Purpose: Although the incidence of de novo neuroendocrine prostate cancer (NEPC) is rare, recent data suggests that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine (NE) hallmarks and androgen receptor (AR)-suppression in prostate cancer (PC). Previous clinical reports indicate that PCs with a phenotype similar to NE tumors can be more amenable to imaging by ¹⁸F-Fluorodeoxyglucose (FDG) rather than PSMA-targeting radioligands. In this study, we evaluated the association between NE gene signature and FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported FDG-avidity of PSMA-suppressed tumors. Methods: Data mining approaches, cell lines and patient-derived xenograft (PDX) models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes: HK1 to 3 and GCK) and PSMA (FOLH1 gene) following AR-inhibition and in correlation with NE hallmarks. Also, we characterize a NE-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no NE histopathology. We measured glucose uptake in a NE-induced in vitro model and a zebrafish model by non-radioactive imaging of glucose uptake using fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrates that a NE gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR-inhibitors, high expression of GCK and low expression of SLC2A12 correlated with NE histopathology and PSMA gene suppression. GLUT12-suppression and amplification of glucokinase was observed in NE-induced PC cell lines and PDX models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: NE gene signature in NEPC and NELPC associates with a distinct transcriptional profile of GLUTs and HKs. PSMA-suppression correlates with GLUT12-suppression and glucokinase-amplification. Alteration of FDG uptake-associated genes correlated positively with higher glucose uptake in AR and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient pre-clinical method for monitoring non-radioactive glucose uptake.

Due to their peculiar mechanism of action, the evaluation of radiological response to immune checkpoint inhibitors (ICI) presents many challenges in solid tumors. We aimed to compare the evaluation of first response to Nivolumab by means of CT-based criteria with respect to fluorodeoxyglucose positron emission tomography (FDG-PET) response criteria in non-small-cell lung cancer (NSCLC) patients. Methods: 72 patients with advanced NSCLC were recruited in a mono-institutional ancillary trial within the expanded access program (EAP; NCT02475382) for Nivolumab. Patients underwent CT scan and FDG-PET at baseline and after 4 cycles (first evaluation). In case of progressive disease (PD), an additional evaluation was performed after two further cycles in order to confirm progression. We evaluated the response to treatment with CT scan by means of response evaluation criteria in solid tumors (RECIST) 1.1 and Immuno-related Response Criteria (IrRC) and with FDG-PET by means of PERCIST and immunotherapy-modified-PERCIST (imPERCIST) criteria. The concordance between CT- and PET-based criteria and the capability of each method to predict overall survival (OS) were evaluated. Results: 48/72 patients were evaluable for first response assessment with both PET- and CT-based criteria. We observed low concordance between CT- and PET-based criteria (Kappa value of 0.346 and 0.355 and Kappa value of 0.128 and 0.198 between PERCIST and imPERCIST versus RECIST and irRC respectively). Looking at OS, IrRC were more reliable to distinguish responders from non-responders. However thanks to the prognostic value of partial metabolic response assessed by both PERCIST and Immuno-PERCIST, PET-based response maintained prognostic significant in patients classified as progressive disease on the basis of irRC. Conclusion: Even though the present study did not support the routine use of FDG-PET in the general population of NSCLC patients treated with ICI, it suggests the added prognostic value of the metabolic response assessment, potentially improving the therapeutic decision-making.

Purpose: To investigate differences between positron emission tomography/magnetic resonance imaging (PET/MRI) and PET/computed tomography (PET/CT) in lesion detection and classification in oncological whole-body examinations and to investigate radiation exposure differences between both modalities. Material and Methods: In this prospective, single-center, observational study 1003 oncological examinations (918 patients, mean age 57.8±14.4y) were included. Patients underwent PET/CT and subsequent PET/MRI (149.8±49.7min after tracer administration). Examinations were reviewed by radiologists and nuclear medicine physicians in consensus. Additional findings, characterization of indetermiante findings in PETCT, missed findings in PET/MRI including their clinical relevance and effective dose of both modalities were investigated. McNemar’s test was used to compare lesion detection between both hybrid imaging modalities (p<0.001 indicating statistical significance). Results: Additional information in PET/MRI was reported in 26.3% (264/1003) of examinations compared to PET/CT (p<0.001). Of these, additional malignant findings were detected in 5.3% (53/1003), leading to a change in TNM-staging in 2.9% (29/1003) due to PET/MRI. Definite lesion classification of indeterminate PET/CT findings was possible in 11.1% (111/1003) with PET/MRI. In 2.9% (29/1003), lesions detected in PET/CT were not visible in PET/MRI. Malignant lesions were missed in 1.2% (12/1003) by PET/MRI leading to a change in TNM-staging in 0.5% (5/1003). The estimated mean effective-dose for whole-body PET/CT amounted to 17.6±8.7mSv in comparison to 3.6±1.4mSv in PET/MRI, resulting in a potential dose reduction of 79.6% (p<0.001). Conclusion: PET/MRI improves lesion detection and potentially reduces additional examinations in tumor staging. Especially younger patients may benefit from the clinically relevant dose reduction of PET/MRI compared to PET/CT.

Acute myocardial infarction (MI) triggers a local and systemic inflammatory response. We recently showed microglia involvement using TSPO imaging. Here, we evaluate whether ¹¹C-methionine provides further insights into heart-brain inflammation networking. Methods: Male Bl6N mice underwent permanent coronary artery ligation followed by ¹¹C-methionine PET at 3 and 7 days (n = 3). In subgroups, leukocyte homing was blocked by integrin antibodies (n = 5). The cellular substrate for PET signal was identified using brain section immunostaining. Results: ¹¹C-methionine uptake peaked in the MI region at d3 (5.9±0.9vs 2.4±0.5 %ID/cc), decreasing to control level by d7 (4.3±0.6 %ID/cc). Brain uptake was proportional to cardiac uptake (r=0.47,p<0.05), peaking also at d3 (2.9±0.4vs 2.4±0.3 %ID/cc) and returning to baseline at d7 (2.3±0.4 %ID/cc). Integrin blockade reduced uptake at every time point. Immunostaining at d3 revealed co-localization of the L-type amino acid transporter with GFAP-positive astrocytes but not CD68-positive microglia. Conclusion: PET imaging with ¹¹C-methionine specifically identifies an astrocyte component, enabling further dissection of the heart-brain axis in post MI inflammation.

We performed post-hoc analyses on the utility of pre-therapeutic and early interim ⁶⁸Ga-DOTA-Tyr3-octreotide (⁶⁸Ga-DOTATOC) positron emission tomography (PET) tumor uptake and volumetric parameters and a recently proposed biomarker, the inflammation-based index (IBI), for peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumor (NET) patients treated with ⁹⁰Y-DOTATOC in the setting of a prospective phase II trial. Methods: Forty-three NET patients received up to four cycles of 1.85 GBq/m²/cycle ⁹⁰Y-DOTATOC with a maximal kidney biologic effective dose of 37 Gy. All patients underwent a ⁶⁸Ga-DOTATOC PET/computed tomography (CT) at baseline and seven weeks after the first PRRT cycle. ⁶⁸Ga-DOTATOC-avid tumor lesions were semi-automatically delineated using a customized standardized uptake value (SUV) threshold-based approach. PRRT response was assessed on CT using RECIST 1.1. Results: Median progression-free survival (PFS) and overall survival (OS) were 13.9 and 22.3 months, respectively. An SUVmean higher than 13.7 (75th percentile (P75)) was associated with better survival (hazard ratio (HR) 0.45; P = 0.024), whereas a ⁶⁸Ga-DOTATOC-avid tumor volume higher than 578 ml (P75) was associated with worse OS (HR 2.18; P = 0.037). Elevated baseline IBI was associated with worse OS (HR 3.90; P = 0.001). Multivariate analysis corroborated independent associations between OS and SUVmean (P = 0.016) and IBI (P = 0.015). No significant correlations with PFS were found. A composite score based on SUVmean and IBI allowed to further stratify patients in three categories with significantly different survival. On early interim PET, a decrease in SUVmean of more than 17% (P75) was associated with worse survival (HR 2.29; P = 0.024). Conclusion: Normal baseline IBI and high ⁶⁸Ga-DOTATOC tumor uptake predict better outcome in NET patients treated with ⁹⁰Y-DOTATOC. This can be used for treatment personalization. Interim ⁶⁸Ga-DOTATOC PET does not provide information for treatment personalization.

P-glycoprotein (ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting the clearance of neurotoxic beta-amyloid (Aß) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease (AD) patients. Treatment with drugs which induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aß deposits in the brain by enhancing the clearance of Aß peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer ¹¹C-metoclopramide can measure ABCB1 induction at the BBB in a beta-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 days underwent ¹¹C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor (PXR) activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 days. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aß levels. In separate groups of mice, radiolabeled metabolites of ¹¹C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain (kE,brain) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in kE,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aß levels. There was a significant positive correlation between kE,brain values and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in kE,brain values was found. Metabolite analysis showed that the majority of radioactivity in the brain was composed of unmetabolized ¹¹C-metoclopramide in all animal groups. Conclusion: ¹¹C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in AD patients to non-invasively evaluate strategies to enhance the clearance properties of the BBB.

