and subsequent different OA progression. Methods. Two rat models of OA were used: the monoiodoacetate (MIA) model, which is a fast progressing biochemical induced model and the anterior cruciate ligament transaction (ACLT) model that induces OA at a slower pace. Images were obtained using high resolution small animal SPECT/CT. Specificity of the technique was tested by eradicating macrophages using clodronate laden liposomes and blockade of the FR-β by cold folic acid. Results. The MIA model had a high initial activation with a peak after two weeks which disappeared after eight weeks. The ACLT model showed less activation but was still active 12 weeks after induction. The technique allowed monitoring of the disease process over time, in which late stage disease showed less macrophage activation than early onset stages especially in the fast progressing MIA model for OA. Conclusion. Macrophage activation in experimental OA could clearly be demonstrated and monitored by the folate radiotracer. The high resolution, high sensitivity and high specificity of the used technique allowed clear localisation of macrophage activity in a disease model, which is not known for abundant macrophage involvement.

ENETS consensus guidelines for the standards of care in neuroendocrine tumors: Somatostatin receptor imaging with IIIIn-pentetreotide (Article)

2009-08-01T00:00:00Z

ENETS consensus guidelines for the standards of care in neuroendocrine tumors: Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs (Article)

2009-08-01T00:00:00Z

The purpose of this guideline is to assist physicians caring for patients with neuroendocrine tumors in considering eligibility criteria for peptide receptor radionuclide therapy (PRRT), and in defining the minimum requirements for PRRT. This guideline also makes recommendations on what minimal patient, tumor, and treatment outcome characteristics should be reported for PRRT in order to make comparisons between studies possible. It is not this guideline's aim to give specific recommendations on the use of specific radiolabeled somatostatin analogs for PRRT because different analogs are being used, and their availability depends on national law and local permissions.

Bone marrow dosimetry in peptide receptor radionuclide therapy with [ 177Lu-DOTA0,Tyr3]octreotate (Article)

2009-07-01T00:00:00Z

Purpose: Adequate dosimetry is mandatory for effective and safe peptide receptor radionuclide therapy (PRRT). Besides the kidneys, the bone marrow is a potentially dose-limiting organ. The radiation dose to the bone marrow is usually calculated according to the MIRD scheme, where the accumulated activity in the bone marrow is calculated from the accumulated radioactivity of the radiopharmaceutical in the blood. This may underestimate the absorbed dose since stem cells express somatostatin receptors. We verified the blood-based method by comparing the activity in the blood with the radioactivity in bone marrow aspirates. Also, we evaluated the absorbed cross-dose from the source organs (liver, spleen, kidneys and blood), tumours and the so-called "remainder of the body" to the bone marrow. Methods: Bone marrow aspirates were drawn in 15 patients after treatment with [177Lu-DOTA0,Tyr3]octreotate. Radioactivity in the bone marrow was compared with radioactivity in the blood drawn simultaneously. The nucleated cell fraction was isolated from the bone marrow aspirate and radioactivity was measured. The absorbed dose to the bone marrow was calculated. The results were correlated to the change in platelet counts 6 weeks after treatment. Results: A strong linear correlation and high agreement between the measured radioactivities in the bone marrow aspirates and in the blood was found (r=0.914, p<0.001). No correlation between the calculated absorbed dose in the bone marrow and the change in platelets was found. There was a considerable contribution from other organs and the remainder of the body to the bone marrow absorbed dose. Conclusion: (1) After PRRT with [177Lu-DOTA0,Tyr3]octreotate, the radioactivity concentration in the bone marrow is identical to that in the blood; (2) There is no significant binding of the radiopharmaceutical to bone marrow precursor stem cells; (3) The contribution of the cross dose from source organs and tumours to the bone marrow dose is significant; and (4) There is considerable variation in bone marrow absorbed dose between patients. These findings imply that for individual dose optimization, individual calculation of the bone marrow absorbed dose is necessary.

Peptide-receptor radionuclide therapy for endocrine tumors (Article)

2009-07-01T00:00:00Z

Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a promising option for the treatment of somatostatin-receptor- positive endocrine tumors. Treatment with somatostatin analogs labeled with 111 In, 90 Y or 177 Lu can result in symptomatic improvement, although tumor remission is seldom achieved with 111 In-labeled analogs. In this Review, the findings of several studies on the use of PRRT for endocrine tumors are evaluated. Large variation in the antitumor effects of 90 Y-octreotide was reported between studies: an objective response (50% tumor regression) was achieved in 9-33% of patients. After treatment with 177 Lu-octreotate, an objective response was achieved in 29% of patients and a minor response (25-50% tumor regression) was achieved in 16% of patients; stable disease was present in 35% of patients. Treatment with 177 Lu-octreotate resulted in a survival benefit of several years and markedly improved quality of life. Serious, delayed adverse effects were rare after PRRT. Although randomized, clinical trials have not yet been performed, data on the use of PRRT compare favorably with those from other treatment approaches, such as chemotherapy. If these results can be replicated in large, controlled trials, PRRT might become the preferred option in patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors.

Effects of therapy with [177Lu-DOTA0,Tyr 3]octreotate on endocrine function (Article)

2009-06-03T00:00:00Z

Purpose: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes. Methods: Hormone levels were measured and adrenal function assessed at baseline and up to 24 months of follow-up. Results: In 35 men, mean serum inhibin B levels were decreased at 3 months post-therapy (205 ± 16 to 25 ± 4 ng/l, p < 0.05) and follicle-stimulating hormone (FSH) levels increased (5.9 ± 0.5 to 22.7 ± 1.4 IU/l, p < 0.05). These levels returned to near baseline levels. Total testosterone and sex hormone binding globulin (SHBG) levels decreased (15.0 ± 0.9 to 10.6 ± 1.0 nmol/l, p < 0.05 and 61.8 ± 8.7 to 33.2 ± 3.7 nmol, p < 0.05), respectively, whereas non-SHBG-bound T did not change. An increase (5.2 ± 0.6 to 7.7 ± 0.7 IU/l, p < 0.05) of luteinizing hormone (LH) levels was found at 3 months of follow-up returning to baseline levels thereafter. In 21 postmenopausal women, a decrease in levels of FSH (74.4 ± 5.6 to 62.4 ± 7.7 IU/l, p < 0.05) and LH (26.8 ± 2.1 to 21.1 ± 3.0 IU/l, p < 0.05) was found. Of 66 patients, 2 developed persistent primary hypothyroidism. Free thyroxine (FT4) levels decreased (17.7 ± 0.4 to 15.6 ± 0.6 pmol/l, p < 0.05), whereas thyroid-stimulating hormone (TSH) and triiodothyronine (T3) levels did not change. Reverse triiodothyronine (rT3) levels decreased (0.38 ± 0.03 to 0.30 ± 0.01 nmol/l, p < 0.05). Before and after therapy adrenocorticotropic hormone (ACTH) stimulation tests showed an adequate response of serum cortisol (> 550 nmol/l, n = 18). Five patients developed elevated HbA1clevels (> 6.5%). Conclusion: In men177Lu-octreotate therapy induced transient inhibitory effects on spermatogenesis, but non-SHBG-bound T levels remained unaffected. In the long term, gonadotropin levels decreased significantly in postmenopausal women. Only a few patients developed hypothyroidism or elevated levels of HbA1c. Therefore, PRRT with177Lu-octreotate can be regarded as a safe treatment modality with respect to short-and long-term endocrine function.

Bone mineral density and body composition in adolescents with childhood-onset growth hormone deficiency (Article)

2009-06-01T00:00:00Z

Background/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.

Bone mineral density, growth, and thyroid function in long-term survivors of pediatric Hodgkin's lymphoma treated with chemotherapy only (Article)

2009-06-01T00:00:00Z

Background: The aim of this study was to investigate the long-term side effects of treatment for childhood Hodgkin's lymphoma with chemotherapy only on growth, bone mineral density (BMD), body composition, and thyroid function. Procedure: A total of 88 patients (56 male, 32 female; 17.6-42.6 yr), treated for childhood Hodgkin's lymphoma from 1974-1998 with combination chemotherapy adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine or epirubicin, bleomycin, vinblastine, dacarbazine with or without mechlorethamine, oncovin (vincristine), procarbazine, and prednisone (MOPP) with the intention to avoid radiotherapy, participated in this study. Median follow-up was 15.5 yr (range 5.6 -30.2). BMD of lumbar spine and total body (BMD-TB), and body composition were measured using dual-energy x-ray absorptiometry. Bone mineral apparent density of the lumbar spine was calculated to correct for bone size. Free T4and TSH were measured. Results: Men treated with MOPP had a significantly reduced height with normal body proportions. Women treated with MOPP had decreased BMD-TB and bone mineral apparent density of the lumbar spine as compared with healthy controls. Percent body fat was significantly increased in female patients treated without MOPP. Body mass index was significantly increased in male patients treated without MOPP, whereas lean body mass was normal in all patients. All patients, except one, treated with chemotherapy only had normal thyroid function. However, five patients who received additional radiation to the thyroid either had abnormal levels of TSH or free T4, or used thyroid hormones. Conclusions: Lean body mass was normal in all patients; thyroid function was normal in all but one patient. The use of MOPP leads to decreased height and increased body mass index in men and decreased BMD-TB in women. Copyright

Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues (Article)

2009-06-01T00:00:00Z

Prostate Cancer (PC) is a type of cancer that is often diagnosed at very early stages due to improved detection among man in the Western world. Current imaging techniques are not optimal to determine extent of minimal early stage PC even though this is of great clinical importance. Human PC and high-grade PIN have shown high Gastrin-Releasing Peptide Receptor (GRPR) expression, while normal prostate tissue and BPH revealed to be predominantly GRPR-negative. Radiolabelled Gastrin-Releasing Peptide (GRP) or bombesin (BN) analogues targeting the GRPR can be used as non-invasive tools to diagnose, monitor and potentially treat PC. These BN analogues have already proven to be able to image PC in both tumour-bearing mice and clinical patients showing no important side effects. It's desirable that new peptides require fast-track standardised comparative testing in relevant PC models to select the best performing BN analogues for further evaluation in patients. Although knowledge about GRPR expression and development of new BN analogues can be extended, it is time to study performance of BN analogues for peptide receptor based imaging in patients validating results of PC imaging using histopathology as a golden standard.

