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Objectives: Three commonly used techniques for localization of nonpalpable breast cancer are radioactive seed localization (RSL), wire-guided localization (WGL) and radioguided occult lesion localization (ROLL). In this study, we analysed the surgical margins of these three techniques., Methods: Women diagnosed with nonpalpable breast cancer undergoing breast-conserving surgery with one of the above-mentioned techniques were retrospectively included. The primary outcome parameter was tumour-free margin rate. Secondary outcomes were re-excision rate, recurrence of disease and volume of removed tissue., Results: In total, 272 women were included in whom RSL (n=69), WGL (n=76) or ROLL (n=137) was performed. RSL showed a higher tumour-free margin rate [64 (92.8%)] compared with WGL [51 (67.1%)] and ROLL [113 (82.5%)] (P=0.001). In our multivariable analysis, RSL showed a higher tumour-free margin rate as well compared with WGL (P=0.036) and ROLL (P=0.049). Also, fewer re-excisions were encountered using RSL [5 (7.2%)] compared with WGL [13 (17.1%)] and ROLL [15 (10.9%)] (P=0.171). In 11 patients (WGL n=2, ROLL n=9), recurrence of disease occurred, despite a radical excision. The mean resection volumes were comparable within the three groups., Conclusion: RSL results in a higher tumour-free margin rate in nonpalpable breast tumours compared with WGL and ROLL. Therefore, we prefer using RSL in nonpalpable breast tumours.

Background: Attenuation correction (AC) improves the diagnostic outcome of stress-only myocardial perfusion imaging (MPI) using conventional SPECT. Our aim was to determine the value of AC using a cadmium zinc telluride-based (CZT)-SPECT camera., Methods and Results: We retrospectively included 107 consecutive patients who underwent stress-optional rest MPI CZT-SPECT/CT. Next, we created three types of images for each patient; (1) only displaying reconstructed data without the CT-based AC (NC), (2) only displaying AC, and (3) with both NC and AC (NC + AC). Next, two experienced physicians visually interpreted these 321 randomized images as normal, equivocal, or abnormal. Image outcome was compared with all hard events over a mean follow-up time of 47.7 ± 9.8 months. The percentage of images interpreted as normal increased from 45% using the NC images to 72% using AC and to 67% using NC + AC images (P < .001). Hard event hazard ratios for images interpreted as normal were not different between using NC and AC (1.01, P = .99), or NC and NC + AC images (0.97, P = .97)., Conclusions: AC lowers the need for additional rest imaging in stress-first MPI using CZT-SPECT, while long-term patient outcome remained identical. Use of AC reduces the need for additional rest imaging, decreasing the mean effective dose by up to 1.2 mSv.

The impact of coronary artery calcium (CAC) scoring on subsequent changes in cardiovascular medication use in symptomatic patients with normal myocardial perfusion imaging (MPI) findings is not well established. The aim of the current study was to evaluate changes in aspirin and statin use in patients suspected for coronary artery disease after CAC scoring and normal single photon emission computed tomography (SPECT) MPI., Methods: In the current study, 1,033 stable symptomatic patients without a known history of coronary artery disease with normal SPECT MPI who underwent concomitant CAC scoring were included. All patients had a clinical indication for imaging, mainly atypical chest pain and dyspnea, and were referred from the outpatient clinic of our hospital. Data regarding posttest medication change (either starting or discontinuation of aspirin and statin therapy at the subsequent outpatient visit) were retrospectively collected. Patients were categorized into 4 groups based on their CAC score., Results: Mean age of the patients was 61±11 years and 39% were male. At baseline, 35% of the patients used aspirin and 39% used statin. In patients with CAC scores 0, 1-99, 100-399, and ≥400, aspirin was started in 1%, 4%, 9%, and 9%, respectively, and statin was started in 0%, 7%, 18%, and 24% of the patients, respectively (P<.001). Aspirin was discontinued in 19%, 11%, 7%, and 1% and statin was discontinued in 8%, 6%, 2%, and 0% (P<.001) of the patients in these respective CAC score categories. After correction for differences in risk factors and baseline medication use, increased CAC was independently associated with posttest aspirin (odds ratio 4.6, 11.2, and 27.1 for CAC scores 1-99, 100-399, and ≥400, respectively; P<.001) and statin use (odds ratio 4.4, 19.4, and 60.9 for CAC scores 1-99, 100-399, and ≥400, respectively; P<.001)., Conclusions: Higher CAC scores are associated with the initiation of aspirin and statin therapy in patients with normal SPECT MPI. In patients with lower CAC scores, discontinuation of cardioprotective medication is more likely. CAC score is independently associated with posttest statin and aspirin use., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Performing both single photon emission computerized tomography (SPECT) and coronary computed tomography angiography (CCTA) in patients suspected for coronary artery disease (CAD) leads to increased radiation exposure. We evaluated the need for additional imaging and following implications for radiation exposure of a sequential SPECT/computed tomography (CT) algorithm., Methods and Results: 5018 consecutive patients without history of CAD were referred for stress-first SPECT and coronary artery calcium (CAC) scoring. If stress SPECT was abnormal, additional rest SPECT and, if feasible, CCTA were acquired. Stress SPECT was normal in 2617 patients (52%). CCTA was not performed in 1289 of the 2401 patients referred for additional imaging (54%), mainly because of severe CAC (47%) or fast/irregular heart rate (22%). 642 patients with abnormal SPECT underwent CCTA, which excluded significant CAD in 378 patients (59%). Mean radiation dose was 4.5 ± 0.3 mSv for stress-only imaging and 13.2 ± 3.3 mSv for additional imaging (P < 0.001)., Conclusions: Half of the patients do not require additional imaging in our sequential SPECT/CT algorithm, which is accompanied with low radiation exposure. CCTA cannot be performed in half of the patients who undergo additional imaging because of (relative) contra-indications. CCTA is able to correct for false-positive SPECT findings in our algorithm.

Objectives: To investigate the impact of left bundle branch block (LBBB) on sequential single photon emission computed tomography (SPECT)/ CT imaging starting with stress-first SPECT., Methods: Consecutive symptomatic low- to intermediate-risk patients without a history of coronary artery disease (CAD) referred for SPECT/CT were included from an observational registry. If stress SPECT was abnormal, additional rest SPECT and, if feasible, coronary CT angiography (CCTA) were acquired., Results: Of the 5,018 patients, 218 (4.3 %) demonstrated LBBB. Patients with LBBB were slightly older than patients without LBBB (65±12 vs. 61±11 years, p<0.001). Stress SPECT was more frequently abnormal in patients with LBBB (82 % vs. 46 %, p<0.001). After reviewing stress and rest images, SPECT was normal in 43 % of the patients with LBBB, compared to 77 % of the patients without LBBB (p<0.001). Sixty-four of the 124 patients with LBBB and abnormal stress-rest SPECT underwent CCTA (52 %), which could exclude obstructive CAD in 46 of the patients (72 %)., Conclusions: Sequential SPECT/CT imaging starting with stress SPECT is not the optimal imaging protocol in patients with LBBB, as the majority of these patients have potentially false-positive stress SPECT. First-line testing using CCTA may be more appropriate in low- to intermediate-risk patients with LBBB., Key Points: • Stress-first SPECT imaging is attractive if many patients demonstrate normal stress perfusion. • The majority of left bundle branch block patients have abnormal stress-first SPECT. • Coronary CT excluded obstructive CAD in many LBBB patients with abnormal SPECT. • Stress-first SPECT imaging is not the optimal imaging protocol in LBBB patients. • In LBBB patients imaging with initial coronary CT may be more appropriate.

