Improvement of motion artifacts using dynamic whole-body 18F-FDG PET/CT imaging.

PURPOSE: Serial dynamic whole-body PET imaging is valuable for assessing serial changes in tracer uptake. The purpose of this study was to evaluate the improvement of motion artifacts in patients using serial dynamic whole-body 18F-fluorodeoxyglyucose (FDG) PET/CT imaging. MATERIALS AND METHODS: In 797 consecutive patients, serial 3-min dynamic whole-body FDG PET imaging was performed seven times, at 60 or 90 min after FDG administration. In cases with large body motion during imaging, we tried to improve the images by summing the images before body motion. An image quality study was performed on another 50 patients without obvious body motion using the same acquisition mode. RESULTS: Obvious body movement was observed in 106 of 797 cases (13.3%), and severe motion artifacts which interfered image interpretation were observed in 18 (2.3%). In these 18 cases, summation of the images before the body movement enabled us to obtain images that excluded the effect of the body motion. In the visual evaluation of the image quality in another 50 patients studied, acceptable image quality was obtained when 2 or more times the serial 3-min image data were added. CONCLUSION: Serial dynamic whole-body FDG PET imaging can minimize body motion artifacts by summation of the images before the body motion. Such serial dynamic study may be a choice for PET imaging to eliminate motion artifacts.

Current status and perspectives of nuclear cardiology.

Nuclear cardiology has long been used to identify myocardial ischemia for appropriate treatment strategies for stable coronary artery disease (CAD). After the Ischemia Trial, it is time to reevaluate the significance of ischemia assessment. Functional imaging continues to play pivotal role in detecting microcirculatory disturbances. PET provides a clear image of blood flow distribution and is useful for the quantitative evaluation of myocardial flow reserve (MFR), which plays an important role in predicting treatment strategies and improving prognosis in CAD. Heart failure has become a major area of focus in cardiovascular medicine. Radionuclide imaging has been widely applied in this field. FDG PET is useful in identifying cardiac sarcoidosis and active inflammation. Clinical values of I-123 MIBG and BMIPP SPECT have been reported worldwide from Japan. Additionally, clinical experiences of Tc-99m pyrophosphate imaging have recently gained attention for assessing cardiac amyloidosis. Cardiac PET/CT and PET/MR imaging permit combined assessment of metabolic/functional/structural analyses of various cardiac diseases. While other non-invasive imaging modalities have rapidly been developed, the roles of radionuclide imaging remain to be valuable for early and accurate diagnosis and patient management in most cases of chronic CAD and various cardiovascular diseases.

Flurpiridaz F-18 PET Myocardial Perfusion Imaging in Patients With Suspected Coronary Artery Disease.

BACKGROUND: Flurpiridaz F-18 (flurpiridaz) is a novel positron emission tomography (PET) myocardial perfusion imaging tracer. OBJECTIVES: The purpose of this study was to further assess the diagnostic efficacy and safety of flurpiridaz for the detection and evaluation of coronary artery disease (CAD) defined as ≥50% stenosis by quantitative invasive coronary angiography (ICA). METHODS: In this second phase 3 prospective multicenter clinical study, 730 patients with suspected CAD from 48 clinical sites in the United States, Canada, and Europe were enrolled. Patients underwent 1-day rest/stress flurpiridaz PET and 1- or 2-day rest-stress Tc-99m-labeled single photon emission computed tomography (SPECT) before ICA. PET and SPECT images were read by 3 experts blinded to clinical and ICA data. RESULTS: A total of 578 patients (age 63.7 ± 9.5 years) were evaluable; 32.5% were women, 52.3% had body mass index ≥30 kg/m2, and 33.6% had diabetes. Flurpiridaz PET met the efficacy endpoints of the study; its sensitivity and specificity were significantly higher than the prespecified threshold value by 2 of the 3 readers. The sensitivity of flurpiridaz PET was higher than SPECT (80.3% vs 68.7%; P = 0.0003) and its specificity was noninferior to SPECT (63.8% vs 61.7%; P = 0.0004). PET area under the receiver-operating characteristic curves were higher than SPECT in the overall population (0.80 vs 0.68; P < 0.001), women, and obese patients (P < 0.001 for both). Flurpiridaz PET was superior to SPECT (P < 0.001) for perfusion defect size/severity evaluation, image quality, diagnostic certainty, and radiation exposure. Flurpiridaz PET was safe and well tolerated. CONCLUSIONS: This second flurpiridaz PET myocardial perfusion imaging trial shows that flurpiridaz has utility as a new tracer for CAD detection, specifically in women and obese patients. (An International Study to Evaluate Diagnostic Efficacy of Flurpiridaz [18F] Injection PET MPI in the Detection of Coronary Artery Disease [CAD]; NCT03354273).

