EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer.

Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti-tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up.

[Therapy of bone metastases with radium-223. German guidelines]. / Radionuklidtherapie von Knochenmetastasen mittels Radium-223. DGN-Handlungsempfehlung.

This document describes the guideline for therapy of bone metastases with radium-223 ((223)Ra) published by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften in Germany (AWMF) under the auspices of the Deutsche Gesellschaft für Nuklearmedizin (DGN), Östereichische Gesellschaft für Nuklearmedizin (OGN), and Schweizerische Gesellschaft für Nuklearmedizin (SGNM). This guidance is based on an interdisciplinary consensus. These recommendations are a prerequisite for the quality management in the treatment of patients with bone metastases from prostate cancer using (223)Ra. They are aimed at guiding nuclear medicine specialists in selecting candidates to receive therapy and to deliver the treatment in a safe and effective manner. The document contains background information and definitions. It covers the rationale, indications and contraindications for therapy with (223)Ra. Essential topics are the requirements for institutions performing the therapy, which patient data have to be available prior to performance of therapy, and how treatment has to be carried out technically and organisationally. Moreover, essential elements of follow-up and aftercare are specified. As a matter of principle, the treatment inclusive aftercare has to be realised in close cooperation with the involved medical disciplines.

Quantitative myocardial perfusion PET combined with coronary anatomy derived from CT angiography: validation of a new fusion and visualisation software.

AIM: Dynamic perfusion PET offers a clinical relevant advantage over myocardial perfusion scintigraphy due to its ability to measure myocardial blood flow quantitatively. This leads to an improved detection of multivessel disease and the possibility to assess not only the culprit lesion but lower grade stenoses as well. For appropriate revascularization, perfusion defects must be matched to coronary lesions. It has been shown that image fusion of morphological and functional images is superior to side-by-side analysis. Still, software for quantitative perfusion PET combined with CT angiography is rare. In this paper we present a new software tool for image fusion and visualization of quantitative perfusion PET and coronary morphology derived from CT angiography. METHODS: In our software, a PET uptake image is used for manual co-registration. Co-registration results are then applied to the functional data derived from compartment modelling. To evaluate the reproducibility of the manual co-registration, we calculated the deviation between a series of manual co-registrations performed on nine pairs of unregistered PET and CT datasets by five trained participants. Two dimensional transfer functions were used to highlight the coronary arteries from the CT study in the combined data sets. RESULTS: The average Euclidian distances for three references points were between 3.7 and 4.1 mm. The maximum distance was 10.6 mm. By the use of the two dimensional transfer functions, coronary anatomy could be easily visualised either by user-interaction or automatically by use of neuronal networks. CONCLUSIONS: With this approach it is possible to combine quantitative perfusion PET with coronary anatomy derived from CT angiography. Our first experiences indicate that manual image fusion with our tool is reproducible and that visualisation of the combined datasets is achieved within short time.

Myocardial perfusion after one year of spinal cord stimulation in patients with refractory angina.

AIM: Spinal cord stimulation (SCS) is recommended for patients with coronary artery disease (CAD) and refractory angina. We used positron emission tomography (PET) to investigate the long-term effect of SCS on regional myocardial perfusion in patients suffering from angina pectoris refractory to medical treatment and without option for coronary intervention. PATIENTS, METHODS: We analyzed data of 44 patients with stable CAD (91% three vessel disease). At baseline, we determined coronary flow reserve (CFR) using 13N-ammonia-PET and myocardial viability with 18F-FDG. SCS was performed for one year (Medtronic Itrell III or Synergy, Düsseldorf, Germany). During follow-up, no cardiac interventions were necessary and no myocardial infarctions occurred. At one year follow-up, CFR was measured again. RESULTS: In the majority of patients (77%), SCS led to an improvement of clinical symptoms. CFR did not change significantly during follow-up. Subjective improvement did not correlate with an increase of CFR. CONCLUSIONS: Despite its clinical effect, SCS does not have a direct impact on CFR in patients with stable CAD. According to our results, the pain relief is not due to an improvement of the myocardial blood supply.

Myocardial sympathetic innervation in patients with symptomatic coronary artery disease: follow-up after 1 year with neurostimulation.