Cri-Du-Chat Syndrome (CdCs) is a rare genetic disease caused by a deletion in the short arm of chromosome 5 (5p) with a variable clinical spectrum. To date no study in literature has ever investigated the alterations of brain glucose metabolism in these subjects by means of [¹⁸F]fluoro-2-deoxy-d-glucose Positron Emission Tomography/Computed Tomography (¹⁸F-FDG PET/CT). The aims of this study were to detect difference in brain FDG metabolism in patients affected by CdCs with different clinical presentations and identify possible "brain metabolic phenotypes" of this syndrome. Methods: 6 patients (age: 5 M and 1 F, age range: 10-27) with CdCs were assessed for presence of cognitive and behavioral symptoms with a battery of neuropsychological tests and then classified as patient with a severe or mild phenotype. Then, patients underwent a brain ¹⁸F-FDG PET/CT scan. PET/CT findings were compared to a control group, matched for age and sex, by using statistical parametric mapping (SPM). Association of different clinical phenotypes and ¹⁸F-FDG PET/CT findings was investigated. Results: Four patients presented a severe phenotype, whereas 2 patients demonstrated mild phenotype. SPM single subject and group analysis compared to the control cohort revealed a significant hypometabolism in the left temporal lobe (BAs 20, 36 and 38), in the right frontal subcallosal gyrus (BA 34) and caudate body, and in the cerebellar tonsils (p<0.001). Hypermetabolism (P = 0.001) was revealed in the right superior and precentral frontal gyrus (BA 6) in patient group compared to the control cohort. In SPM single subject analysis the hypermetabolic areas were detected only in patients with a severe phenotype. Conclusion: This study revealed different patterns of brain glucose metabolism in patients with severe and mild phenotype compared to control subjects. In particular, the hypermetabolic abnormalities in the brain, evaluated by¹⁸F-FDG PET/CT, seem to correlate with the severe phenotype in patients with CdCs.

Due to improvements in quantitative SPECT/CT, voxel-based dosimetry for radionuclide therapies has aroused growing interest as it promises the visualization of absorbed doses at a voxel level. In this work, SPECT/CT-based voxel-based dosimetry of a 3D printed 2-compartment kidney phantom was performed, and the resulting absorbed dose distributions were examined. Additionally, the potential of the PETPVC partial-volume correction tool was investigated. Methods: Both kidney compartments (70% cortex, 30% medulla) were filled with different activity concentrations and SPECT/CT imaging was performed. The images were reconstructed using varying reconstruction settings (iterations, subsets, and post-filtering). Based on these activity concentration maps, absorbed dose distributions were calculated with pre-calculated ¹⁷⁷Lu voxel S values and an empirical kidney half-life. An additional set of absorbed doses was calculated after applying PETPVC for partial-volume correction of the SPECT reconstructions. Results: SPECT/CT imaging blurs the two discrete sub-organ absorbed dose values into a continuous distribution. While this effect is slightly improved by applying more iterations, it is enhanced by additional post-filtering. By applying PETPVC, the absorbed dose values are separated into 2 peaks. Although this leads to a better agreement between SPECT/CT-based and nominal values, considerable discrepancies remain. In contrast to the calculated nominal absorbed doses of 7.8/1.6 Gy (cortex/medulla), SPECT/CT-based voxel-level dosimetry resulted in mean absorbed doses ranging from 3.0-6.6 Gy (cortex) and 2.7-5.1 Gy (medulla). PETPVC led to improved ranges of 6.1-8.9 Gy (cortex) and 2.1-5.4 Gy (medulla). Conclusion: Our study shows that ¹⁷⁷Lu quantitative SPECT/CT imaging leads to voxel-based dose distributions largely differing from the real organ distribution. SPECT/CT imaging and reconstruction deficiencies might directly translate into unrealistic absorbed dose distributions, thus questioning the reliability of SPECT-based voxel-level dosimetry. Therefore, SPECT/CT reconstructions should be adapted to ensure an accurate quantification of the underlying activity and, therefore, absorbed dose in a volume-of-interest of the expected object size (e.g. organs, organ sub-structures, lesions or voxels). As an example, PETPVC largely improves the match between SPECT/CT-based and nominal dose distributions. In conclusion, the concept of voxel-based dosimetry should be treated with caution. Specifically, it should be kept in mind that the absorbed dose distribution is mainly a convolved version of the underlying SPECT reconstruction.

⁶⁸Ga-DOTATOC-PET/MRI (⁶⁸Gallium-DOTATOC-positron emission tomography/magnetic resonance imaging) combines the advantages of PET in the acquisition of metabolic-functional information with the high soft tissue contrast of MRI. Standardized uptake values (SUV) in tumors were suggested as a measure of somatostatin receptor expression. A challenge with receptor ligands is, that the distribution volume is confined to tissues with tracer-uptake, potentially limiting SUV quantification. In this study, different functional, three-dimensional (3D) SUV, apparent diffusion coefficient (ADC) parameters and arterial tumor enhancement were tested for the characterization of gastroendopancreatic neuroendocrine tumors (GEP-NET). Methods: For this single-center, cross-sectional study, 22 patients with 24 histologically confirmed GEP-NET lesions (15 men/7 women; median, 61 years, range, 43-81 years), who received hybrid ⁶⁸Ga-DOTA-PET/MRI examinations at 3T between January 2017 and July 2019 met eligibility criteria. SUVs, tumor-to-background ratios (TBR), the total functional tumor volume (TFTV), ADCmean and ADCmin were measured based on volumes of interest (VOI) and examined with receiver operating characteristic analysis to determine cut-off values for differentiation between low and intermediate grade GEP-NET. Spearman’s rank correlation coefficients were used to assess correlations between functional imaging parameters. Results: The ratio of PET-derived SUVmean and diffusion-weighted imaging (DWI)-derived ADCmin was introduced as a combined variable to predict tumor grade, outperforming single predictors. Based on a threshold ratio of 0.03 to be exceeded, tumors could be classified as grade 2 with a sensitivity of 86% and specificity of 100%. SUV and functional ADC values as well as arterial contrast enhancement parameters showed non-significant and mostly negligible correlations. Conclusion: As receptor density and tumor cellularity appear to be independent, potentially complementary phenomena, the combined PET/MRI ratio SUVmean/ADCmin may be used as a novel biomarker, allowing to differentiate between grade 1 and 2 GEP-NET.

Introduction: A new pattern of response, so-called hyper-progressive disease (HPD), is emerging during treatment with immune checkpoint inhibitors (ICI). Our aim was to investigate the prevalence of such phenomenon and to assess its association with clinical variables and metabolic parameters by ¹⁸F-fludeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT). Methods: Data from 50 patients (34 male, 16 female, median age 73) with non-small cell lung carcinoma (NSCLC) and treated with ICI were prospectively collected. All patients underwent contrast-enhanced CT, ¹⁸F-FDG PET/CT, and complete peripheral blood sample at baseline before ICI. HPD was defined according to clinical and radiologic criteria. Because of the rapid disease progression or worsening of clinic conditions, radiologic response assessment was available for 46 patients. OS were analyzed using the Kaplan–Meier method and the log-rank test. A Cox proportional hazards regression analysis was used to evaluate factors independently associated with OS. Median follow-up was 12.4 months (9.7-15.2 months). Results: We identified the following response categories: 10 cases as complete/partial response (CR/PR), 17 cases with stable disease (SD), 5 patients with progressive disease (PD), and 14 with HPD. Among metabolic parameters we observed a statistically significant association between HPD status and tumor burden, expressed by both MTV (756.1ml for HPD vs 475.6ml for non-HPD, P = 0.011) and TLG (287.3 for HPD vs 62.1 for non-HPD, P = 0.042). Among clinical variables, 12/14 patients (85.7%) within the HPD group compared with 8/32 patients (25%) in the non-HDP group had more than two metastatic sites (p<0.001). In addition, the derived neutrophil-to-lymphocyte ratio (dNLR) and platelet counts was significantly associated with HPD status (P = 0.038, P = 0.025, respectively). Survival analysis showed a median OS of 4 months for HPD group compared with 15 months within non-HPD patients (P = 0.003). Likewise, median OS was significantly different when we considered all the response categories: CR/PR, SD, PD, and HPD (P = 0.001). Finally, Multivariate analysis identified MTV and dNLR as independent predictors for OS. Conclusion: Our results suggest that the use of ICI might represent a concern in patients with high metabolic tumor burden and inflammatory indexes at baseline. However Additional studies are needed.

Objectives: Radioactive iodine (¹³¹I) therapy may be used to treat thyroid cancer in end-stage renal disease patients who undergo hemodialysis. Because iodine predominantly utilizes renal clearance, treatment management in hemodialysis patients may be problematic, and no formal recommendations on hemodialysis currently exist. This work details our experience with treating thyroid cancer with iodine in chronic renal failure patients who require hemodialysis and details the therapeutic dosimetry results obtained during treatment to ensure that the dose to the bone marrow (BM) was acceptable. Methods: We treated 6 patients in the metabolic radiotherapy unit after thyroid stimulation. Two hemodialysis sessions in the metabolic radiotherapy unit were performed at 42 and 90 hours after radiopharmaceutical administration. BM toxicity was estimated with activity measurements from blood samples and with whole-body measurements that were regularly repeated during hospitalization and measured with a gamma counter. The patients underwent thyroid and hematologic monitoring to assess treatment efficacy and therapeutic toxicity in the short, medium and long term. Results: Whole-body activity was reduced on average by 66.7% [60.1-71.5] after the first dialysis session and by 53.3% [30.4-67.8] after the second. The mean estimated total absorbed dose to the BM was 0.992 Gy for all patients [0.431 – 2.323]. We did not observe any significant hematologic toxicity, and the clinical, biological and ultrasound test results confirmed the success of ablative treatment for the majority of patients. Conclusion: An approximately 30% reduction from the nominal dose in the amount of ¹³¹I activity for hemodialysis patients with thyroid cancer appears to strike an appropriate balance between the absence of BM toxicity and therapeutic efficacy. To avoid overirradiation, we recommend pretherapeutic dosimetry studies for metastatic patients to calculate the amount of activity to be administered as well as dosimetry monitoring during the hemodialysis sessions performed after therapeutic dose administration and under the same conditions.