Comparison of three radiolabelled peptide analogues for CCK-2 receptor scintigraphy in medullary thyroid carcinoma (Article)

2009-03-06T00:00:00Z

Purpose: Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in a high percentage of medullary thyroid carcinomas (MTC). Analogous to somatostatin receptors, CCK-2 receptors might be viable targets for radionuclide scintigraphy and/or radionuclide therapy. Several CCK-2 receptor-binding radiopeptides have been developed, and some have been carried through into clinical studies. However, these studies are mostly limited and difficult to compare. The aim of this study was to evaluate the diagnostic and therapeutic potential of three promising CCK-2 receptor-binding radiopeptides in patients with MTC. Methods: 111In-DOTA-(D)Asp-Tyr-Nle-Gly-Trp-Nle- Asp-Phe-NH2 (111In-DOTA-CCK), a CCK analogue, and the gastrin-based ligands 99mTc-N4-Gly-(D)Glu-(Glu) 5-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (99mTc- demogastrin 2) and 111In-DOTA-(D)Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe- NH2 (111In-DOTA-MG11) were each administered to the same group of six patients. Planar images made at 3-5, 7 and 24 h p.i. were used for comparison of tumour visualisation and renal uptake. Results: 99mTc-demogastrin 2 scintigraphy visualised all known lesions and new lesions in four of six patients. 111In-DOTA-CCK and 111In-DOTA-MG11 on the other hand missed several lesions; tumour uptake of these two radiopharmaceuticals was quite low. Comparison of retention of renal activity showed no major differences between the three radiopeptides. Conclusion: 99mTc-demogastrin 2 scintigraphy appeared most promising as a diagnostic tool in patients with MTC. Further studies are required to evaluate its value in patient management. Direct comparisons of the compounds studied strongly suggests that 111In-DOTA-CCK and 111In-DOTA-MG11 have less potential as imaging agents than 99mTc-demogastrin 2. These DOTA-linked compounds are considered unlikely to be useful for radionuclide therapy because of low tumour uptake.

Optimised labeling, preclinical and initial clinical aspects of CCK-2 receptor-targeting with 3 radiolabeled peptides (Article)

2008-11-01T00:00:00Z

Medullary thyroid carcinoma (MTC) expresses CCK-2 receptors.111In-labeled DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2(DOTA-MG11), DOTA-DAsp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2(DOTA-CCK), and99mTc-labeled N4-Gly-DGlu-(Glu)5-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2(99mTc-Demogastrin 2) are analogs developed for CCK-2 receptor-targeted scintigraphy. All 3 radiolabeled analogs were selected on the basis of their high CCK-2 receptor affinity and their good in vitro serum stability, with in vitro serum t1/2values of several hours. Radiolabeling of DOTA-peptides with111In requires a heating procedure, typically in the range of 80°-100°C up to 30 min. Following this procedure with DOTA-MG11 resulted in a >98 % incorporation of111In, however, with a radiochemical purity (RCP) of <50 %. The decrease in RCP was found to be due to oxidation of the methionine residue in the molecule. Moreover, this oxidized compound lost its CCK-2 receptor affinity. Therefore, conditions during radiolabeling were optimised: labeling of DOTA-MG11 and DOTA-CCK with111In involved 5 min heating at 80°C and led to an incorporation of111In of >98 %. In addition, all analogs were radiolabeled in the presence of quenchers to prevent radiolysis and oxidation resulting in a RCP of >90 %. All 3 radiolabeled analogs were i.v. administered to 6 MTC patients: radioactivity cleared rapidly by the kidneys, with no significant differences in the excretion pattern of the 3 radiotracers. All 3 radiolabeled analogs exhibited a low in vivo stability in patients, as revealed during analysis of blood samples, with the respective t1/2found in the order of minutes. In patient blood, the rank of radiopeptide in vivo stability was:99mTc-Demogastrin 2 (t1/210-15 min)>111In-DOTA-CCK (t1/2≈5-10 min)>111In-DOTA-MG11 (t1/2<5 min).

Treatment with the radiolabeled somatostatin analog [177Lu- DOTA0,Tyr3]octreotate: Toxicity, efficacy, and survival (Article)

2008-09-22T00:00:00Z

Purpose: Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slowgrowing, median overall survival (OS) in patients with liver metastases is 2 to 4 years. In metastatic disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate. Here we report on the toxicity and efficacy of this treatment, performed in over 500 patients. Patients and Methods: Patients were treated up to a cumulative dose of 750 to 800 mCi (27.8-29.6 GBq), usually in four treatment cycles, with treatment intervals of 6 to 10 weeks. Toxicity analysis was done in 504 patients, and efficacy analysis in 310 patients. Results: Any hematologic toxicity grade 3 or 4 occurred after 3.6% of administrations. Serious adverse events that were likely attributable to the treatment were myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. Complete and partial tumor remissions occurred in 2% and 28% of 310 GEPNET patients, respectively. Minor tumor response (decrease in size > 25% and < 50%) occurred in 16%. Median time to progression was 40 months. Median OS from start of treatment was 46 months, median OS from diagnosis was 128 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis. Conclusion: Treatment with [177Lu-DOTA0, Tyr3]octreotate has few adverse effects. Tumor response rates and progression-free survival compare favorably to the limited number of alternative treatment modalities. Compared with historical controls, there is a benefit in OS from time of diagnosis of several years.

Pemetrexed improves tumor selectivity of 111In-DTPA-folate in mice with folate receptor-positive ovarian cancer (Article)

2008-04-01T00:00:00Z

Folate-based radiopharmaceuticals can be used as imaging agents and for potential radiotherapy of folate receptor (FR)-positive malignant tissue (e.g., ovarian carcinomas). However, substantial FR expression in the kidneys results in undesired renal retention of radioactivity. Recently, we found that the preinjection of an antifolate significantly improved tumor selectivity of organometallic99mTc-radiofolates in mice. The aim of this study was to corroborate the effect of pemetrexed with the clinically tested111In-DTPA-folate (DTPA is diethylenetriaminepentaacetic acid) in a human ovarian cancer xenografted mouse model. Methods: In vivo studies were performed in female athymic nude mice bearing subcutaneous FR-positive ovarian tumors (IGROV-1 and SKOV-3) or metastases (after intraperitoneal SKOV-3 cell inoculation). Biodistribution studies were performed 1, 4, and 24 h after administration of111In-DTPA-folate (0.7 MBq/mouse, 0.35 μg) with or without preinjection of pemetrexed (PMX, 400 mg) 1 h before the radiofolate. Images were acquired with a high-resolution, high-sensitivity SPECT/CT camera, 4 and 24 h after injection of the radiotracer (30-50 MBq/ mouse, 4.5-10 μg). Results: In biodistribution studies the tumor uptake of111In-DTPA- folate (IGROV-1: 9.79 ± 3.21 %ID/g [percentage injected dose per gram]; SKOV-3: 7.57 ± 0.61 %ID/g, 4 h after injection) was high and retained over the time of investigation. However, considerable retention of radioactivity was found in kidneys (85-105 %ID/g, 4 h after injection), resulting in unfavorably low tumor-to-kidney ratios (∼0.10). Preinjection of PMX resulted in a significant reduction of renal uptake (20%-30% of control values, P < 0.03) at all time points after injection of111In-DTPA-folate, whereas the tumor uptake was retained. Thus, the tumor-to-kidney ratio was significantly increased to ∼0.50. SPECT/CT images confirmed the superior tumor-to-background ratio in mice injected with PMX. These findings were particularly evident in mice with SKOV-3 metastases that could be visualized only when111In-DTPA-folate was administered in combination with PMX. Conclusion: The application of PMX resulted in a significant reduction of undesired radioactivity accumulation in kidneys, whereas the tumor uptake remained unaffected. These observations suggest a general validity of the reducing effect of PMX on the uptake of radiofolates in kidneys. Our findings will lead the way toward the development of folate-based radiotherapy. Copyright

Report on short-term side effects of treatments with 177Lu- octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours (Article)

2008-04-01T00:00:00Z

Purpose: Treatment with the radiolabelled somatostatin analogue177Lu-octreotate results in tumour remission in 47% of patients with gastroenteropancreatic neuroendocrine tumours. Adding capecitabine to177Lu-octreotate, as a radio-sensitiser, may enhance these anti-tumour effects. We now present the short-term toxicity profile of this novel combination. Methods: Seven patients were treated with 7.4 GBq177Lu-octreotate and capecitabine (1650 mg/m2per day) for 2 weeks with an intended number of four cycles. Toxicity, and especially haematological and renal parameters, were monitored on a weekly basis for the first two cycles and 4 and 6 weeks after subsequent cycles. Results: None of the patients had hand-foot syndrome. One patient had grade 1 stomatitis occurring after one of four cycles. Grade 3 or 4 leukopenia or neutropenia did not occur. One patient had grade 3 anaemia, but none had grade 4 anaemia. One patient had grade 2 thrombocytopenia after the fourth cycle, and one had grade 3 thrombocytopenia. Grade 4 thrombocytopenia did not occur. No significant changes in serum creatinine levels were observed. None of the patients had symptoms of cardiac ischaemia. Conclusions: Treatment with the combination of177Lu-octreotate and capecitabine was feasible and safe considering acute and subacute side effects. We therefore started a randomised, controlled clinical trial to compare this combination with177Lu-octreotate as single agent with regard to anti-tumour effects and side effects.

Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr 3]octreotate (Article)

2008-04-01T00:00:00Z

Introduction: Receptor radionuclide therapy is a promising treatment modality for patients with neuroendocrine tumors for whom alternative treatments are limited. The aim of this study was to investigate the incidence of hormonal crises after therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). Materials and methods: All177Lu- octreotate treatments between January 2000 and January 2007 were investigated. Four hundred seventy-six patients with gastroenteropancreatic neuroendocrine tumors and three patients with metastatic pheochromocytoma were included for analysis. Results: Four hundred seventy-nine patients received a total of 1,693 administrations of177Lu-octreotate. Six of 479 patients (1%) developed severe symptoms because of massive release of bioactive substances after the first cycle of177Lu-octreotate. One patient had a metastatic hormone-producing small intestinal carcinoid; two patients had metastatic, hormone-producing bronchial carcinoids; two patients had vasoactive intestinal polypeptide-producing pancreatic endocrine tumors (VIPomas); and one patient had a metastatic pheochromocytoma. With adequate treatment, all patients eventually recovered. Conclusion: Hormonal crises after177Lu- octreotate therapy occur in 1% of patients. Generally,177Lu- octreotate therapy is well tolerated.

Therapy using labelled somatostatin analogues: Comparison of the absorbed doses with 111In-DTPA-D-Phe1-octreotide and yttrium-labelled DOTA-D-Phe1-Tyr3-octreotide (Article)

2008-03-01T00:00:00Z

OBJECTIVE: We estimated the absorbed doses for In-DTPA-D-Phe-octreotide and Y-DOTA-D-Phe-Tyr-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. METHODS: Six patients with neuroendocrine tumours underwent quantitative In-DTPA-D-Phe-octreotide SPECT and Y-DOTA-D-Phe-Tyr-octreotide PET scan at intervals of 1 week. All studies were performed with a co-infusion of amino acids for renal protection. PET and SPECT were reconstructed using iterative algorithms, incorporating attenuation and scatter corrections. Tissue uptakes (IA%) were measured and used to calculate residence times. Absorbed doses to tissues were estimated and the maximal allowed activity, defined as either the activity delivering 23 Gy to the kidneys (MAAK) or 2 Gy to the red marrow (MAARM), was calculated and the resulting tumour absorbed doses were computed. RESULTS: For the MAAK the mean absorbed dose to the red marrow was lower for Y-DOTA-D-Phe-Tyr-octreotide than for In-DTPA-D-Phe-octreotide (1.8±0.9 Gy vs. 6.4±1.6 Gy; P<0.001). The median absorbed dose to tumours for the MAAK was two-fold higher for Y-DOTA-D-Phe-Tyr-octreotide as compared to In-DTPA-D-Phe-octreotide (30.1 vs. 12.6 Gy; P<0.05). The median absorbed dose to tumours estimated for the MAARM was 10-fold higher for Y-DOTA-D-Phe-Tyr-octreotide than for In-DTPA-D-Phe-octreotide (35.1 Gy vs. 3.9 Gy; P<0.05). CONCLUSIONS: This direct intra-patient comparison confirms that the use of Y-DOTA-D-Phe-Tyr-octreotide is more appropriate for therapy of somatostatin receptor bearing tumours. When using In-DTPA-D-Phe-octreotide, the red marrow represents the major critical organ; this can result in significant toxicity if high activities have to be administered to obtain efficient tumour irradiation.