Purpose: New X-ray technology providing new image processing techniques may reduce radiation exposure. The aim of this study was to quantify this radiation exposure reduction for patients during pacemaker and implantable cardioverter defibrillator (ICD) implantation., Methods: In this retrospective study, 1185 consecutive patients who had undergone de novo pacemaker or ICD implantation during a 2-year period were included. All implantations in the first year were performed using the reference technology (Allura Xper), whereas in the second year, the new X-ray technology (AlluraClarity) was used. Radiation exposure, expressed as the dose area product (DAP), was compared between the two time periods to determine the radiation exposure reduction for pacemaker and ICD implantations without cardiac resynchronization therapy (CRT) and with CRT. Procedure duration and contrast volume were used as measures to compare complexity and image quality., Results: The study population consisted of 591 patients who had undergone an implantation using the reference technology, and 594 patients with the new X-ray technology. The two groups did not differ in age, gender, or body mass index. The DAP decreased with 69 % from 16.4 ± 18.5 to 5.2 ± 6.6 Gy cm 2 for the non-CRT implantations (p < 0.001). The DAP decreased with 75 % from 72.1 ± 60.0 to 17.8 ± 17.4 Gy cm 2 for the CRT implantations (p < 0.001). Nevertheless, procedure duration and contrast volume did not differ when using the new technology (p = 0.09 and p = 0.20, respectively)., Conclusions: Introduction of new X-ray technology resulted in a radiation exposure reduction of more than 69 % for patients during pacemaker and ICD implantation while image quality was unaffected., Competing Interests: The authors declare that they have no conflict of interests.

Hybrid cardiac SPECT-CT is a technique in which data from both nuclear single photon emission tomography (SPECT) and a CT scan are combined. These techniques are complementary to each other, as CT provides information about anatomy of coronary arteries (stenosis, calcification, aberrant vessels) while SPECT detects functional consequences such as myocardial ischemia. In 2009, the Isala Hospital in Zwolle (the Netherlands) was one of the first centres in Europe to introduce this technique. Hybrid cardiac SPECT-CT has proved to be effective and safe in reaching a comprehensive diagnosis and gives the physician the ability to reach a diagnosis in only one day. In addition, it has led to about 20% fewer invasive coronary angiograms. Utilising this technique requires close collaboration between cardiologists and nuclear medicine specialists.

The coronary artery calcium (CAC) score provides independent prognostic value on top of single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). We sought to determine whether the prognostic value of the CAC score in patients with normal SPECT MPI is gender specific. We studied 3,705 consecutive symptomatic patients without a history of coronary artery disease with normal SPECT MPI. All patients underwent concomitant CAC scoring, which was categorized as CAC score 0, 1 to 99, 100 to 399, 400 to 999, or ≥1,000. Major adverse cardiac events were defined as revascularization, nonfatal myocardial infarction, or all-cause mortality. The median CAC score was 9 in women (interquartile range 0 to 113) and 47 in men (interquartile range 1 to 307, p <0.001). The annual event rate was lower in women than in men (1.6% and 2.7%, respectively, p <0.001). When stratified by CAC score, annual event rates were similar (for women and men, respectively: CAC score 0, 0.6% and 0.5%, p = 0.95; CAC score 1 to 99, 0.9% and 1.2%, p = 0.45; CAC score 100 to 399, 2.7% and 3.8%, p = 0.23; CAC score 400 to 999, 3.8% and 5.3%, p = 0.34; CAC score ≥1,000, 8.4% and 8.7%, p = 0.99). The CAC score was an independent predictor of major adverse cardiac events in both genders (CAC score ≥1,000: hazard ratio for women 8.5, 95% confidence interval 4.0 to 18.1; hazard ratio for men 14.8, 95% confidence interval 5.3 to 41.1). In conclusion, risk for events is similar for both genders when stratified by CAC score, wherein a high CAC score carries a high risk for events despite normal SPECT MPI. Our findings do not reveal a gender-specific prognostic value of the CAC score., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: For tumour imaging with PET, the literature proposes to administer a patient-specific FDG activity that depends quadratically on a patient's body weight. However, a practical approach on how to implement such a protocol in clinical practice is currently lacking. We aimed to provide a practical method to determine a FDG activity formula for whole-body PET examinations that satisfies both the EANM guidelines and this quadratic relation., Results: We have developed a methodology that results in a formula describing the patient-specific FDG activity to administer. A PET study using the NEMA NU-2001 image quality phantom forms the basis of our method. This phantom needs to be filled with 2.0 and 20.0 kBq FDG/mL in the background and spheres, respectively. After a PET acquisition of 10 min, a reconstruction has to be performed that results in sphere recovery coefficients (RCs) that are within the specifications as defined by the EANM Research Ltd (EARL). By performing reconstructions based on shorter scan durations, the minimal scan time per bed position (T min) needs to be extracted using an image coefficient of variation (COV) of 15 %. At T min, the RCs should be within EARL specifications as well. Finally, the FDG activity (in MBq) to administer can be described by [Formula: see text] with c a constant that is typically 0.0533 (MBq/kg(2)), w the patient's body weight (in kg), and t the scan time per bed position that is chosen in a clinical setting (in seconds). We successfully demonstrated this methodology using a state-of-the-art PET/CT scanner., Conclusions: We provide a practical method that results in a formula describing the FDG activity to administer to individual patients for whole-body PET examinations, taking into account both the EANM guidelines and a quadratic relation between FDG activity and patient's body weight. This formula is generally applicable to any PET system, using a specified image reconstruction and scan time per bed position.

Complaints of a dry mouth (xerostomia) and sialoadenitis are frequent side effects of radioiodine treatment in differentiated thyroid cancer (DTC) patients. However, detailed prospective data on alterations in salivary gland functioning after radioiodine treatment ( 131 I) are scarce. Therefore, the primary aim of this study was to prospectively assess the effect of high-activity radioiodine treatment on stimulated whole saliva flow rate. Secondary aims were to study unstimulated whole and stimulated glandular (i.e., parotid and submandibular) saliva flow rate and composition alterations, development of xerostomia, characteristics of patients at risk for salivary gland dysfunction, and whether radioiodine uptake in salivary glands on diagnostic scans correlates to flow rate alterations., Methods: In a multicenter prospective study, whole and glandular saliva were collected both before and 5 mo after radioiodine treatment. Furthermore, patients completed the validated xerostomia inventory. Alterations in salivary flow rate, composition, and xerostomia inventory score were analyzed. Salivary gland radioiodine uptake on diagnostic scans was correlated with saliva flow rate changes after radioiodine treatment., Results: Sixty-seven patients (mean age ± SD, 48 ± 17 y; 63% women, 84% underwent ablation therapy) completed both study visits. Stimulated whole saliva flow rate decreased after ablation therapy (from 0.92 [interquartile range, 0.74-1.25] to 0.80 [interquartile range, 0.58-1.18] mL/min, P = 0.003), as well as unstimulated whole- and stimulated glandular flow rates (P < 0.05). The concentration of salivary electrolytes was similar at both study visits, whereas the output of proteins, especially amylase (P < 0.05), was decreased. The subjective feeling of dry mouth increased (P = 0.001). Alterations in saliva flow rate were not associated with semiquantitatively assessed radioiodine uptake in salivary glands on diagnostic scans. For the small cohort of patients undergoing repeated radioiodine therapy, we could not demonstrate alterations in salivary parameters., Conclusion: We prospectively showed that salivary gland function is affected after high-activity radioiodine ablation therapy in patients with DTC. Therefore, more emphasis should be placed on salivary gland dysfunction during follow-up for DTC patients receiving high-activity radioiodine treatment., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: The coronary calcium score (CCS) provides independent diagnostic and prognostic information on top of myocardial perfusion imaging (MPI) in patients suspected for coronary artery disease, but requires an additional computed tomography (CT) scan., Objective: We investigated the accuracy and inter-reader reproducibility of visual estimation of the CCS on the CT used for attenuation correction., Methods: 250 patients undergoing single photon emission computed tomography MPI and Agatston CCS were included. The CCS was also visually estimated on the CT for attenuation correction by two separate readers blinded to the Agatston CCS, and was categorized into a six-point scale (0, 1-10, 11-100, 101-400, 401-1000 and > 1000)., Results: The median Agatston CCS was 82 [25th-75th percentile: 0-562], with a range from 0 to 7287. Of the visually estimated CCS, 60% (reader 1) and 65% (reader 2) were classified correctly into the 6 categories. 93% (reader 1) and 88% (reader 2) of the visually estimated CCS did not vary by more than one category from the Agatston CCS. The intraclass correlation coefficient for agreement between the Agatston CCS and the visually estimated CCS was 0.95 for reader 1 and 0.94 for reader 2. The intraclass correlation coefficient for inter-reader reproducibility of the visually estimated CCS was 0.96., Conclusion: The CCS can be accurately estimated on the CT for attenuation correction, as high agreement is demonstrated with the Agatston CCS and inter-reader reproducibility is excellent. If no traditional Agatston CCS is performed, the degree of atherosclerosis should be assessed by means of estimating CCS on the CT for attenuation correction., (Copyright © 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies reported on the impact of pulmonary vein orientation on pulmonary vein isolation (PVI) outcome in atrial fibrillation patients undergoing laser balloon PVI and point-by-point radiofrequency ablation., Objective: Demonstrate the association between pulmonary vein orientation and PVI outcome after multi-electrode radiofrequency ablation., Methods: 120 patients undergoing PVI with a circular MER catheter were included. A left atrial ECG-triggered CT was performed in all patients prior to PVI. The orientation of all pulmonary veins at the insertion into the left atrium was measured in the axial and coronal planes. pulmonary veins were classified as having a ventral/dorsal and caudal/cranial orientation depending on the pulmonary vein trunk angle as compared to the median angle., Results: Mean age was 56 years, arrhythmia-free survival after a median follow-up of 20 months was 54.2%. Left upper pulmonary vein orientation within the coronal plane was associated with arrhythmia-free survival, ranging from 58% with a cranial pulmonary vein orientation to 21% with a caudal orientation (p = 0.003). Similarly, arrhythmia-free survival was 50% in patients with a caudal orientation and 33% in patients with a cranial orientation of the left lower pulmonary vein in the coronal plane (p = 0.036). Pulmonary vein orientation in the axial plane and orientation of the right-sided pulmonary veins were not associated with arrhythmia-free survival. Multivariable analysis showed an independent association between both left upper (hazard ratio 2.8, p = 0.001) and left lower (hazard ratio 0.490, p = 0.034) pulmonary vein orientation and arrhythmia-free survival., Conclusion: In MER ablation, orientation of the left upper and caudalpulmonary veins in the coronal plane were independently associated with arrhythmia-free survival after multi-electrode PVI., (Copyright © 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic value of coronary artery calcium (CAC) scoring on top of myocardial perfusion imaging with single-photon emission computed tomography (SPECT) in patients suspected for coronary artery disease is not well established., Methods and Results: Four thousand eight hundred ninety-seven symptomatic patients without a history of coronary artery disease referred for SPECT and CAC scoring were included. Major adverse cardiac events (MACEs) were defined as late revascularization (>90 days after scanning), nonfatal myocardial infarction, and all-cause mortality. The frequency of abnormal SPECT increased with higher CAC scores, from 12% in patients with CAC scores of 0 to 19%, 32%, 37%, and 50% among those with CAC scores 1 to 99, 100 to 399, 400 to 999, and ≥1000, respectively (P<0.001). During a median follow-up of 940 days (25th to 75th percentile, 581-1377), a total of 278 MACEs were observed. Overall incidence of MACE was 2.3% per year. A stepwise increase of MACE was present with increasing CAC scores, both in patients with normal SPECT (annual event rate CAC score 0: 0.6%; CAC score ≥1000: 5.5%) and abnormal SPECT (annual event rate CAC score 0: 0.4%; CAC score ≥1000: 7.6%). After multivariate analysis, both SPECT and CAC score were independent predictors of MACE (CAC score ≥1000: hazard ratio, 7.7; P<0.001 and large perfusion defect on SPECT: hazard ratio, 3.7; P<0.001)., Conclusions: CAC score and SPECT are independent predictors of MACE in patients suspected for coronary artery disease. Our findings strongly support performing a CAC score in addition to SPECT in symptomatic patients to better define the risk of events during follow-up., (© 2016 American Heart Association, Inc.)

