Valkema, R.

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.

Brain perfusion patterns in familial frontotemporal lobar degeneration (Article)

2011-07-26T00:00:00Z

Objective: Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and pathologically heterogeneous disorder. The aim of this study was to compare clinical features and perfusion patterns on SPECT of patients with familial FTLD-TAR DNA binding protein 43 kDa (TDP) and MAPT mutations. Methods: Patients were included if they had MAPT or GRN mutations, positive family history with pathologically proven FTLD in the patient or first-degree relative, or were part of FTD-MND families. All patients and 10 age- and gender-matched controls underwent measurement of brain perfusion using99mTc-HMPAO SPECT. We used SPM8 to perform image processing and oxelbased group analyses (p < 0.001). Gender and age were included as nuisance variables in the design matrices. Results: Of the 29 patients with familial FTLD, 19 had familial FTLD-TDP (GRN mutations in 6), and 10 had MAPT mutations. At clinical presentation, familial FTLD-TDP patients were older at onset (p = 0.030) and had more memory deficits (p < 0.011), whereas patients with MAPT had more naming deficits (p = 0.001) and obsessive-compulsive behavior (p = 0.001). The betweengroups SPECT analyses revealed significantly less perfusion in the right frontal lobe, precuneus, cuneus, and inferior parietal lobule in familial FTLD-TDP, whereas significantly less perfusion was found in the left temporal and inferior frontal gyri in MAPT. Post hoc analysis of familial FTLD-TDP with unknown genetic defect vs MAPT revealed less perfusion in the right frontal and parietal lobe. Conclusion: Familial FTLD-TDP shows relatively more posterior hypoperfusion, including the precuneus and inferior parietal lobule, possibly related to significant memory impairment. Patients with MAPT were characterized by impaired perfusion of the temporal regions and naming deficits.

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.

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.

Molecular imaging of inflammation and intraplaque vasa vasorum: A step forward to identification of vulnerable plaques? (Article)

2010-10-01T00:00:00Z

Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis, most likely under influence of hypoxic and inflammatory stimuli. Several molecular imaging techniques are currently available. Most experience has been obtained with molecular imaging using positron emission tomography and single photon emission computed tomography. Recently, the development of targeted contrast agents has allowed molecular imaging with magnetic resonance imaging, ultrasound and computed tomography. The present review discusses the use of these molecular imaging techniques to identify inflammation and intraplaque vasa vasorum to identify vulnerable atherosclerotic plaques at risk of rupture and thrombosis. The available literature on molecular imaging techniques and molecular targets associated with inflammation and angiogenesis is discussed, and the clinical applications of molecular cardiovascular imaging and the use of molecular techniques for local drug delivery are addressed.

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 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.

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.

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.

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.

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.

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.

Anaphylactoid reaction from amifostine (Article)

2007-01-01T00:00:00Z

Pulsed wave tissue Doppler imaging for the quantification of contractile reserve in stunned, hibernating, and scarred myocardium (Article)

2004-01-01T00:00:00Z

OBJECTIVES: To assess whether quantification of myocardial systolic velocities by pulsed wave tissue Doppler imaging can differentiate between stunned, hibernating, and scarred myocardium. DESIGN: Observational study. SETTING: Tertiary referral centre. PATIENTS: 70 patients with reduced left ventricular function caused by chronic coronary artery disease. METHODS: Pulsed wave tissue Doppler imaging was done close to the mitral annulus at rest and during low dose dobutamine; systolic ejection velocity (Vs) and the difference in Vs between low dose dobutamine and the resting value (DeltaVs) were assessed using a six segment model. Assessment of perfusion (with Tc-99m-tetrofosmin SPECT) and glucose utilisation (by 18F-fluorodeoxyglucose SPECT) was used to classify dysfunctional regions (by resting cross sectional echocardiography) as stunned, hibernating, or scarred. RESULTS: 253 of 420 regions (60%) were dysfunctional. Of these, 132 (52%) were classified as stunned, 25 (10%) as hibernating, and 96 (38%) as scarred. At rest, Vs in stunned, hibernating, and scar tissue was, respectively, 6.3 (1.8), 6.6 (2.2), and 5.5 (1.5) cm/s (p = 0.001 by ANOVA). There was a gradual decline in Vs during low dose dobutamine infusion between stunned, hibernating, and scar tissue (8.3 (2.6) v 7.8 (1.5) v 6.8 (1.9) cm/s, p < 0.001 by ANOVA). DeltaVs was higher in stunned (2.1 (1.9) cm/s) than in hibernating (1.2 (1.4) cm/s, p < 0.05) or scarred regions (1.3 (1.2) cm/s, p = 0.001). CONCLUSIONS: Quantitative tissue Doppler imaging showed a gradual reduction in regional velocities between stunned, hibernating, and scarred myocardium. Dobutamine induced contractile reserve was higher in stunned regions than in hibernating and scarred myocardium, reflecting different severities of myocardial damage

