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

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.     

Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate

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 of ^99mTc-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 of ^99mTc-DMSA SPECT scintigrams at 130 days after [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate therapy correlated well with 1/creatinine (r ² = 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.     

Prognostic value of stress Tc-99m tetrofosmin SPECT in patients with previous myocardial infarction: Impact of scintigraphic extent of coronary artery disease

BACKGROUND: Our objective was to assess the prognostic value of the scintigraphic extent of coronary artery disease on stress technetium 99m tetrofosmin single photon emission computed tomography in patients with previous myocardial infarction. METHODS AND RESULTS: We studied 383 patients (280 men and 103 women; mean age, 60 +/- 11 years) more than 3 months after an acute myocardial infarction by exercise bicycle or dobutamine (up to 40 mug . kg -1 . min -1 ) stress Tc-99m tetrofosmin myocardial perfusion tomography. Stress images were acquired 1 hour after stress, and rest images were acquired 24 hours after stress testing. An abnormal study was defined as one demonstrating a reversible or fixed perfusion abnormality. Myocardial segments were assigned to corresponding coronary arteries as follows: the apex, anterior wall, and anterior septum were assigned to the left anterior descending coronary artery; the posterolateral wall was assigned to the left circumflex artery; and the basal posterior septum and inferior wall were assigned to the right coronary artery. During a mean follow-up of 4.3 +/- 2.1 years, 48 cardiac events occurred (36 cardiac deaths and 12 nonfatal myocardial infarctions). Myocardial perfusion was normal in 51 patients, abnormal in a single-vessel distribution in 170 patients, and abnormal in a multivessel distribution in 162 patients. The annual cardiac event rates in these groups were 0.4%, 2.6%, and 4%, respectively. In a multivariate analysis model, independent predictors of cardiac events were diabetes mellitus (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.4-4.5), history of congestive heart failure (OR, 2.7; 95% CI, 1.4-4), age (OR, 1.05; 95% CI, 1.01-1.08), and scintigraphic extent of coronary artery disease (OR, 4.2; 95% CI, 1.8-9.1). CONCLUSION: Stress Tc-99m tetrofosmin myocardial perfusion imaging provides independent prognostic information for the risk stratification of patients with previous myocardial infarction. The event rate is directly related to the scintigraphic extent of coronary artery disease. Patients with normal perfusion have an excellent event-free survival rate.     

Preoperative comparison of different noninvasive strategies for predicting improvement in left ventricular function after coronary artery bypass grafting

Thallium-201 (Tl-201) imaging and dobutamine stress echocardiography (DSE) are the most frequently used tests in the clinical setting for assessing viability. However, Tl-201 has a suboptimal specificity and DSE a suboptimal sensitivity to predict functional improvement after revascularization. F18-fluorodeoxyglucose (FDG) imaging is considered highly accurate, but availability is limited. Sequential imaging of Tl-201 and DSE may improve accuracy for assessing viability and may be comparable to FDG. Forty-seven patients with ischemic cardiomyopathy underwent Tl-201 single-photon emission computed tomography (SPECT) at rest (4-hour delayed imaging), DSE, and FDG SPECT before bypass surgery. Sensitivity, specificity, and accuracy of 2 sequential strategies were compared with those of FDG SPECT. Strategy 1 considered Tl-201 imaging as the first step, followed by DSE in patients with an intermediate likelihood of viability on Tl-201. Strategy 2 considered DSE as the first step, followed by Tl-201 imaging. Left ventricular ejection fraction was assessed before and 6 months after revascularization, and improvement of >/=5% was considered significant. Tl-201 had a high sensitivity (95%, p <0.05 vs DSE) with a low specificity (57%, p <0.05 vs DSE). DSE had a low sensitivity (63%, p <0.05 vs Tl-201) with a high specificity (89%, p <0.05 vs Tl-201). Both strategies 1 and 2 resulted in high sensitivities (89% and 89%, respectively) and high specificities (89% and 86%, respectively), compared with FDG SPECT (sensitivity 89%, specificity 86%). Sequential testing by Tl-201 SPECT and DSE has a comparable accuracy to FDG SPECT to predict improvement in left ventricular ejection fraction after revascularization. In centers without access to FDG, sequential imaging with Tl-201 and DSE offers an accurate alternative for assessing myocardial viability.     

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

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.     

Therapy of neuroendocrine tumors with radiolabeled somatostatin-analogues.