To derive and validate a practical patient-specific dose protocol to obtain an image quality, expressed by the image noise, independent of patients' size and a better radiation dose justification in coronary CT angiography (CCTA) using prospective ECG triggering. 43 patients underwent clinically indicated CCTA. The image noise, defined as the standard deviation of pixel attenuation values in a homogeneous region in the liver, was determined in all scans. Subsequently, this noise was normalized to the radiation exposure. Next, three patient-specific parameters, body weight, body mass index and mass per length (MPL), were tested for the best correlation with normalized image noise. From these data, a new dose protocol to provide a less variable image noise was derived and subsequently validated in 84 new patients. The normalized image noise increased for heavier patients for all patients' specific parameters (p < 0.001). MPL correlated best with the normalized image noise and was selected for dose protocol optimization. This new protocol resulted in image noise levels independent of patients' MPL (p = 0.28). A practical method to obtain CCTA images with noise levels independent of patients' MPL was derived and validated. It results in a less variable image quality and better radiation exposure justification and can also be used for CT scanners from other vendors.

Objective: Modern PET/CT scanners have significantly improved detectors and fast time-of-flight (TOF) performance and this may improve clinical performance. The aim of this study was to analyze the impact of a current generation TOF PET/CT scanner on standardized uptake values (SUV), lesion-background contrast and characterization of the adrenal glands in patients with suspected lung cancer, in comparison with literature data and commonly used SUV cut-off levels., Methods: We included 149 adrenal glands from 88 patients with suspected lung cancer, who underwent (18)F-FDG PET/CT. We measured the SUVmax in the adrenal gland and compared this with liver SUVmean to calculate the adrenal-to-liver ratio (AL ratio). Results were compared with literature derived with older scanners, with SUVmax values of 1.0 and 1.8 for normal glands [1, 2]. Final diagnosis was based on histological proof or follow-up imaging. We proposed cut-off values for optimal separation of benign from malignant glands., Results: In 127 benign and 22 malignant adrenal glands, SUVmax values were 2.3 ± 0.7 (mean ± SD) and 7.8 ± 3.2 respectively (p < 0.01). Corresponding AL ratios were 1.0 ± 0.3 and 3.5 ± 1.4 respectively (p < 0.01). With a SUVmax cut-off value of 3.7, 96% sensitivity and 96% specificity was reached. An AL ratio cut-off value of 1.8 resulted in 91% sensitivity and 97% specificity. The ability of both SUVmax and AL ratio to separate benign from malignant glands was similar (AUC 0.989 vs. 0.993, p = 0.22)., Conclusions: Compared with literature based on the previous generation of PET scanners, current generation TOF (18)F-FDG PET/CT imaging provides higher SUVs for benign adrenal glands, while it maintains a highly accurate distinction between benign and malignant glands. Clinical implementation of current generation TOF PET/CT requires not only the use of higher cut-off levels but also visual adaptation by PET readers.

Purpose: Single photon emission computed tomography (SPECT) myocardial perfusion imaging has proven to have prognostic importance in patients with suspected stable coronary artery disease (CAD). The recently introduced ultrafast cadmium zinc telluride (CZT)-based gamma cameras have been associated with less equivocal findings and more normal interpretations, allowing stress-only imaging to be performed more often. However, it is yet unclear whether normal stress-only CZT SPECT has comparable prognostic value as normally interpreted stress-only conventional SPECT., Methods: The study population consisted of 1,650 consecutive patients without known CAD with normal stress-only myocardial perfusion results with either conventional (n = 362) or CZT SPECT (n = 1,288). The incidence of major adverse cardiac events (MACE, all-cause death, non-fatal myocardial infarction and/or coronary revascularization) was compared between the conventional SPECT and CZT SPECT groups. Multivariable analyses using the Cox model were used to adjust for differences in baseline variables., Results: Patients scanned with CZT were less often male (33 vs 39 %), had less often hypercholesterolaemia (41 vs 50 %) and had more often a family history of CAD (57 vs 49 %). At a median follow-up time of 37 months (interquartile range 28-45 months) MACE occurred in 68 patients. The incidence of MACE was 1.5 %/year in the CZT group, compared to 2.0 %/year in the conventional group (p = 0.08). After multivariate analyses, there was a trend to a lower incidence of MACE in the CZT SPECT group (hazard ratio 0.61, 95 % confidence interval 0.35-1.04, p = 0.07)., Conclusion: The prognostic value of normal stress-only CZT SPECT is at least comparable and may be even better than that of normal conventional stress SPECT.