Rationale: The treatment of choice for insulinomas and focal lesions in congenital hyperinsulinism (CHI) is surgery. However, intra-operative detection can be challenging. This could be overcome with intra-operative fluorescence imaging, which provides real-time lesion detection with a high spatial resolution. Here, a novel method for targeted near-infrared (NIR) fluorescence imaging of glucagon-like peptide 1 receptor (GLP-1R) positive lesions, using the GLP-1 agonist exendin-4, labeled with IRDye800CW, was examined in vitro and in vivo. Methods: A competitive binding assay was performed using Chinese hamster lung (CHL) cells transfected with the GLP-1R. Tracer biodistribution was determined in BALB/c nude mice bearing subcutaneous CHL-GLP-1R xenografts. In vivo NIR fluorescence imaging of CHL-GLP-1R xenografts was performed. Localization of the tracer in the pancreatic islets of BALB/c nude mice was examined using fluorescence microscopy. Laparoscopic imaging was performed to detect the fluorescent signal of the tracer in the pancreas of mini pigs. Results: Exendin-4-IRDye800CW binds the GLP-1R with an IC50 value of 3.96 nM. The tracer accumulates in CHL-GLP-1R xenografts. Subcutaneous CHL-GLP-1R xenografts were visualized using in vivo NIR fluorescence imaging. The tracer accumulates specifically in the pancreatic islets of mice and a clear fluorescent signal was detected in the pancreas of mini pigs. Conclusion: These date provide the first in vivo evidence of the feasibility of targeted fluorescence imaging of GLP-1R positive lesions. Intra-operative lesion delineation using exendin-4-IRDye800CW could benefit open as well as laparoscopic surgical procedures for removal of insulinomas and focal lesions in CHI.

[S-Methyl-¹¹C](±)-7-methoxy-3-(4-(4-(methylthio)phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol (¹¹C-NR2B-SMe) and its enantiomers were synthesized as candidates for imaging the NR2B subunit within the N-methyl-D-aspartate receptor with positron emission tomography (PET). Methods: Brains were scanned with PET for 90 min after intravenous injection of one of the candidate radioligands into rats. To detect any NR2B specific binding of radioligand in brain, various pre-blocking or displacing agents were evaluated for their impact on the PET brain imaging data. Radiometabolites from brain and other tissues were measured ex vivo and in vitro. Results: Each radioligand gave high early whole brain uptake of radioactivity, followed by a brief fast decline and then a slow final decline. ¹¹C-(S)-NR2B-SMe was studied extensively. Ex vivo measurements showed that radioactivity in rat brain at 30 min after radioligand injection was virtually unchanged radioligand. Only less lipophilic radiometabolites appeared in plasma. High-affinity NR2B ligands, Ro-25-6981, ifenprodil, and CO10124, showed increasing preblock of whole brain radioactivity retention with increasing dose (0.01 to 1.25 mg/kg, i.v.). Five 1 antagonists (FTC146, BD1407, F3, F4, and NE100) and four 1 agonists ((+)-pentazocine, (±)-PPCC, PRE-084, (+)-SKF10047) were ineffective preblocking agents, except FTC146 and F4 at high dose. Two potent 1 receptor agonists, TC1 and SA4503, showed dose-dependent preblocking effects in the presence or absence of pharmacological 1 receptor blockade with FTC146. Conclusion: ¹¹C-(S)-NR2B-SMe has adequate NR2B-specific PET signal in rat brain to warrant further evaluation in higher species. TC1 and SA4503 likely have off-target binding to NR2B in vivo.

Methods that provide rapid access to radiolabeled antibodies are vital in the development of diagnostic and radiotherapeutic agents for positron emission tomography (PET) or radioimmunotherapy. The human hepatocyte growth factor receptor (c-MET) signaling pathway is dysregulated in a number of malignancies including gastric cancer, and is an important biomarker in drug discovery. Here, we used a photoradiochemical approach to produce ⁸⁹Zr-radiolabeled onartuzumab (a monovalent, anti-human c-MET antibody), starting directly from the fully formulated drug (MetMAb). Methods: Simultaneous ⁸⁹Zr-radiolabeling and protein conjugation was performed in one-pot reactions containing ⁸⁹Zr-oxalate, the photoactive chelate DFO-aryl azide (DFO-ArN3) and MetMAb to give ⁸⁹ZrDFO-azepin-onartuzumab. As a control, ⁸⁹ZrDFO-Bn-NCS-onartuzumab was prepared via a conventional two-step process using pre-purified onartuzumab and DFO-Bn-NCS. Radiotracers were purified by using size-exclusion methods and evaluated by radiochromatography. Radiochemical stability was studied in human serum and immunoreactivity was determined by cellular binding assays using MKN-45 gastric carcinoma cells. PET imaging at multiple time points (0–72 h) was performed in female athymic nude mice bearing subcutaneous MKN-45 xenografts. Biodistribution experiments were performed after the final image. Tumor specificity of ⁸⁹ZrDFO-azepin-onartuzumab was assessed by competitive inhibition (blocking) studies. Results: Initial photoradiosynthesis experiments produced ⁸⁹ZrDFO-azepin-onartuzumab in <15 min. with an isolated decay-corrected radiochemical yield (RCY) of 24.8%, a radiochemical purity (RCP) ~90% and a molar activity (Am) of ~1.5 MBq nmol^-1. Reaction optimization improved the radiochemical conversion (RCC) of ⁸⁹ZrDFO-azepin-onartuzumab to 56.9±4.1% (n = 3), with isolated RCYs of 41.2±10.6% (n = 3), and RCPs >90%. Conventional methods produced ⁸⁹ZrDFO-Bn-NCS-onartuzumab with isolated RCY >97%, RCP >97% and Am ~14.0 MBq nmol^-1. Both radiotracers were immunoreactive and stable in human serum. PET imaging and biodistribution studies showed high tumor uptake for both radiotracers. By 72 h, tumor and liver uptake reached 15.37±5.21 %ID g^-1, 6.56±4.03 %ID g^-1, respectively for ⁸⁹ZrDFO-azepin-onartuzumab (n = 4), and 21.38±11.57 %ID g^-1 and 18.84±6.03 %ID g^-1 for ⁸⁹ZrDFO-Bn-NCS-onartuzumab (n = 4). Blocking experiments gave a statistically significant reduction in tumor uptake (6.34±0.47 %ID g^-1) of ⁸⁹ZrDFO-azepin-onartuzumab (n = 4). Conclusion: Experiments demonstrate that photoradiosynthesis is a viable alternative approach for producing ⁸⁹Zr-radiolabeled antibodies direct in protein formulation buffer which reduces protein aggregation and liver uptake.

Immune checkpoint blockade represents a promising approach in oncology, showing anti-tumor activities in various cancers. However, although being generally far more well-tolerated than classical cytotoxic chemotherapy, this treatment, too, may be accompanied by considerable side effects and not all patients benefit equally. Therefore, careful patient selection and monitoring of the treatment response is mandatory. At present, checkpoint-specific molecular imaging is increasingly investigated as a tool for patient selection and response evaluation. Here, an overview of the current developments in immune checkpoint imaging is provided.

Purpose: To assess the performance of full dose (FD) positron emission tomography (PET) image synthesis in both image and projection space from low-dose (LD) PET images/sinograms without sacrificing diagnostic quality using deep learning techniques. Methods: Clinical brain PET/CT studies of 140 patients were retrospectively employed for LD to FD PET conversion. 5% of the events were randomly selected from the FD list-mode PET data to simulate a realistic LD acquisition. A modified 3D U-Net model was implemented to predict FD sinograms in the projection-space (PSS) and FD images in image-space (PIS) from their corresponding LD sinograms/images, respectively. The quality of the predicted PET images was assessed by two nuclear medicine specialists using a five-point grading scheme. Quantitative analysis using established metrics including the peak signal-to-noise ratio (PSNR), structural similarity index metric (SSIM), region-wise standardized uptake value (SUV) bias, as well as first-, second- and high-order texture radiomic features in 83 brain regions for the test and evaluation dataset was also performed. Results: All PSS images were scored 4 or higher (good to excellent) by the nuclear medicine specialists. PSNR and SSIM values of 0.96 ± 0.03, 0.97 ± 0.02 and 31.70 ± 0.75, 37.30 ± 0.71 were obtained for PIS and PSS, respectively. The average SUV bias calculated over all brain regions was 0.24 ± 0.96% and 1.05 ± 1.44% for PSS and PIS, respectively. The Bland-Altman plots reported the lowest SUV bias (0.02) and variance (95% CI: -0.92, +0.84) for PSS compared with the reference FD images. The relative error of the homogeneity radiomic feature belonging to the Grey Level Co-occurrence Matrix category was -1.07 ± 1.77 and 0.28 ± 1.4 for PIS and PSS, respectively Conclusion: The qualitative assessment and quantitative analysis demonstrated that the FD PET prediction in projection space led to superior performance, resulting in higher image quality and lower SUV bias and variance compared to FD PET prediction in the image domain.

Objective: To develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using ¹⁸F-DPA-714 translocator protein (TSPO) positron emission tomography (PET), and to explore the relationship between these maps and individual trajectories of disability worsening in patients with multiple sclerosis (MS). Methods: Patients with MS (n = 37), whose trajectories of disability worsening over the 2 years preceding study entry were calculated, and healthy controls (n = 19) underwent magnetic resonance magnetic and ¹⁸F-DPA-714 PET. A threshold of significant activation of ¹⁸F-DPA-714 binding was calculated with a voxel-wise randomized permutation-based comparison between patients and controls, and used to classify each WM voxel in patients as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were employed to calculate the extent of activation in WM regions-of-interests and to classify each WM lesion as "DPA-active", "DPA-inactive" or "unclassified". Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM, (NAWM in patients=24.9±9.7%; WM in controls=14.0±7.8%, p<0.001). In patients with MS, the percentage of DPA+ voxels showed a significant increase from NAWM, to perilesional areas, T2 hyperintense lesions and T1 hypointense lesions (38.1±13.5%, 45.0±17.9%, and 51.9±22.9%, respectively, p<0.001). Among the 1379 T2 lesions identified, 512 were defined as DPA-active and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (OR=1.13, P = 0.009), a higher percentage of DPA+ voxels in the NAWM (OR=1.16, P = 0.009) and in T1-spin-echo lesions (OR=1.06, P = 0.036), were significantly associated with a retrospective more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with an innate immune cells activation inside and around WM lesions. ¹⁸F-DPA-714 PET may provide a promising biomarker to identify patients at risk of severe clinical trajectory.