Four-dimensional quantitative analysis using FDG-PET in clinical oncology.

Positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) has been commonly used in many oncological areas. High-resolution PET permits a three-dimensional analysis of FDG distributions on various lesions in vivo, which can be applied for tissue characterization, risk analysis, and treatment monitoring after chemoradiotherapy and immunotherapy. Metabolic changes can be assessed using the tumor absolute FDG uptake as standardized uptake value (SUV) and metabolic tumor volume (MTV). In addition, tumor heterogeneity assessment can potentially estimate tumor aggressiveness and resistance to chemoradiotherapy. Attempts have been made to quantify intratumoral heterogeneity using radiomics. Recent reports have indicated the clinical feasibility of a dynamic FDG PET-computed tomography (CT) in pilot cohort studies of oncological cases. Dynamic imaging permits the assessment of temporal changes in FDG uptake after administration, which is particularly useful for differentiating pathological from physiological uptakes with high diagnostic accuracy. In addition, several new parameters have been introduced for the in vivo quantitative analysis of FDG metabolic processes. Thus, a four-dimensional FDG PET-CT is available for precise tissue characterization of various lesions. This review introduces various new techniques for the quantitative analysis of FDG distribution and glucose metabolism using a four-dimensional FDG analysis with PET-CT. This elegant study reveals the important role of tissue characterization and treatment strategies in oncology.

＜Editors' Choice＞ Elective nodal irradiation versus involved field radiotherapy for limited disease small cell lung cancer: a single-institution experience.

Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with limited-disease small cell lung cancer (LD-SCLC). However, no solid consensus exists on their optimal target volume. The current study aimed to assess the clinical outcomes of patients with LD-SCLC who received definitive ENI or IFRT. A retrospective single-institution study of patients who received definitive radiotherapy between 2008 and 2020 was performed. All patients underwent whole-body positron emission tomography/computed tomography before three-dimensional conformal radiotherapy. Among the 37 patients analyzed, 22 and 15 received ENI and IFRT, respectively. The thoracic radiotherapy dose was mostly either 60 Gy in 30 fractions delivered in 2-Gy fractions once daily or 45 Gy in 30 fractions delivered in 1.5-Gy fractions twice daily. The median follow-up period was 21.4 months. A total of 12 patients (32%) experienced locoregional relapse: 10 within and 2 outside the irradiation fields. One patient in the IFRT group experienced isolated nodal failure. Differences in locoregional relapse-free, progression-free, and overall survival rates between ENI and IFRT were not significant. Overall, IFRT did not promote a significant increase in locoregional recurrence compared to ENI. Our findings suggested the utility of IFRT in standard clinical practice and support its use for patients with LD-SCLC.

Association of the extent of myocardial ischemia with outcomes in patients with suspected coronary artery disease in Japan.