Background: The decreasing image quality in heavier patients can be compensated by administration of a patient-specific dose in myocardial perfusion imaging (MPI) using a cadmium zinc telluride-based SPECT camera. Our aim was to determine if the same can be achieved when using a conventional SPECT camera., Methods: 148 patients underwent SPECT stress MPI using a fixed Tc-99m tetrofosmin tracer dose. Measured photon counts were normalized to administered tracer dose and scan time and were correlated with body weight, body mass index, and mass per length to find the best predicting parameter. From these data, a protocol to provide constant image quality was derived, and subsequently validated in 125 new patients., Results: Body weight was found to be the best predicting parameter for image quality and was used to derive a new dose formula; A admin (MBq) = 223·body weight (kg)(0.65)/T scan (min). The measured photon counts decreased in heavier patients when using a fixed dose (P < .01) but this was no longer observed after applying a body-weight-dependent protocol (P = .20)., Conclusions: Application of a patient-specific protocol resulted in an image quality less depending on patient's weight. The results are most likely independent of the type of SPECT camera used, and, hence, adoption of patient-specific dose and scan time protocols is recommended.

We describe a 45-year-old male survivor of Hodgkin lymphoma, treated with mediastinal radiation therapy, referred for single-photon emission computed tomography (SPECT) myocardial perfusion imaging in combination with coronary artery calcium (CAC) scoring. SPECT demonstrated a reversible moderate-sized lateral perfusion defect, and the CAC score was zero. A calcium score of zero markedly reduces the probability of having coronary artery disease (CAD) and is associated with a very low risk of future cardiovascular events. However, a CAC score of zero does not completely rule out obstructive CAD. In this case, invasive coronary angiography revealed three-vessel CAD with left main involvement. Whether mediastinal radiation therapy in general is associated with CAD without accompanying CAC is yet unclear.

Aims: Obtaining optimal pulmonary vein (PV) occlusion with the endoscopic laser balloon ablation system (EAS) can be difficult, hypothetically influenced by PV geometry. The aim of this study was to determine the impact of PV orientation on atrial fibrillation (AF)-free survival after PV isolation (PVI) using the EAS., Methods and Results: Forty-three patients undergoing a single EAS PVI were included. Left atrial electrocardiogram -triggered computed tomography was performed in all patients prior to PVI. Of all four PVs, the orientation at the insertion in the left atrium was measured in both the transverse and frontal plane and assigned to one of the four orientation groups: ventral-caudal, dorsal-caudal, ventral-cranial, and dorsal-cranial. Mean age was 56 years; 86% had paroxysmal AF. Overall, AF-free survival after a median follow-up of 18.2 months was 51.2%. AF-free survival varied between 21 and 88% depending on left upper PV orientation (P = 0.045). Furthermore, AF-free survival varied between 21 and 86% depending on left lower PV orientation (P = 0.010) and AF-free survival varied between 29 and 88% depending on right lower PV orientation (P = 0.053). No association was found between right upper PV orientation and AF-free survival after EAS PVI (P = 0.794). In multivariate analysis, only left lower PV orientation was associated with AF-free survival [hazards ratio (HR) 10.4, P = 0.019]., Conclusion: PV orientation is associated with AF-free survival after EAS PVI. PV orientation assessment may be useful for selecting the most suitable patients for EAS PVI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Purpose: We hypothesized that pulmonary vein (PV) orientation influences tissue contact of the contact force (CF) sensing radiofrequency ablation catheter (CFC) and therefore atrial fibrillation (AF) free survival after pulmonary vein isolation (PVI). The aim of this study was to determine the association between PV orientation, CF and AF free survival in patients undergoing CFC PVI., Methods: Sixty consecutive patients undergoing CFC PVI were included. ECG-triggered cardiac CT scans were obtained in all patients before PVI, and the PV orientation was measured at the insertion in the LA for all PVs in both the transverse and frontal plane. PVs were assigned to 1 of 4 orientation groups: ventral-caudal, dorsal-caudal, ventral-cranial and dorsal-cranial., Results: Mean age was 59 years, 88% had paroxysmal AF. AF free survival off anti-arrhythmic drugs after a median follow-up of 12 months was 58% after a single PVI procedure. No association was found between PV orientation and CF. Furthermore, no association was found between PV orientation and AF free survival. In univariate analysis, the number of lesions with a mean CF of 10 g was associated with AF free survival. However, in multivariate analysis, only the AF duration was significantly associated with AF free survival., Conclusions: This study shows that in patients undergoing PVI with the CFC ablation system, PV orientation does not affect CF and is not associated with AF free survival. PV orientation assessment does not appear to be necessary in patients undergoing CFC PVI.

Unlabelled: A major disadvantage of (18)F-FDG PET involves poor detection of small lesions and lesions with low metabolism, caused by limited spatial resolution and relatively large image voxel size. As spatial resolution and sensitivity are better in new PET systems, it is expected that small-lesion detection could be improved using smaller voxels. The aim of this study was to test this hypothesis using a state-of-the-art time-of-flight PET/CT device., Methods: (18)F-FDG PET scans of 2 image-quality phantoms (sphere sizes, 4-37 mm) and 39 consecutive patients with lung cancer were analyzed on a time-of-flight PET/CT system. Images were iteratively reconstructed with standard 4 × 4 × 4 mm voxels and smaller 2 × 2 × 2 mm voxels. For the phantom study, we determined contrast-recovery coefficients and signal-to-noise ratios (SNRs). For the patient study, (18)F-FDG PET-positive lesions in the chest and upper abdomen with a volume less than 3.0 mL (diameter, <18 mm) were included. Lesion mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) were determined in both image sets. SNRs were determined by comparing SUVmax and SUVmean with background noise levels. A subanalysis was performed for lesions less than 0.75 mL (diameter, <11 mm). For qualitative analysis of patient data, 3 experienced nuclear medicine physicians gave their preference after visual side-by-side analysis., Results: For phantom spheres 13 mm or less, we found higher contrast-recovery coefficients and SNRs using small-voxel reconstructions. For 66 included (18)F-FDG PET-positive lesions, the average increase in SUVmean and SUVmax using the small-voxel images was 17% and 32%, respectively (P < 0.01). For lesions less than 0.75 mL (21 in total), the average increase was 21% and 44%, respectively. Moreover, averaged over all lesions, the mean and maximum SNR increased by 20% and 27%, respectively (P < 0.01). For lesions less than 0.75 mL, these values increased up to 23% and 46%, respectively. The physicians preferred the small-voxel reconstructions in 76% of cases., Conclusion: Supported by a phantom study, there was a visual preference toward (18)F-FDG PET images reconstructed with 2 × 2 × 2 mm voxels and a profound increase in standardized uptake value and SNR for small lesions. Hence, it is expected that small-lesion detection improves using small-voxel reconstructions., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: Myocardial perfusion imaging (MPI) with SPECT is widely adopted in clinical practice but is associated with a relatively high radiation dose. The aim of this study was to determine the minimum product of tracer dose and scan time that will maintain diagnostic value for cadmium zinc telluride (CZT) SPECT MPI., Methods: Twenty-four patients underwent clinically indicated stress MPI using CZT SPECT and a body weight-dependent (3 MBq/kg) (99m)Tc-tetrofosmin tracer dose. Data were acquired for 8 min in list mode. Next, images were reconstructed using 2-, 4-, 6-, and 8-min time frames. Differences between the 8-min reference scan and the shorter scans were determined in segmental uptake values (using the 17-segment cardiac model), ejection fraction, and end-diastolic volume. A 5% difference in segmental uptake was considered to significantly influence the diagnostic value. Next, the quality of the 4-, 6-, and 8-min scans was scored on a 4-point scale by consensus by 3 experienced nuclear medicine physicians. The physicians did not know the scan time or patient information., Results: Differences in segmental uptake values, ejection fraction, and end-diastolic volume were greater for shorter scans than for the 8-min reference scan. On average, the diagnostic value was influenced in 7.7 segments per patient using the 2-min scans, in comparison to 2.0 and 0.8 segments per patient using the 4- and 6-min scans, respectively. In addition, the 4-min scans led to a significantly reduced image quality compared with the 8-min scans (P < 0.05). This was not the case for the 6-min scan., Conclusion: Six minutes was the shortest acquisition time in stress MPI using CZT SPECT that did not affect the diagnostic value for a tracer dose of 3 MBq/kg. Hence, the patient-specific product of tracer dose and scan time can be reduced to a minimum of 18 MBq·min/kg, which may lower the effective radiation dose for patients to values below 1 mSv., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Proton-pump inhibitors (PPIs) induce potentially interfering stomach wall activity in single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) with technetium-99m ((99m)Tc)-sestamibi. However, no data are available for (99m)Tc-tetrofosmin. We assessed the influence of prolonged (>2 weeks) PPI use on the stomach wall uptake of (99m)Tc-tetrofosmin in patients referred for stress MPI with a cadmium-zinc-telluride-based SPECT camera and its relation with dyspepsia symptoms., Methods and Results: Consecutive patients (n=127) underwent a 1-day adenosine stress-first SPECT-MPI with (99m)Tc-tetrofosmin, of whom 54 (43%) patients had been on PPIs for more than 2 weeks. Stomach wall activity was identified on stress SPECT using computed tomographic attenuation maps and was scored using a four-point grading scale into clinically relevant (scores 2 or 3) or nonrelevant (scores 0 or 1).Patients on PPIs had stomach wall uptake more frequently as compared with patients not using PPIs (22 vs. 7%, P=0.017). Dyspepsia was similar in both groups., Conclusion: Prolonged use of PPIs is associated with stomach wall uptake of (99m)Tc-tetrofosmin in stress cadmium-zinc-telluride-SPECT images. Gastric symptoms were not associated with stomach wall uptake.