UNLABELLED: In both diabetic and nondiabetic patients, there is a loose correlation between coronary flow reserve (CFR) and sympathetic innervation in viable myocardial segments. The loose correlation implies that sympathetic innervation may be preserved even with major impairment of myocardial blood supply. In some patients, denervation is due to repetitive episodes of ischemia in areas with severely reduced CFR. We investigated the long-term effect of reduced CFR on myocardial sympathetic innervation in diabetic and nondiabetic patients with spinal cord stimulation. METHODS: We analyzed 23 patients (10 diabetic and 13 nondiabetic) with coronary artery disease and without known cardiac autonomic neuropathy. At baseline, we determined quantitative myocardial blood flow using (13)N-ammonia PET, myocardial viability using (18)F-FDG PET, and cardiac innervation using (11)C-hydroxyephedrine (HED) PET. At the 1-y follow-up we measured CFR and (11)C-HED retention. During follow-up, no cardiac intervention was performed and no myocardial infarction occurred. In all patients, spinal cord stimulation was performed for relief of angina. RESULTS: There was no significant difference in segmental (11)C-HED retention between baseline and follow-up in the whole patient group. In diabetic patients, as well as in segments with severely reduced CFR (<1.5), (11)C-HED retention showed a small but significant decrease (P<0.05). Linear regression of segmental (11)C-HED retention between baseline and follow-up was high (r(2)=0.81), confirming good reproducibility of the investigation on the one hand and little change in regional sympathetic innervation on the other hand. CONCLUSION: In patients with stable chronic coronary artery disease, sympathetic innervation of the myocardium is almost unchanged in both diabetic and nondiabetic patients in a 1-y follow-up. In myocardial segments with severely altered blood supply, a small but significant decrease in (11)C-HED retention most probably reflects ischemic neuronal damage. The prognostic relevance of sympathetic denervation in viable myocardium still has to be determined.

Comparison of 99mTc- and 18F-ubiquicidin autoradiography to anti-Staphylococcus aureus immunofluorescence in rat muscle abscesses.

UNLABELLED: 99mTc-ubiquicidin (UBI) 29-41 is under clinical evaluation for discrimination between bacterial infection and unspecific inflammation. We compared the distribution of 99mTc-UBI 29-41, the potential PET tracers 18F-UBI 29-41 and 18F-UBI 28-41, and 3H-deoxyglucose (DG) in rat muscle abscesses to that of anti-Staphylococcus aureus immunofluorescent imaging. METHODS: Calf abscesses were induced in 15 CDF-Fischer rats after inoculation of Staphylococcus aureus. One to 6 d later, either 18F-UBI 29-41 and 3H-DG (n = 5) or 18F-UBI 28-41 and 3H-DG (n = 6) or 99mTc-UBI 29-41 and 3H-DG (n = 4) were injected simultaneously. Dual-tracer autoradiography of the abscess area was compared with the distribution of bacteria and macrophages. RESULTS: The UBI derivates exhibited increased uptake in the abscess area that partly matched 3H-DG uptake and macrophage infiltration but showed no congruity with areas that were highly positive for bacteria. CONCLUSION: A specific binding of UBI derivatives to Staphylococcus aureus in vivo could not be confirmed in this study.

Respiratory resistance of patients during cardiac stress testing with adenosine: is dyspnea a sign of bronchospasm?

BACKGROUND: Adenosine is widely used for stress-testing in myocardial perfusion imaging. During adenosine infusion, dyspnea is one of the main complaints of patients. The aim of this study was to determine whether dyspnea during adenosine infusion is caused by bronchospasm. METHODS: Fifty-four patients were enrolled in the study. Seven of these 54 suffered from mild chronic obstructive pulmonary disease (COPD). We continuously measured respiratory resistance (Rrs), using impulse oscillometry. Respiratory resistance was measured before, during, and after a continuous infusion of 140 microg/kg/min adenosine. RESULTS: Sixty-seven percent of patients suffered from dyspnea during adenosine infusion. In patients with mild COPD, Rrs was higher compared with other patients (0.48 vs 0.27 kPa/L/s, P < .05). Neither patients with COPD nor those without COPD exhibited a significant increase in Rrs during adenosine infusion. The Rrs of patients with dyspnea was insignificantly lower compared with patients without dyspnea (P = .469). CONCLUSIONS: Dyspnea as a side effect of adenosine infusion is not correlated with impaired respiratory resistance in nonasthmatic patients and in patients with mild COPD. Thus bronchospasm is ruled out as cause of this clinical symptom. Despite the small number of COPD patients enrolled in the study, adenosine infusion might be possible in patients with mild COPD.

Optimisation of protocol for low dose CT-derived attenuation correction in myocardial perfusion SPECT imaging.

