Cardiac Sympathetic Activity and Rhythm Control Following Pulmonary Vein Isolation in Patients with Paroxysmal Atrial Fibrillation-A Prospective 123I-mIBG-SPECT/CT Imaging Study.

BACKGROUND: Pulmonary vein isolation (PVI) and antiarrhythmic drug therapy are established treatment strategies to preserve sinus rhythm in atrial fibrillation (AF). However, the efficacy of both interventional and pharmaceutical therapy is still limited. Solid evidence suggests an important role of the cardiac sympathetic nervous system in AF. In this blinded, prospective observational study, we studied left ventricular cardiac sympathetic activity in patients treated with PVI and with antiarrhythmic drugs. Prospectively, Iodine-123-benzyl-guanidine single photon emission computer tomography (123I-mIBG-SPECT) was performed in a total of 23 patients with paroxysmal AF, who underwent PVI (n = 20) or received antiarrhythmic drug therapy only (n = 3), respectively. 123I-mIBG planar and SPECT/CT scans were performed before and 4 to 8 weeks after PVI (or initiation of drug therapy, respectively). For semiquantitative SPECT image analysis, attenuation-corrected early/late images were analyzed. Quantitative SPECT analysis was performed using the AHA 17-segment model of the left ventricle. RESULTS: PVI with point-by-point radiofrequency ablation led to a significantly (p < 0.05) higher visual sympathetic innervation defect score when comparing pre-and post PVI. Newly emerging innervation deficits post PVI were localized predominantly in the inferior lateral wall. These findings were corroborated by semiquantitative SPECT analysis identifying inferolateral segments with a reduced tracer uptake in comparison to SPECT before PVI. Following PVI, patients with an AF relapse showed a different sympathetic innervation pattern compared to patients with sufficient rhythm control. CONCLUSIONS: PVI results in novel defects of cardiac sympathetic innervation. Differences in cardiac sympathetic innervation remodelling following PVI suggest an important role of the cardiac autonomous nervous system in the maintenance of sinus rhythm following PVI.

18F-FDG PET/CT Uptake Classification in Lymphoma and Lung Cancer by Using Deep Convolutional Neural Networks.

Background Fluorine 18 (18F)-fluorodeoxyglucose (FDG) PET/CT is a routine tool for staging patients with lymphoma and lung cancer. Purpose To evaluate configurations of deep convolutional neural networks (CNNs) to localize and classify uptake patterns of whole-body 18F-FDG PET/CT images in patients with lung cancer and lymphoma. Materials and Methods This was a retrospective analysis of consecutive patients with lung cancer or lymphoma referred to a single center from August 2011 to August 2013. Two nuclear medicine experts manually delineated foci with increased 18F-FDG uptake, specified the anatomic location, and classified these findings as suspicious for tumor or metastasis or nonsuspicious. By using these expert readings as the reference standard, a CNN was developed to detect foci positive for 18F-FDG uptake, predict the anatomic location, and determine the expert classification. Examinations were divided into independent training (60%), validation (20%), and test (20%) subsets. Results This study included 629 patients (mean age, 52.2 years ± 20.4 [standard deviation]; 394 men). There were 302 patients with lung cancer and 327 patients with lymphoma. For the test set (123 patients; 10 782 foci), the CNN areas under the receiver operating characteristic curve (AUCs) for determining hypermetabolic 18F-FDG PET/CT foci that were suspicious for cancer versus nonsuspicious by using the five input features were as follows: CT alone, 0.78 (95% confidence interval [CI]: 0.72, 0.83); 18F-FDG PET alone, 0.97 (95% CI: 0.97, 0.98); 18F-FDG PET/CT, 0.98 (95% CI: 0.97, 0.99); 18F-FDG PET/CT maximum intensity projection (MIP), 0.98 (95% CI: 0.98, 0.99); and 18F-FDG PET/CT MIP atlas, 0.99 (95% CI: 0.98, 1.00). The combination of 18F-FDG PET and CT information improved overall classification accuracy (AUC, 0.975 vs 0.981, respectively; P < .001). Anatomic localization accuracy of the CNN was 2543 of 2639 (96.4%; 95% CI: 95.5%, 97.1%) for body part, 2292 of 2639 (86.9%; 95% CI: 85.3%, 88.5%) for region (ie, organ), and 2149 of 2639 (81.4%; 95% CI: 79.3%-83.5%) for subregion. Conclusion The fully automated anatomic localization and classification of fluorine 18-fluorodeoxyglucose PET uptake patterns in foci suspicious and nonsuspicious for cancer in patients with lung cancer and lymphoma by using a convolutional neural network is feasible and achieves high diagnostic performance when both CT and PET images are used. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Froelich and Salavati in this issue.