Peptide receptor scintigraphy with the radioactive somatostatin-analogue [111In-DTPA0]octreotide (DTPA = diethylenetriaminepentaacetic acid) is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumors. With this technique primary tumors and metastases of neuroendocrine cancers as well as of many other cancer types can be localised. A new application is the use of peptide receptor radionuclide therapy, administrating high doses of 111In- or 90Y-labeled octreotide-analogues. PRECLINICAL: We investigated the radiotherapeutic effect of 90Y- and 111In-labeled [DOTA0,Tyr3]octreotide (DOTA = tetraazacyclododecanetetraacetic acid) or [111In-DTPA0]octreotide in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumor CA20948 in A) the flank or B) in the liver. PATIENTS: Thirty end-stage patients with mostly neuroendocrine progressing tumors were treated with [111In-DTPA0]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase 1 trial. PRECLINICAL RESULTS: A) Flank model: at least two 111MBq injections of [111In-DOTA0,Tyr3]octreotide were needed to reach tumor response, in 40% of the animals complete tumor remission was found after a follow-up period of 10 months. One or two injections of [90Y-DOTA0,Tyr3] octreotide yielded transient stable disease. B) Liver model: we found that peptide receptor radionuclide therapy is only effective if somatostatin receptors are present on the tumors, and is therefore receptor-mediated. High radioactive doses of 370 MBq [111In-DTPA0]octreotide or 93 MBq [90Y-DOTA0,Tyr3]octreotide can inhibit the growth of somatostatin receptor-positive metastases. CLINICAL RESULTS: There were no major clinical side effects after up to 2 years treatment, except that a transient decline in platelet counts and lymphocyte subsets can occur. Promising beneficial effects on clinical symptoms, hormone production and tumor proliferation were found. Of the 21 patients with progressive disease at baseline and who received a cumulative dose of more than 20 GBq [111In-DTPA0]octreotide, 8 patients showed stabilisation of disease and 6 other patients a reduction in size of tumors. There is a tendency towards better results in patients whose tumors have a higher accumulation of the radioligand. CONCLUSION: Radionuclide therapy with octreotide-derivatives is feasible, both with 111In and 90Y as radionuclides.     

Spatial channels of visual processing in cortical blindness

Blindsight is the ability of some cortically blind patients to discriminate visual events presented within their field defect. We have examined a fundamental aspect of visual processing, namely the detection of spatial structures presented within the field defect of 10 cortically blind patients. The method outlined is based on the detection of high-contrast stimuli and is effective in flagging a 'window of detection' in the spatial frequency spectrum, should it exist. Here we report on the presence of a narrowly tuned psychophysical spatial channel optimally responding to frequencies less than 4 cycles/ degrees in eight out of 10 patients tested. The two patients who did not show any evidence of blindsight appear to have intact midbrain structures, but have lesions that extend from the occipital cortex to the thalamus. In addition, we have recorded subjective reports of awareness of the visual events in each trial. Detection scores of eight blindsight patients were subsequently subdivided based on the subjective reports of awareness. It appears that the psychophysical spatial channel-mediating responses in the absence of any awareness of the visual event have a narrower frequency response than those involved when the patients report some awareness of the visual event. The findings are discussed in relation to previous reports on the incidence of blindsight and performance on tasks involving spatial processing.     

Properties of glycerol-75Se-triether: A lipid-soluble marker for the estimation of intestinal fat absorption.

The properties of a 75Se-labeled glycerol triether were investigated in rat experiments designed to test this substance as a nonabsorbable marker for the assessment of intestinal fat absorption. After oral administration of 75Se-triether, the radioactivity was excreted almost completely with the feces. Amounts in excess of the quantity required tor clinical use did not interfere with overall fat absorption. No evidence for toxicity of 75Se-triether was observed. 131l-triolein was used as tracer fat and fat absorption was calculated by the following methods: (1) isotope balance method-oral intake minus fecal excretion of 131L; (2) isotope ratio method-comparison of the 131L to 75Se ratios in the test dose and in a stool sample. Results obtained from the isotope ratio method were in close agreement with those of the isotope balance method over a range of fat absorption of 80 to 95 per cent, thus indicating that the marker and the radioactive fat pass the gastrointestinal tract at the same rate under these experimental conditions. These results show that 75Se-triether possesses several of the properties of an ideal marker for fat absorption studies. Its advantages over other proposed markers for fat absorption studies are discussed. Simultaneous administration of 131L-TRIOLEIN AND 75Se-triether in a single dose may provide a reliable, rapid, and simple method to estimate intestinal fat absorption in man.