Acidosis is a key driver for many diseases, including cancer, sepsis, and stroke. The spatiotemporal dynamics of dysregulated pH across disease remains elusive and current diagnostic strategies do not provide localization of pH alterations. We sought to explore if PET imaging using hydrophobic cyclic peptides that partition into the cellular membrane at low extracellular pH (denoted as "pHLIC") can permit accurate in vivo visualization of acidosis. Methods: Acid-sensitive cyclic peptide c[E4W5C] pHLIC was conjugated to bifunctional maleimide-NO2A and radiolabeled with copper-64 (t1/2 = 12.7 h). C57BL/6J mice were administered LPS (15 mg/kg) or saline (vehicle) and serially imaged with [⁶⁴Cu]Cu-c[E4W5C] over 24 h. Ex vivo autoradiography was performed on resected brain slices and subsequently stained with cresyl violet to enable high-resolution spatial analysis of tracer accumulation. A non- pH-sensitive cell-penetrating control peptide (c[R4W5C]) was used to confirm specificity of [⁶⁴Cu]Cu-c[E4W5C]. CD11b (macrophage/microglia) and TMEM119 (microglia) immunostaining was performed to correlate extent of neuroinflammation with [⁶⁴Cu]Cu-c[E4W5C] PET signal. Results: [⁶⁴Cu]Cu-c[E4W5C] radiochemical yield and purity was >95% and >99% respectively, with molar activity >0.925 MBq/nmol. Significantly increased [⁶⁴Cu]Cu-c[E4W5C] uptake was observed in LPS-treated mice (vs. vehicle) within peripheral tissues including blood, lungs, liver, and small intestines (P < 0.001-0.05). Additionally, there was significantly increased [⁶⁴Cu]Cu-c[E4W5C] uptake in the brains of LPS-treated animals. Autoradiography confirmed increased uptake in the cerebellum, cortex, hippocampus, striatum, and hypothalamus of LPS-treated mice (vs. vehicle). Immunohistochemical (IHC) analysis revealed microglial/macrophage infiltrate, suggesting activation in brain regions containing increased tracer uptake. [⁶⁴Cu]Cu-c[R4W5C] demonstrated significantly reduced uptake in the brain and periphery of LPS mice compared to the acid-mediated [⁶⁴Cu]Cu-c[E4W5C] tracer. Conclusion: Here, we demonstrate that a pH-sensitive PET tracer specifically detects acidosis in regions associated with sepsis-driven pro-inflammatory responses. This study suggests that [⁶⁴Cu]Cu-pHLIC is a valuable tool to noninvasively assess acidosis associated with both central and peripheral innate immune activation.

Respiratory motion during the CT and PET parts of a PET/CT scan leads to imperfect alignment of anatomical features seen by the two modalities. In this work, we concentrate on the effects of motion during CT. We propose a novel approach for improving the alignment. Methods: Respiratory waveform data were gathered during the CT and PET parts of 28 PET/CT scans of cancer patients with 40 lesions up to 3 cm size in the lung or upper abdomen. PET list-mode data were reconstructed by three reconstruction methods: PET/static, PET/EX or end of expiration (OncoFreeze), and a novel PET/matched method that used both waveforms. The three methods were compared. The distance between tumor positions in PET and CT were characterized in visual interpretation by physicians as well as quantitatively. Tumor standardized uptake values (SUV_max and SUVpeak) were determined relative to SUV based on the static method. Image noise was evaluated in the liver and compared to PET/static. Results: In visual interpretation, the rate of good alignment was 13/21, 13/23 and 18/21 for PET/static, PET/EX and PET/matched methods, respectively, and the mean PET-CT distances were 3.5, 5.1 and 2.8 mm. In visual comparison with PET/EX, the rate of good alignment was increased in 1/10 and 7/10 cases for PET/static and PET/matched. SUV_max was on average 21% higher than PET/static when either PET/EX or PET/matched was used. SUVpeak was 12% higher. Image noise in the liver was 15% higher than static for the PET/EX method, and 40% higher for PET/matched; that is, noise was much lower than in gated PET. Conclusion: Acquiring respiratory waveforms both in PET (as in the current state of the art) and in CT (an unusual key step in this approach) has the potential to improve the alignment of PET and CT images. A proposed method for using this information was tested. Improved alignment was demonstrated.

Studies demonstrate that the investigational ⁶⁴Cu-DOTATATE radiopharmaceutical may provide diagnostic and logistical benefits over available imaging agents for patients with somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs). Accordingly, we aimed to prospectively determine the lowest dose of ⁶⁴Cu-DOTATATE that facilitates diagnostic quality scans and evaluated the diagnostic performance and safety in a phase III study of patients with SSTR-expressing NETs. Methods: A dose-ranging study was conducted in 12 patients divided into 3 dose groups (111 MBq [3.0 mCi], 148 MBq [4.0 mCi], and 185 MBq [5.0 mCi] ± 10%) to determine the lowest dose of ⁶⁴Cu-DOTATATE that produced diagnostic quality PET/CT images. Using the ⁶⁴Cu-DOTATATE dose identified in the dose-ranging study, 3 independent nuclear medicine physicians who were blinded to all clinical information read PET/CT scans from 21 healthy volunteers and 42 NET-positive patients to determine those with "Disease" and "No Disease," as well as "Localized" versus "Metastatic" status. Blinded-reader evaluations were compared to a patient-specific standard of truth (SOT), which was established by an independent oncologist who used all previously available pathology, clinical, and conventional imaging data. Diagnostic performance calculated for ⁶⁴Cu-DOTATATE included sensitivity, specificity, negative predictive value, positive predictive value, and accuracy. Inter- and intra-reader reliability, as well as ability to differentiate between localized and metastatic disease, was also determined. Adverse events (AEs) were recorded from ⁶⁴Cu-DOTATATE injection through 48 hours post-injection. Results: The dose-ranging study identified 148 MBq (4.0 mCi) as the optimal dose to obtain diagnostic quality PET/CT images. Following database lock, diagnostic performance from an initial majority read of the 3 independent readers showed a significant 90.9% sensitivity (P = 0.0042) and 96.6% specificity (P < 0.0001) for detecting NETs, which translated to a 100.0% sensitivity and 96.8% specificity after correcting for an initial SOT misread. Excellent inter- and intra-reader reliability, as well as ability to distinguish between localized and metastatic disease, was also noted. No AEs were related to ⁶⁴Cu-DOTATATE, and no serious AEs were observed. Conclusion: ⁶⁴Cu-DOTATATE PET/CT is a safe imaging technique that provides high-quality and accurate images at a dose of 148 MBq (4.0 mCi) for the detection of somatostatin-expressing NETs.

Galectins are carbohydrate-binding proteins overexpressed in bladder cancer (BCa) cells. Dendritic galactose moieties have a high affinity for galectin-expressing tumor cells. We radiolabeled a dendritic galactose carbohydrate with fluorine-18 – ¹⁸F-labeled galactodendritic unit 4 – and examined its potential in imaging urothelial malignancies. Methods: The ¹⁸F-labeled 1st generation galactodendritic unit 4 was obtained from its tosylate precursor. We conducted in vivo studies in galectin-expressing UMUC3 orthotopic BCa model to determine the ability of ¹⁸F-labeled galactodendritic unit 4 to image BCa. Results: Intravesical administration of ¹⁸F-labeled galactodendritic unit 4 allowed specific accumulation of the carbohydrate radiotracer in galectin-1 overexpressing UMUC3 orthotopic tumors when imaged with PET. The ¹⁸F-labeled galactodendritic unit 4 was not found to accumulate in non-tumor murine bladders. Conclusion: The ¹⁸F-labeled galactodendritic unit 4 and similar analogs may be clinically relevant and exploitable for PET imaging of galectin-1 overexpressing bladder tumors.

Rationale: The effects of tobacco smoking on the brain’s immune system are not well elucidated. While nicotine is immunosuppressive, other constituents in tobacco smoke have inflammatory effects. Positron Emission Tomography (PET) imaging of the 18-kDa translocator protein (TSPO) provide a biomarker for microglia, the brain’s primary immunocompetent cells. This work compared brain TSPO levels in 20 tobacco smokers (abstinent for at least 2 hours) and 20 nonsmokers using a fully quantitative modeling approach for the first time. Methods: [¹¹C]PBR28 PET scans were acquired with arterial blood sampling to estimate the metabolite-corrected input function. [¹¹C]PBR28 volumes of distribution (V_T) were estimated throughout the brain with multilinear analysis. Results: Statistical analyses revealed no evidence for significant differences in regional [¹¹C]PBR28 V_T between smokers and non-smokers (whole-brain Cohen’s d=0.09) despite adequate power to detect medium effect sizes. Conclusion: These findings inform previous PET studies reporting lower TSPO radiotracer concentrations in brain (measured as standardized uptake value, SUV) of tobacco smokers compared to nonsmokers by demonstrating the importance of accounting for radiotracer concentrations in plasma. These findings suggest that compared to nonsmokers, smokers have comparable TSPO levels in brain. Additional work with other biomarkers is needed to fully characterize effects of tobacco smoking on the brain’s immune system.

