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Abstract Purpose Radiolabelled fibroblast activation protein inhibitors (FAPIs) are becoming increasingly important for imaging various tumour diseases. However, it is essential to be aware of potential pitfalls. Here, we investigate FAP expression in the thyroid gland in autoimmune thyroiditis (AIT). Methods AIT patients with pathological thyroid uptake on [68Ga]Ga-FAPI PET were compared with glucose metabolism on 2-[18F]FDG PET in terms of SUVmax/SUVpeak/SUVmean/tissue-to-background ratio (TBR), and with a healthy control group. Results Between September 2019 and July 2021, 6 patients presented with a visually increased thyroid uptake and TBR on [68Ga]Ga-FAPI PET. In the retrospective clinical work-up, all patients had known or newly diagnosed AIT. Compared to a matched healthy control group, FAP expression and glucose metabolism were significantly increased ([68Ga]Ga-FAPI (SUVpeak): 7.0 vs. 1.7; p = 0.004/(TBRbloodpool): 6.8 vs. 1.7; p = 0.002; 2-[18F]FDG (SUVpeak): 3.9 vs. 1.4; p = 0.004/(TBRbloodpool): 4.0 vs. 1.2; p = 0.041). However, there was no significant difference in median uptake between [68Ga]Ga-FAPI and 2-[18F]FDG PET (SUVpeak: 7.3 vs. 5.6; p = 0.104). Conclusion Patients with AIT show higher thyroid uptake on [68Ga]Ga-FAPI and 2-[18F]FDG PET. Incidental thyroid uptake is another pitfall in the interpretation of [68Ga]Ga-FAPI PET and should prompt a clinical work-up.

In this prospective two-center feasibility study, we evaluate the diagnostic value of intraoperative ex vivo specimenPET/CT imaging of radical prostatectomy (RP) and lymphadenectomy specimens. Ten patients with high-risk prostate cancer underwent clinical prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) preoperatively on the day of surgery. Six patients received 68Ga-PSMA-11 and four 18F-PSMA-1007. Radioactivity of the resected specimen was measured again using a novel specimenPET/CT device (AURA10; XEOS Medical, Gent, Belgium) developed for intraoperative margin assessment. All index lesions of staging multiparametric magnetic resonance imaging could be visualized. Overall, specimenPET/CT correlated well with conventional PET/CT regarding detection of suspicious tracer foci (Pearson coefficient 0.935). In addition, specimenPET/CT demonstrated all lymph node metastases detected on conventional PET/CT (n = 3), as well as three previously undetected lymph node metastases. Importantly, all positive or close (

Purpose of the Report: Combined cardiac 68Ga-Fibroblast-Activation Protein-alpha inhibitor (FAPI) positron-emission tomography (PET) and cardiac magnetic resonance imaging (MRI) constitute a novel diagnostic tool in patients for the assessment of myocardial damage after an acute myocardial infarction (AMI). Purpose of this pilot study was to evaluate simultaneous Ga-68-FAPI-46-PET/MR imaging in the delayed phase after AMI. Material and Methods: Eleven patients underwent hybrid 68Ga-FAPI-46 PET/MRI post AMI. Standardized uptake values and fibroblast activation volume (FAV) were calculated and correlated with serum biomarkers and MRI parameters. Results: Significant 68Ga-FAPI-46 uptake could be demonstrated in 11 (100 %) patients after a mean period of 30.9 ± 22.0 days. FAV significantly exceeded the infarction size in MRI and showed a good correlation to MRI parameters as well as to serum biomarkers of myocardial damage. Conclusions: 68Ga-FAPI-46 PET/MRI offers molecular and morphological imaging of affected myocardium after AMI. This study demonstrates ongoing fibroblast activation in a delayed phase after AMI and generates hypotheses for future studies while aiming for a better understanding of myocardial remodeling following ischemic tissue damage.