Long-term prognostic value of dobutamine stress 99mTc-sestamibi SPECT: single-center experience with 8-year follow-up (Article)

2002-01-01T00:00:00Z

PURPOSE: To determine the long-term prognostic value of dobutamine stress technetium 99m (99mTc)-labeled sestamibi single photon emission computed tomography (SPECT) in patients with limited exercise capacity. MATERIALS AND METHODS: Clinical data and SPECT results were analyzed in 531 consecutive patients. Follow-up was successful in 528 (99.4%) patients; 55 underwent early revascularization and were excluded. Normal or abnormal findings were considered in the absence or presence of fixed and/or reversible perfusion defects. A summed stress score was calculated to estimate the extent and severity of perfusion defects. Univariate and multivariate Cox proportional hazards regression models were used to identify independent predictors of late cardiac events. The incremental value of myocardial perfusion scintigraphy over clinical variables in predicting events was determined according to two models. The probability of survival was calculated by using the Kaplan-Meier method. RESULTS: Findings were abnormal in 312 patients. During 8.0 years +/- 1.5 of follow-up (range, 4.5-10.6 years), cardiac death occurred in 67 patients (total deaths, 165); nonfatal myocardial infarction, in 34; and late revascularization, in 49. The annual rates for cardiac death, cardiac death or infarction, and all events were 0.9%, 1.2%, and 1.5%, respectively, after normal findings and 2.7%, 3.4%, and 4.4%, respectively, after abnormal findings (P <.05). In a multivariable Cox proportional hazards model, not only an abnormal finding but also the summed stress score provided incremental prognostic information in addition to clinical data. The hazard ratio for cardiac death was 1.09 (95% CI: 1.01, 1.18) per 1-unit increment of the summed stress score. CONCLUSION: The incremental prognostic value of dobutamine stress 99mTc-sestamibi SPECT over clinical data was maintained over an 8-year follow-up in patients with limited exercise capacity.

Prevalence of myocardial viability assessed by single photon emission computed tomography in patients with chronic ischaemic left ventricular dysfunction (Article)

2002-01-01T00:00:00Z

OBJECTIVE: To assess the prevalence of myocardial viability by technetium-99m (Tc-99m)-tetrofosmin/fluorine-18-fluorodeoxyglucose (FDG) single photon emission computed tomography (SPECT) in patients with ischaemic cardiomyopathy. DESIGN: A retrospective observational study. SETTING: Thoraxcenter Rotterdam (a tertiary referral centre). PATIENTS: 104 patients with chronic coronary artery disease and severely depressed left ventricular function presenting with heart failure symptoms. MAIN OUTCOME MEASURES: Prevalence of myocardial viability as evaluated by Tc-99m-tetrofosmin/FDG SPECT imaging. Two strategies for assessing viability in dysfunctional myocardium were used: perfusion imaging alone, and the combination of perfusion and metabolic imaging. RESULTS: On perfusion imaging alone, 56 patients (54%) had a significant amount of viable myocardium, whereas 48 patients (46%) did not. Among the 48 patients with no significant viability by perfusion imaging alone, seven additional patients (15%) had significantly viable myocardium on combined perfusion and metabolic imaging. Thus with a combination of perfusion and metabolic imaging, 63 patients (61%) had viable myocardium and 41 (39%) did not. CONCLUSIONS: On the basis of the presence of viable dysfunctional myocardium, 61% of patients with chronic coronary artery disease and depressed left ventricular ejection fraction presenting with heart failure symptoms may be considered for coronary revascularisation. The combination of perfusion and metabolic imaging identified more patients with significant viability than myocardial perfusion imaging alone.

Prognostic value of dobutamine-atropine stress myocardial perfusion imaging in patients with diabetes (Article)