The purpose of this study was to investigate the feasibility and diagnostic efficacy of ⁶⁸Ga-PSMA positron emission tomography/computed tomography (PET/CT) combined with PET-ultrasound image-guided biopsy in the diagnosis of prostate cancer. Methods: A total of 31 patients with previously negative prostate biopsy, but persistent elevated serum prostate specific antigen (PSA), were imaged with a ⁶⁸Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT ligand prior to undergoing repeat prostate biopsy. Based on the proposed PROMISE criteria, PSMA PET/CT results were interpreted as negative (miPSMA-ES 0-1) or positive (miPSMA-ES 2-3). All patients underwent standard template systematic biopsy with up to four additional PSMA PET-ultrasound fusion image-guided biopsy cores. The sensitivity, specificity, positive and negative predictive values, and accuracy of PSMA PET/CT were determined. In addition, the correlation between miPSMA-ES and detection rate of prostate cancer was also analyzed. Univariate logistic regression models were established using PSMA PET/CT semi-quantitative analysis parameters to predict the outcome of repeat prostate biopsy. Results: The median age of patients was 65 years (range 53-81), and the median PSA level was 18.0 ng/ml (range 5.48-49.77 ng/ml). Prostate cancer was detected in 15/31 patients (48.4%) and 12/31 patients (38.7%) had clinically significant disease. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ⁶⁸Ga-PSMA PET/CT in the diagnosis of clinically significant prostate cancer were 100.0%, 68.4%, 66.7%, 100.0% and 80.6%, respectively. The detection rate of prostate cancer increased with the increase of miPSMA-ES score. The detection rate of clinically significant prostate cancer in miPSMA-ES 0-1, 2 and 3 groups were 0%, 54.5% and 85.7% respectively. Semi-quantitative analysis of ⁶⁸Ga-PSMA PET/CT images showed that predictive models based on maximum standardized uptake value (SUV_max), tumor-to-background normal prostate SUV (SUVT/BGp) and tumor-to-background normal liver SUV (SUVratio) could effectively predict clinically significant prostate cancer; area under the curves were 0.930, 0.877, and 0.956, respectively. Conclusion: This study preliminarily confirmed that ⁶⁸Ga-PSMA PET/CT imaging combined with PET-ultrasound fusion image-guided prostate biopsy can effectively detect clinically significant prostate cancer. Prebiopsy ⁶⁸Ga-PSMA PET/CT has predictive value for clinically significant cancer in the studied patient population.

Introduction: To use positron emission tomography coupled with computed tomography (¹⁸FDG-PET/CT) to identify a high-risk subgroup requiring therapeutic intensification among patients with locally advanced cervical cancer (LACC) and para-aortic lymph node (PALN) involvement. Methods: In this retrospective multicentric study, patients with LACC and PALN involvement concurrently treated with chemoradiotherapy and extended-field radiotherapy (EFR) between 2006 and 2016 were included. A senior nuclear medicine specialist in PET for gynaecologic oncology reviewed all ¹⁸FDG-PET/CT scans. Metabolic parameters including maximum standardised uptake value (SUV_max), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were determined for the primary tumour, pelvic lymph nodes and PALN. Associations between these parameters and overall survival (OS) were assessed with Cox's proportional hazards model. Results: Sixty-eight patients were enrolled in the study. Three-year OS was 55.5% (95% CI (40.8-68.0)). When adjusted for age, stage and histology, pelvic lymph node TLG, PALN TLG and PALN SUV_max were significantly associated with OS (p<0.005). Conclusion: FDG-PET/CT was able to identify predictors of survival in the homogeneous subgroup of patients with LACC and PALN involvement, thus allowing therapeutic intensification to be proposed.

Head motion degrades image quality and causes erroneous parameter estimates in tracer kinetic modeling in brain PET studies. Existing motion correction methods include frame-based image-registration (FIR) and correction using real-time hardware-based motion tracking (HMT) information. However, FIR cannot correct for motion within one predefined scan period while HMT is not readily available in the clinic since it typically requires attaching a tracking device to the patient. In this study, we propose a motion correction framework with a data-driven algorithm, i.e., using the PET raw data itself, to address these limitations. Methods: We propose a data-driven algorithm, Centroid of Distribution (COD), to detect head motion. In COD, the central coordinates of the line of response (LOR) of all events are averaged over 1-sec intervals to generate a COD trace. A point-to-point change in the COD trace in one direction that exceeded a user-defined threshold was defined as a time point of head motion, which was followed by manually adding additional motion time points. All the frames defined by such time points were reconstructed without attenuation correction and rigidly registered to a reference frame. The resulting transformation matrices were then used to perform the final motion compensated reconstruction. We applied the new COD framework to 23 human dynamic datasets, all containing large head motions, with ¹⁸F-FDG (N = 13) and ¹¹C-UCB-J (N = 10), and compared its performance with FIR and with HMT using the Vicra, which can be considered as the "gold standard". Results: The COD method yielded 1.0±3.2% (mean ± standard deviation across all subjects and 12 grey matter regions) SUV difference for ¹⁸F-FDG (3.7±5.4% for ¹¹C-UCB-J) compared to HMT while no motion correction (NMC) and FIR yielded -15.7±12.2% (-20.5±15.8%) and -4.7±6.9% (-6.2±11.0%), respectively. For ¹⁸F-FDG dynamic studies, COD yielded differences of 3.6±10.9% in Ki value as compared to HMT, while NMC and FIR yielded -18.0±39.2% and -2.6±19.8%, respectively. For ¹¹C-UCB-J, COD yielded 3.7±5.2% differences in VT compared to HMT, while NMC and FIR yielded -20.0±12.5% and -5.3±9.4%, respectively. Conclusion: The proposed COD-based data-driven motion correction method outperformed FIR and achieved comparable or even better performance as compared to the Vicra HMT method in both static and dynamic studies.

Respiratory gating is the standard to overcome respiration effects degrading image quality in positron emission tomography (PET). Data-driven gating (DDG) using signals derived from PET raw data are promising alternatives to gating approaches requiring additional hardware. However, continuous bed motion (CBM) scans require dedicated DDG approaches for axially-extended PET, compared to DDG for conventional step-and-shoot scans. In this study, a CBM-capable DDG algorithm was investigated in a clinical cohort, comparing it to hardware-based gating using gated and fully motion-corrected reconstructions. Methods: 56 patients with suspected malignancies in thorax or abdomen underwent whole-body ¹⁸F-FDG CBM-PET/CT imaging using DDG and hardware-based respiratory gating (pressure-sensitive belt gating, BG). Correlation analyses were performed on both gating signals. Besides static reconstructions, BG and DDG were used for optimally-gated PET (BG-OG, DDG-OG) and fully motion-corrected PET (elastic motion correction; BG-EMOCO, DDG-EMOCO). Metabolic volumes, SUV_max and SUVmean of lesions were compared amongst the reconstructions. Additionally, the quality of lesion delineation in different PET reconstructions was independently evaluated by three experts. Results: Global correlation coefficients between BG and DDG signals amounted to 0.48±0.11, peaking at 0.89±0.07 when scanning the kidney and liver region. In total, 196 lesions were analyzed. SUV measurements were significantly higher in BG-OG, DDG-OG, BG-EMOCO and DDG-EMOCO compared to static images (P<0.001; median SUV_max: static, 14.3±13.4; BG-EMOCO, 19.8±15.7; DDG-EMOCO, 20.5±15.6; BG-OG, 19.6±17.1; DDG-OG, 18.9±16.6). No significant differences between BG-OG and DDG-OG, and BG-EMOCO and DDG-EMOCO, respectively, were found. Visual lesion delineation was significantly better in BG-EMOCO and DDG-EMOCO than in static reconstructions (P<0.001); no significant difference was found comparing BG and DDG (EMOCO, OG, respectively). Conclusion: DDG-based motion-compensation of CBM-PET acquisitions outperforms static reconstructions, delivering qualities comparable to hardware-based approaches. The new algorithm may be a valuable alternative for CBM-PET systems.

For oncological management or radiotherapy planning, reliable staging tools are essential. Recent development of quinoline-based ligands targeting cancer-associated fibroblasts demonstrated promising preclinical and clinical results. The current study aimed to evaluate the role of fibroblast activation protein inhibitors (FAPI)-positron-emission tomography (PET)/computed tomography (CT) for primary malignancies located within the lower gastrointestinal tract (LGT) as a very first clinical analysis. Methods: ⁶⁸Ga-FAPI-PET/CT was performed in a cohort of 22 patients with LGT including 15 patients with metastatic disease, 1 patient with suspected local relapse and 6 treatment-naïve patients. ⁶⁸Ga-FAPI-04 and ⁶⁸Ga-FAPI-46 uptake was quantified by standardized uptake values (SUV)max and (SUV)mean. After comparison with standard imaging, changes in tumor stage/ localization and (radio)oncological management were recorded. Results: The highest uptake of FAPI tracer was observed in liver metastases and anal cancer with a SUV_max of 9.1 and 13.9, respectively. Due to a low background activity in normal tissue, there was a high tumor-to-background ratio of more than 3 in most lesions. In treatment-naïve patients, TNM was changed in 50% while for patients with metastases new findings occurred in 47%. In total, FAPI-imaging caused a high, medium and low change of (radio)oncological management in 19%, 33% and 29%, respectively. For almost every patient undergoing irradiation, target volume delineation was improved by ⁶⁸Ga-FAPI-PET/CT. Conclusion: The present study demonstrated that both primary and metastatic LGT were reliably detected by ⁶⁸Ga-FAPI-PET/CT leading to relevant changes in TNM status and (radio)oncological management. ⁶⁸Ga-FAPI-PET/CT seems to be a highly promising imaging agent for the diagnosis and management of LGT, potentially opening new applications for tumor (re-)staging.