Targeting PSMA by radioligands in non-prostate disease-current status and future perspectives.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is the up-and-coming target for molecular imaging of prostate cancer. Despite its name, non-prostate-related PSMA expression in physiologic tissue as well as in benign and malignant disease has been reported in various publications. Unlike in prostate cancer, PSMA expression is only rarely observed in non-prostate tumor cells. Instead, expression occurs in endothelial cells of tumor-associated neovasculature, although no endothelial expression is observed under physiologic conditions. The resulting potential for tumor staging in non-prostate malignant tumors has been demonstrated in first patient studies. This review summarizes the first clinical studies and deduces future perspectives in staging, molecular characterization, and PSMA-targeted radionuclide therapy based on histopathologic examinations of PSMA expression. CONCLUSIONS: The non-exclusivity of PSMA in prostate cancer opens a window to utilize the spectrum of available radioactive PSMA ligands for imaging and molecular characterization and maybe even therapy of non-prostate disease.

Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography for improving diagnosis of infection in patients on CF-LVAD: longing for more 'insights'.

Aim: Presence and consequent extent of infection in patients on continuous-flow left ventricular assist devices (CF-LVADs) can be challenging with the current diagnostic tools. The present study sought to demonstrate the diagnostic power of 18F-Fluorodeoxyglucose-Positron-Emission Tomography/Computed Tomography (18F-FDG PET/CT) in detecting infection in patients supported with CF-LVAD. Background: The present study sought to demonstrate the diagnostic power of 18F-fluorodeoxyglucose-positron-emission tomography/computed tomography (18F-FDG PET/CT) in detecting infection in patients supported with CF-LVAD. Methods and results: Between July 2009 and April 2016, 61 PET/CT examinations were performed in 47 patients (median age 64.13 years, IQR 18.77) supported with a CF-LVAD. PET/CT assessments were performed qualitatively and quantitatively at three different levels: at the piercing site of driveline (first level), along the intracorporeal course of driveline (second level), and around the device (third level). Final diagnosis of LVAD infection was prospectively performed and was based upon microbiological samples taken at hospital admission, during the surgical revision/transplantation and recurrence of symptoms on long-term follow-up. At last follow-up a total of 40 (65.57%) final diagnoses of LVAD-infection could be ascertained. Matching the final diagnosis with the PET/CT assessments the sensitivity, specificity, and positive and negative predictive value were 90.0, 71.4, 85.71, and 78.94%, respectively. Level sub-analyses of SUV max showed an optimal discriminator power for levels 1 and 2 (AUC of level 1-0.824, P < 0.001; AUC of level 2-0.849, P < 0.001, respectively). At the third level semi-quantitative analysis showed poor discriminator power (AUC 0.589, P = 0.33). Qualitative visual analysis instead indicated a trend toward significance (P = 0.07). Conclusions: Quantitative 18F-FDG PET/CT is an optimal diagnostic tool in detecting superficial and deep driveline infections. However, diagnostic accuracy with regard to the diagnosis of pump housing infection is limited. Here, clinical and qualitative PET/CT analyses must be better considered.

Metabolic volume performs better than SUVmax in the detection of left ventricular assist device driveline infection.