PURPOSE: In clinical routine, attenuation correction (AC) using X-ray CT is a relatively new method for reducing attenuation artefacts. We evaluated the quality of attenuation maps generated with very low tube current to minimise exposure due to transmission scanning. METHODS: SPECT/CT acquisitions were performed with a Millenium VG3 gamma camera with the Hawkeye CT device (GE Medical Systems). In phantom studies, determination of linear absorption coefficients (mu) for air, water and Teflon was carried out. The attenuation maps in both stress and resting studies from 62 patients (21 females and 41 males, age 63.7 +/- 11.0 years, BMI 30.0 +/- 5.7 kg/m(2)) were compared. All patients underwent exercise or pharmacologic stress testing and a resting study for comparison using Tc-99m MIBI or Tc-99m Tetrofosmin. AC in stress studies was performed using 2.5 mA tube current (set as default), whereas 1.0 mA was used in resting studies. RESULTS: In both phantom and patient studies, differences of linear absorption coefficients were not significant (p > 0.05). Effective dose decreased from 0.90 mSv down to 0.36 mSv, respectively. CONCLUSION: Our results indicate that reliable attenuation maps (mu-maps) of the thorax can be obtained even with the use of very low tube current. In our study, radiation exposure in CT-based AC for myocardial perfusion SPECT was substantially lowered (60% reduction). This is of particular importance in high-risk patients who may have to undergo follow-up scans and in research studies on volunteers. The procedure introduced is relatively simple and can be transferred to other SPECT/CT devices, which allow adjustment of tube current.

Myocardial sympathetic innervation in patients with chronic coronary artery disease: is reduction in coronary flow reserve correlated with sympathetic denervation?

PURPOSE: Higher sensitivity of sympathetic nerves to ischaemia in comparison with myocytes has been observed and has been claimed to contribute to poor prognosis in patients with coronary artery disease (CAD). The aim of this study was to evaluate the dependency of myocardial sympathetic innervation on restrictions in coronary flow reserve (CFR). METHODS: We analysed 27 non-diabetic patients with advanced CAD. We determined quantitative myocardial blood flow using (13)N-ammonia PET, myocardial viability with (18)F-FDG PET and cardiac innervation with (11)C-HED PET. Scarred segments were excluded from analysis. We investigated the relationship between regional HED retention, blood flow and CFR. RESULTS: There was no correlation between rest perfusion and HED retention within a flow range from approximately 30 to 120 ml/(100 ml x min). A slight correlation was observed between stress perfusion values and HED retention (p<0.001), and between CFR and HED retention (p<0.001). CONCLUSION: In non-diabetic CAD patients, HED retention in vital myocardium does not correlate with myocardial rest perfusion over a large flow range. The observed relation between HED retention and CFR indicates that sympathetic innervation can be preserved even when there is major impairment of myocardial blood supply. Most probably the occurrence of denervation depends not only on reductions in CFR, but also on the duration and severity of resulting ischaemic episodes.

Cardiac efficiency and oxygen consumption measured with 11C-acetate PET after long-term cardiac resynchronization therapy.

UNLABELLED: Cardiac resynchronization therapy (CRT) is a treatment option in patients with severe heart failure and left bundle-branch block (LBBB). This study evaluated the effects of 4 and 13 mo of CRT on myocardial oxygen consumption (MVO2) and cardiac efficiency as compared with mild heart failure patients without LBBB. METHODS: Sixteen patients with severe heart failure and LBBB due to idiopathic cardiomyopathy were studied at baseline and after 4 and after 13 mo of therapy. Thirteen patients with mild heart failure without LBBB served as a comparison group. The clearance rate (k2) of 11C-acetate was measured with PET to assess MVO2. Stroke volume was derived from the dynamic PET data according to the Stewart-Hamilton principle and, furthermore, cardiac efficiency using the work metabolic index. RESULTS: After 4 mo of CRT, stroke volume index (SVI) increased by 50% (P = 0.012) and cardiac efficiency increased by 41% (P < 0.001). Global k2 remained unchanged but regional k2 demonstrated a more homogeneous distribution pattern. The parameters showed no significant changes during therapy. Under CRT, cardiac efficiency, SVI, and the distribution pattern of regional k2 did not differ from mild heart failure patients without LBBB. CONCLUSION: CRT improves cardiac efficiency for at least 13 mo, as demonstrated by a higher SVI, whereas MVO2 remains unchanged. Cardiac efficiency, SVI, and the MVO2 distribution pattern reach the level of patients with mild heart failure without LBBB. The unfavorable hemodynamic performance in heart failure with LBBB is effectively restored by long-term CRT to the level of an earlier disease state.

Attenuation correction of myocardial SPECT perfusion images with low-dose CT: evaluation of the method by comparison with perfusion PET.