BACKGROUND: There is an ongoing controversy regarding the necessity of single-photon emission computed tomography (SPECT) for patients with ischemic heart diseases after the publication of the results of the ISCHEMIA trial. We aimed to evaluate the association of the extent of myocardial ischemia with outcomes in patients with suspected coronary artery disease in Japan. METHODS: From the data of 2780 patients with stable angina who were enrolled prospectively between January 2006 and March 2008 in Japan and had undergone physician-referred non-invasive imaging tests (Japanese Coronary-Angiography or Myocardial Imaging for Angina Pectoris Study), 1205 patients managed with SPECT were stratified by 10 % myocardial ischemia. Major adverse cardiac events (MACEs), including death, myocardial infarction, hospitalization for heart failure, and late revascularization, were followed-up for 1 year. RESULTS: Patients with ≥10 % myocardial ischemia (n = 173) were less likely to be women than patients with <10 % myocardial ischemia (n = 1032) and had a significantly higher 1-year cumulative incidence of MACEs (6.9 % vs. 1.8 %, p < 0.0001). After adjusting for confounders, the risk of ≥10 % myocardial ischemia relative to <10 % myocardial ischemia for MACEs remained significant [adjusted hazard ratio (95 % confidence interval), 2.40 (1.09-5.26), p = 0.029]. After adjusting including treatments, the risk of MACEs became insignificant between the ≥10 % myocardial ischemia group and the <10 % myocardial ischemia group [adjusted hazard ratio (95 % confidence interval), 1.04 (0.45-2.45), p = 0.92]. CONCLUSION: The presence of ≥10 % myocardial ischemia at diagnosis was significantly associated with the 1-year risk for MACEs in Japanese patients with suspected coronary artery disease.

A deep learning method for translating 3DCT to SPECT ventilation imaging: First comparison with 81m Kr-gas SPECT ventilation imaging.

PURPOSE: This study aimed to evaluate the accuracy of deep learning (DL)-based computed tomography (CT) ventilation imaging (CTVI). METHODS: A total of 71 cases that underwent single-photon emission CT 81m Kr-gas ventilation (SPECT V) and CT imaging were included. Sixty cases were assigned to the training and validation sets, and the remaining 11 cases were assigned to the test set. To directly transform three-dimensional (3D) CT (free-breathing CT) images to SPECT V images, a DL-based model was implemented based on the U-Net architecture. The input and output data were 3DCT- and SPECT V-masked, respectively, except for whole-lung volumes. These data were rearranged in voxel size, registered rigidly, cropped, and normalized in preprocessing. In addition to a standard estimation method (i.e., without dropout during the estimation process), a Monte Carlo dropout (MCD) method (i.e., with dropout during the estimation process) was used to calculate prediction uncertainty. To evaluate the two models' (CTVIMCD U-Net , CTVIU-Net ) performance, we used fivefold cross-validation for the training and validation sets. To test the final model performances for both approaches, we applied the test set to each trained model and averaged the test prediction results from the five trained models to acquire the mean test result (bagging) for each approach. For the MCD method, the models were predicted repeatedly (sample size = 200), and the average and standard deviation (SD) maps were calculated in each voxel from the predicted results: The average maps were defined as test prediction results in each fold. As an evaluation index, the voxel-wise Spearman rank correlation coefficient (Spearman rs ) and Dice similarity coefficient (DSC) were calculated. The DSC was calculated for three functional regions (high, moderate, and low) separated by an almost equal volume. The coefficient of variation was defined as prediction uncertainty, and these average values were calculated within three functional regions. The Wilcoxon signed-rank test was used to test for a significant difference between the two DL-based approaches. RESULTS: The average indexes with one SD (1SD) between CTVIMCD U-Net and SPECT V were 0.76 ± 0.06, 0.69 ± 0.07, 0.51 ± 0.06, and 0.75 ± 0.04 for Spearman rs , DSChigh , DSCmoderate , and DSClow , respectively. The average indexes with 1SD between CTVIU-Net and SPECT V were 0.72 ± 0.05, 0.66 ± 0.04, 0.48 ± 0.04, and 0.74 ± 0.06 for Spearman rs , DSChigh , DSCmoderate , and DSClow , respectively. These indexes between CTVIMCD U-Net and CTVIU-Net showed no significance difference (Spearman rs , p = 0.175; DSChigh , p = 0.123; DSCmoderate , p = 0.278; DSClow , p = 0.520). The average coefficient of variations with 1SD were 0.27 ± 0.00, 0.27 ± 0.01, and 0.36 ± 0.03 for the high-, moderate-, and low-functional regions, respectively, and the low-functional region showed a tendency to exhibit larger uncertainties than the others. CONCLUSION: We evaluated DL-based framework for estimating lung-functional ventilation images only from CT images. The results indicated that the DL-based approach could potentially be used for lung-ventilation estimation.