PURPOSE: A continuous-flow left ventricular assist device (LVAD) is a new and highly promising therapy in supporting end-stage heart failure patients, either bridging them to heart transplantation or as a destination therapy. Infection is one of the major complications associated with LVAD implants. 18F-FDG PET/CT has already been shown to be useful in the detection of LVAD infection. The goal of this study was to compare the diagnostic accuracy of different PET analysis techniques (visual grading versus SUVmax and metabolic volume). METHODS: We retrospectively analyzed 48 patients with implanted LVAD who underwent an 18F-FDG PET/CT that were either suspected to have a driveline or device infection or inflammation of unknown origin. PET/CT was analyzed qualitatively (visual grading) and quantitatively (SUVmax and metabolic volume) and matched to the final clinical diagnosis concerning driveline infection. The final diagnosis (standard of reference) was made at the end of clinically recorded follow-up or transplantation and included microbiological cultures of the driveline exit site and/or surgical samples, and clinical signs of infection despite negative cultures as well as recurrence of symptoms. RESULTS: Sensitivity, specificity, positive and negative predictive value were 87.5%, 79%, 81% and 86% for visual score, 87.5%, 87.5%, 87.5% and 87.5% for SUVmax and 96%, 87.5%, 88.5%, 95.5% for metabolic volume, respectively. ROC analysis revealed an AUC of .929 for SUVmax and .969 for metabolic volume. Both SUVmax and metabolic volume had a high detection rate of patients with driveline infection (21/24 = 91.5% true positive vs. 23/26 = 88.5% true positive, respectively). However, metabolic volume detected more patients without any infection correctly (1/22 = 4.5% false negative vs. 3/24 = 12.5% false negative). CONCLUSIONS: 18F-FDG PET/CT is a valuable tool for the diagnosis of LVAD driveline infection with high diagnostic accuracy. Particularly the use of the metabolic volume yields very high accuracy and performs slightly better than SUVmax.

Supporting imaging modalities for improving diagnosis of prosthesis endocarditis: preliminary results of a single-center experience with 18F-FDG-PET/CT.

BACKGROUND: The aim of the current study was to evaluate the role of PET-CT in the diagnosis of prosthetic valve endocarditis (PVE). METHODS: This is a single-center study including 13 PET/CT examinations performed between February 2009 and March 2016 in 13 patients (76.9% men, mean age 68.1 years, IQR 11.1) because of suspect of PVE. Median interval time between first operation and PET/CT examination was 19.02 months (IQR 85.5). Final diagnosis was made according to pathological criteria (histological and microbiological) of the Duke classification. RESULTS: Eleven patients (84.6%) presented at the hospital admission positive blood cultures. Eight patients (61.5%) had inconclusive transesophageal echocardiography (TEE). Abnormal 18F-FDG uptake suggestive of active PVE was observed in 10 patients (76.9%), whereas in 3 patients (23.1%) PET/CT did not show any pathological tracer uptake at the level of the previous implanted prostheses. PET/CT revealed 15 (115.4%) new extracardiac findings and one (7.7%) new cardiac focus not previously detected in TEE. All patients underwent redo surgery. Matching the intraoperative findings with those of PET/CT, a total of 10 true positives, 2 true negatives, no false positive and 1 false negative finding was reported. Sensitivity, specificity, and positive and negative predictive values of PET/CT were 90.9%, 100%, 100% and 50% whereas for TEE they were 81.82%, 50%, 81.82%, and 50% respectively. In 61.63% of patients (N. 8) PET/CT and echo findings were concordant. In those cases the diagnosis of endocarditis was confirmed in all. CONCLUSIONS: This study highlights the potential advantages of PET-CT in patients with suspected prosthesis endocarditis. Further prospective evaluations are needed to confirm those preliminary results.

Routine 18F-FDG PET/CT does not detect inflammation in the left atrium in patients with atrial fibrillation.