Purpose: The main objective of this prospective study was to determine the impact of multi-phasic acquisition of ⁶⁸Ga-PSMA PET/CT in the detection of recurrent prostate cancer (PCa) in the early stage of biochemical recurrence (BR) with prostate-serum-antigen (PSA) level <1ng/ml. Also, ⁶⁸Ga-PSMA PET/CT positivity was correlated with clinical parameters for the assessment of predictive markers. Methods: A prospective monocentric study was conducted on 135 PCa patients with BR and PSA<1ng/ml. All patients have undergone initial prostatectomy with additional radiation therapy in 19.3% and androgen-deprivation therapy (ADT) in 7.4% of patients. Dynamic acquisition [1–8min. post-injection (p.i.)] from the prostate bed, standard whole-body (60min. p.i.) and limited bed positions of delayed studies (120-150min. p.i.), were performed. Studies were reviewed by two board-certified nuclear medicine specialists, independently. A combination of visual and semi-quantitative analyses and correlation with morphological (e.g. MRI) and/or clinical follow-up findings was used for the final interpretation of abnormal lesions as benign or malignant. ⁶⁸Ga-PSMA PET/CT positivity was also correlated with primary clinical findings. Results: Incorporating the information of all phases, 116 lesions were detected in 49.6% of patients (22 local recurrences, 63 lymph nodes, and 31 distant metastases). The detection rates were 31.8%, 44.9%, and 71.4% for PSA<0.2ng/ml, 0.2≤PSA<0.5, and 0.5≤PSA<1, respectively. Additional dynamic and/or delayed phases resulted in better determination of equivocal lesions and a higher diagnostic performance in 25.9% of patients. Stand-alone dynamic and delayed images led to better interpretation of equivocal findings in the prostate bed (31.4%) and other (lymph node/bone) lesions (20%), respectively. Conclusion: ⁶⁸Ga-PSMA PET/CT revealed promising results for the early detection of recurrent disease in patients with PSA level of 0.5-1.0ng/ml. However, it showed limited value in cases with PSA<0.5ng/ml. Multi-phasic ⁶⁸Ga-PSMA PET/CT led to better determination of equivocal findings. Although, dynamic images may provide helpful information in assessment of the prostate bed; however, delayed acquisitions seem to have higher impact in clarifying of the equivocal findings.

Recently introduced PET systems using silicon photomultipliers with digital readout (dPET) have an improved timing and spatial resolution, aiming at a better image quality, over conventional PET (cPET) systems. We prospectively evaluated the performance of a dPET system in patients with cancer, as compared to high-resolution (HR) cPET imaging. Methods: After a single FDG-injection, 66 patients underwent dPET (Vereos, Philips Healthcare) and cPET (Ingenuity TF, Philips Healthcare) imaging in a randomized order. We used HR-reconstructions (2x2x2 mm³ voxels) for both scanners and determined SUV_max, SUVmean, lesion-to-background ratio (LBR), metabolic tumor volume (MTV) and lesion diameter in up to 5 FDG-positive lesions per patient. Furthermore, we counted the number of visible and measurable lesions on each PET scan. Two nuclear medicine specialists blindly determined the Tumor Node Metastasis (TNM) score from both image sets in 30 patients referred for initial staging. For all 66 patients, these specialists separately and blindly evaluated image quality (4-point scale) and determined the scan preference. Results: We included 238 lesions that were visible and measurable on both PET scans. We found 37 additional lesions on dPET in 27 patients (41%), which were unmeasurable (n = 14) or invisible (n = 23) on cPET. SUVmean, SUV_max, LBR and MTV on cPET were 5.2±3.9 (mean±SD), 6.9±5.6, 5.0±3.6 and 2991±13251 mm³, respectively. On dPET SUVmean, SUV_max and LBR increased 24%, 23% and 27%, respectively (p<0.001) while MTV decreased 13% (p<0.001) compared to cPET. Visual analysis showed TNM upstaging with dPET in 13% of the patients (4/30). dPET images also scored higher in image quality (P = 0.003) and were visually preferred in the majority of cases (65%). Conclusion: Digital PET improved the detection of small lesions, upstaged the disease and images were visually preferred as compared to high-resolution conventional PET. More studies are necessary to confirm the superior diagnostic performance of digital PET.

The aim of this work was to quantify the uptake of [¹⁸F]BMS-986192, a PD-L1 adnectin PET tracer, in patients with non-small-cell lung cancer (NSCLC). To this end, plasma input kinetic modeling of dynamic tumor uptake data with online arterial blood sampling was performed. In addition, the accuracy of simplified uptake metrics such as standardized uptake value (SUV) was investigated. Methods: Data from a study with [¹⁸F]BMS-986192 in patients with advanced stage NSCLC eligible for nivolumab treatment were used if a dynamic scan was available and lesions were present in the field of view of the dynamic scan. After injection of [¹⁸F]BMS-986192, a 60-minutes dynamic PET-CT scan was started, followed by a 30-min whole body PET-CT scan. Continuous arterial and discrete arterial and venous blood sampling were performed to determine a plasma input function. Tumor time activity curves were fitted by several plasma input kinetic models. Simplified uptake parameters included tumor to blood ratio as well as several SUV measures. Results: Twenty two tumors in nine patients were analyzed. The arterial plasma input single-tissue reversible compartment model with fitted blood volume fraction seems to be the most preferred model as it best fitted 11 out of 18 tumor time activity curves. The distribution volume V_T ranged from 0.4 to 4.8 mL·cm-3. Similar values were obtained with an image derived input function. From the simplified measures, SUV normalized for body weight (SUV_BW) at 50 and 67 minutes post injection correlated best with V_T, with an R² > 0.9. Conclusion: A single tissue reversible model can be used for the quantification of tumor uptake of the PD-L1 PET tracer [¹⁸F]BMS-986192. SUV_BW at 60 minutes post injection, normalized for body weight, is an accurate simplified parameter for uptake assessment of baseline studies. In order to assess its predictive value for response evaluation during PD-(L)1 immune checkpoint inhibition further validation of SUV against V_T based on an image derived input function is recommended.

Depth-encoding detectors with single-ended readout provide a practical, cost-effective approach for constructing high resolution and high sensitivity PET scanners. However, the current iteration of such detectors utilizes a uniform glass light guide to achieve depth-encoding, resulting in non-uniform performance throughout the detector array due to suboptimal intercrystal light sharing. We introduce Prism-PET, a single-ended readout PET detector module with a segmented light guide composed of an array of prismatoids that introduces enhanced, deterministic light sharing. Methods: High resolution PET detector modules were fabricated with single-ended readout of polished multicrystal lutetium yttrium orthosilicate (LYSO) scintillator arrays directly coupled 4-to-1 and 9-to-1 to arrays of 3.2 x 3.2 mm² silicon photomultiplier pixels. Each scintillator array was coupled at the non-readout side to a light guide (one 4-to-1 module with a uniform glass light guide, one 4-to-1 Prism-PET module and one 9-to-1 Prism-PET module) to introduce intercrystal light sharing, which closely mimics the behavior of dual-ended readout with the additional benefit of improved crystal identification. Flood histogram data was acquired using a 3 MBq Na-22 source to characterize crystal identification and energy resolution. Lead collimation was used to acquire data at specific depths to determine depth-of-interaction (DOI) resolution. Results: The flood histogram measurements showed excellent and uniform crystal separation throughout the Prism-PET modules while the uniform glass light guide module had performance degradation at the edges and corners. A DOI resolution of 5.0 mm full width at half maximum (FWHM) and energy resolution of 13% were obtained in the uniform glass light guide module. By comparison, the 4-to-1 coupled Prism-PET module achieved 2.5 mm FWHM DOI resolution and 9% energy resolution. Conclusion: PET scanners based on our Prism-PET modules with segmented prismatoid light guide arrays can achieve high and uniform spatial resolution (9-to-1 coupling with ~ 1 mm crystals), high sensitivity, good energy and timing resolutions (using polished crystals and after applying DOI-correction), and compact size (depth-encoding eliminates parallax error and permits smaller ring-diameter).

Overexpression of somatostatin receptors in patients with neuroendocrine neoplasms (NEN) is utilized for both diagnosis and treatment. Receptor density may reflect tumor differentiation and thus be associated with prognosis. Non-invasive visualization and quantification of somatostatin receptor density is possible by somatostatin receptor imaging (SRI) using positron emission tomography (PET). Recently, we introduced ⁶⁴Cu-DOTATATE for SRI and we hypothesized that uptake of this tracer could be associated with overall (OS) and progression-free survival (PFS). Methods: We evaluated patients with NEN that had a ⁶⁴Cu-DOTATATE PET/CT SRI performed in two prospective studies. Tracer uptake was determined as the maximal standardized uptake value (SUV_max) for each patient. Kaplan-Meier analysis with log-rank was used to determine the predictive value of ⁶⁴Cu-DOTATATE SUV_max for OS and PFS. Specificity, sensitivity and accuracy was calculated for prediction of outcome at 24 months after ⁶⁴Cu-DOTATATE PET/CT. Results: A total of 128 patients with NEN were included and followed for a median of 73 (1-112) months. During follow-up, 112 experienced disease progression and 69 patients died. The optimal cutoff for ⁶⁴Cu-DOTATATE SUV_max was 43.3 for prediction of PFS with a hazard ratio of 0.56 (95% CI: 0.38-0.84) for patients with SUV_max > 43.3. However, no significant cutoff was found for prediction of OS. In multiple Cox regression adjusted for age, sex, primary tumor site and tumor grade, the SUV_max cutoff hazard ratio was 0.50 (0.32-0.77) for PFS. The accuracy was moderate for predicting PFS (57%) at 24 months after ⁶⁴Cu-DOTATATE PET/CT. Conclusion: In this first study to report the association of ⁶⁴Cu-DOTATATE PET/CT and outcome in patients with NEN, tumor somatostatin receptor density visualized with ⁶⁴Cu-DOTATATE PET/CT was prognostic for PFS but not OS. However, the accuracy of prediction of PFS at 24 months after ⁶⁴Cu-DOTATATE PET/CT SRI was moderate limiting the value on an individual patient basis.