Influences of mitral annuloplasty on left ventricular flow dynamics assessed with 3-dimensional cine phase-contrast flow magnetic resonance imaging.

OBJECTIVES: We assessed the influence of annuloplasty procedures in mitral repair on left ventricular (LV) vortex flow patterns and aortic outflow patterns, and flow energy loss (EL). METHODS: Twenty healthy volunteers and 14 patients who had undergone mitral valve repair were examined using 3-dimensional cine phase-contrast magnetic resonance imaging. A band group included 7 patients with semi-rigid and 2 with flexible partial bands. The ring group included 5 patients with semi-rigid complete rings. LV vortex flow patterns, aortic outflow patterns, EL, and aortic annulus changes during one cardiac cycle were evaluated. RESULTS: Mitral repair induced different vortex flow patterns compared with that of healthy volunteers. The vortex beneath the anterior mitral leaflet with semi-rigid devices was double-stranded in early diastole, and it was single-stranded with flexible bands with a large shift toward the apex during diastole. LVEL in patients who underwent mitral repair (0.84 ± 0.42 mW) was greater than that in healthy volunteers (0.47 ± 0.10 mW). Complete rings disturbed aortic outflow patterns, with EL distribution changes. Smaller devices relative to patient body size disturbed LV flow patterns and caused high EL. No significant relationship was found between indexed ring orifice area and transmitral mean pressure gradient (r = -0.25, P = .414), but a negative relationship exists between indexed ring orifice area and LVEL (r = -0.84, P < .001). CONCLUSIONS: Mitral repair, especially with relatively small annuloplasty rings, induced abnormal LV flow patterns and EL elevation, which have the potential to be a novel hemodynamic evaluation method after mitral repair.

Serial changes in cardiac sympathetic nervous function after transcatheter aortic valve replacement: A prospective observational study using 123I-meta-iodobenzylguanidine imaging.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) can rapidly improve cardiac sympathetic nervous function (CSNF) within 2 weeks in patients with aortic stenosis (AS). However, whether such short-term improvements will be sustained thereafter remains unclear. METHODS: Patients with severe AS who underwent TAVR between October 2017 and June 2019 were enrolled in this single-center, prospective, observational study. 123I-meta-iodobenzylguanidine imaging was performed at baseline, within 2 weeks after TAVR, and at 6 to 12 months post-TAVR to evaluate the heart-mediastinum ratio (H/M) and washout rate. RESULTS: Of 183 consecutive patients, 75 (19 men; median age: 86 years) were evaluated. The late H/M significantly improved within 2 weeks after TAVR (P = .041) and further improved over 6 to 12 months after TAVR (P = .041). Multivariate analysis revealed that the baseline mean aortic valve pressure gradient (mPG) was an independent predictor of mid-term improvement in the late H/M (> 0.1) (P = .037). Patients with a high baseline mPG (≥ 58 mmHg) exhibited a significantly greater increase in the late H/M than those with a low baseline mPG (< 42 mmHg) (0.24 vs 0.01; P = .029). CONCLUSION: CSNF demonstrated sustained improvement from within 2 weeks after TAVR until 6 to 12 months later. Such improvement was related to baseline hemodynamic AS severity.

Advances in Diagnostic Imaging for Cardiac Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown etiology, and its clinical presentation depends on the affected organ. Cardiac sarcoidosis (CS) is one of the leading causes of death among patients with sarcoidosis. The clinical manifestations of CS are heterogeneous, and range from asymptomatic to life-threatening arrhythmias and progressive heart failure due to the extent and location of granulomatous inflammation in the myocardium. Advances in imaging techniques have played a pivotal role in the evaluation of CS because histological diagnoses obtained by myocardial biopsy tend to have lower sensitivity. The diagnosis of CS is challenging, and several approaches, notably those using positron emission tomography and cardiac magnetic resonance imaging (MRI), have been reported. Delayed-enhanced computed tomography (CT) may also be used for diagnosing CS in patients with MRI-incompatible devices and allows acceptable evaluation of myocardial hyperenhancement in such patients. This article reviews the advances in imaging techniques for the evaluation of CS.