Increasing evidence supports a role of inflammation in the development of atrial fibrillation (AF). However, direct evidence of persistent inflammatory activity in the atria of AF patients is scarce. In this study, we used 18-Fluor-Deoxyglucose positron emission tomography computed tomography (18F-FDG PET/CT) to determine atrial inflammation in patients with and without AF. Retrospectively, 18F-FDG PET/CT scans were analyzed. 37 patients with a history of AF were compared to an age and sex matched control group with no history of AF. Standardized uptake values were obtained in the atrial walls, in the left ventricular wall, and in the right ventricular blood pool, respectively. Target to background ratios (TBR) were determined in the atrial and left ventricular walls and compared between the two groups. TBR values of the left atrial wall were slightly but not significantly higher in patients with AF (1.21 ± 0.27) compared to those without AF (1.14 ± 0.29; p = 0.85). Likewise, a weak but not significant difference was observed in signal intensities in the right atrial wall between patients in the AF (1.14 ± 0.45) and the control group (0.96 ± 0.2; p = 0.41). TBR values of the left ventricular myocardium did not differ between the groups; no significant correlation was found between the TBR in the left and right atrial wall and blood glucose levels. 18F-FDG PET/CT performed under routine conditions did not detect a significant difference in inflammatory activity in the left or right atrium between patients with and without AF. Contrary to previous reports, these results therefore do not clearly support a role for ongoing atrial inflammation in patients with AF. Prospective clinical studies using myocardial glucose uptake suppression strategies may be helpful to clarify these issues.

Impact of PET acquisition durations on image quality and lesion detectability in whole-body 68Ga-PSMA PET-MRI.

BACKGROUND: While 68Ga-PSMA PET-MRI might be superior to PET-CT with regard to soft tissue assessment in prostate cancer evaluation, it is also known to potentially introduce additional PET image artefacts. Therefore, the impact of PET acquisition duration and attenuation data on artefact occurrence, lesion detectability, and quantification was investigated. To this end, whole-body PET list mode data from 12 patients with prostate cancer were acquired 1 h after injection of 2 MBq/kg [68Ga]HBED-CC-PSMA on a hybrid PET-MRI system. List mode data were further transformed into data sets representing 300, 180, 90, and 30 s acquisition duration per bed position. Standard attenuation and scatter corrections were performed based on MRI-derived attenuation maps, complemented by emission-based attenuation data in areas not covered by MRI. A total of 288 image data sets were reconstructed with varying acquisition durations for emission and attenuation data with and without scatter and prompt gamma correction, and further analysed regarding image quality and diagnostic performance. RESULTS: Decreased PET acquisition durations resulted in a significantly increased incidence of halo artefacts around kidneys and bladder, decreased lesion detectability and lower SUV as well as markedly lower arm attenuation values: Halo artefacts were present in 5 out of 12 cases at 300-s duration, in 6 at 180 s, in 10 at 90 s, and in 11 cases at 30 s. Using attenuation data of the 300 s scans restored artefact occurrence to the original 300-s level. Prompt gamma correction only led to small improvements in terms of artefact occurrence and size. Of the 141 detected lesions in the 300-s images one lesion was not detected at 180 s, 28 at 90 s, and 64 at 30 s. Using the 300-s attenuation map decreased non-detectability of lesions to zero at 180 s, 9 at 90 s, and 52 at 30 s. Attenuation maps at 90 and 30 s demonstrated markedly lower mean arm attenuation values (0.002 cm-1) than those at 300 s (0.084 cm-1), and 180 s (0.062 cm-1). CONCLUSIONS: Short acquisition durations of less than 3 minutes per bed position result in unacceptable image artefacts and decreased diagnostic performance in current whole-body 68Ga-PSMA PET-MRI and should be avoided. Increased image noise and imperfections in generated attenuation maps were identified as a paramount cause for image degradation.

Gastrointestinal Stromal Tumor Showing Intense Tracer Uptake on PSMA PET/CT.

A 70-year-old man with suspected prostate cancer was referred for Ga-PSMA-HBED-CC PET/CT (short PSMA PET/CT) for staging of tumor extent. Apart from vivid tracer uptake in the prostate gland and osseous metastasis, PSMA PET/CT revealed a large soft tissue mass with calcifications in the left upper abdomen showing intense tracer uptake. Histologic examination revealed the mass to be a gastrointestinal stromal tumor.

Long Distance Endovascular Growth of Jugulotympanic Paraganglioma Evident in 68Ga-DOTATATE PET but Concealed on CT.