Background: Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer (mCRPC). However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes following ¹⁷⁷Lu-labelled prostate specific membrane antigen (LuPSMA) radionuclide treatment in mCRPC patients. Methods: Men who were treated under a compassionate access program with LuPSMA at our institution and had available PSA values at baseline, at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to three groups based on PSA changes: 1) response: ≥30% decline, 2) progression: ≥25% increase and 3) stable: <30% decline and <25% increase. The co-primary endpoints were overall survival and imaging-based progression-free survival. The secondary end points were PSA changes at 12 wk and PSA flare-up. Results: We identified 124 eligible patients with PSA values at 6 wk. A ≥30% decline in PSA at 6 wk was associated with longer overall survival (median 16.7 mo; 95%CI 14.4–19.0) compared with patients with stable PSA (median: 11.8 mo; 95%CI 8.6–15.1; P = 0.007) and progression (median: 6.5 mo; 95%CI 5.2–7.8; p<0.001). Patients with ≥30% decline in PSA at 6 wk also had a reduced risk of imaging-based progression compared with patients with stable PSA (HR: 0.60; 95%CI 0.38–0.94; P = 0.02), while patients with PSA progression had a higher risk of imaging-based progression compared with those showing stable PSA (HR: 3.18; 95%CI 1.95–5.21; p<0.001). The percentage changes of PSA at 6 wk and 12 wk were highly associated (r=0.90; p<0.001). 29 of 31 (94%) patients who experienced early PSA progression at 6 wk achieved biochemical progression at 12 wk. Overall, only 1 of 36 (3%) patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). Limitations of the study included its retrospective nature and the single center experience. Conclusion: PSA changes at 6 wk after LuPSMA initiation are an early indicator of long-term clinical outcome. Patients progressing by PSA after 6 wk of treatment could benefit from a very early treatment switch decision. PSA flare-up during LuPSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of LuPSMA.

The objective of this retrospective study was to determine the role of ¹⁸F-FDG PET/CT in a large cohort of 495 patients with metastatic neuroendocrine neoplasms (NENs) who were treated with peptide receptor radionuclide therapy (PRRT) with a long-term follow-up. Methods: The 495 patients were treated with ¹⁷⁷Lu- and/or ⁹⁰Y- DOTATOC/DOTATATE PRRT between 2/2002 and 7/2018. All subjects received both ⁶⁸Ga-DOTATOC/TATE/NOC and ¹⁸F-FDG PET/CT prior to treatment and were followed 3-189 months. Kaplan-Meier analysis, log-rank test (Mantel-Cox), and Cox regression analysis were performed for overall survival (OS) and progression-free survival (PFS). Results: 199 patients (40.2%) presented with pancreatic NEN, 49 with CUP (cancer of unknown primary), 139 with midgut NEN, whereas the primary tumor was present in the rectum in 20, in the lung in 38, in the stomach in 8 and other locations in 42 patients. FDG-PET/CT was positive in 382 (77.2%) patients and 113 (22.8%) were FDG-negative before PRRT, while 100% were ⁶⁸Ga-DOTATOC/TATE/NOC positive. For all patients, the median PFS and OS, defined from start of PRRT, were 19.6 mo and 58.7 mo, respectively. Positive FDG predicted shorter PFS (18.5 mo vs 24.1 mo; P = 0.0015) and OS (53.2 mo vs 83.1 mo; P < 0.001) than negative FDG. Amongst the pancreatic NEN, the median OS was 52.8 mo in FDG positive and 114.3 mo in FDG negative subjects (P = 0.0006). For all patients with positive ¹⁸F-FDG uptake, and a ratio of the highest SUV_max on ⁶⁸Ga-SSTR PET to the most ¹⁸F-FDG-avid tumor lesions >2, the median OS was 53.0 mo, compared to 43.4 mo in those patients with a ratio <2 (P = 0.030). For patients with no ¹⁸F-FDG uptake (complete "mismatch" imaging pattern), the median OS was 108.3 mo vs 76.9 mo for SUV_max >15.0 and ≤15.0 on ⁶⁸Ga-SSTR PET/CT, respectively. Conclusion: The presence of positive lesions on ¹⁸F-FDG PET is an independent prognostic factor in patients with NEN treated with PRRT. Metabolic imaging with ¹⁸F-FDG PET/CT compliments the molecular imaging aspect of ⁶⁸Ga-SSTR PET/CT for the prognosis of survival after PRRT. High SSTR expression combined with negative ¹⁸F-FDG PET/CT imaging is associated with the most favorable long-term prognosis.

Rationale: Fluorescence molecular endoscopy (FME) is an emerging technique that has the potential to improve the 22% colorectal polyp detection miss-rate. We determined the optimal dose-to-imaging interval and safety of FME using EMI-137, a c-Met targeted fluorescent peptide, in a population at high-risk for colorectal cancer. Methods: We performed in vivo FME and quantification of fluorescence by multi-diameter single-fiber reflectance, single-fiber fluorescence spectroscopy in 15 patients with a dysplastic colorectal adenoma. EMI-137 was intravenously administered (0.13mg/kg) at a one-, two- or three-hour dose-to-imaging interval (N = 3 patients per cohort). Two cohorts were expanded to six patients based on target-to-background ratios (TBR). Fluorescence was correlated to histopathology and c-Met expression. EMI-137 binding specificity was assessed by fluorescence microscopy and in vitro experiments. Results: FME using EMI-137 appeared to be safe and well tolerated. All dose-to-imaging intervals showed significantly increased fluorescence in the colorectal lesions compared to surrounding tissue, with a TBR of 1.53, 1.66 and 1.74 respectively (mean intrinsic fluorescence (Q·μ^f_a,x) = 0.035 vs. 0.023mm^-1, P<0.0003; 0.034 vs. 0.021mm^-1, P<0.0001; 0.033 vs. 0.019mm^-1, P<0.0001). Fluorescence correlated to histopathology on a macroscopic and microscopic level, with significant c-Met overexpression in dysplastic mucosa. In vitro, a dose-dependent specific binding was confirmed. Conclusion: FME using EMI-137 appeared to be safe and feasible within a one-to-three hour dose-to-imaging interval. No clinically significant differences were observed between the cohorts, although a one-hour dose-to-imaging interval was preferred from a clinical perspective. Future studies will investigate EMI-137 for improved colorectal polyp detection during screening colonoscopies.

Purpose: To determine the effect of smooth filter and partial volume correction (PVC) method on measured prostate-specific membrane antigen (PSMA) activity in small metastatic lesions and to determine the impact of these changes on the molecular imaging (mi) PSMA scoring. Materials & Methods: Men with biochemical recurrence of prostate cancer with negative CT and bone scintigraphy were referred for ¹⁸F-DCFPyL PET/CT. Examinations were performed on one of 2 PET/CT scanners (GE Discovery 610 or Siemens mCT40). All suspected tumor sites were manually contoured on co-registered CT and PET images, and each was assigned a miPSMA score as per the PROMISE criteria. The PVC factors were calculated for every lesion using the anatomical CT and then applied to the unsmoothed PET images. The miPSMA scores, with and without the corrections, were compared, and a simplified "rule of thumb" (RoT) correction factor (CF) was derived for lesions at various sizes (<4mm, 4-7mm, 7-9mm, 9-12mm). This was then applied to the original dataset and miPSMA scores obtained using the RoT CF were compared to those found using the actual corrections. Results: There were 75 men (median age, 69 years; median serum PSA of 3.69 ug/L) with 232 metastatic nodes < 12 mm in diameter (mean lesion volume of 313.5 ± 309.6 mm³). Mean SUV_max before and after correction was 11.0 ± 9.3 and 28.5 ± 22.8, respectively (p<0.00001). The mean CF for lesions <4mm (n = 22), 4-7mm (n = 140), 7-9mm (n = 50), 9-12 mm (n = 20) was 4 (range: 2.5-6.4), 2.8 (range: 1.6-4.9), 2.3 (range: 1.6-3.3) and 1.8 (range 1.4-2.4), respectively. Overall miPSMA scores were concordant between the corrected dataset and RoT in 205/232 lesions (88.4%). Conclusion: There is a significant effect of smooth filter and partial volume correction on measured PSMA activity in small nodal metastases, impacting the miPSMA score.

Latest digital whole-body PET scanners provide a combination of higher sensitivity and improved spatial and timing resolution. We performed a lesion detectability study on two generations of Siemens Biograph PET/CT scanners, the mCT and Vision, to study the impact of improved physical performance on clinical performance. Our hypothesis is that the improved performance of the Vision will result in improved lesion detectability, allowing shorter imaging times or equivalently, lower injected dose. Methods: Data were acquired with the Society of Nuclear Medicine and Molecular Imaging Clinical Trials Network torso phantom combined with a 20-cm diameter cylindrical phantom. Spherical lesions were emulated by acquiring spheres-in-air data, and combining it with the phantom data to generate combined datasets with embedded lesions of known contrast. Two sphere sizes and uptakes were used: 9.89 mm diameter spheres with 6:1 (lung) and 3:1 (cylinder) and 4.95 mm diameter spheres with 9.6:1 (lung) and 4.5:1 (cylinder) local activity concentration uptakes. Standard image reconstruction was performed: ordinary Poisson ordered subsets expectation maximization algorithm with point spread function and time-of-flight modeling and post-reconstruction smoothing with a 5 mm Gaussian filter. The Vision images were also generated without any post-reconstruction smoothing. Generalized scan statistics methodology was used to estimate the area under the localization receiver operating characteristic curve (ALROC). Results: Higher sensitivity and improved TOF performance of Vision leads to reduced contrast in the background noise nodule distribution. Measured lesion contrast is also higher on the Vision due to its improved spatial resolution. Hence, the ALROC values are noticeably higher for the Vision relative to the mCT. Conclusion: Improved overall performance of the Vision provides a factor of 4-6 reduction in imaging time (or injected dose) over the mCT when using the ALROC metric for lesions >9.89 mm in diameter. Smaller lesions are barely detected in the mCT, leading to even higher ALROC gains with the Vision. Improved spatial resolution of the Vision also leads to a higher measured contrast that is closer to the real uptake, implying improved quantification. Post-reconstruction smoothing, however, reduces this improvement in measured contrast, thereby reducing the ALROC values for small, high uptake lesions.