Comparison between dynamic whole-body FDG-PET and early-delayed imaging for the assessment of motion in focal uptake in colorectal area.

OBJECTIVES: Serial changes of focal uptake in whole-body dynamic positron emission tomography (PET) imaging were assessed and compared with those in early-delayed imaging to differentiate pathological uptake from physiological uptake in the colorectal area, based on the change in uptake shape. METHODS: In 60 patients with at least 1 pathologically diagnosed colorectal cancer or adenoma, a serial 3 min dynamic whole-body PET/computed tomography imaging was performed four times around 60 min after the administration of 18F-fluorodeoxyglucose (FDG) to create a conventional (early) image by summation. Delayed imaging was performed separately at 110 min after FDG administration. High focal uptake lesions in the colorectal area were visually assessed as "changed" or "unchanged" on serial dynamic imaging and early-delayed imaging, based on the alteration in uptake shape over time. These criteria on the images were used to differentiate pathological uptake from physiological uptake. RESULTS: In this study, 334 lesions with high focal FDG uptake were observed. Among 73 histologically proven pathological FDG uptakes, no change was observed in 69 on serial dynamic imaging and 72 on early-delayed imaging (sensitivity of 95 vs. 99%, respectively; ns). In contrast, out of 261 physiological FDG uptakes, a change in uptake shape was seen in 159 on dynamic PET imaging and 66 on early-delayed imaging (specificity of 61 vs. 25%, respectively; p < 0.01). High and similar negative predictive values for identifying pathological uptake were obtained by both methods (98 vs 99%, respectively). Thus, the overall accuracy for differentiating pathological from physiological FDG uptake based on change in uptake shape tended to be higher on serial dynamic imaging (68%) than on early-delayed imaging (41%; p < 0.01). CONCLUSIONS: Dynamic whole-body FDG imaging enables differentiation of pathological uptake from physiological uptake based on the serial changes in uptake shape in the colorectal area. It may provide greater diagnostic value than early-delayed PET imaging. Thus, this technique holds a promise for minimizing the need for delayed imaging.

Determination of brain tumor recurrence using 11 C-methionine positron emission tomography after radiotherapy.

We conducted a prospective multicenter trial to compare the usefulness of 11 C-methionine (MET) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both 11 C-MET and 18 F-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at 3 months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either 11 C-MET or 18 F-FDG underwent surgery; 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in one of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of 11 C-MET PET and 18 F-FDG PET were 0.97 (32/33, 95% confidence interval [CI]: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (P < .0001). The diagnostic accuracy of 11 C-MET PET was significantly better than that of 18 F-FDG PET (87.5% vs. 69.6%, P = .033). No examination-related adverse events were observed. The results of the study demonstrated that 11 C-MET PET was superior to 18 F-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis.

Clinical Perspectives of Theranostics.

Theranostics is a precision medicine which integrates diagnostic nuclear medicine and radionuclide therapy for various cancers throughout body using suitable tracers and treatment that target specific biological pathways or receptors. This review covers traditional theranostics for thyroid cancer and pheochromocytoma with radioiodine compounds. In addition, recent theranostics of radioimmunotherapy for non-Hodgkin lymphoma, and treatment of bone metastasis using bone seeking radiopharmaceuticals are described. Furthermore, new radiopharmaceuticals for prostatic cancer and pancreatic cancer have been added. Of particular, F-18 Fluoro-2-Deoxyglucose (FDG) Positron Emission Tomography (PET) is often used for treatment monitoring and estimating patient outcome. A recent clinical study highlighted the ability of alpha-radiotherapy with high linear energy transfer (LET) to overcome treatment resistance to beta--particle therapy. Theranostics will become an ever-increasing part of clinical nuclear medicine.

Quantitative FDG PET Assessment for Oncology Therapy.