Abstract Biliary-tract-carcinomas (BTC), pancreatic-ductal-adenocarcinomas (PDAC) and adenoidcystic-carcinomas (AC) have in common that they are traditionally treated with large clinical-target-volumes (CTV). The aim of this study is to examine the impact of pretreatment-[68Ga]FAPI-PET/CT on target-volume-definition and posttreatment-[68Ga]FAPI-PET/CT-response-assessment for BTC-, PDAC- and AC-patients referred to radiation-therapy. All consecutive BTC-, PDAC-, and AC-patients who received pretreatment-[68Ga]FAPI-PET/CT±[18F]FDG-PET/CT were included from 01.01.2020 to 01.03.2022. MTV and SUVmax were separately generated based on [68Ga]FAPI- and [18F]FDG-PET/CT-images. A [68Ga]FAPI- and [18F]FDG-based-CTV was defined. Treatment-plans were compared. Treatment-response was reassessed by a second [68Ga]FAPI-PET/CT and [18F]FDG-PET/CT after treatment-completion. Intermodality comparison of lesion-to-background-ratios [SUVmax_lesion/SUVmean_background] for individual timepoints t 1 and t 2 revealed significant higher values for [68Ga]FAPI compared to [18F]FDG (t 1 , p = 0.008; t 2 , p = 0.005). Intermodality comparison of radiation-therapy-plans showed that [68Ga]FAPI-based planning resulted in D100% = 97.2% and V95% = 98.8% for the [18F]FDG-MTV. [18F]FDG-based-planning resulted in D100% = 35.9% and V95% = 78.1% for [68Ga]FAPI-MTV. [18F]FDG-based-planning resulted only in 2 patients in V95% > 95% for [68Ga]FAPI-MTV, and in 1 patient in D100% > 97% for [68Ga]FAPI-MTV. GTV-coverage in terms of V95% was 76.4% by [18F]FDG-based-planning and 99.5% by [68Ga]FAPI-based-planning. Pretreatment [68Ga]FAPI-PET/CT enhances radiation-treatment-planning in this particular group of patients. While perilesional and tumoral follow-up [18F]FDG-uptake behaved uniformly, perilesional and tumoral reaction may differ in follow-up [68Ga]FAPI-imaging. Complementary [68Ga]FAPI- and [18F]FDG-imaging enhance treatment-response-assessment.

Abstract Background New-generation silicon-photomultiplier (SiPM)-based PET/CT systems exhibit an improved lesion detectability and image quality due to a higher detector sensitivity. Consequently, the acquisition time can be reduced while maintaining diagnostic quality. The aim of this study was to determine the lowest 18F-FDG PET acquisition time without loss of diagnostic information and to optimise image reconstruction parameters (image reconstruction algorithm, number of iterations, voxel size, Gaussian filter) by phantom imaging. Moreover, patient data are evaluated to confirm the phantom results. Methods Three phantoms were used: a soft-tissue tumour phantom, a bone-lung tumour phantom, and a resolution phantom. Phantom conditions (lesion sizes from 6.5 mm to 28.8 mm in diameter, lesion activity concentration of 15 kBq/mL, and signal-to-background ratio of 5:1) were derived from patient data. PET data were acquired on an SiPM-based Biograph Vision PET/CT system for 10 min in list-mode format and resampled into time frames from 30 to 300 s in 30-s increments to simulate different acquisition times. Different image reconstructions with varying iterations, voxel sizes, and Gaussian filters were probed. Contrast-to-noise-ratio (CNR), maximum, and peak signal were evaluated using the 10-min acquisition time image as reference. A threshold CNR value ≥ 5 and a maximum (peak) deviation of ± 20% were considered acceptable. 20 patient data sets were evaluated regarding lesion quantification as well as agreement and correlation between reduced and full acquisition time standard uptake values (assessed by Pearson correlation coefficient, intraclass correlation coefficient, Bland–Altman analyses, and Krippendorff’s alpha). Results An acquisition time of 60 s per bed position yielded acceptable detectability and quantification results for clinically relevant phantom lesions ≥ 9.7 mm in diameter using OSEM-TOF or OSEM-TOF+PSF image reconstruction, a 4-mm Gaussian filter, and a 1.65 × 1.65 x 2.00-mm3 or 3.30 × 3.30 x 3.00-mm3 voxel size. Correlation and agreement of patient lesion quantification between full and reduced acquisition times were excellent. Conclusion A threefold reduction in acquisition time is possible. Patients might benefit from more comfortable examinations or reduced radiation exposure, if instead of the acquisition time the applied activity is reduced.

Abstract Background The free-breathing T1-weighted 3D Stack of Stars GRE (StarVIBE) MR sequence potentially reduces artifacts in chest MRI. The purpose of this study was to evaluate StarVIBE for the detection of pulmonary nodules in 18F-FDG PET/MRI. Material and methods In this retrospective analysis, conducted on a prospective clinical trial cohort, 88 consecutive women with newly diagnosed breast cancer underwent both contrast-enhanced whole-body 18F-FDG PET/MRI and computed tomography (CT). Patients’ chests were examined on CT as well as on StarVIBE and conventional T1-weighted VIBE and T2-weighted HASTE MR sequences, with CT serving as the reference standard. Presence, size, and location of all detectable lung nodules were assessed. Wilcoxon test was applied to compare nodule features and Pearson’s, and Spearman’s correlation coefficients were calculated. Results Out of 65 lung nodules detected in 36 patients with CT (3.7 ± 1.4 mm), StarVIBE was able to detect 31 (47.7%), VIBE 26 (40%) and HASTE 11 (16.8%), respectively. Overall, CT showed a significantly higher detectability than all MRI sequences combined (65 vs. 36, difference 44.6%, p