A 60-year-old woman was referred to contrast-enhanced CT for evaluation of jugular vein thrombosis incidentally detected by ultrasound. Contrast-enhanced CT showed an enhanced tumor of the right skull base highly suspicious of jugulotympanic paraganglioma. However, the jugular veins showed a nearly symmetric contrast enhancement without clear evidence of thrombosis. Consecutive Ga-DOTATATE PET/CT depicted high tumor uptake, which comprised the entire internal jugular vein. Endovascular growth of paraganglioma might be missed on contrast-enhanced CT because of high vascularization of the lesion. Ga-DOTATATE PET is suited for accurate determination of tumor extent.

Radioligand Therapy With 177Lu-PSMA-617 as A Novel Therapeutic Option in Patients With Metastatic Castration Resistant Prostate Cancer.

BACKGROUND: Despite progress in treatment of metastatic castration-resistant prostate cancer (mCRPC), new approaches are urgently needed. Recently theranostic concepts using radiolabeled ligands of the prostate-specific membrane antigen (PSMA) have been developed for diagnostics and therapy of patients with advanced mCRPC. The aim of this study was to evaluate tumor response, adverse effects, and survival in patients undergoing radioligand therapy with Lu-PSMA-617. METHODS: Fifty therapies using Lu-PSMA-617 were performed in 28 consecutive patients with mCRPC and exhausted conventional therapeutic options (median age, 73.4 years; range, 45-87 years). Data were retrospectively analyzed with focus on response, safety, and survival. The median overall survival was compared with that of a recent historical patient cohort treated with best supportive care prior to availability of Lu-PSMA-617. RESULTS: Any PSA decline occurred in 59% and 75% of patients after 1 and 2 therapies. Moreover, a PSA decline of 50% or greater occurred in 32% and 50%. Therapies were well tolerated. Hematologic and renal parameters changed insignificantly; permanent xerostomia or other safety-related toxicity did not occur. The estimated median survival was 29.4 weeks, significantly longer than survival in the historical best supportive care group (19.7 weeks [hazard ratio, 0.44; 95% confidence interval, 0.20-0.95]; P = 0.031). CONCLUSIONS: Results from 50 therapies show that radioligand therapy with Lu-PSMA-617 is effective and well tolerated and seems to increase overall survival. A future randomized controlled prospective study will be necessary to confirm these results.

Endothelial-specific deficiency of Junctional Adhesion Molecule-C promotes vessel normalisation in proliferative retinopathy.

In proliferative retinopathies, like proliferative diabetic retinopathy and retinopathy of prematurity (ROP), the hypoxia response is sustained by the failure of the retina to revascularise its ischaemic areas. Non-resolving retina ischaemia/hypoxia results in upregulation of pro-angiogenic factors and pathologic neovascularisation with ectopic, fragile neovessels. Promoting revascularisation of the retinal avascular area could interfere with this vicious cycle and lead to vessel normalisation. Here, we examined the function of endothelial junctional adhesion molecule-C (JAM-C) in the context of ROP. Endothelial-specific JAM-C-deficient (EC-JAM-C KO) mice and littermate JAM-C-proficient (EC-JAM-C WT) mice were subjected to the ROP model. An increase in total retinal vascularisation was found at p17 owing to endothelial JAM-C deficiency, which was the result of enhanced revascularisation and vessel normalisation, thereby leading to significantly reduced avascular area in EC-JAM-C KO mice. In contrast, pathologic neovessel formation was not affected by endothelial JAM-C deficiency. Consistent with improved vessel normalisation, tip cell formation at the interface between vascular and avascular area was higher in EC-JAM-C KO mice, as compared to their littermate controls. Consistently, JAM-C inactivation in endothelial cells resulted in increased spreading on fibronectin and enhanced sprouting in vitro in a manner dependent on ß1-integrin and on the activation of the small GTPase RAP1. Together, endothelial deletion of JAM-C promoted endothelial cell sprouting, and consequently vessel normalisation and revascularisation of the hypoxic retina without altering pathologic neovascularisation. Thus, targeting endothelial JAM-C may provide a novel therapeutic strategy for promoting revascularisation and vessel normalisation in the treatment of proliferative retinopathies.