SPECT study of folate receptor-positive malignant and normal tissues in mice using a novel 99mTc-radiofolate (Article)

2008-02-01T00:00:00Z

The folate receptor (FR) is overexpressed on epithelial cancers (FR-α) and on activated, but not resting, macrophages (FR-β) involved in a variety of inflammatory and autoimmune diseases. Therefore, folate-based radiopharmaceuticals have the potential to be used as imaging agents of FR-positive tumor and inflammatory cells. In this study SPECT/CT of FR-positive malignant and normal tissues and organs in mice was performed using an improved organometallic99mTc-radiofolate. Methods: The99mTc radiolabeling of the histidine-folate was performed using the tricarbonyl technique described earlier for preparation of other organometallic radiofolates. Nude male mice with FR-positive KB tumor xenografts were used. Biodistribution studies were performed 1, 4, and 24 h after injection of the99mTc-Hisfolate (1.5 MBq/mouse). Images were acquired with a dedicated small-animal SPECT/CT camera 24 h after injection of the radiofolate (500 MBq/mouse). Ex vivo autoradiography was performed on tumors and FR-positive normal tissues. Adjacent sections were used for in vitro autoradiography of FRs after decay of the injected radioactivity. Results: The SPECT/CT studies revealed accumulation of the radiotracer in FR-positive KB tumor xenografts and kidneys as reported previously. At the same time, specific uptake of the radiofolate in normal tissues - that is, salivary glands and choroid plexus - could be visualized with SPECT. FR-specific accumulation in these tissues and organs was confirmed by coinjection of excess folic acid, which resulted in a complete blockade of radiofolate uptake. In addition, ex vivo and in vitro autoradiography of these organs and tissues confirmed FR expression and displayed radioactivity distribution patterns almost identical to those found on SPECT images. In biodistribution studies we found a high tumor uptake (4.29 ± 0.67 %ID/g [percentage of the injected dose per gram of tissue], 4 h after injection) that was almost completely retained over time (3.51 ± 0.37 %ID/g, 24 h after injection). Conclusion: The novel99mTc- histidine-folate showed improved in vivo characteristics compared with other organometallic radiofolates that allowed imaging of FR-positive malignant (KB tumor xenografts) and kidneys. For the first time, to our knowledge, specific tracer uptake in salivary glands and the choroid plexus could be visualized using a high-resolution animal SPECT/CT camera. Copyright

Gastroenteropancreatic neuroendocrine tumours (Article)

2008-01-01T00:00:00Z

Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.

Poorly-differentiated endocrine carcinomas of midgut and hindgut origin (Article)

2007-12-01T00:00:00Z

Consensus guidelines for the management of patients with digestive neuroendocrine tumors - Well-differentiated jejunal-ileal tumor/carcinoma (Article)

2007-12-01T00:00:00Z

Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: Foregut, midgut, hindgut, and unknown primary (Article)

2007-12-01T00:00:00Z

Consensus guidelines for the management of patients with digestive neuroendocrine tumours: Well-differentiated colon and rectum tumour/carcinoma (Article)

2007-12-01T00:00:00Z

Consensus guidelines for the management of patients with digestive neuroendocrine tumours: Well-differentiated tumour/carcinoma of the appendix and goblet cell carcinoma (Article)

2007-12-01T00:00:00Z

Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney (Article)

2007-11-01T00:00:00Z

Purpose: Renal irradiation is a dose-limiting factor in peptide receptor radionuclide therapy using radiolabelled somatostatin analogues. This irradiation is mainly caused by reabsorption of radiolabelled peptides in the proximal tubule. In the human kidney, somatostatin receptors are expressed in the vasa recta, tubuli and glomeruli. It is not clear to what extent these receptors contribute to the total kidney radioactivity uptake. Methods: Retrospectively, [111In-DTPA0]octreotide scans of ten selected patients with carcinoids (well-differentiated gastrointestinal endocrine tumour) with liver metastases were evaluated. For each patient, two scans were obtained: one scan was performed without (control) and one during treatment with unlabelled octreotide. Kidney, tumour, spleen and liver uptake was measured in both scans. Results: The interval between the two scans per patient varied from 50 to 397 days. Octreotide treatment substantially lowered kidney [111In-DTPA0]octreotide uptake in eight out of ten patients. Kidney uptake in all patients was reduced to 82%±15% of control, (p<0.01). A correlation between kidney uptake and spleen uptake was found (r=0.67, p<0.05). Serum creatinine was unchanged. Surprisingly, tumour and liver [111In-DTPA0]octreotide uptake was not significantly influenced by unlabelled octreotide therapy, but spleen uptake was significantly lowered by treatment (30.6% of control, p<0.002). Conclusion: We conclude that the somatostatin receptor plays a role in the total renal uptake of radiolabelled somatostatin analogues. The long interval between scans might explain the finding that tumour and liver metastasis uptake of [111In-DTPA0]octreotide was unchanged. Further studies are needed to confirm and eludicate the results of this study.

Peptide Receptor Radionuclide Therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours (Article)

2007-08-01T00:00:00Z

Peptide Receptor Radionuclide Therapy (PRRT) with radiolabelled somatostatin analogues is a promising treatment option for patients with inoperable or metastasised neuroendocrine tumours. Symptomatic improvement may occur with all of the various 111In, 90Y, or 177Lu-labelled somatostatin analogues that have been used. Since tumour size reduction was seldom achieved with 111Indium labelled somatostatin analogues, radiolabelled somatostatin analogues with beta-emitting isotopes like 90Y and 177Lu were developed. Reported anti-tumour effects of [90Y-DOTA0,Tyr3]octreotide vary considerably between various studies: Tumour regression of 50% or more was achieved in 9 to 33% (mean 22%). With [177Lu-DOTA0,Tyr3]octreotate treatments, tumour regression of 50% or more was achieved in 28% of patients and tumour regression of 25 to 50% in 19% of patients, stable disease was demonstrated in 35% and progressive disease in 18%. Predictive factors for tumour remission were high tumour uptake on somatostatin receptor scintigraphy and limited amount of liver metastases. The side-effects of PRRT are few and mostly mild, certainly when using renal protective agents: Serious side-effects like myelodysplastic syndrome or renal failure are rare. The median duration of the therapy response for [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate is 30 months and more than 36 months respectively. Lastly, quality of life improves significantly after treatment with [177Lu-DOTA0,Tyr3]octreotate. These data compare favourably with the limited number of alternative treatment approaches, like chemotherapy. If more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasised or inoperable gastroenteropancreatic neuroendocrine tumours. Also the role in somatostatin receptor expressing non-GEP tumours, like metastasised paraganglioma/ pheochromocytoma and non-radioiodine-avid differentiated thyroid carcinoma might become more important.

Renal uptake and retention of radiolabeled somatostatin, bombesin, neurotensin, minigastrin and CCK analogues: species and gender differences (Article)

2007-08-01T00:00:00Z

Introduction: During therapy with radiolabeled peptides, the kidney is most often the critical organ. Newly developed peptides are evaluated preclinically in different animal models before their application in humans. In this study, the renal retention of several radiolabeled peptides was compared in male and female rats and mice. Methods: After intravenous injection of radiolabeled peptides [somatostatin, cholecystokinin (CCK), minigastrin, bombesin and neurotensin analogues], renal uptake was determined in both male and female Lewis rats and C57Bl mice. In addition, ex vivo autoradiography of renal sections was performed to localize accumulated radioactivity. Results: An equal distribution pattern of renal radioactivity was found for all peptides: high accumulation in the cortex, lower accumulation in the outer medulla and no radioactivity in the inner medulla of the kidneys. In both male rats and mice, an increasing renal uptake was found: [111In-DTPA]CCK8<[111In-DTPA-Pro1,Tyr4]bombesin≈[111In-DTPA]neurotensin<[111In-DTPA]octreotide≪[111In-DTPA]MG0. Renal uptake of [111In-DTPA]octreotide in rats showed no gender difference, and renal radioactivity was about constant over time. In mice, however, renal uptake in females was significantly higher than that in males and decreased rapidly over time in both genders. Moreover, renal radioactivity in female mice injected with [111In-DTPA]octreotide showed a different localization pattern. Conclusions: Regarding the renal uptake of different radiolabeled peptides, both species showed the same ranking order. Similar to findings in patients, rats showed comparable and constant renal retention of radioactivity in both genders, in contrast to mice. Therefore, rats appear to be the more favorable species for the study of the renal retention of radioactivity.

Dose-dependent effects of (anti)folate preinjection on 99mTc-radiofolate uptake in tumors and kidneys (Article)

2007-08-01T00:00:00Z

Introduction: The folate receptor (FR) is frequently overexpressed in tumors and can be targeted with folate-based (radio)pharmaceuticals. However, significant accumulation of radiofolates in FR-positive kidneys represents a drawback. We have shown that preadministration of the antifolate pemetrexed (PMX) significantly improved the tumor-to-kidney ratio of radiofolates in mice. The aim of this study was to investigate the dose dependence of these effects and whether the same results could be achieved with folic acid (FA) or 5-methyl-tetrahydrofolate (5-Me-THF). Methods: Biodistribution was assessed 4 h postinjection of the organometallic99mTc-picolylamine monoacetic acid folate in nude mice bearing FR-positive KB tumor xenografts. PMX (50-400 μg/mouse) was injected 1 h previous to radioactivity. The effects of FA and 5-Me-THF (0.5-50 μg/mouse) were investigated likewise. Tissues and organs were collected and counted for radioactivity and the values tabulated as percentage of injected dose per gram tissue (% ID/g). Results: PMX administration reduced renal retention (<1.6% ID/g vs. control: >10% ID/g), while the tumor uptake (average 1.35%±0.40% ID/g vs. control: 1.79%±0.49% ID/g) was only slightly affected independent of the PMX dose. Replacement of PMX by FA or 5-Me-THF (50 μg/mouse) resulted in a significant renal blockade (<0.1% ID/g) but at the same time in an undesired reduction of tumor uptake (<0.2% ID/g). Conclusions: Selective reduction of radiofolate uptake in kidneys under retention of high tumor accumulation could be achieved in combination with PMX over a broad dose range but not with FA or 5-Me-THF.