2002-01-01T00:00:00Z

OBJECTIVE: Exercise tolerance in patients with diabetes is frequently impaired due to noncardiac disease such as claudication and polyneuropathy. This study assesses the prognostic value of dobutamine stress myocardial perfusion imaging in patients with diabetes. RESEARCH DESIGN AND METHODS: A total of 207 consecutive diabetic patients who were unable to undergo exercise stress testing underwent dobutamine-atropine stress myocardial perfusion imaging. Follow-up was successful in 206 of 207 (99.5%) patients. A total of 12 patients underwent early (<60 days) revascularization and were excluded from the analysis. End points during follow-up were hard cardiac events, defined as cardiac death and nonfatal myocardial infarction. RESULTS: Abnormal myocardial perfusion was detected in 125 (64%) patients. During 4.1 +/- 2.4 years of follow-up, 73 (38%) deaths occurred, 36 (49%) of which were due to cardiac causes. Nonfatal myocardial infarction occurred in 7 (4%) patients, and 45 (23%) patients underwent late coronary revascularization. Cardiac death occurred in 2 of 69 (3%) patients with normal myocardial perfusion and in 34 of 125 (27%) patients with perfusion abnormalities (P < 0.0001). A multivariable Cox proportional hazard model demonstrated that, in addition to clinical and stress test data, an abnormal scan had an incremental prognostic value for prediction of cardiac death (hazard ratio 7.2, 95% CI 1.7-30). The summed stress score was an important predictor of cardiac death; the hazard ratio was 1.2 (95% CI 1.07-1.34) per one-unit increment. CONCLUSIONS: Dobutamine-atropine stress myocardial perfusion imaging provides additional prognostic information incremental to clinical data in patients with diabetes who are unable to undergo exercise stress testing.

Improved identification of viable myocardium using second harmonic imaging during dobutamine stress echocardiography (Article)

2001-01-01T00:00:00Z

OBJECTIVE: To determine whether, compared with fundamental imaging, second harmonic imaging can improve the accuracy of dobutamine stress echocardiography for identifying viable myocardium, using nuclear imaging as a reference. PATIENTS: 30 patients with chronic left ventricular dysfunction (mean (SD) age, 60 (8) years; 22 men). METHODS: Dobutamine stress echocardiography was carried out in all patients using both fundamental and second harmonic imaging. All patients underwent dual isotope simultaneous acquisition single photon emission computed tomography (DISA-SPECT) with (99m)technetium-tetrofosmin/(18)F-fluorodeoxyglucose on a separate day. Myocardial viability was considered present by dobutamine stress echocardiography when segments with severe dysfunction showed a biphasic sustained improvement or an ischaemic response. Viability criteria on DISA-SPECT were normal or mildly reduced perfusion and metabolism, or perfusion/metabolism mismatch. RESULTS: Using fundamental imaging, 330 segments showed severe dysfunction at baseline; 144 (44%) were considered viable. The agreement between dobutamine stress echocardiography by fundamental imaging and DISA-SPECT was 78%, kappa = 0.56. Using second harmonic imaging, 288 segments showed severe dysfunction; 138 (48%) were viable. The agreement between dobutamine stress echocardiography and DISA-SPECT was significantly better when second harmonic imaging was used (89%, kappa = 0.77, p = 0.001 v fundamental imaging). CONCLUSIONS: Second harmonic imaging applied during dobutamine stress echocardiography increases the agreement with DISA-SPECT for detecting myocardial viability.

Doppler tissue velocity sampling improves diagnostic accuracy during dobutamine stress echocardiography for the assessment of viable myocardium in patients with severe left ventricular dysfunction. (Article)

2000-07-01T00:00:00Z

BACKGROUND: Both nuclear imaging with F18-fluorodeoxyglucose and dobutamine stress echocardiography have been used to identify viable myocardium, although dobutamine-stress echocardiography has been demonstrated to be the less sensitive of the two. AIM: To compare the accuracy of pulsed-wave Doppler tissue sampling with dobutamine-stress echocardiography for the detection of viable myocardium, using F18-fluorodeoxyglucose imaging as a reference. Methods Forty patients with chronic coronary artery disease and left ventricular dysfunction (mean ejection fraction 33+/-11%), underwent F18-fluorodeoxyglucose imaging, dobutamine-stress echocardiography and pulsed-wave Doppler tissue sampling. Evaluation was performed using a six-segment model. RESULTS: Visual assessment by resting echo was feasible in 230 out of 240 segments (96%); 177 (77%) segments showed severe dyssynergy at rest. F18-fluorodeoxyglucose imaging showed viability in 95 (54%) segments while 82 (46%) were non-viable. Ejection phase velocity at rest was not significantly different; ejection velocities during low-dose and peak-dose dobutamine, however, were significantly higher in viable myocardium (8.6+/-2.9 vs 6.0+/-1.8 and 9.3+/-3.1 vs 6.2+/-2.1 cm x s(-1)). Using receiver operating characteristic curves the optimal cut-off value for viability assessment was an increase in the ejection phase velocity low-dose of 1+/-0.5 cm x s(-1), while 0+/-0.5 cm x s(-1)predicted non-viability. The sensitivity and specificity (95%CI) of pulsed-wave Doppler tissue sampling and dobutamine-stress echocardiography for the prediction of viability was respectively 87% (82-92) vs 75% (67-81) (P<0.05) and 52% (44-59) vs 51% (45-59) (P=ns). CONCLUSIONS: The sensitivity of pulsed-wave Doppler tissue sampling is superior to dobutamine-stress echocardiography for the assessment of myocardial viability.

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.