Abstract Aims In contrast to all prior AJCC/TNM classifications for differentiated thyroid cancer (DTC) the 8th edition does not take minimal extrathyroidal extension (M-ETE) into consideration for local tumor staging. We therefore aimed to retrospectively assess the specific impact of M-ETE on the outcome of M-ETE patients treated in our clinic. Methods DTC patients with M-ETE and a follow-up time of ≥ 5 years were included and matched with an identical number of patients without M-ETE, but with equal histopathological tumor subtype and size. The frequency of initially metastatic disease among groups was compared using Fisher’s exact test, the recurrence rate by virtue of log-rank test. Fisher’s exact test and multivariate analysis were used to account for the presence of confounding risk factors. Results One hundred sixty patients (80 matching pairs) were eligible. With other confounding risk factors being equal, the prevalence of N1-/M1-disease at initial diagnosis was comparable among groups (M-ETE: 42.5 %; no M-ETE: 32.5 %; p = 0.25). No differences with regard to the recurrence rate were shown. However, M-ETE patients were treated with external beam radiation therapy more often (16.3 % vs. 1.3 %; p = 0.004) and received higher median cumulative activities of 131I (10.0 vs. 8.0 GBq; p

Abstract Background Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare entity occurring in less than 4% of all lung cancers. Due to its low differentiation and high glucose transporter 1 (GLUT1) expression, LCNEC demonstrates an increased glucose turnover. Thus, PET/CT with 2-[18F]-fluoro-deoxyglucose ([18F]FDG) is suitable for LCNEC staging. Surgery with curative intent is the treatment of choice in early stage LCNEC. Prerequisite for this is correct lymph node staging. This study aimed at evaluating the diagnostic performance of [18F]FDG PET/CT validated by histopathology following surgical resection or mediastinoscopy. N-staging interrater-reliability was assessed to test for robustness of the [18F]FDG PET/CT findings. Methods Between 03/2014 and 12/2020, 46 patients with LCNEC were included in this single center retrospective analysis. All underwent [18F]FDG PET/CT for pre-operative staging and subsequently either surgery (n = 38) or mediastinoscopy (n = 8). Regarding the lymph node involvement, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for [18F]FDG PET/CT using the final histopathological N-staging (pN0 to pN3) as reference. Results Per patient 14 ± 7 (range 4–32) lymph nodes were resected and histologically processed. 31/46 patients had no LCNEC spread into the lymph nodes. In 8/46 patients, the final stage was pN1, in 5/46 pN2 and in 2/46 pN3. [18F]FDG PET/CT diagnosed lymph node metastasis of LCNEC with a sensitivity of 93%, a specificity of 87%, an accuracy of 89%, a PPV of 78% and a NPV of 96%. In the four false positive cases, the [18F]FDG uptake of the lymph nodes was 33 to 67% less in comparison with that of the respective LCNEC primary. Interrater-reliability was high with a strong level of agreement (κ = 0.82). Conclusions In LCNEC N-staging with [18F]FDG PET/CT demonstrates both high sensitivity and specificity, an excellent NPV but a slightly reduced PPV. Accordingly, preoperative invasive mediastinal staging may be omitted in cases with cN0 disease by [18F]FDG PET/CT. In [18F]FDG PET/CT cN1-cN3 stages histological confirmation is warranted, particularly in case of only moderate [18F]FDG uptake as compared to the LCNEC primary.

Corentin Warnier, Thibault Gendron, Muhammad Otabashi, Charles Vriamont and Alex Jackson were not included as authors in the original publication [...]