Novel 111In-labelled bombesin analogues for molecular imaging of prostate tumours (Article)

2007-08-01T00:00:00Z

Purpose: It has been shown that some primary human tumours and their metastases, including prostate and breast tumours, overexpress gastrin-releasing peptide (GRP) receptors. Bombesin (BN) is a neuropeptide with a high affinity for these GRP receptors. We demonstrated successful scintigraphic visualisation of BN receptor-positive tumours in preclinical studies using the radiolabelled BN analogue [111In-DTPA-Pro1,Tyr4]BN. However, the receptor affinity as well as the serum stability of this analogue leave room for improvement. Therefore new111In-labelled BN analogues were synthesised and evaluated in vitro and in vivo. Methods and results: The receptor affinity of the new BN analogues was tested on human GRP receptor-expressing prostate tumour xenografts and rat colon sections. Analogues with high receptor affinity (low nM range) were selected for further evaluation. Incubation in vitro of GRP receptor-expressing rat CA20948 and human PC3 tumour cells with the111In-labelled analogues resulted in rapid receptor-mediated uptake and internalisation. The BN analogue with the best receptor affinity and in vitro internalisation characteristics, Cmp 3 ([111In-DTPA-ACMpip5,Tha6,βAla11,Tha13,Nle14]BN(5-14)), was tested in vivo in biodistribution studies using rats bearing GRP receptor-expressing CA20948 tumours, and nude mice bearing human PC3 xenografts. Injection of111In-labelled Cmp 3 in these animals showed high, receptor-mediated uptake in receptor-positive organs and tumours which could be visualised using planar gamma camera and microSPECT/CT imaging. Conclusion: With their enhanced receptor affinity and their rapid receptor-mediated internalisation in vitro and in vivo, the new BN analogues, and especially Cmp 3, are promising candidates for use in diagnostic molecular imaging and targeted radionuclide therapy of GRP receptor-expressing cancers.

Peptide receptor radionuclide therapy with 177Lu-octreotate in patients with foregut carcinoid tumours of bronchial, gastric and thymic origin (Article)

2007-08-01T00:00:00Z

Purpose: Foregut carcinoid tumours have a different embryological origin than other gastroenteropancreatic neuroendocrine tumours (GEP NETs). In the total group of GEP NETs (n = 131), treatment with177Lu-octreotate resulted in tumour remission in 47% of patients, with a median time to progression (TTP) of >36 months. As patients with foregut carcinoids may respond differently, we here present the effects of this treatment in a subgroup of patients with foregut carcinoids of bronchial, gastric or thymic origin. Methods: Nine patients with bronchial, five with gastric and two with thymic carcinoids were treated. All patients had metastasised disease. The intended cumulative dose of177Lu-octreotate was 22.2-29.6 GBq. Southwest Oncology Group criteria were used for response evaluation. Results: Bronchial carcinoids: Five patients had partial remission, one had minor response (MR, tumour size reduction: ≥ 25%, <50%), two had stable disease (SD) and one had progressive disease (PD). Median TTP was 31 months. Gastric carcinoids: One patient had complete remission, one had MR and two had SD, including one with PD at baseline. One patient developed PD. Thymic carcinoids: One patient had SD. In the other patient, disease remained progressive. All patients: Overall remission rate was 50%, including MR. Conclusion:177Lu-octreotate treatment can be effective in patients with bronchial and gastric carcinoids. Its role in thymic carcinoids cannot be determined yet because of the limited number of patients. The overall remission rate of 50% in patients with the studied foregut carcinoids is comparable to that in the total group of GEP NETs.

Treatment of Patients Who Have Endocrine Gastroenteropancreatic Tumors with Radiolabeled Somatostatin Analogues (Article)

2007-06-01T00:00:00Z

Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients who have inoperable or metastasized endocrine tumors. Symptomatic improvement may occur with all111In-,90Y-, or177Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy. The results that were obtained with [90Y-DOTA°,Tyr3]octreotide and [177Lu-DOTA°,Tyr3]octreotate are encouraging in tumor regression. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild. These data compare favorably with the limited number of alternative treatment approaches.

Five stabilized 111in-labeled neurotensin analogs in nude mice bearing HT29 tumors (Article)

2007-06-01T00:00:00Z

Neurotensin (NT) receptors are overexpressed in different human tumors, such as human ductal pancreatic adenocarcinoma. New stable neurotensin analogs with high receptor affinity have been synthesized by replacing arginine residues with lysine and arginine derivatives. The aim of this study was to explore the biodistribution, tumor uptake, kidney localization, and stability characteristics of these new analogs in order to develop new diagnostic tools for exocrine pancreatic cancer. Four111In-labeled DTPA-chelated NT analogs and one111In-labeled DOTA-chelated NT analog were evaluated in NMRI nude mice bearing NT receptor-positive HT29 tumors. Experiments with a coinjection of unlabeled NT or lysine were performed to investigate receptor-mediated uptake and kidney protection, respectively. In addition, the in vivo serum stability of the most promising analog was analyzed. In the biodistribution study in mice, at 4 hours postinjection, a low percentage of the injected dose per gram (%ID/g) of tissue for all compounds was found in NT receptor-negative organs, such as the blood, spleen, pancreas, liver, muscle, and femur. A high uptake was found in the colon, intestine, kidneys, and in implanted HT29 tumors. The coinjection of excess unlabeled neurotensin significantly reduced tumor uptake, showing tumor uptake to be receptor-mediated. To a lesser extent, this was also observed for the colon, but not for other tissues. We concluded that DTPA-(Pip)Gly-Pro-(PipAm)Gly-Arg-Pro- Tyr-tBuGly-Leu-OH and the DOTA-linked counterpart have the most favorable biodistribution properties regarding tumor uptake.

The kinetics of thyroid hormone transporters and their role in non-thyroidal illness and starvation (Article)

2007-06-01T00:00:00Z

Kinetic tracer studies show that thyroid hormones are transported into target tissues by stereospecific, high-affinity, low-capacity transporters, both in animals and humans. The Kdof binding to the transporter varies within the nanomolar range. The different thyroid hormones (T4, T3, and rT3) are transported via different transporters, except in the pituitary, where they share the same transporter. The molecular mass of the transport proteins varies between 52 and 65 kDa. The transport mechanisms are dependent on the energy charge of the cell and - often - the sodium gradient over the plasma membrane. A relationship exists with the transport systems of the aromatic amino acids. In non-thyroidal illness and starvation T4transport into T3-producing tissues is decreased, resulting in a low plasma T3concentration, by some considered to be an energy saving mechanism in situations of stress.

Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate (Article)

2007-05-01T00:00:00Z

Purpose: In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [177Lu-DOTA0,Tyr3]octreotate. Methods: Male Lewis rats were injected with 278 or 555 MBq [177Lu-DOTA0,Tyr3]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of99mTc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Results: Treatment with 555 MBq [177Lu-DOTA0,Tyr3]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [177Lu-DOTA0,Tyr3]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of99mTc-DMSA SPECT scintigrams at 130 days after [177Lu- DOTA0,Tyr3]octreotate therapy correlated well with 1/creatinine (r2=0.772, p<0.001). Conclusion: Amifostine and lysine effectively decreased functional renal damage caused by high-dose [177Lu-DOTA0,Tyr3]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy.

Diagnostic imaging of dopamine receptors in pituitary adenomas (Article)

2007-04-01T00:00:00Z

Dopamine D2 receptor scintigraphy of pituitary adenomas is feasible by single-photon emission computed tomography using123I-S-(-)-N-[(1- ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6-methoxybenzamide (123I-IBZM) and123I-epidepride.123I-epidepride is generally superior to123I-IBZM for the visualization of D2 receptors on pituitary macroadenomas. However,123I-IBZM and123I-epidepride scintigraphy are generally not useful to predict the response to dopaminergic treatment in pituitary tumour patients. These techniques might allow discrimination of non-functioning pituitary macroadenomas from other non-tumour pathologies in the sellar region. Dopamine D2 receptors on pituitary tumours can also be studied using positron emission tomography with11C-N-raclopride and11C-N-methylspiperone.

Peptide receptor radionuclide therapy (Article)

2007-03-01T00:00:00Z

Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues is an emerging and convincing treatment modality for patients with unresectable, somatostatin-receptor-positive neuroendocrine tumours. Using radiolabelled somatostatin analogues for imaging became the gold standard for staging of neuroendocrine tumours. The somatostatin receptor is strongly over-expressed in most tumours, resulting in high tumour-to-background ratios. Consequently, the next step was to try to treat these patients by increasing the radioactivity of the administered radiolabelled somatostatin analogue in an attempt to bring about tumour cure. Many patients have been treated successfully with this approach, roughly 25% of them achieving objective tumour shrinkage >50%. Serious side-effects have been rare. This article reviews the effectiveness and safety of the different radiolabelled somatostatin analogues used. Furthermore, clinical issues - including indication and timing of therapy - are discussed. Finally, important directions for future research are mentioned to illustrate new strategies for increasing therapy efficacy.

Rare functioning pancreatic endocrine tumors (Article)

2007-02-01T00:00:00Z

Long-term toxicity of [177Lu-DOTA0,Tyr 3]octreotate in rats (Article)

2007-02-01T00:00:00Z

Purpose and methods: Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [177Lu-DOTA0,Tyr3]octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models. Results: Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [177Lu-DOTA0,Tyr3]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2x278 MBq groups. Three doses of 185 MBq [177Lu-DOTA0,Tyr3]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469±18, 134±70 and 65±15 μmol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria. Conclusion: Injection of high doses of [177Lu-DOTA0,Tyr3]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage.

Anaphylactoid reaction from amifostine (Article)

2007-01-01T00:00:00Z

Considerations concerning a tailored, individualized therapeutic management of patients with (neuro)endocrine tumours of the gastrointestinal tract and pancreas (Article)

2004-01-01T00:00:00Z

Endocrine tumours of the gastrointestinal tract and pancreas may present at different disease stages with either hormonal or hormone-related symptoms/syndromes, or without hormonal symptoms. They may occur either sporadically or as part of hereditary syndromes. In the therapeutic approach to a patient with these tumours, excessive hormonal secretion and/or its effects should always be controlled first. Tumour-related deficiencies or disorders should also be corrected. Subsequently, control should be aimed at the tumour growth. Surgery is generally considered as first-line therapy for patients with localized disease, as it can be curative. However, in patients with metastatic disease the role of first-line surgery is not clearly established and other therapies should be considered, such as non-surgical cytoreductive therapies, biotherapy (with somatostatin analogues or interferon-alpha), embolization and chemoembolization of liver metastases, chemotherapy (with single or multiple dose regimens) and peptide receptor-targeted radiotherapy. The delicate balance of the use of the different therapeutical options in patients with endocrine tumours of the gastrointestinal tract and pancreas emphasizes the importance of team approach and team expertise.

