Impact of clinically tested NEP/ACE inhibitors on tumor uptake of [111In-DOTA]MG11

Background: We have recently shown that treatment of mice with the neutral endopeptidase (NEP) inhibitor phosphoramidon (PA) improves the bioavailability and tumor uptake of biodegradable radiopeptides. For the truncated gastrin radiotracer [111In-DOTA]MG11 ([(DOTA)DGlu10]gastrin(10–17)), this method led to impressively high tumor-to-kidney ratios. Translation of this concept in the clinic requires the use of certified NEP inhibitors, such as thiorphan (TO) and its orally administered prodrug racecadotril (Race). Besides NEP, angiotensin-converting enzyme (ACE) has also been implicated in the catabolism of gastrin analogs. In the present study, we first compared the effects induced by NEP inhibition (using PA, TO, or Race) and/or by ACE inhibition (using lisinopril, Lis) on the biodistribution profile of [111In-DOTA]MG11 in mice. In addition, we compared the efficacy of PA and TO at different administered doses to enhance tumor uptake. Methods: [111In-DOTA]MG11 was coinjected with (a) vehicle, (b) PA (300 μg), (c) TO (150 μg), (d) Lis (100 μg), (e) PA (300 μg) plus Lis (100 μg), or (f) 30–40 min after intraperitoneal (ip) injection of Race (3 mg) in SCID mice bearing AR42J xenografts. In addition, [111In-DOTA]MG11 was coinjected with vehicle, or with progressively increasing amounts of PA (3, 30, or 300 μg) or TO (1.5, 15, and 150 μg) in SCID mice bearing twin A431-CCK2R(+/−) tumors. In all above cases, biodistribution was conducted at 4 h postinjection (pi). Results: During NEP inhibition, the uptake of [111In-DOTA]MG11 in the AR42J tumors impressively increased from 1.8 ± 1.0 % ID/g (controls) to 15.3 ± 4.7 % ID/g (PA) and 12.3 ± 3.6 % ID/g (TO), while with Race tumor values reached 6.8 ± 2.8 % ID/g. Conversely, Lis had no effect on tumor uptake and no additive effect when coinjected with PA. During the dose dependence study in mice, PA turned out to be more efficacious in enhancing tumor uptake of [111In-DOTA]MG11 in the CCK2R-positive tumors compared to equimolar amounts of TO. In all cases, renal accumulation remained low, resulting in notable increases of tumor-to-kidney ratios. Conclusions: This study has confirmed NEP as the predominant degrading enzyme of [111In-DOTA]MG11 and ruled out the involvement of ACE in the in vivo catabolism of the radiotracer. NEP inhibition with the clinically tested NEP

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

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

Peptide receptor radionuclide therapy

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

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

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

Ischemia burden on stress SPECT MPI predicts long-term outcomes after revascularization in stable coronary artery disease

Background: It is not entirely clear whether ischemia burden on stress single-photon emission computed tomography (SPECT) effectively identifies patients who have a long-term benefit from coronary revascularization. Methods: The study population consisted of 719 patients with ischemia on stress SPECT. Early coronary revascularization was defined as percutaneous coronary intervention or coronary artery bypass grafting ≤90 days after SPECT. Patients who underwent late revascularization (>90 days after SPECT) were excluded (n = 164). Results: Of the 538 patients (73% men, mean age 59.8 ± 11 years), 348 patients had low ischemia burden (<3 ischemic segments) and 190 patients had moderate to high ischemia burden (≥3 ischemic segments). A total of 76 patients underwent early revascularization. During a median follow-up of 12 years (range 4-17), 283 patients died of whom 125 due to cardiac causes. Early revascularization was beneficial on all-cause mortality (HR 0.46, 95% CI 0.30-0.46) and cardiac mortality (HR 0.54, 95% CI 0.29-0.99). Conclusions: Patients with myocardial ischemia on stress SPECT who underwent early revascularization had a lower all-cause mortality and cardiac mortality during long-term follow-up as compared to patients who received pharmacological therapy alone. This difference in long-term outcomes was mainly influenced by the survival benefit of early revascularization in the patients with moderate to high ischemia burden

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

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

Prednisone treatment of elderly-onset rheumatoid arthritis: Disease activity and bone mass in comparison with chloroquine treatment

Objective. Prednisone is frequently used in the treatment of elderly-onset rheumatoid arthritis (RA), but the balance between efficacy and toxicity, including the effect on bone mass, has not been investigated in long-term studies. This prospective, randomized study was undertaken to compare disease activity and bone mass during long-term treatment with prednisone versus chloroquine in this patient population. Methods. Patients with active RA diagnosed at age ≥ 60 were randomized to receive prednisone (15 mg/day for 1 month, with the dosage tapered as low as possible thereafter) (n = 28) or chloroquine (n = 28). Patients who did not show a response received other second-line drugs as an adjunct to prednisone or as a replacement for chloroquine. Bone mass was measured by dual-energy x-ray absorptiometry. The study duration was 2 years. Results. During the 2 years, treatment with other second-line drugs was needed for 12 patients in the prednisone group (43%) and 8 in the chloroquine group (29%). Functional capacity and disease activity improved significantly in both groups and did not differ significantly between the groups, except for a greater improvement in the prednisone group at 1 month. Radiographic scores for joint destruction progressed similarly in both groups. There was a nonsignificant excess bone loss of 1.8% in the spine and 1.5% in the hip in the prednisone group, compared with the chloroquine group. Conclusion. Neither treatment was entirely satisfactory since a significant number of patients needed an additional second-line drug over the 2-year period

Long-term prognostic value of exercise technetium-99m tetrofosmin myocardial perfusion single-photon emission computed tomography

Background. Exercise 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) is a useful tool for short- and medium-term risk stratifications. Cur

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

Cardiac stress imaging for the prediction of very long-term outcomes: Dobutamine stress echocardiography or dobutamine 99mTc-sestamibi SPECT?

Background: Both dobutamine stress echocardiography (DSE) and myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) are frequently used for cardiac risk stratification. The long-term relative prognostic