Abstract Background Definitive radiation therapy (dRT) is an effective initial treatment of intermediate-risk (IR) and high-risk (HR) prostate cancer (PCa). PSMA PET/CT is superior to standard of care imaging (CT, MRI, bone scan) for detecting regional and distant metastatic PCa. PSMA PET/CT thus has the potential to guide patient selection and the planning for dRT and improve patient outcomes. Methods This is a multicenter randomized phase 3 trial (NCT04457245). We will randomize 312 patients to proceed with standard dRT (control Arm, n = 150), or undergo a PSMA PET/CT scan at the study site (both 18F-DCFPyL and 68Ga-PSMA-11 can be used) prior to dRT planning (intervention arm, n = 162). dRT will be performed at the treating radiation oncologist facility. In the control arm, dRT will be performed as routinely planned. In the intervention arm, the treating radiation oncologist can incorporate PSMA PET/CT findings into the RT planning. Androgen deprivation therapy (ADT) is administered per discretion of the treating radiation oncologist and may be modified as a result of the PSMA PET/CT results. We assume that approximately 8% of subjects randomized to the PSMA PET arm will be found to have M1 disease and thus will be more appropriate candidates for long-term systemic or multimodal therapy, rather than curative intent dRT. PET M1 patients will thus not be included in the primary endpoint analysis. The primary endpoint is the success rate of patients with unfavorable IR and HR PCa after standard dRT versus PSMA PET-based dRT. Secondary Endpoints (whole cohort) include progression free survival (PFS), metastasis-free survival after initiation of RT, overall survival (OS), % of change in initial treatment intent and Safety. Discussion This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET/CT molecular imaging can improve outcomes in patients with PCa who receive dRT. In this trial the incorporation of PSMA PET/CT may improve the success rate of curative intent radiotherapy in two ways: to optimize patient selection as a biomarker and to personalizes the radiotherapy plan. Clinical trial registration UCLA IND#147591 ○ Submission: 02.27.2020 ○ Safe-to-proceed letter issued by FDA: 04.01.2020 UCLA IRB #20–000378 ClinicalTrials.gov Identifier NCT04457245 . Date of Registry: 07.07.2020. Essen EudraCT 2020–003526-23

The cardiac bioavailability of peptide drugs that inhibit harmful intracellular protein–protein interactions in cardiovascular diseases remains a challenging task in drug development. This study investigates whether a non-specific cell-targeted peptide drug is available in a timely manner at its intended biological destination, the heart, using a combined stepwise nuclear molecular imaging approach. An octapeptide (heart8P) was covalently coupled with the trans-activator of transcription (TAT) protein transduction domain residues 48–59 of human immunodeficiency virus-1 (TAT-heart8P) for efficient internalization into mammalian cells. The pharmacokinetics of TAT-heart8P were evaluated in dogs and rats. The cellular internalization of TAT-heart8P-Cy(5.5) was examined on cardiomyocytes. The real-time cardiac delivery of 68Ga-NODAGA-TAT-heart8P was tested in mice under physiological and pathological conditions. Pharmacokinetic studies of TAT-heart8P in dogs and rats revealed a fast blood clearance, high tissue distribution, and high extraction by the liver. TAT-heart-8P-Cy(5.5) was rapidly internalized in mouse and human cardiomyocytes. Correspondingly, organ uptake of hydrophilic 68Ga-NODAGA-TAT-heart8P occurred rapidly after injection with an initial cardiac bioavailability already 10 min post-injection. The saturable cardiac uptake was revailed by the pre-injection of the unlabeled compound. The cardiac uptake of 68Ga-NODAGA-TAT-heart8P did not change in a model of cell membrane toxicity. This study provides a sequential stepwise workflow to evaluate the cardiac delivery of a hydrophilic, non-specific cell-targeting peptide. 68Ga-NODAGA-TAT-heart8P showed rapid accumulation in the target tissue early after injection. The implementation of PET/CT radionuclide-based imaging methodology as a means to assess effective and temporal cardiac uptake represents a useful and critical application in drug development and pharmacological research and can be extended to the evaluation of comparable drug candidates.

[18F]PARPi is currently undergoing clinical trials as a PET tracer for many applications. However, only manual radiosynthesis was reported; this has several drawbacks, including an increased risk of contamination from the operator, and the need to limit the starting activity. The automation of the previously reported protocol for [18F]PARPi synthesis is challenging, as it requires transferring microvolumes of reagents, which many platforms cannot accommodate. We report a revised, high yield, and automated protocol for the radiosynthesis of [18F]PARPi, with final doses of over 20 GBq.

Abstract Background Salvage radiotherapy (SRT) for prostate cancer (PCa) recurrence after prostatectomy offers long-term biochemical control in about 50–60% of patients. SRT is commonly initiated in patients with serum PSA levels