Somatostatin receptor gene therapy combined with targeted therapy with radiolabeled octreotide: a new treatment for liver metastases. (Article)

2002-01-01T00:00:00Z

OBJECTIVE: To evaluate the effect of peptide receptor radionuclide therapy (PRRT) on somatostatin receptor (SSR)-transfected colon carcinoma cells in a rat liver metastases model.SUMMARY BACKGROUND DATA: Previously the authors have shown highly effective therapy with PRRT of SSR-positive tumors. This treatment is SSR-mediated; successful treatment is seen only in SSR-positive tumors, with no effect in SSR-negative tumors. As many tumors lack this receptor, the idea arose to transfect SSR-negative tumor cells with an SSR gene to apply PRRT on these SSR-transfected tumor cells. METHODS: CC531 colon carcinoma cells (SSR-negative) were transfected in vitro with an SSR (subtype 2) gene (CC2B). Liver metastases were produced after intraportal injection of these tumor cells in rats. On day 7, animals were treated with 185 or 370 MBq [177 Lu-DOTA0, Tyr3 ]octreotate. After 21 days rats were killed and liver metastases were counted. RESULTS: Treatment with 370 MBq [177 Lu-DOTA0, Tyr3 ]octreotate showed a significant antitumor response in rats with CC2B liver metastases (SSR-positive) in comparison with controls. No significant antitumor effect was seen in PRRT-treated rats with CC531 liver metastases (SSR-negative). Also, a dose-dependent tumor response was seen in rats with CC2B liver metastases treated with 185 MBq [ 177Lu-DOTA0, Tyr3 ]octreotate compared with controls. In addition, rats with mixed liver metastases treated with 185 MBq [177 Lu-DOTA0, Tyr3 ]octreotate had significantly fewer metastases compared with controls. CONCLUSIONS: The authors showed an impressive antitumor effect of SSR (subtype 2)-transfected colon carcinoma cells with PRRT in a rat liver metastasis model. Moreover, rats with mixed liver metastases had significantly fewer liver metastases compared with control rats, which may be due to a radiologic bystander effect of [177 Lu-DOTA0, Tyr3 ]octreotate. This phenomenon is beneficial in the concept of in vivo gene therapy.

Reference data for bone density and body composition measured with dual energy x ray absorptiometry in white children and young adults (Article)

2002-01-01T00:00:00Z

AIMS: To obtain normative data on bone mineral density and body composition measured with dual energy x ray absorptiometry (DXA) from early childhood to young adulthood. METHODS: Cross sectional results from 444 healthy white volunteers (4-20 years) in the Netherlands were combined with the results from 198 children who agreed to participate in the follow up study approximately four years later. DXA (Lunar, DPXL) of lumbar spine and total body was performed to assess bone density and body composition. RESULTS: Bone density and lean body mass (LBM) increased with age. Maximal increase in bone density and LBM occurred around the age of 13 years in girls and approximately two years later in boys. Bone density of total body and lumbar spine showed an ongoing slight increase in the third decade. Mean fat percentage in boys remained at 10.5% throughout childhood, but increased in girls. CONCLUSIONS: Most of the skeletal mass in lumbar spine and total body is reached before the end of the second decade, with a slight increase thereafter. This study provides reference values for bone density and body composition measured with DXA for children and young adults.

Longitudinal follow-up of bone density and body composition in children with precocious or early puberty before, during and after cessation of GnRH agonist therapy (Article)

2002-01-01T00:00:00Z

We studied bone mineral density (BMD), bone metabolism, and body composition in 47 children with central precocious puberty (n = 36) or early puberty (n = 11) before, during, and after cessation of GnRH agonist. Bone density and body composition were measured with dual energy x-ray absorptiometry and expressed as SD scores. Bone age and biochemical parameters of bone turnover were assessed. Measurements were performed at baseline, after 6 months, and on a yearly basis thereafter. Mean lumbar spine BMD SD scores for chronological age were significantly higher than zero at baseline and decreased during treatment. Lumbar spine bone mineral apparent density and total body BMD did not differ from normal at baseline and showed no significant changes during treatment. In contrast, BMD SD scores for bone age were significantly lower than zero at baseline and at cessation of therapy. Two years after therapy, bone mineral apparent density and BMD SD scores for bone age and chronological age did not differ from normal. Markers of bone turnover decreased during treatment, mainly in the first 6 months. Patients had increased percentage of fat and lean body mass at baseline. After an initial increase of percentage body fat during treatment, percentage body fat decreased and normalized within 1 yr after cessation of treatment. Our longitudinal analysis suggests that peak bone mass or body composition will not be impaired in patients with precocious or early puberty after GnRH agonist therapy.

[(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas (Article)

2001-01-01T00:00:00Z

Selecting the appropriate approach for resection and follow-up of pheochromocytomas (PCCs) is highly dependent upon reliable localization and exclusion of multifocal, bilateral, or metastatic disease. Metaiodobenzylguanidine (MIBG) scintigraphy was developed for functional localization of catecholamine-secreting tissues. Somatostatin receptor imaging (SRI) has a high sensitivity for localizing head and neck paragangliomas, but studies of intraabdominal PCCs are rare. In this study we review our experience of [(123)I]MIBG and SRI, performed since 1983 and 1989, respectively, in the work-up of primary and recurrent PCCs. Scintigraphic results were correlated with catecholamine secretion, size and site, malignancy, associated tumor syndromes, and morphological features. [(123)I]MIBG scans were performed in a total of 75 patients, in 70 cases before resection of primary PCCs and in 5 cases because of recurrent disease. Ninety-one PCCs were resected. The overall detection rates were 83.3% and 89.8% for PCCs larger than 1.0 cm. Multifocal disease was detected in 4 patients with [(123)I]MIBG. [(123)I]MIBG uptake correlated with greater size of PCC (r = 0.33; P = 0.008) and greater concentration of plasma epinephrine (r = 0.32; P = 0.006). [(123)I]MIBG-negative PCCs (n = 14) had significantly (P = 0.01) smaller diameters than [(123I)]MIBG-positive tumors. Furthermore, [(123)I]MIBG uptake was significantly higher in unilateral (P = 0.02), benign (P = 0.02), sporadic (P = 0.02), intraadrenal (P = 0.02), and capsular invasive (P = 0.03) PCCs than in bilateral, malignant, MEN2A/2B-related, extraadrenal, and noninvasive PCCs, respectively. The detection rate of SRI was only 25% (8 of 32) for primary benign PCCs. In 14 patients metastases occurred, which were effectively visualized with [(123)I]MIBG in 8 of 14 cases. SRI was able to detect metastases in 7 of 8 cases, including 3 [(123)I]MIBG-negative metastatic cases. In addition, [(123)I]MIBG and SRI detected 2 recurrences. In conclusion, [(123)I]MIBG uptake is correlated with the size, epinephrine production, and site of PCCs. Its role in bilateral and MEN2A/2B-related PCCs seems limited. In cases of recurrent elevation of catecholamines, localization of metastases and/or recurrence should be attempted with [(123)I]MIBG scintigraphy. In suspicious metastatic PCCs, SRI might be considered to supplement [(123)I]MIBG scintigraphy.

Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability (Article)

2001-01-01T00:00:00Z

Although it was originally believed that thyroid hormones enter target cells by passive diffusion, it is now clear that cellular uptake is effected by carrier-mediated processes. Two stereospecific binding sites for each T4 and T3 have been detected in cell membranes and on intact cells from humans and other species. The apparent Michaelis-Menten values of the high-affinity, low-capacity binding sites for T4 and T3 are in the nanomolar range, whereas the apparent Michaelis- Menten values of the low-affinity, high-capacity binding sites are usually in the lower micromolar range. Cellular uptake of T4 and T3 by the high-affinity sites is energy, temperature, and often Na+ dependent and represents the translocation of thyroid hormone over the plasma membrane. Uptake by the low-affinity sites is not dependent on energy, temperature, and Na+ and represents binding of thyroid hormone to proteins associated with the plasma membrane. In rat erythrocytes and hepatocytes, T3 plasma membrane carriers have been tentatively identified as proteins with apparent molecular masses of 52 and 55 kDa. In different cells, such as rat erythrocytes, pituitary cells, astrocytes, and mouse neuroblastoma cells, uptake of T4 and T3 appears to be mediated largely by system L or T amino acid transporters. Efflux of T3 from different cell types is saturable, but saturable efflux of T4 has not yet been demonstrated. Saturable uptake of T4 and T3 in the brain occurs both via the blood-brain barrier and the choroid plexus-cerebrospinal fluid barrier. Thyroid hormone uptake in the intact rat and human liver is ATP dependent and rate limiting for subsequent iodothyronine metabolism. In starvation and nonthyroidal illness in man, T4 uptake in the liver is decreased, resulting in lowered plasma T3 production. Inhibition of liver T4 uptake in these conditions is explained by liver ATP depletion and increased concentrations of circulating inhibitors, such as 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indoxyl sulfate, nonesterified fatty acids, and bilirubin. Recently, several organic anion transporters and L type amino acid transporters have been shown to facilitate plasma membrane transport of thyroid hormone. Future research should be directed to elucidate which of these and possible other transporters are of physiological significance, and how they are regulated at the molecular level.

Thyroid hormone transport by the heterodimeric human system L amino acid transporter (Article)

2001-01-01T00:00:00Z

Transport of thyroid hormone across the cell membrane is required for thyroid hormone action and metabolism. We have investigated the possible transport of iodothyronines by the human system L amino acid transporter, a protein consisting of the human 4F2 heavy chain and the human LAT1 light chain. Xenopus oocytes were injected with the cRNAs coding for human 4F2 heavy chain and/or human LAT1 light chain, and after 2 d were incubated at 25 C with 0.01-10 microM [(125)I]T(4), [(125)I]T(3), [(125)I]rT(3), or [(125)I]3,3'-diiodothyronine or with 10-100 microM [(3)H]arginine, [(3)H]leucine, [(3)H]phenylalanine, [(3)H]tyrosine, or [(3)H]tryptophan. Injection of human 4F2 heavy chain cRNA alone stimulated the uptake of leucine and arginine due to dimerization of human 4F2 heavy chain with an endogenous Xenopus light chain, but did not affect the uptake of other ligands. Injection of human LAT1 light chain cRNA alone did not stimulate the uptake of any ligand. Coinjection of cRNAs for human 4F2 heavy chain and human LAT1 light chain stimulated the uptake of phenylalanine > tyrosine > leucine > tryptophan (100 microM) and of 3,3'-diiodothyronine > rT(3) approximately T(3) > T(4) (10 nM), which in all cases was Na(+) independent. Saturation analysis provided apparent Michaelis constant (K(m)) values of 7.9 microM for T(4), 0.8 microM for T(3), 12.5 microM for rT(3), 7.9 microM for 3,3'-diiodothyronine, 46 microM for leucine, and 19 microM for tryptophan. Uptake of leucine, tyrosine, and tryptophan (10 microM) was inhibited by the different iodothyronines (10 microM), in particular T(3). Vice versa, uptake of 0.1 microM T(3) was almost completely blocked by coincubation with 100 microM leucine, tryptophan, tyrosine, or phenylalanine. Our results demonstrate stereospecific Na(+)-independent transport of iodothyronines by the human heterodimeric system L amino acid transporter.