Background: The new multipinhole cardiac single photon emission computed tomography/computed tomography (SPECT/CT) cameras with cadmium-zinc-telluride (CZT) detectors are highly sensitive and produce images of high quality but rely on complex dedicated reconstruction algorithms. The aim of this study was to determine the impact of various processing steps on image formation and in the detection of ischaemia in CZT-SPECT/CT both with and without attenuation correction (AC)., Materials and Methods: Data on 20 consecutive patients who underwent a 1-day protocol stress-rest SPECT/CT using 99mTc-tetrofosmin were processed twice by three experienced operators, yielding 120 AC and 120 noncorrected (NC) data sets. Processing steps included selection and determination of myocardial axes, manual SPECT/CT coregistration for AC and myocardial masking. Using the 17-segment cardiac model, differences between stress and rest segmental uptake (%) were calculated for NC and AC image sets. Both interoperator and intraoperator variations were considered significant for the diagnosis of ischaemia when greater than 5%., Results: The mean interoperator variations were 2.4±1.4% (NC) and 3.8±1.9% (AC) (P<0.01). In 6% (NC) and 23% (AC) of the 120 processed cases, operator variation was larger than 5% and therefore potentially clinically interfering with the diagnosis of ischaemia. Differences between interoperator and intraoperator variations were nonsignificant., Conclusion: Operator variations in the processing of myocardial perfusion image data using CZT-SPECT/CT are significant and may influence the diagnosis of ischaemia, especially when AC is applied. Clearer guidelines for image processing are necessary to improve the reproducibility of the studies and to obtain a more reliable diagnosis of ischaemia.

Background: Guidelines for SPECT myocardial perfusion imaging (MPI) traditionally recommend a fixed tracer dose. Yet, clinical practice shows degraded image quality in heavier patients. The aim was to optimize and validate the tracer dose and scan time to obtain a constant image quality less dependent on patients' physical characteristics., Methods: 125 patients underwent Cadmium Zinc Telluride (CZT)-SPECT stress MPI using a fixed Tc-99m-tetrofosmin tracer dose. Image quality was scored by three physicians on a 4-point grading scale and related to the number of photon counts normalized to tracer dose and scan time. Counts were correlated with various patient-specific parameters dealing with patient size and weight to find the best predicting parameter. From these data, a formula to provide constant image quality was derived, and subsequently tested in 92 new patients., Results: Degradation in image quality and photon counts was observed for heavier patients for all patients' specific parameters (P < .01). We found body weight to be the best-predicting parameter for image quality and derived a new dose formula. After applying this new body weight-depended tracer dose and scan time in a new group, image quality was found to be constant (P > .19) in all patients., Conclusions: Also in CZT SPECT image quality decreases with weight. The use of a tracer dose and scan time that depends linearly on patient's body weight corrected for the varying image quality in CZT-SPECT MPI. This leads to better radiation exposure justification.

Objective: Regadenoson is a recently approved selective adenosine-2A receptor agonist to induce pharmacological stress in myocardial perfusion imaging (MPI) procedures using a single bolus injection., Material and Methods: We included 123 patients referred for MPI because of suspected coronary arterial disease (CAD). Of these, 66 patients underwent a regadenoson stress test and 57 patients underwent an adenosine stress test preceding standard myocardial SPECT imaging. Technicians, physicians and patients were asked to report their experience using questionnaires., Results: As compared to adenosine, regadenoson did not produce any atrio-ventricular block (0 vs. 10% with adenosine), but did produce minor tachycardia and minimal blood pressure changes while all other side effects were milder and shorter. There were fewer patients with severe complaints after taking regadenoson than adenosine (17% vs. 32%, respectively, p<0.01). The most frequent complaint reported was dyspnea, followed by flushing and chest pain. However, when they did occur, they usually disappeared rapidly. The overall symptom score, including severity and duration of side effects, was significantly lower after regadenoson than after adenosine (6.7±6.3 vs. 10.0±7.9, respectively; p<0.01.) SPECT imaging results were similar. The regadenoson procedure was faster and more practical., Conclusion: Regadenoson, the new selective adenosine-2A receptor agonist, is a stress agent for MPI with a patient- and department friendly profile., (Copyright © 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved.)

Iterative reconstruction techniques for coronary CT angiography have been introduced as an alternative for traditional filter back projection (FBP) to reduce image noise, allowing improved image quality and a potential for dose reduction. However, the impact of iterative reconstruction on the coronary artery calcium score is not fully known. In 112 consecutive stable patients with suspected coronary artery disease, the coronary calcium scores were assessed. Comparisons were made between the Agatston, volume and mass scores obtained with traditional FBP, and by using adaptive statistical iterative reconstruction (ASIR). A significant reduction of the Agatston score, volume score and mass score was observed for ASIR when compared to FBP, with median differences of resp. 26, 5 mm(3) and 1 mg. Using the ASIR reconstruction, the number of patients with a calcium score of zero increased by 13 %. Iterative CT reconstruction significantly reduces the Agatston, volume and mass scores. Since the calcium score is used as a prognostic tool for coronary artery disease, caution must be taken when using iterative reconstruction.

Purpose: Recently introduced ultrafast cardiac SPECT cameras with cadmium zinc telluride-based (CZT) detectors may provide superior image quality allowing faster acquisition with reduced radiation doses. Although the level of concordance between conventional SPECT and invasive fractional flow reserve (FFR) measurement has been studied, that between FFR and CZT-based SPECT is not yet known. Therefore, we aimed to assess the level of concordance between CZT SPECT and FFR in a large patient group with stable coronary artery disease., Methods: Both invasive FFR and myocardial perfusion imaging with a CZT-based SPECT camera, using Tc-tetrofosmin as tracer, were performed in 100 patients with stable angina and intermediate grade stenosis on invasive coronary angiography. A cut-off value of <0.75 was used to define abnormal FFR., Results: The mean age of the patients was 64 ± 11 years, and 64 % were men. SPECT demonstrated ischaemia in 31 % of the patients, and 20 % had FFR <0.75. The concordance between CZT SPECT and FFR was 73 % on a per-patient basis and 79 % on a per-vessel basis. Discordant findings were more often seen in older patients and were mainly (19 %) the result of ischaemic SPECT findings in patients with FFR ≥ 0.75, whereas only 8 % had an abnormal FFR without ischaemia as demonstrated by CZT SPECT., Conclusion: Only 20 - 30 % of patients with intermediate coronary stenoses had significant ischaemia as assessed by CZT SPECT or invasive FFR. CZT SPECT showed a modest degree of concordance with FFR, which is comparable with previous results with conventional SPECT. Further investigations are particularly necessary in patients with normal SPECT and abnormal FFR, especially to determine whether these patients should undergo revascularization.

Background: False-negative myocardial perfusion imaging (MPI) can by due to left main (LM) or three-vessel disease causing "balanced ischemia". However, so far prevalence of LM or three-vessel-disease in patients with normal MPI is unclear. We assessed prevalence, location, and extent of significant coronary artery disease (CAD) in patients with normal MPI., Methods: Between 2006 and 2010, 256 patients with normal MPI who had invasive angiography because of persisting or worsening of the same initial symptoms were studied. Significant CAD was defined as stenosis > 70% or LM > 50%., Results: A total of 93 patients (36%) had significant CAD. Significant CAD was observed more frequently in males, higher age and those with typical angina complaints. Significant LM disease was present in 7%, three-vessel disease in 10%, two-vessel disease in 22%, and single vessel disease (not left main) in 61%. In those with single vessel disease, the location was the LAD in 40%, the RCA in 30%, and the LCX in 30%., Conclusions: In selected patients with normal MPI, one-third had significant CAD. The majority of these patients had single vessel disease (not left main). LM or three vessel disease, causing "balanced ischemia", is a less common cause of false-negative MPI.