UNLABELLED: In cardiac SPECT, specificity is significantly affected by artifacts due to photon absorption. As the success of attenuation correction depends mainly on high-quality attenuation maps, SPECT low-dose CT devices are promising. We wanted to evaluate the usefulness of a SPECT low-dose CT device in myocardial perfusion scintigraphy. For the evaluation of attenuation correction systems, primarily comparisons with coronary angiography are used. Because the comparison of a method showing myocardial perfusion with an investigation displaying the morphology of vessels yields some difficulties, we chose perfusion PET with (13)N-ammonia as the reference method. METHODS: We prospectively analyzed 23 patients (6 women, 17 men) with known or suspected coronary artery disease. Rest studies and studies under pharmacologic stress with adenosine were performed. After simultaneous injection of (13)N-ammonia and (99m)Tc-sestamibi, a dynamic PET acquisition was started. The SPECT study was performed about 2 h later. Based on 20-segment polar maps, SPECT with and without attenuation correction was compared with PET-derived perfusion values and ammonia uptake values. The PET uptake images were also smoothed to adjust their resolution to the resolution of the SPECT images. RESULTS: The concordance of SPECT and PET studies was improved after attenuation correction. The main effect was seen in the inferior wall. Especially in the apex and anterolateral wall, there were differences between SPECT and PET studies not attributable to attenuation artifacts. Because these differences diminished after smoothing of the PET studies, they might be due to partial-volume effects caused by the inferior resolution of the SPECT images. CONCLUSION: The x-ray-derived attenuation correction leads to SPECT images that represent myocardial perfusion more accurately than nonattenuation-corrected SPECT images. The benefit of the method is seen primarily in the inferior wall. The low resolution of the SPECT system may lead to artifacts due to partial-volume effects. This phenomenon must be considered when perfusion PET is used as a reference method to investigate the effect of attenuation correction.

Scintigraphy for risk stratification of iodine-induced thyrotoxicosis in patients receiving contrast agent for coronary angiography: a prospective study of patients with low thyrotropin.

The risk of iodine-induced thyrotoxicosis in euthyroid patients receiving iodine-containing contrast agents is known to be low, but data on this risk in patients with latent hyperthyroidism are scarce. We investigated the role of thyroid scintigraphy using Tc-99m preceding the application of iodine-containing contrast material to estimate the risk of iodine-induced thyrotoxicosis in patients with low levels of TSH. In a prospective study on 91 patients, thyroid scintigraphy was performed before coronary angiography (CA). In patients with technetium thyroid uptake (TCTU) less than 1%, CA was done without prophylactic drugs (n = 56). Patients with TCTU greater than 1% were treated either with 900 mg of perchlorate or, depending on the autonomous volume, combined with 20 to 60 mg thiamazole. In the 56 patients with TCTU less than 1%, no case of iodine-induced hyperthyroidism occurred within 4 wk after CA. In the patients who received prophylactic drugs, two cases of mild thyrotoxicosis were observed. Our data suggest that in patients with low levels of TSH, the risk of hyperthyroidism after application of iodine-containing contrast media is negligible if TCTU is less than 1%. In these patients, CA can be performed without administration of prophylactic drugs.

A method to remove artifacts in attenuation-corrected myocardial perfusion SPECT Introduced by misalignment between emission scan and CT-derived attenuation maps.

UNLABELLED: Nonuniform soft-tissue attenuation affects the diagnostic accuracy of SPECT in myocardial perfusion imaging. The attenuation map required for attenuation correction can be acquired using x-ray tomography (CT). Frequent findings in attenuation-corrected images are defects in the apical and anterior myocardial wall. We assume that these are artifacts produced by misalignment of SPECT images and the attenuation map. METHODS: One hundred forty patients underwent myocardial perfusion imaging with 99mTc-methoxyisobutylisonitrile. Twenty-seven of 140 showed pronounced defects in the apical or anterior wall only after CT-based attenuation correction. SPECT and corresponding CT slices were examined for misalignment in the ventrodorsal direction (y-direction) visually and by threshold-based delineation of the body surface. Mismatched studies were realigned and image reconstruction and analysis were redone. The effect of the correction was assessed visually and by semiquantitative analysis based on a 20-segment model using 4D-MSPECT. RESULTS: In 15 of 27 patients, the improved coregistration led to smaller and less-pronounced defects in the regions mentioned. In 6 of 27 patients, former defects were judged as normal. No improvement was seen in only 4 patients. In these 4 subjects, the mismatch in the y-direction was <1 pixel (7 mm), and visual inspection suggested a coincident mismatch in the craniocaudal direction. In 2 cases, coregistration was not possible because the body outline extended beyond the CT field of view. Semiquantitative analysis revealed a significant increase of the relative uptake in the apex; in the apical segments of the anterior, septal, and inferior wall; and in the mid-anterior and mid-anteroseptal segment. Basal segments of the anterolateral, lateral, and inferolateral wall and the middle inferolateral segment showed a significant decrease of relative uptake. CONCLUSION: Misalignment in the y-direction between SPECT and the attenuation map can lead to artifacts in the apical, septal, and anterior wall, which will appear as defects. It also can cause overcorrection in the basal inferior and lateral segments. There is evidence that mismatches along the other directions may have a similar effect. The coregistration of SPECT and the attenuation map needs to be verified for every patient, even when using integrated dual-modality imaging devices.