Changes in renal tri-iodothyronine and thyroxine handling during fasting (Article)

2000-01-01T00:00:00Z

OBJECTIVE: Liver handling of thyroid hormones (TH) has been known to alter significantly during fasting. This study investigates whether renal handling of TH is also changed during fasting. METHODS: We measured urinary excretion rates and clearances of free tri-iodothyronine (T(3)) and free thyroxine (T(4)) in healthy subjects prior to and on the third day of fasting. RESULTS: During fasting, both mean T(3) and T(4) urinary excretion decreased significantly to a mean value of 42% of control. Also, total and free (F) serum T(3) concentrations declined significantly, but serum T(4) did not change. Both FT(3) and FT(4) clearance decreased significantly during fasting (62% and 42% of control). The fasting-induced decrease in uric acid clearance correlated well with the decrease in FT(3) clearance (r=0.94; P<0.001). Serum concentrations of non-esterified fatty acids (NEFA) were significantly elevated during fasting. CONCLUSIONS: The findings cannot be fully explained by the fasting-induced decrease in serum T(3), and are in accordance with inhibition of uptake of T(3) and T(4) at the basolateral membrane of the tubular cell. This inhibition may be caused by a decreased energy state of the tubular cell and by other factors such as ketoacidosis and/or increased NEFA concentrations during fasting.

Safety, hemodynamic profile, and feasibility of dobutamine stress technetium myocardial perfusion single-photon emission CT imaging for evaluation of coronary artery disease in the elderly (Article)

2000-01-01T00:00:00Z

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 inability to exercise. Although pharmacologic stress testing with dobutamine is an alternative, the safety of dobutamine myocardial perfusion scintigraphy in the elderly has not been previously studied. PATIENTS AND METHODS: We studied the safety and feasibility of dobutamine (up to 40 microg/kg/min)-atropine (up to 1 mg) stress myocardial perfusion scintigraphy using technetium single-photon emission CT imaging in 227 patients > or = 70 years old (mean +/- SD age, 75 +/- 4 years). A control group of 227 patients < 70 years old (mean age, 55 +/- 11 years; matched for gender, prevalence of previous infarction, beta-blocker therapy, and severity of resting perfusion abnormalities) was studied to assess age-related differences in the safety and the hemodynamic response. A feasible test was defined as the achievement of the target heart rate and/or an ischemic end point (angina, ST-segment depression, or reversible perfusion abnormalities). RESULTS: No myocardial infarction or death occurred during the test. The target heart rate was achieved more frequently in the elderly patients (87% vs 79%; p < 0.05). The elderly patients had a higher prevalence of supraventricular tachycardia (7% vs 1%; p < 0.005) and premature ventricular contraction (74% vs 32%; p < 0.005) during the test, as compared to the younger patients. There was a trend to a higher prevalence of ventricular tachycardia (5% vs 2%) and atrial fibrillation (3% vs 0.4%) in the elderly patients. Arrhythmias were terminated spontaneously by termination of dobutamine infusion or by administration of metoprolol. Independent predictors of supraventricular tachyarrhythmias and ventricular tachycardia were older age (p < 0.001; chi(2), 9.8) and myocardial perfusion defect score at rest (p < 0.01; chi(2), 6.8) respectively, by using a multivariate analysis of clinical and stress test variables. Elderly patients had a higher prevalence of systolic BP drop > 20 mm Hg during the test (37% vs 12%; p < 0.05). The test was terminated due to hypotension in 2% of the elderly patients and in 1% of the control group. Age was the most powerful predictor of hypotension (p < 0.005; chi(2), 10.3). The test was considered feasible in 216 elderly patients (95%) and in 209 patients of the control group (92%). CONCLUSION: Dobutamine-atropine stress myocardial perfusion scintigraphy is a highly feasible method for the evaluation of coronary artery disease in the elderly. Elderly patients have a higher risk for developing hypotension and supraventricular tachyarrhythmias during a dobutamine stress test. However, dobutamine-induced hypotension is often asymptomatic and rarely necessitates the termination of the test.

Refractory immune-mediated and haematological diseases: candidates for peptide receptor radiotherapy? (Article)

2000-01-01T00:00:00Z

Thyroid hormones (Article)

1999-01-01T00:00:00Z

Rapid sulfation of 3,3',5'-triiodothyronine in native Xenopus laevis oocytes (Article)

1998-01-01T00:00:00Z

Sulfation is an important metabolic pathway facilitating the degradation of thyroid hormone by the type I iodothyronine deiodinase. Different human and rat tissues contain cytoplasmic sulfotransferases that show a substrate preference for 3,3'-diiodothyronine (3,3'-T2) > T3 > rT3 > T4. During investigation of the expression of plasma membrane transporters for thyroid hormone by injection of rat liver RNA in Xenopus laevis oocytes, we found uptake and metabolism of iodothyronines by native oocytes. Groups of 10 oocytes were incubated for 20 h at 18 C in 0.1 ml medium containing 500,000 cpm (1-5 nM) [125I]T4, [125I]T3, [125I]rT3, or [125I]3,3'-T2. In addition, cytosol prepared from oocytes was tested for iodothyronine sulfotransferase activity by incubation of 1 mg cytosolic protein/ml for 30 min at 21 C with 1 microM [125I]T4, [125I]T3, [125I]rT3, or [125I]3,3'-T2 and 50 microM 3'-phosphoadenosine-5'-phosphosulfate. Incubation media, oocyte extracts, and assay mixtures were analyzed by Sephadex LH-20 chromatography for production of conjugates and iodide. After 20-h incubation, the percentage of added radioactivity present as conjugates in the media and oocytes amounted to 0.9 +/- 0.2 and 1.0 +/- 0.1 for T4, less than 0.1 and less than 0.1 for T3, 32.5 +/- 0.4 and 29.3 +/- 0.2 for rT3, and 3.8 +/- 0.3 and 2.3 +/- 0.2 for 3,3'-T2, respectively (mean +/- SEM; n = 3). The conjugate produced from rT3 was identified as rT3 sulfate, as it was hydrolyzed by acid treatment. After injection of oocytes with copy RNA coding for rat type I iodothyronine deiodinase, we found an increase in iodide production from rT3 from 2.3% (water-injected oocytes) to 46.2% accompanied by a reciprocal decrease in rT3 sulfate accumulation from 53.7% to 7.1%. After 30-min incubation with cytosol and 3'-phosphoadenosine-5'-phosphosulfate, sulfate formation amounted to 1.8% for T4, less than 0.1% for T3, 77.9% for rT3, and 2.9% for 3,3'-T2. These results show that rT3 is rapidly metabolized in native oocytes by sulfation. The substrate preference of the sulfotransferase activity in oocytes is rT3 >> 3,3'-T2 > T4 > T3. The physiological significance of the high activity for rT3 sulfation in X. laevis oocytes remains to be established.

Bone mineral density and body composition before and during treatment with gonadotropin-releasing hormone agonist in children with central precocious and early puberty (Article)

1998-01-01T00:00:00Z

Major changes in bone mineral density (BMD) and body composition occur during puberty. In the present longitudinal study, we evaluated BMD and calculated volumetric BMD [bone mineral apparent density (BMAD)], bone metabolism, and body composition of children (32 girls and 2 boys) with central precocious and early puberty before and during treatment with GnRH agonist (GnRH). Patients were studied at baseline and during treatment for 6 months (n = 34), 1 yr (n = 33), and 2 yr (n = 16). Lumbar spine and total body BMD and body composition were measured with dual-energy x-ray absorptiometry. The variables were compared with age- and sex-matched reference values of the same population and expressed as SD score (SDS). Bone age was assessed. Serum calcium, phosphate, alkaline phosphatase, osteocalcin, the carboxyterminal propeptide of type I collagen (PICP), cross-linked telopeptide of collagen I (ICTP), 1,25 dihydroxyvitamin D and urinary hydroxyproline/creatinine, and calcium/ creatinine ratios were measured. Mean lumbar spine BMD SDS was significantly higher than zero at baseline (P < 0.02) and did not differ from normal, after 2 yr of treatment. Mean spinal BMAD SDS and total body BMD SDS were not significantly different from zero at baseline and had not changed significantly after 2 yr of treatment. During therapy, fat mass and percentage body fat SDS increased, whereas lean tissue mass SDS decreased. Mean lumbar spine BMD and BMAD and total body BMD SDS, calculated for bone age, were all lower than zero at baseline (BMD P < 0.001 and BMAD P < 0.05) and also after 2 yr treatment (respectively, P < 0.001, P < 0.05, and P < 0.01). Biochemical bone parameters were significantly higher than prepubertal values at baseline, and they decreased during treatment. In conclusion, patients with central precocious and early puberty had normal BMD for chronological age but low BMD for bone age, after 2 yr of treatment with GnRH. Bone turnover decreased during treatment. Changes in body composition resembled those seen in patients with GH deficiency.

Bone mineral density and nutritional status in children with chronic inflammatory bowel disease (Article)

1998-01-01T00:00:00Z

BACKGROUND: Osteoporosis has been reported in adult patients with inflammatory bowel disease. AIMS: To evaluate bone mineral density (BMD), nutritional status, and determinants of BMD in children with inflammatory bowel disease. PATIENTS: Fifty five patients (34 boys and 21 girls, age range 4-18) were studied; 22 had Crohn's disease and 33 ulcerative colitis. METHODS: Lumbar spine and total body BMD, and body composition were assessed by dual energy x ray absorptiometry (DXA). Results were expressed as standard deviation scores (SDS). Lean body mass was also assessed by bioelectrical impedance analysis (BIA). Yearly measurements during two years were performed in 21 patients. RESULTS: The mean SDS of lumbar spine BMD and total body BMD were significantly lower than normal (-0.75 and -0.95, both p < 0.001). Height SDS and body mass index SDS were also decreased. The decrease in BMD SDS could not be explained by delay in bone maturation. The cumulative dose of prednisolone correlated negatively with lumbar spine BMD SDS (r = -0.32, p < 0.02). Body mass index SDS correlated positively with total body BMD SDS (r = 0.36, p < 0.02). Patients with Crohn's disease had significantly lower lumbar spine and total body BMD SDS than patients with ulcerative colitis, even after adjustment for cumulative dose of prednisolone. In the longitudinal data cumulative dose of prednisolone between the measurements correlated negatively with the change in lumbar spine and total body BMD SDS. Lean tissue mass measured by DXA had a strong correlation with lean body mass measured by BIA (r = 0.98). CONCLUSIONS: Children with inflammatory bowel disease have a decreased BMD. Children with Crohn's disease have a higher risk of developing osteopaenia than children with ulcerative colitis. Corticosteroid therapy and nutritional status are important determinants of BMD in these patients.