Purpose: Coronary artery calcium (CAC) scores influence the pre-test likelihood of ischemia in patients undergoing myocardial perfusion imaging (MPI). We investigated the influence of CAC score knowledge on the visual interpretation of MPI in patients referred for the diagnostic work-up of suspected coronary artery disease., Methods: We retrospectively analyzed symptomatic patients who were referred for MPI. For the current analysis, we selected 151 patients who underwent SPECT MPI with simultaneous CAC scoring. MPI was visually interpreted in two separate sessions, first without and then with knowledge of the CAC score. MPI results were classified into four groups: normal, fixed defects, ischemia, and equivocal., Results: Mean age of the patients was 64 ± 11 years, 56% were male. Without knowledge of the CAC score MPI was evaluated as normal in 36%, compared to 40% with knowledge of the CAC score (P = 0.636). Overall, the addition of the CAC score changed the interpretation of MPI in 56 patients (37%). Importantly, the frequency of equivocal MPI interpretations decreased from 21% without knowledge of CAC score to 9% with knowledge of CAC score (P = 0.002)., Conclusions: Knowledge of the CAC score has a major impact on the interpretation of MPI, increasing the interpretative certainty.

Purpose: High coronary artery calcium (CAC) scores are associated with a high likelihood of ischaemia and obstructive coronary disease. Myocardial perfusion imaging (MPI) is a key investigation to determine the need for revascularization. However, the value of MPI in presence of extensive CAC has so far only been demonstrated in asymptomatic patients, whereas its value in symptomatic patients remains largely unclear. Therefore, we studied the impact of MPI in symptomatic patients with a CAC score ≥ 1,000., Methods: We included 282 patients (mean age 69 ± 9 years, 63% men) without a history of coronary disease with suspected stable angina referred for MPI and with a CAC score ≥ 1,000. On follow-up at 18 months invasive angiography, coronary revascularization, nonfatal myocardial infarction and death were recorded., Results: MPI was normal in 54 %, equivocal in 10 % and abnormal in 37 % (fixed defect 9 % and ischaemia 28 %) of patients. More abnormal MPI findings were observed in men, smokers and those with even higher CAC scores. During follow-up, 1 patient (with nonischaemic MPI) died from a cardiac cause, 1 patient (with ischaemic MPI) suffered a myocardial infarction and 92 patients (33 %) underwent revascularization. Ischaemia on MPI was a strong predictor of coronary revascularization (odds ratio 13.1; 95 % CI 7.1-24.3; p < 0.001)., Conclusion: Ischaemia on MPI is observed in approximately 30 % of patients with a CAC score ≥ 1,000, and is a strong predictor of coronary revascularization. However, nonischaemic MPI does not exclude revascularization, and patients with persisting complaints should be considered for invasive angiography.

Purpose: To assess the capability of a zero coronary artery calcium (CAC) score to help exclude flow-limiting coronary artery disease (CAD) in a homogeneous population with stable anginal complaints and a low-to-intermediate pretest likelihood., Materials and Methods: The study protocol had institutional ethics committee approval, with written informed consent from all patients. Between 2009 and 2011, a total of 3501 consecutive stable patients without known CAD underwent prospectively simultaneous myocardial perfusion imaging and CAC scoring on a hybrid, 64-section single photon emission computed tomography (SPECT)/computed tomography (CT) scanner. In 868 (25%) of 3501 patients, the CAC score was zero, and these patients constituted the current study population. When feasible, additional coronary CT angiography was performed in those with abnormal SPECT findings. Clinical follow-up was recorded with regard to invasive coronary angiography, coronary revascularization, nonfatal myocardial infarction, or death. Results were analyzed by using descriptive statistics., Results: In 868 patients (mean age, 54 years ± 11 [standard deviation]; 610 [70%] female, 258 [30%] male), SPECT findings were normal in 766 (88%) and abnormal in 102 (12%), with equivocal results in 41 (5%), persistent defect in 35 (4%), and ischemia in 26 (3%). In the group with abnormal SPECT findings, additional coronary CT angiography was performed in 93 patients (91%), showing nonobstructive CAD in eight patients (9%) and normal coronary arteries in 85 patients (91%). In the other nine patients (9%), invasive angiography was used to exclude obstructive CAD. At a median follow-up of 17 months (25th percentile, 11; 75th percentile, 24 months), no coronary events were recorded., Conclusion: A CAC score of zero in stable patients at low or intermediate risk excludes flow-limiting CAD. These findings support the possibility of CAC scoring as a simple and safe tool to select patients for additional testing or discharge, as recommended in the literature., (© RSNA, 2013.)

Aim: To establish the prevalence of vertebral fracture (VF) in a representative sample of 750 Canadians and to examine the relationships between VF prevalence and bone mineral density (BMD) at the spine and proximal femur., Materials and Methods: X-ray-based dual-photon absorptiometry (DXA) was used to perform measurements of lumbar spine BMD, proximal femur BMD, and VF assessment (VFA)., Results: Two hundred and fifty-nine VFs were identified in 156 patients and the prevalence of unknown or unsuspected VF was 18.7%. For premenopausal women and for men, there was no difference in BMD at either the spine or the hip whether or not there was at least one VF. For postmenopausal women, BMD of the total region of the proximal femur was statistically lower (p < 0.001) in women with at least one VF whereas spine BMD only tended to be less (0.10 > p > 0.05). Proximal femur BMD was lower for postmenopausal women with more VF, while spine BMD was virtually unchanged as the number of VF increased. Neither spine nor hip BMD was lower for men with more VF. A strong association was observed in postmenopausal women between an age-dependent increase in VF prevalence and a reduction in femoral BMD. Such an association was not present in men., Conclusion: VFs are common, are often independent of either spine or hip BMD, and frequently go unnoticed. Therefore, VFA should be part of a routine assessment of fracture risk., (Copyright © 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: The new ultrafast cardiac single photon emission computed tomography (SPECT) cameras with cadmium-zinc-telluride (CZT)-based detectors are faster and produce higher quality images as compared to conventional SPECT cameras. We assessed the need for additional imaging, total imaging time, tracer dose and 1-year outcome between patients scanned with the CZT camera and a conventional SPECT camera., Methods: A total of 456 consecutive stable patients without known coronary artery disease underwent myocardial perfusion imaging on a hybrid SPECT/CT (64-slice) scanner using either conventional (n = 225) or CZT SPECT (n = 231). All patients started with low-dose stress imaging, combined with coronary calcium scoring. Rest imaging was only done when initial stress SPECT testing was equivocal or abnormal. Coronary CT angiography was subsequently performed in cases of ischaemic or equivocal SPECT findings. Furthermore, 1-year clinical follow-up was obtained with regard to coronary revascularization, nonfatal myocardial infarction or death., Results: Baseline characteristics were comparable between the two groups. With the CZT camera, the need for rest imaging (35 vs 56%, p < 0.001) and additional coronary CT angiography (20 vs 28%, p = 0.025) was significantly lower as compared with the conventional camera. This resulted in a lower mean total administered isotope dose per patient (658 ± 390 vs 840 ± 421 MBq, p < 0.001) and shorter imaging time (6.39 ± 1.91 vs 20.40 ± 7.46 min, p < 0.001) with the CZT camera. After 1 year, clinical outcome was comparable between the two groups., Conclusion: As compared to images on a conventional SPECT camera, stress myocardial perfusion images acquired on a CZT camera are more frequently interpreted as normal with identical clinical outcome after 1-year follow-up. This lowers the need for additional testing, results in lower mean radiation dose and shortens imaging time.