Positron emission tomography (PET) has unique characteristics for quantitative assessment of tumour biology in vivo. Accumulation of F-18 fluorodeoxyglucose (FDG) may reflect tumour characteristics based on its metabolic activity. Quantitative assessment of FDG uptake can often be applied for treatment monitoring after chemotherapy or chemoradiotherapy. Numerous studies indicated biochemical change assessed by FDG PET as a more sensitive marker than morphological change estimated by CT or MRI. In addition, those with complete metabolic response after therapy may show better disease-free survival and overall survival than those with other responses. Assessment of metabolic change may be performed using absolute FDG uptake in the tumour (standardized uptake value: SUV). In addition, volumetric parameters such as metabolic tumour volume (MTV) have been introduced for quantitative assessment of FDG uptake in tumour. More recently, radiomics approaches that focus on image-based precision medicine have been applied to FDG PET, as well as other radiological imaging. Among these, texture analysis extracts intratumoral heterogeneity on a voxel-by-voxel basis. Combined with various machine learning techniques, these new quantitative parameters hold a promise for assessing tissue characterization and predicting treatment effect, and could also be used for future prognosis of various tumours, although multicentre clinical trials are needed before application in clinical settings.

Assessment of biventricular hemodynamics and energy dynamics using lumen-tracking 4D flow MRI without contrast medium.

BACKGROUND: Biventricular physiological interaction remains a challenging problem in cardiology. We developed a four-dimensional (4D) flow magnetic resonance imaging (MRI) scan and clinically available analysis protocol based on beat tracking of the cardiovascular lumen without contrast medium, which enabled measurement of the biventricular hemodynamics and energetic performance by calculating flow energy loss (EL) and kinetic energy (KE). The aim of this study was to observe the flow patterns and energy dynamics to reveal the physiology of the right and left ventricular systems. METHODS: 4D flow MRI studies were performed in 19 healthy volunteers including 11 male and 8 female. The right and left ventricular systems were segmented to visualize the flow patterns and to quantify the hemodynamics and energy dynamics. RESULTS: A large vortex was observed in the left ventricle (LV), along the longitudinal axis, during end diastole and early systole. At early systole, the vortex appeared to facilitate smooth ejection with little EL. In contrast, in the right ventricle (RV), there were vortices near the free wall in both the short and long axes during the diastolic filling phase. Mean EL index during a single cardiac cycle in the right and left heart systems was 0.63 ± 0.16 (0.42-0.99) mW/m2, and 1.02 ± 0.26 (0.58-1.58) mW/m2, respectively. EL is inevitable loss caused by the vortex flow to facilitate smooth right and left ventricular function and left-sided EL tended to correlate positively with heart rate and right ventricular stroke volume. Kinetic energy at the aortic valve was influenced by LV end-diastolic volume/stroke volume. No gender difference was observed. CONCLUSIONS: The RV appears to function as a regulator of the energy dynamics of the LV system.

Assessing myocardial perfusion in suspected coronary artery disease: rationale and design of the second phase 3, open-label multi-center study of flurpiridaz (F-18) injection for positron emission tomography (PET) imaging.

BACKGROUND: Positron emission tomography (PET) myocardial perfusion imaging (MPI) with the novel radiopharmaceutical Fluorine-18 Flurpiridaz has been shown in Phase 1, 2, and first Phase 3 clinical studies to be safe and effective in diagnosing coronary artery disease (CAD). We describe the methodology of the second FDA-mandated phase 3 prospective, open-label, international, multi-center trial of F-18 Flurpiridaz PET MPI. METHODS: The primary study end point is to assess the diagnostic efficacy of F-18 Flurpiridaz PET MPI in the detection of significant CAD [≥ 50% by quantitative invasive coronary angiography (ICA)] in patients with suspected CAD. The secondary endpoints are to evaluate the diagnostic efficacy of F-18 Flurpiridaz PET MPI compared to Tc-99 m-labeled SPECT MPI in the detection of CAD in all patients and in the following subgroups: (1) females; (2) patients with body mass index ≥ 30 kg/m2; and (3) diabetic patients. This trial's design differs from the first phase 3 trial in that (1) comparison to SPECT is now a secondary end point; (2) patients with known CAD are excluded; and (3) both SPECT and PET MPI are performed before ICA. CONCLUSIONS: This second phase 3 study will provide additional evidence on the diagnostic efficacy of F-18 Flurpiridaz PET MPI in the detection of significant CAD. TRIAL REGISTRATION NUMBER: NCT03354273.