Ontogeny of iodothyronine deiodinases in human liver (Article)

1998-01-01T00:00:00Z

The role of the deiodinases D1, D2, and D3 in the tissue-specific and time-dependent regulation of thyroid hormone bioactivity during fetal development has been investigated in animals but little is known about the ontogeny of these enzymes in humans. We analyzed D1, D2, and D3 activities in liver microsomes from 10 fetuses of 15-20 weeks gestation and from 8 apparently healthy adult tissue transplant donors, and in liver homogenates from 2 fetuses (20 weeks gestation), 5 preterm infants (27-32 weeks gestation), and 13 term infants who survived up to 39 weeks postnatally. D1 activity was determined using 1 microM [3',5'-125I]rT3 as substrate and 10 mM dithiothreitol (DTT) as cofactor, D2 activity using 1 nM [3',5'-125I]T4 and 25 mM DTT in the presence of 1 mM 6-propyl-2-thiouracil (to block D1 activity) and 1 microM T3 (to block D3 activity), and D3 activity using 10 nM [3,5-125I]T3 and 50 mM DTT, by quantitation of the release of 125I. The assays were validated by high performance liquid chromatography of the products, and kinetic analysis [Michaelis-Menten constant (Km) of rT3 for D1: 0.5 microM; Km of T3 for D3: 2 nM]. In liver homogenates, D1 activity was not correlated with age, whereas D3 activity showed a strong negative correlation with age (r -0.84), with high D3 activities in preterm infants and (except in 1 infant of 35 weeks) absent D3 activity in full-term infants. In microsomes, D1 activities amounted to 4.3-60 pmol/min/mg protein in fetal livers and to 170-313 pmol/min/mg protein in adult livers, whereas microsomal D3 activities were 0.15-1.45 pmol/min/mg protein in fetuses and <0.1 pmol/min/mg protein in all but one adult. In the latter sample, D3 activity amounted to 0.36 pmol/min/mg protein. D2 activity was negligible in both fetal and adult livers. These findings indicate high D1 and D3 activities in fetal human liver, and high D1 and mostly absent D3 activities in adult human liver. Therefore, the low serum T3 levels in the human fetus appear to be caused by high hepatic (and placental) D3 activity rather than caused by low hepatic D1 activity. The occasional expression of D3 in adult human liver is intriguing and deserves further investigation.

Site-Specific Intracoronary Heparin Delivery in Humans After Balloon Angioplasty (Article)

1997-01-01T00:00:00Z

Background Demonstration and quantification of site-specific intracoronary administration of compounds has been confined thus far to the experimental animal laboratory. The aim of this study was to describe a scintigraphic method to demonstrate site-specific intracoronary drug delivery in humans. The methods allow on-line visualization and off-line quantification of site-specifically infused -emitting compounds. Methods and Results In 12 patients after balloon angioplasty, 99mTc-labeled heparin was administered at the site of dilatation by use of a coil balloon. Both the infusion period and the washout period after the end of infusion were monitored with a -camera. A curve of counts per pixel as a function of time was derived that showed an accumulation phase during infusion followed by a washout phase after the end of infusion. Both phases were fitted by regression analysis and showed a linear accumulation pattern and a biexponential washout pattern. After correction for background counts, 99mTc decay, and body attenuation, peak heparin amount and regional bioavailability were calculated. Peak amount was defined as the initial point of the slow washout component of the biexponential curve (elimination component), and regional bioavailability was defined as the area under the curve of accumulation and washout phase. Half-life and retention time, defined as seven half-lives, were obtained by use of the elimination component after correction for 99mTc decay. Mean peak delivered amount was 45±44 IU (236±228 µg), corresponding to an efficiency of delivery ranging from 1% to 8% of the totally infused dose. Total regionally bioavailable heparin reached 244±194 IU·h (1.28±1.01 mg·h). Retention time varied from 12 to 90 hours (mean, 50:33±22:50 hours:minutes). Conclusions Site-specific intracoronary heparin delivery after angioplasty by means of the coil balloon was demonstrated in humans, and regional pharmacokinetics was quantified by use of a radioisotopic technique.

Bone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity (Article)

1997-01-01T00:00:00Z

The association of height, weight, pubertal stage, calcium intake, and physical activity with bone mineral density (BMD) was evaluated in 500 children and adolescents (205 boys and 295 girls), aged 4-20 yr. The BMD (grams per cm2) of lumbar spine and total body was measured with dual energy x-ray absorptiometry. Lumbar spine volumetric BMD was calculated to correct for bone size. BMD and volumetric BMD increased with age. During puberty, the age-dependent increment was higher. After adjustment for age, the Tanner stage was significantly associated with all three BMD variables in girls and with spinal BMD in boys. In boys, positive correlations were found between BMD and both calcium intake and physical activity after adjustment for age. Stepwise regression analysis with weight, height, Tanner stage, calcium intake, and physical activity as determinants with adjustment for age resulted in a model with Tanner stage in girls and weight in boys for all three BMD variables. The major independent determinant of BMD was the Tanner stage in girls and weight in boys.

Expression of rat liver cell membrane transporters for thyroid hormone in Xenopus laevis oocytes (Article)

1997-01-01T00:00:00Z

The present study was conducted to explore the possible use of Xenopus laevis oocytes for the expression cloning of cell membrane transporters for iodothyronines. Injection of stage V-VI X. laevis oocytes with 23 ng Wistar rat liver polyadenylated RNA (mRNA) resulted after 3-4 days in a highly significant increase in [125I]T3 (5 nM) uptake from 6.4 +/- 0.8 fmol/oocyte x h in water-injected oocytes to 9.2 +/- 0.65 fmol/oocyte x h (mean +/- SEM; n = 19). In contrast, [125I]T4 (4 nM) uptake was not significantly stimulated by injection of total liver mRNA. T3 uptake induced by liver mRNA was significantly inhibited by replacement of Na+ in the incubation medium by choline+ or by simultaneous incubation with 1 microM unlabeled T3. In contrast, T3 uptake by water-injected oocytes was not Na+ dependent. Fractionation of liver mRNA on a 6-20% sucrose gradient showed that maximal stimulation of T3 uptake was obtained with mRNA of 0.8-2.1 kilobases (kb). In contrast to unfractionated mRNA, the 0.7- to 2.1-kb fraction also significantly stimulated transport of T4, and it was found to induce uptake of T3 sulfate (T3S). Because T3S is a good substrate for type I deiodinase (D1), 2.3 ng rat D1 complementary RNA (cRNA) were injected either alone or together with 23 ng of the 0.8- to 2.1-kb fraction of rat liver mRNA. Compared with water-injected oocytes, injection of D1 cRNA alone did not stimulate uptake of [125I]T3S (1.25 nM). T3S uptake in liver mRNA and D1 cRNA-injected oocytes was similar to that in oocytes injected with mRNA alone, showing that transport of T3S is independent of the metabolic capacity of the oocyte. Furthermore, coinjection of liver mRNA and D1 cRNA strongly increased the production of 125I-, showing that the T3S taken up by the oocyte is indeed transported to the cell interior. In conclusion, injection of rat liver mRNA into X. laevis oocytes resulted in a stimulation of saturable, Na+-dependent T4, T3 and T3S transport, indicating that rat liver contains mRNA(s) coding for plasma membrane transporters for these iodothyronine derivatives.

Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency (Article)

1997-01-01T00:00:00Z

Adults with childhood onset GH deficiency (GHD) have reduced bone mass, increased fat mass, and disorders of lipid metabolism. The aim of the present study was to evaluate bone mineral density (BMD), bone metabolism, body composition, and lipid metabolism in GHD children before and during 2-3 yr of GH treatment (GHRx). Forty children with GHD, mean age 7.9 yr, participated in the study of bone metabolism and body composition; and an additional group of 17 GHD children, in the study of lipid metabolism. Lumbar spine BMD, total body BMD, and body composition were measured with dual-energy x-ray absorptiometry. Volumetric BMD (bone mineral apparent density, BMAD) was calculated to correct for bone size. BMD, BMAD, lean tissue mass, bone mineral content, fat mass, and percentage body fat were expressed as SD scores (SDS), in comparison with normative data of the same population. Lumbar spine BMD and BMAD and total body BMD were all decreased at baseline. All BMD variables increased significantly during GHRx, lumbar spine BMD SDS, already after 6 months of treatment. Lean tissue mass SDS increased continuously. Bone mineral content SDS started to increase after 6 months GHRx. Fat mass SDS decreased during the first 6 months of GHRx and remained stable thereafter. Biochemical parameters of bone formation and bone resorption did not differ from normal at baseline and increased during the first 6 months of GHRx. Serum 1,25 dihydroxyvitamin D increased continuously during GHRx, whereas PTH and serum calcium remained stable. Lipid profile was normal at baseline: Atherogenic index had decreased and apolipoprotein A1(Apo-A1) had increased after 3 yr of treatment. In conclusion, children with GHD have decreased bone mass. BMD, together with height and lean tissue mass, increased during GHRx. GHRx had a beneficial effect on lipid metabolism.

Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones (Article)

1997-01-01T00:00:00Z

Chromogranin A (CgA) is gaining acceptance as a serum marker of neuroendocrine tumors. Its specificity in differentiating between neuroendocrine and nonneuroendocrine tumors, its sensitivity to detect small tumors, and its clinical value, compared with other neuroendocrine markers, have not clearly been defined, however. The objectives of this study were to evaluate the clinical usefulness of CgA as neuroendocrine serum marker. Serum levels of CgA, neuron-specific enolase (NSE), and the alpha-subunit of glycoprotein hormones (alpha-SU) were determined in 211 patients with neuroendocrine tumors and 180 control subjects with nonendocrine tumors. The concentrations of CgA, NSE, and alpha-SU were elevated in 50%, 43%, and 24% of patients with neuroendocrine tumors, respectively. Serum CgA was most frequently increased in subjects with gastrinomas (100%), pheochromocytomas (89%), carcinoid tumors (80%), nonfunctioning tumors of the endocrine pancreas (69%), and medullary thyroid carcinomas (50%). The highest levels were observed in subjects with carcinoid tumors. NSE was most frequently elevated in patients with small cell lung carcinoma (74%), and alpha-SU was most frequently elevated in patients with carcinoid tumors (39%). Most subjects with elevated alpha-SU levels also had elevated CgA concentrations. A significant positive relationship was demonstrated between the tumor load and serum CgA levels (P < 0.01, by chi 2 test). Elevated concentrations of CgA, NSE, and alpha-SU were present in, respectively, 7%, 35%, and 15% of control subjects. Markedly elevated serum levels of CgA, exceeding 300 micrograms/L, were observed in only 2% of control patients (n = 3) compared to 40% of patients with neuroendocrine tumors (n = 76). We conclude that CgA is the best general neuroendocrine serum marker available. It has the highest specificity for the detection of neuroendocrine tumors compared to the other neuroendocrine markers, NSE and alpha-SU. Elevated levels are strongly correlated with tumor volume; therefore, small tumors may go undetected. Although its specificity cannot compete with that of the specific hormonal secretion products of most neuroendocrine tumors, it can have useful clinical applications in subjects with neuroendocrine tumors for whom either no marker is available or the marker is inconvenient for routine clinical use.