Abstract Background Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a promising yet not curative approach in castration-resistant (CR) prostate cancer (PC). Rational combination therapies may improve treatment efficacy. Here, we explored the effect of androgen receptor blockade (ARB) on PSMA expression visualized by PET and its potential additive effect when combined with 177Lu-PSMA RLT in a mouse model of prostate cancer. Methods Mice bearing human CRPC (C4-2 cells) xenografts were treated with 10 mg/kg enzalutamide (ENZ), with 50 mg/kg bicalutamide (BIC), or vehicle (control) for 21 days. PSMA expression was evaluated by 68Ga-PSMA11 PET/CT and quantified by flow cytometry of tumor fine needle aspirations before treatment and on days 23, 29, 34, and 39 post-therapy induction. For the RLT combination approach, mice bearing C4-2 tumors were treated with 10 mg/kg ENZ or vehicle for 21 days before receiving either 15 MBq (84 GBq/μmol) 177Lu-PSMA617 or vehicle. DNA damage was assessed as phospho-γH2A.X foci in tumor biopsies. Reduction of tumor volume on CT and survival were used as study endpoints. Results Tumor growth was delayed by ARB while 68Ga-PSMA11 uptake increased up to 2.3-fold over time when compared to controls. ABR-induced upregulation of PSMA expression was confirmed by flow cytometry. Phospho-γH2A.X levels increased 1.8- and 3.4-fold at 48 h in response to single treatment ENZ or RLT and ENZ+RLT, respectively. Despite significantly greater DNA damage and persistent increase of PSMA expression at the time of RLT, no additional tumor growth retardation was observed in the ENZ+RLT group (vs. RLT only, p = 0.372 at day 81). Median survival did not improve significantly when ENZ was combined with RLT. Conclusion ARB-mediated increases in PSMA expression in PC xenografts were evident by 68Ga-PSMA11 PET imaging and flow cytometry. 177Lu-PSMA617 effectively decreased C4-2 tumor size. However, while pre-treatment with ARB increased DNA damage significantly, it did not result in synergistic effects when combined with RLT.

Prostate specific membrane antigen (PSMA) scanning is a sensitive method of prostate cancer detection. In a 71 y.o. man with a PSA of 49 (6%F), 4 negative MRI studies and 6 negative biopsies over an 8 year interval, a 68Ga-PSMA PET/CT scan showed a PSMA-avid spot in the prostate. Using image fusion technology, the lesion was target-biopsied and Gleason 3 + 4 = 7 (cancer core length of 12 mm) was identified. This case may herald a new application for PSMA scanning and prostate cancer imaging.

INTRODUCTION:Limbic encephalitis (LE) is an immune-related, sometimes paraneoplastic process of the central nervous system. Initial diagnosis and treatment are based on the clinical presentation as well as antibody profiles and MRI. This study investigated the diagnostic value of integrated 18F-FDG-PET/MRI in the diagnostic work-up of patients with LE for a cerebral and whole-body imaging concept. MATERIAL AND METHODS:Twenty patients with suspected LE were enrolled in this prospective study. All patients underwent a dedicated PET/MRI protocol of the brain as well as the whole-body. Two neuroradiologists, one body radiologist and one nuclear medicine physician performed blinded consensus readings of each corresponding MRI and PET/MRI dataset of the brain and whole-body. Diagnostic confidence was evaluated on a Likert scale. RESULTS:Based on integrated PET/MRI 19 / 20 patients were found to show morphologic and / or metabolic changes indicative of LE, whereas sole MRI enabled correct identification in 16 / 20 patients. Three patients with negative MRI showed metabolic changes of the limbic system or extra-limbic regions, shifting the diagnosis from (negative) MRI to positive for LE in PET/MRI. Whole-body staging revealed suspected lesions in 2/20 patients, identified by MRI and PET, one confirmed as malignant and one false positive. Diagnostic confidence for cerebral and whole-body imaging reached higher scores for PET/MRI (cerebral: 2.7 and whole body: 4.8) compared to MRI alone (cerebral: 2.4 and whole body: 4.5). CONCLUSION:LE diagnosis remains challenging for imaging as it shows only subtle imaging findings in most patients. Nevertheless, based on the simultaneous and combined analysis of morphologic and metabolic data, integrated PET/MRI may enable a dual platform for improved diagnostic confidence and overall detection of LE as well as whole-body imaging for exclusion of paraneoplastic LE.

The impact of inflammation on the outcome of many medical conditions such as cardiovascular diseases, neurological disorders, infections, cancer, and autoimmune diseases has been widely acknowledged. However, in contrast to neurological, oncologic, and cardiovascular disorders, imaging plays a minor role in research and management of inflammation. Imaging can provide insights into individual and temporospatial biology and grade of inflammation which can be of diagnostic, therapeutic, and prognostic value. There is therefore an urgent need to evaluate and understand current approaches and potential applications for imaging of inflammation. This review discusses radiotracers for positron emission tomography (PET) that have been used to image inflammation in cardiovascular diseases and other inflammatory conditions with a special emphasis on radiotracers that have already been successfully applied in clinical settings.