Background and Purpose: The TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis through activation of the death receptors, TRAIL-R1 and TRAIL-R2. Recombinant human (rh) TRAIL and the TRAIL-R1 directed monoclonal antibody mapatumumab are currently clinically evaluated as anticancer agents. The objective of this study was to develop radiopharmaceuticals targeting the TRAIL-R1, suitable for clinical use to help understand and predict clinical efficacy in patients., Experimental Approach: rhTRAIL was radioiodinated with (125) I, and conjugated mapatumumab was radiolabelled with (111) In. The radiopharmaceuticals were characterized, their in vitro stability and death receptor targeting capacities were determined and in vivo biodistribution was studied in nude mice bearing human tumour xenografts with different expression of TRAIL-R1., Key Results: Labelling efficiencies, radiochemical purity, stability and binding properties were optimized for the radioimmunoconjugates. In vivo biodistribution showed rapid renal clearance of [(125) I]rhTRAIL, with highest kidney activity at 15 min and almost no detectable activity after 4 h. Activity rapidly decreased in almost all organs, except for the xenografts. Radiolabelled mapatumumab showed blood clearance between 24 and 168 h and a reduced decrease in radioactivity in the high receptor expression xenograft., Conclusions and Implications: rhTRAIL and mapatumumab can be efficiently radiolabelled. The new radiopharmaceuticals can be used clinically to study pharmacokinetics, biodistribution and tumour targeting, which could support evaluation of the native targeted agents in phase I/II trials., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Aim: In Canada, staging of carcinoid tumors is largely based on computed tomography (CT) imaging sometimes complemented with somatostatin receptor scintigraphy (SRS). This study assessed the diagnostic accuracy of 6-[¹⁸F]fluoro-3,4-dihydroxyphenylalanine (¹⁸F-FDOPA) PET/CT in neuroendocrine tumors., Methods: We prospectively included 27 patients with either suspected carcinoid (n=6, with all prior tests negative) or with an established diagnosis of intestinal carcinoid tumor (n=21) from two Canadian treatment centers. Findings of ¹⁸F-FDOPA PET/CT were compared with SRS, CT, and combined SRS/CT using a composite reference standard comprising all available imaging, biochemistry, surgery, and follow-up data. Sensitivity was calculated per patient, per body region, and per lesion. The contribution to patient management was estimated from the feedback of attending physicians., Results: In documented carcinoid patients, ¹⁸F-FDOPA PET/CT identified disease in 20 of 21 patients (patient-based sensitivity 95%). In 56 positive regions, ¹⁸F-FDOPA PET/CT detected 53, CT detected 34, SRS detected 34, and CT+SRS detected 39 regions, leading to region-based sensitivities of 95, 61, 62, and 71%, respectively. Lesion-based sensitivities were 96, 69, 50, and 72%, respectively. In the six patients with suspected disease only, one CT scan was positive, but ¹⁸F-FDOPA PET/CT was negative for all. ¹⁸F-FDOPA PET contributed to patient management in 12/21 patients (57%)., Conclusion: ¹⁸F-FDOPA PET/CT proved to be an excellent modality for staging of carcinoid tumor patients, with superior performance compared with currently applied methods in Canada. In patients with suspected disease with negative prior imaging investigations, ¹⁸F-FDOPA was not helpful.

Unlabelled: Vertebral Fracture Analysis enables the detection of vertebral fractures in the same session as bone mineral density testing. Using this method in 2,424 patients, we found unknown vertebral fractures in approximately one out of each six patients with significant impact on management., Introduction: The presence of osteoporotic vertebral fractures (VF) is an important risk factor for all future fractures independent of BMD. Yet, determination of the VF status has not become standard practice. Vertebral Fracture Assessment (VFA) is a new feature available on modern densitometers. In this study we aimed to determine the prevalence of VF using VFA in all patients referred for BMD testing in a university medical center and to evaluate its added clinical value., Methods: Prospective diagnostic evaluation study in 2,500 consecutive patients referred for BMD. Patients underwent VFA in supine position after BMD testing. Questionnaires were used to assess perceived added value of VFA., Results: In 2,424 patients (1,573 women), results were evaluable. In 541 patients (22%), VFA detected a prevalent VF that was unknown in 69%. In women, the prevalence was 20% versus 27% found in men (p < 0.0001). The prevalence of VF was 14% in patients with normal BMD (97/678), increased to 21% (229/1,100) in osteopenia and to 26% in those with osteoporosis (215/646) by WHO criteria. After excluding mild fractures VF prevalence was 13% (322/2,424). In 468 of 942 questionnaires (50% response rate), 27% of the referring physicians reported VFA results to impact on patient management., Conclusions: VFA is a patient friendly new tool with a high diagnostic yield, as it detected unknown VF in one out of each six patients, with significant impact on management. We believe these findings justify considering VFA in all new patients referred for osteoporosis assessment in similar populations.

Cardiac SPECT-CT is a new hybrid technique that simultaneously produces non-invasive functional information (SPECT) and anatomical information about the coronary arteries (CT). Both types of information are crucial for optimal decision making regarding coronary revascularisation. The hybrid SPECT-CT scanner is very suitable for individual patient-tailored algorithms in which SPECT based ischaemia detection can be complemented with CT coronary angiography or vice-versa. In such approaches CT corrects the limitations of SPECT and SPECT corrects the limitations of CT. Initial studies report high diagnostic performance. The SPECT-CT technique is fast, comprehensive, efficient and even financially advantageous. SPECT-CT probably contributes to a more efficient use of invasive diagnostic coronary angiography.

Purpose: Vertebral fractures often go unnoticed, while they constitute a significant risk factor for new fractures, independent of the bone density. Vertebral Fracture Assessment (VFA) is a new feature on DXA bone densitometry equipment. Our purpose was to determine the added value of VFA and its impact on the Canadian fracture risk classification using data from a Dutch academic cohort., Methods: All 958 consecutive patients (64% female, mean age 53 [20-94], mean weight 75 kg [32-150]) who underwent BMD measurement at the University Medical Center Groningen, The Netherlands also underwent VFA in the same session., Results: The prevalence of vertebral fractures was 26%. In 68% of these patients this fracture was unknown. The severity was "mild" (20%-25% height loss) in 43%, "moderate" (25%-35%) in 44% and "severe" (>35% height loss) in 13%. Even after excluding mild fractures, the prevalence of vertebral fractures was 17%. In the 28% with normal BMD the vertebral fracture prevalence was still 18%, in the 43% with osteopenia 23%, and in the 29% with osteoporosis 36%. The Canadian risk classification was "low fracture risk" in 68%, "moderate" in 19%, and "high" in 13%. Adding VFA altered the classification in 20% of the patients, to become 54%, 27%, and 19%, respectively., Conclusions: VFA added to BMD is a patient friendly diagnostic tool with a high diagnostic yield, as it detected unknown vertebral fractures and altered diagnostic classification in approximately 1 out of every 5 patients. These results suggest that BMD plus VFA may become the new standard in osteoporosis testing., (Copyright © 2010 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.)

Target volume definition in modern radiotherapy is based on planning computed tomography (CT). So far, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) has not been included in planning modality in volume definition of esophageal cancer. This study evaluates fusion of FDG-PET and CT in patients with esophageal cancer in terms of geographic misses and inter-observer variability in volume definition. In 28 esophageal cancer patients, gross, clinical and planning tumor volumes (GTV; CTV; PTV) were defined on planning CT by three radiation oncologists. After software-based emission tomography and computed tomography (PET/CT) fusion, tumor delineations were redefined by the same radiation-oncologists. Concordance indexes (CCI's) for CT and PET/CT based GTV, CTV and PTV were calculated for each pair of observers. Incorporation of PET/CT modified tumor delineation in 17/28 subjects (61%) in cranial and/or caudal direction. Mean concordance indexes for CT-based CTV and PTV were 72 (55-86)% and 77 (61-88)%, respectively, vs. 72 (47-99)% and 76 (54-87)% for PET/CT-based CTV and PTV. Paired analyses showed no significant difference in CCI between CT and PET/CT. Combining FDG-PET and CT may improve target volume definition with less geographic misses, but without significant effects on inter-observer variability in esophageal cancer.