Somatostatin-receptor scintigraphy in Graves' orbitopathy (Article)

1996-07-02T00:00:00Z

The use of somatostatin receptor scintigraphy in the differential diagnosis of pancreatic duct cancers and islet cell tumors (Article)

1996-01-01T00:00:00Z

OBJECTIVE: In the present study, the diagnostic value of somatostatin receptor scintigraphy (SRS) was evaluated in the preoperative workup in patients with pancreatic duct cancers and islet cell tumors, as well as in the follow-up of these patients. METHODS: Twenty-six patients with suspected primary pancreatic duct cancers and 48 patients with islet cell tumors were studied. The SRS was performed using the radionuclide-labeled somatostatin analogue 111In-octreotide. Another group of 12 patients who were still alive more than 3 years after pancreaticoduodenectomy for pancreatic duct adenocarcinomas also underwent SRS. RESULTS: In 31 (65%) of 48 patients, the primary pancreatic islet cell tumor as well as its often previously not yet recognized metastases could be visualized. In contrast, none of the 26 pancreatic adenocarcinomas or their metastases could be seen. In 5 of 12 patients who were alive more than 3 years after pancreaticoduodenectomy for pancreatic duct adenocarcinomas, metastatic lesions were visualized at SRS. In retrospect, these patients were not operated on for adenocarcinomas but for "nonfunctioning" islet cell tumors. CONCLUSIONS: The present study supports the concept that SRS has a place in the preoperative differential diagnosis of islet cell tumors and pancreatic duct cancers as well as in the follow-up, especially in those cases in which no tumor histologic analysis was obtained, or the pathologic examination of the tumor tissue had not included special staining procedures for neuroendocrine characteristics. Our results also indicate that the evaluation of the results of investigations on the role of surgery or radiation therapy and chemotherapy or both in pancreatic duct cancer have to be interpreted with caution, if no histologic analysis and staining for neuroendocrine characteristics was performed.

Uptake of 3,3',5,5'-tetraiodothyroacetic acid and 3,3',5'-triiodothyronine in cultured rat anterior pituitary cells and their effects on thyrotropin secretion (Article)

1995-01-01T00:00:00Z

We compared the uptake, metabolism, and biological effects of tetraiodothyroacetic acid (Tetrac) and rT3 in anterior pituitary cells with those of T4 and T3. Cells were isolated from adult male Wistar rats and cultured for 3 days in medium with 10% fetal calf serum. Uptake was measured at 37 C in medium with 0.1% BSA for [125I]Tetrac (200,000 cpm; 240 pM) and [125I]T4 (100,000 cpm; 175 pM) or with 0.5% BSA for [125I]rT3 (100,000 cpm; 250 pM) and [125I]T3 (50,000 cpm; 50 pM). The free fraction of Tetrac was 1% that of T4 (in medium with 0.1 and with 0.5% BSA), and the free fraction of rT3 was half that of T3. Uptake of the four tracers increased sharply up to 1 h of incubation and then leveled off. Expressed as femtomoles per pM free hormone, uptake at equilibrium was 1.16 +/- 0.16 (n = 6) for Tetrac, 0.15 +/- 0.01 (n = 6) for T4, 0.023 +/- 0.003 (n = 6) for rT3, and 0.21 +/- 0.02 (n = 6) for T3. Cell-associated radioactivity after incubation for 24 h with [125I]Tetrac was represented for 15% by [125I]Triac; after incubation with [125I]T4 for 15-20% by [125I]T3, after incubation with [125I]rT3 for 6% by [125I]3,3'-T2, while [125I]T3 was still for 98% [125I]T3. Exposure of cells for 2 h to 100 nM TRH stimulated TSH release by 90-135%. Tetrac was effective in reducing this response at a free concentration of 0.05 pM, but rT3 was effective only at a free concentration of 16 nM. A free Tetrac concentration of 5 pM was equally effective as 50 pM free T4 in reducing the TSH response to TRH. In human serum, Tetrac was exclusively bound to T4-binding prealbumin. The free Tetrac fraction was 0.001% in control subjects and rose 2- to 12-fold in patients with nonthyroidal illness. As uptake of [125I]Tetrac in the pituitary was higher than that of T4 and T3, and it was more potent than T4 in reducing TSH release, Tetrac may be of potential significance for the regulation of TSH secretion in vivo.

Uptake of triiodothyroacetic acid and its effect on thyrotropin secretion in cultured anterior pituitary cells (Article)

1994-01-01T00:00:00Z

The uptake of [125I]triiodothyroacetic acid ([125I]Triac) in anterior pituitary cells was investigated and compared with that of [125I]T3. Furthermore, the effects of Triac, T3, and T4 on TSH release were compared. Cells isolated from adult male Wistar rats were cultured for 3 days in medium with 10% fetal calf serum. Uptake was measured at 37 C with [125I]Triac (100,000 cpm; 120 pM) or [125I]T3 (50,000 cpm; 50 pM) in medium with 0.5% BSA. In this medium, the ratio of the free fractions of Triac, T3, and T4 was 1:8:1. Exposure of cells to 100 nM TRH for 2 h stimulated TSH release by 80-110% (P < 0.001). Comparing total hormone levels (1 nM to 1 microM), Triac and T3 were equally effective in reducing this response, and both were 10-fold more effective than T4. The time course (15 min to 4 h) of [125I]Triac uptake was similar to that of [125I]T3, showing equilibrium after 1 h. Unlabeled Triac (1 microM) reduced the uptake of [125I]Triac and [125I]T3 at all time intervals. Expressed per pM free hormone, the cellular and nuclear uptake of [125I]Triac were twice those of [125I]T3. The 15-min uptake of [125I]Triac was reduced by incubation with 10 nM unlabeled Triac (35%; P < 0.001). Maximum inhibition (56%; P < 0.001) was found with 10 microM Triac. A similar effect was seen with 10 microM T3, T4, or 3,3',5,5'-tetraiodothyroacetic acid. Preincubation (30 min) and incubation (15 min) with 10 microM oligomycin reduced the cellular ATP content by 51% (P < 0.001), [125I]T3 uptake by 77% (P < 0.001), and [125I]Triac uptake by only 25% (P < 0.001). The temperature dependence of [125I]Triac and [125I]T3 uptake was the same. Preincubation and incubation with 10 microM monensin (reduces the Na+ gradient) or 10 microM monodansylcadaverine (inhibits receptor-mediated endocytosis) reduced 15-min [125I] Triac uptake by 15% (P < 0.005) and 19% (P < 0.005), respectively. The data show that 1) Triac, on the basis of the free hormone concentration, is more potent than T3 or T4 in suppressing TSH secretion; and 2) the rapid uptake of [125I]Triac by the anterior pituitary occurs by a carrier-mediated mechanism that is only partially dependent on ATP or the Na+ gradient.

Uptake of thyroxine in cultured anterior pituitary cells of euthyroid rats (Article)

1994-01-01T00:00:00Z

The uptake of [125I]T4 was investigated in cultured anterior pituitary cells isolated from adult fed Wistar rats and cultured for 3 days in medium containing 10% fetal calf serum. Experiments were performed with [125I]T4 (10(5) to 2 x 10(6) cpm; 0.35-7 nM) in medium containing 0.5% or 0.1% BSA. The uptake of [125I]T4 increased with time and showed equilibrium after around 1 h of incubation. The presence of 10 microM unlabeled T4 during incubation decreased the uptake of [125I]T4 by 65-70% at all time intervals. After 24 h of incubation, 1.5% iodide and 3.2% conjugates were detected in the medium, whereas around 20% of cellular radioactivity represented [125I]T3. The 15-min uptake of [125I]T4 was significantly reduced by simultaneous incubation with 100 nM T4 (by 24%; P < 0.05), 100 nM T3 (by 38%; P < 0.001), or 10 microM rT3 (by 32%; P < 0.001), whereas 10 microM tetraiodothyroacetic acid (Tetrac) had no effect. Furthermore, preincubation (30 min) and incubation (15 min) with 10 microM monodansylcadaverine, oligomycin, or monensin reduced the uptake of [125I]T4 by 30%, 50%, and 40%, respectively (all P < 0.001). Substitution of Na+ in the buffer by K+ diminished the uptake of [125I]T4 by 39% (P < 0.005); 2 mM phenylalanine, tyrosine, or tryptophan reduced [125I]T4 uptake by 18% (P < 0.05), 18% (P = NS), and 33% (P < 0.005), respectively. Our data suggest that the pituitary contains a specific carrier-mediated energy-requiring mechanism for [125I]T4 uptake that is partly dependent on the Na+ gradient. In addition, part of [125I]T4 uptake in the pituitary might occur through an amino acid transport system. When expressed per pM of free hormone, the 15-min uptake of [125I]T4 was approximately as high as that of [125I]T3. Because the reduction of [125I]T4 uptake by T4, T3, monodansylcadaverine, oligomycin, and monensin was roughly the same as the previously reported reduction of [125I]T3 uptake by the same compounds, it is further suggested that T4 and T3 share a common carrier in cultured anterior pituitary cells.

The effect of immunoscintigraphy with monoclonal antibodies on assays of hormones and tumor markers. This is not the end of the matter! (Article)

1989-01-01T00:00:00Z

The use of monoclonal antibodies in medicine for in-vivo diagnostic methods and for therapeutic purposes will increase in the future. Although monoclonal antibodies possess a high specificity, the animal origin of these antibodies remains a problem. Repeated administration of animal monoclonal antibodies (in vivo) may induce the formation of human antibodies against these monoclonal antibodies. Because animal monoclonal antibodies are also used in laboratory assays (in vitro), the presence of human antibodies against these animal monoclonal antibodies may cause spuriously elevated or depressed results of these assays. The clinician should be alert to this possibility. A case history is presented to demonstrate the problem.

Thyroid hormone uptake by rat hepatocytes in primary culture (Doctoral Thesis)

1983-06-10T00:00:00Z

Iodide is taken up by the thyroid follicular cell, oxydized and bound to thyroglobulin at the apical membrane facing the colloid in the follicular lumen. Iodinated colloid is subsequently engulfed by the follicular cell and hydrolysed, liberating thyroxine and triiodothyronine from their peptide linkage to thyroglobulin. Iodothyronines are then secreted into the blood stream. These and other steps in the synthesis and secretion of thyroid hormones are conditioned by the extent of thyroid stimulation by pituitary thyrotropin. The synthesis and release of thyrotropin is stimulated by the hypothalamic thyrotropinreleasing hormone, while thyroid hormone inhibits these processes (Larsen, 1982). In this way, a negative feedback mechanism is formed between the thyroid and pituitary. The main product secreted by the human thyroid is thyroxine (mean 115 nmol/day per 70 kg body weight). Other products are triiodothyronine (mean 9 nrnol/day, which accounts for 20% of the total daily production) and reverse triiodothyronine (mean 2 nmol/day; 6%) (Chopra, 1976; Chopra et al., 1978a; Visser, 1980). From these figures it will be clear that synthesis of the latter iodothyronines occurs mainly outside the thyroid gland by monodeiodination of thyroxine, the so-called peripheral production. In pathophysiological conditions, like iodine deficiency and Graves' disease, thyroidal secretion of triiodothyronine is increased relative to that of thyroxine (Izumi and Larsen, 1977). The relative contribution of different tissues to the daily production of triiodothyronine and reverse triiodothyronine is at present unknown. However, deiodination has been observed in vitro in almost all tissues studied (see review by Visser, 1980). Based on circumstantial evidence, it is generally believed that the liver is the main site of triiodothyronine synthesise For instance, in liver cirrhosis triiodothyronine production is decreased, while apparent reverse triiodothyronine synthesis is unaltered (Chopra, 1976). The latter finding is in favour of extra-hepatic thyroxine_.reverse triiodothyronine conversion. The low serum reverse triiodothyronine levels in patients with severe, chronic renal failure may suggest that substantial amounts of reverse triiodothyronine are produced in the kidneys (Chopra et al., 1975; Weissel et al., 1977; Weissel and Stummvoll, 1981).