We performed a feasibility study to determine the optimal dosage and time of administration of the monoclonal antibody zirconium-89 ((89)Zr)-trastuzumab to enable positron emission tomography (PET) imaging of human epidermal growth factor receptor 2 (HER2)-positive lesions. Fourteen patients with HER2-positive metastatic breast cancer received 37 MBq of (89)Zr-trastuzumab at one of three doses (10 or 50 mg for those who were trastuzumab-naive and 10 mg for those who were already on trastuzumab treatment). The patients underwent at least two PET scans between days 2 and 5. The results of the study showed that the best time for assessment of (89)Zr-trastuzumab uptake by tumors was 4-5 days after the injection. For optimal PET-scan results, trastuzumab-naive patients required a 50 mg dose of (89)Zr-trastuzumab, and patients already on trastuzumab treatment required a 10 mg dose. The accumulation of (89)Zr-trastuzumab in lesions allowed PET imaging of most of the known lesions and some that had been undetected earlier. The relative uptake values (RUVs) (mean +/- SEM) were 12.8 +/- 5.8, 4.1 +/- 1.6, and 3.5 +/- 4.2 in liver, bone, and brain lesions, respectively, and 5.9 +/- 2.4, 2.8 +/- 0.7, 4.0 +/- 0.7, and 0.20 +/- 0.1 in normal liver, spleen, kidneys, and brain tissue, respectively. PET scanning after administration of (89)Zr-trastuzumab at appropriate doses allows visualization and quantification of uptake in HER2-positive lesions in patients with metastatic breast cancer.

Objective: The severity of systemic amyloidosis is thought to be related to the extent of amyloid deposition. We studied whether amyloid load in fat tissue reflects disease severity and predicts survival., Methods: We studied all consecutive patients with systemic amyloidosis seen between January 1994 and January 2007 in our tertiary referral center. Congo red-stained abdominal fat smears were graded by 2 observers using a validated semiquantitative scoring system. Disease severity was measured by the total number of major organs involved and the extravascular retention of the serum amyloid P component (EVR(24)). The association of amyloid load in fat tissue with disease severity and overall survival was studied using multiple regression analysis., Results: Two hundred twenty patients were included in the study (120 with AL amyloidosis, 66 with AA amyloidosis, and 34 with ATTR amyloidosis). Amyloid grade in fat tissue was associated with the number of major organs involved and EVR(24). Female sex turned out to be associated with a higher grade of amyloid in fat tissue than male sex. Amyloid grade in fat tissue was an independent predictor of decreased survival, as were heart involvement, the number of organs involved, AA or AL type of amyloid, and age., Conclusion: The amount of amyloid in subcutaneous fat tissue in systemic amyloidosis reflects disease severity, as measured by the number of organs involved and EVR(24), and predicts decreased survival independent of other well-known factors.

Purpose: Somatostatin receptor expression has been demonstrated on a number of plasma cell lines. Therefore, we questioned whether somatostatin receptor scintigraphy (SRS) can be used to demonstrate in vivo multiple myeloma (MM) activity., Methods: SRS was performed in newly diagnosed (n = 9) or relapsing (n = 18) MM patients or in patients with localized plasmacytoma (n = 2). The results were compared with radiographic findings., Results: A positive SRS was demonstrated in 44% of the newly diagnosed patients, in 83% of the relapsed patients and in both patients with plasmacytoma. The SRS findings corresponded with radiographic abnormalities in 40% of the patients. However, in relapsed patients 60% demonstrated increased SRS uptake in areas without new radiographic abnormalities. The positive SRS corresponded with histologically proven disease activity and responded upon treatment. Moreover, immunohistochemical staining of MM material demonstrated concordant somatostatin receptor sst3 staining in five of six patients., Conclusion: These results demonstrate that SRS is a valuable tool to detect disease activity, especially in relapsing MM patients.

The evaluation of response to radiotherapy in patients with laryngeal cancer is a challenge because of the difficulty to differentiate between post-therapy changes and recurrent or residual tumor. Positron emission tomography is a non-invasive imaging tool that may be helpful in this differentiation. In this study, [(18)F]-fluoro-3'-deoxy-L-thymidine ([(18)F]FLT), a proliferation tracer is compared with 2-[(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]FDG). Patients with primary laryngeal cancer, scheduled to undergo radiotherapy were included in this study. Patients underwent both [(18)F]FLT-PET and [(18)F]FDG-PET shortly before radiotherapy. Ten patients underwent [(18)F]FLT-PET and [(18)F]FDG-PET 2-3 months after radiotherapy. Scans were analyzed visually for areas of increased tracer uptake. The standardized uptake value (SUV) was measured as a semi-quantitative value of tracer uptake. Fourteen patients, all male, were included in this study. Both [(18)F]FLT-PET and [(18)F]FDG-PET showed increased tracer uptake in 12 out of 14 patients (86%). [(18)F]FDG uptake was significantly higher than [(18)F]FLT uptake (SUV(max): 4.5 vs. 2.4 (P=0.002); SUV(mean): 3.4 vs. 1.9 (P=0.002)). After radiotherapy, 3 patients had histologically proven residual or recurrent laryngeal cancer. [(18)F]FDG was true positive in 2 out of 3 patients, whereas [(18)F]FLT showed increased tracer uptake in only one. Of the remaining 7 patients, [(18)F]FLT was true negative in all, whereas [(18)F]FDG showed increased uptake in one (false positive). [(18)F]FLT-PET is feasible in visualizing laryngeal cancer and its evaluation of treatment. The overall uptake of this tracer is significantly lower as compared with [(18)F]FDG, but tumor to background ratios are comparable.

Context: Catecholamine excess is rare, but symptoms may be life threatening., Objective: The objective of the study was to investigate the sensitivity of 6-[F-18]fluoro-l-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET), compared with (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy and computer tomography (CT)/magnetic resonance imaging (MRI) for tumor localization in patients with catecholamine excess., Design and Setting: All consecutive patients with catecholamine excess visiting the University Medical Center Groningen, Groningen, The Netherlands, between March 2003 and January 2008 were eligible., Patients: Forty-eight patients were included. The final diagnosis was pheochromocytoma in 40, adrenal hyperplasia in two, paraganglioma in two, ganglioneuroma in one, and unknown in three., Main Outcome Measures: Sensitivities and discordancy between (18)F-DOPA PET, (123)I-MIBG, and CT or MRI were analyzed for individual patients and lesions. Metanephrines and 3-methoxytyramine in plasma and urine and uptake of (18)F-DOPA with PET were measured to determine the whole-body metabolic burden and correlated with biochemical tumor activity. The gold standard was a composite reference standard., Results: (18)F-DOPA PET showed lesions in 43 patients, (123)I-MIBG in 31, and CT/MRI in 32. Patient-based sensitivity for (18)F-DOPA PET, (123)I-MIBG, and CT/MRI was 90, 65, and 67% (P < 0.01 for (18)F-DOPA PET vs. both (123)I-MIBG and CT/MRI, P = 1.0 (123)I-MIBG vs. CT/MRI). Lesion-based sensitivities were 73, 48, and 44% (P < 0.001 for (18)F-DOPA PET vs. both (123)I-MIBG and CT/MRI, P = 0.51 (123)I-MIBG vs. CT/MRI). The combination of (18)F-DOPA PET with CT/MRI was superior to (123)I-MIBG with CT/MRI (93 vs. 76%, P < 0.001). Whole-body metabolic burden measured with (18)F-DOPA PET correlated with plasma normetanephrine (r = 0.82), urinary normetanephrine (r = 0.84), and metanephrine (r = 0.57)., Conclusion: To localize tumors causing catecholamine excess, (18)F-DOPA PET is superior to (123)I-MIBG scintigraphy and CT/MRI.

Neuroendocrine tumors can originate almost everywhere in the body and consist of a great variety of subtypes. This paper focuses on molecular imaging methods using nuclear medicine techniques in neuroendocrine tumors, coupling molecular uptake mechanisms of radiotracers with clinical results. A non-systematic review is presented on receptor based and metabolic imaging methods. Receptor-based imaging covers the molecular backgrounds of somatostatin, vaso-intestinal peptide (VIP), bombesin and cholecystokinin (CCK) receptors and their link with nuclear imaging. Imaging methods based on specific metabolic properties include meta-iodo-benzylguanide (MIBG) and dimercapto-sulphuric acid (DMSA-V) scintigraphy as well as more modern positron emission tomography (PET)-based methods using radio-labeled analogues of amino acids, glucose, dihydroxyphenylalanine (DOPA), dopamine and tryptophan. Diagnostic sensitivities are presented for each imaging method and for each neuroendocrine tumor subtype. Finally, a Forest plot analysis of diagnostic performance is presented for each tumor type in order to provide a comprehensive overview for clinical use.