Rationale: Neuroinflammation has been implicated in Amyotrophic Lateral Sclerosis (ALS) and can be visualized using translocator protein (TSPO) radioligands. To become a reliable pharmacodynamic biomarker for ALS multicenter trials, some challenges have to be overcome. We aimed to investigate whether multicenter data pooling of different TSPO tracers (¹¹C-PBR28 and ¹⁸F-DPA714) is feasible, after validation of an established ¹¹C-PBR28 PET pseudoreference analysis technique for ¹⁸F-DPA714. Methods: 7 ALS-Belgium (58.9±6.7 years,5M) and 8 HV-Belgium (52.1±15.2 years,3M); and 7 ALS-US (53.4±9.8 years,5M) and 7 HV-US (54.6±9.6 years,4M) from a previously published study (1) underwent dynamic ¹⁸F-DPA714 (Leuven, Belgium) or ¹¹C-PBR28 (Boston, US) PET-MR scans. For ¹⁸F-DPA714, volume of distribution (VT) maps were compared to standardized uptake value ratios (SUVR)40-60 calculated using the pseudoreference regions (1)cerebellum, (2)occipital cortex, and (3)whole brain without ventricles (WB-ventricles). Also for ¹¹C-PBR28, SUVR60-90 using WB-ventricles were calculated. Results: In line with previous studies, increased ¹⁸F-DPA714 uptake (17.0±5.6%) in primary motor cortices was observed in ALS, as measured by both VT and SUVR40-60 approaches. Highest sensitivity was found for SUVRWB-ventricles (average cluster 21.6±0.1%). ¹⁸F-DPA714 VT ratio and SUVR40-60 results were highly correlated (r>0.8, p<0.001). A similar pattern of increased uptake (average cluster 20.5±0.5%) in primary motor cortices was observed in ALS with ¹¹C-PBR28 using the SUVRWB-ventricles. Analysis of the ¹⁸F-DPA714 and ¹¹C-PBR28 data together, resulted in a more extensive pattern of significant increased glial activation in the bilateral primary motor cortices. Conclusion: The same pseudoreference region analysis technique for ¹¹C-PBR28 PET imaging can be extended towards ¹⁸F-DPA714 PET. Therefore, in ALS, standardized analysis across these two tracers enables pooling of TSPO PET data across multiple centers and increase power of TSPO as biomarker for future therapeutic trials.

Radionuclide imaging of myocardial perfusion, function, and viability has been established for decades and remains a robust, evidence-based and broadly available means for clinical workup and therapeutic guidance in ischemic heart disease. Yet, powerful alternative modalities have emerged for this purpose, and their growth has resulted in increasing competition. But the potential of the tracer principle goes beyond the assessment of physiology and function, towards the interrogation of biology and molecular pathways. This is a unique selling point of radionuclide imaging, which has been under-recognized in cardiovascular medicine until recently. Now, molecular imaging methods for the detection of myocardial infiltration, device infection and cardiovascular inflammation are successfully gaining clinical acceptance. This is further strengthened by the symbiotic quest of cardiac imaging and therapy for an increasing implementation of molecular-targeted procedures, where specific therapeutic interventions require specific diagnostic guidance towards the most suitable candidates. This review will summarize the current advent of clinical cardiovascular molecular imaging and highlight its transformative contribution to the evolution of cardiovascular therapy beyond mechanical interventions and broad "blockbuster" medication, towards a future of novel, individualized molecular targeted and molecular imaging-guided therapies.

Prostate specific membrane antigen (PSMA) targeting Positron Emission Tomography (PET) imaging is becoming the reference standard for prostate cancer (PC) staging, especially in advanced disease. Yet, the implications of PSMA-PET derived whole-body tumor volume for overall survival are poorly elucidated to date. This might be due to the fact that (semi-) automated quantification of whole-body tumor volume as PSMA-PET biomarker is an unmet clinical challenge. Therefore, a novel semi-automated software is proposed and evaluated by the present study, which enables the semi-automated quantification of PSMA-PET biomarkers such as whole-body tumor volume. Methods: The proposed quantification is implemented as a research prototype (MI Whole Body Analysis Suite, v1.0, Siemens Medical Solutions USA, Inc., Knoxville, TN). PSMA accumulating foci were automatically segmented by a percental threshold (50% of local SUV_max). Neural networks were trained to segment organs in PET-CT acquisitions (training CTs: 8,632, validation CTs: 53). Thereby, PSMA foci within organs of physiologic PSMA uptake were semi-automatically excluded from the analysis. Pretherapeutic PSMA-PET-CTs of 40 consecutive patients treated with ¹⁷⁷Lu-PSMA-617 therapy were evaluated in this analysis. The volumetric whole-body tumor volume (PSMATV50), SUV_max, SUVmean and other whole-body imaging biomarkers were calculated for each patient. Semi-automatically derived results were compared with manual readings in a sub-cohort (by one nuclear medicine physician using syngo.MM Oncology software, Siemens Healthineers, Knoxville, TN). Additionally, an inter-observer evaluation of the semi-automated approach was performed in a sub-cohort (by two nuclear medicine physicians). Results: Manually and semi automatically derived PSMA metrics were highly correlated (PSMATV50: R2=1.000; p<0.001; SUV_max: R2=0.988; p<0.001). The inter-observer agreement of the semi-automated workflow was also high (PSMATV50: R2=1.000; p<0.001; ICC=1.000; SUV_max: R2=0.988; p<0.001; ICC=0.997). PSMATV50 [ml] was a significant predictor of overall survival (HR: 1.004; 95%CI: 1.001-1.006, P = 0.002) and remained so in a multivariate regression including other biomarkers (HR: 1.004; 95%CI: 1.001-1.006 P = 0.004). Conclusion: PSMATV50 is a promising PSMA-PET biomarker that is reproducible and easily quantified by the proposed semi-automated software. Moreover, PSMATV50 is a significant predictor of overall survival in patients with advanced prostate cancer that receive ¹⁷⁷Lu-PSMA-617 therapy.

Purpose: We aimed to conduct a systematic review and meta-analysis of studies reporting the performance of radioactive iodine therapy (131-I therapy) in differentiating thyroid cancer (DTC) patients requiring a completion treatment following lobectomy. We also evaluated the response to 131-I therapy according to 2015ATA guidelines and the adverse events. Methods: A specific search strategy was designed to find articles evaluating the use of I-131 in patients with evidence of DTC after lobectomy. PubMed, CENTRAL, Scopus and Web of Science were searched. The search was updated until January 2020, without language restriction. Data were cross-checked and any discrepancy discussed. A proportion meta-analysis (with 95%CI) was performed using the random-effects model. Meta-regressions on I-131 success were attempted. Results: The pooled success ablation rate was 69% with better results in patients receiving a single administration of about 3.7 GBq; high heterogeneity was found (I2 85%), and publication bias was absent (Egger test: P = 0.57). Incomplete structural responses were recorded in only 14 of 695 (2%) patients enrolled in our analysis. Incomplete biochemical responses were observed in 8 to 24% of patients, with higher rates (24%) in patients receiving low radioiodine activities (~1.1 GBq) and lower rates (from 8 to 18%) in patients receiving higher activities of radioiodine (~3.7 Gbq). Neck pain due to thyroiditis was reported in up to 18% of patients but, in most cases, symptoms resolved after oral paracetamol or a short course of prednisone. Conclusion: Lobar ablation with 131-I is effective especially when high ¹³¹I activities are used. However, the rate of incomplete biochemical response to initial treatment appears to be slightly higher than the classical scheme of initial treatment of DTC. "Radioisotopic lobectomy" should be considered for patients with low-to-intermediate risk DTC requiring completion treatment after lobectomy due to specific individual risk factors and/or patient’s preferences.

Background: Functional magnetic resonance imaging (fMRI) studies have reported altered integrity of large-scale neurocognitive networks (NCNs) in dementing disorders. However, findings on specificity of these alterations in patients with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are still very limited. Recently, NCNs have been successfully captured using positron emission tomography (PET) with F18-fluordesoxyglucose (FDG). Methods: Network integrity was measured in 72 individuals (38 male) with mild AD, bvFTD, and healthy controls using a simultaneous resting state fMRI and FDG-PET. Indices of network integrity were calculated for each subject, network, and imaging modality. Results: In either modality, independent component analysis revealed four major NCNs: anterior default mode network (DMN), posterior DMN, salience network, and right central executive network (CEN). In fMRI data, integrity of posterior DMN was found to be significantly reduced in both patient groups relative to controls. In the AD group anterior DMN and CEN appeared to be additionally affected. In PET data, only integrity of posterior DMN in patients with AD was reduced, while three remaining networks appeared to be affected only in patients with bvFTD. In a logistic regression analysis, integrity of anterior DMN as measured with PET alone accurately differentiated between the patient groups. A correlation between indices of two imaging modalities was overall low. Conclusion: FMRI and FDG-PET capture partly different aspects of network integrity. A higher disease specificity of NCNs as derived from PET data supports metabolic connectivity imaging as a promising diagnostic tool.

¹⁸F-BMS-986192, an adnectin-based human programmed cell death ligand 1 (PD-L1) tracer, was developed to non-invasively determine whole-body PD-L1 expression by positron emission tomography (PET). We evaluated usability of ¹⁸F-BMS-986192 PET to detect different PD-L1 expression levels and therapy-induced changes of PD-L1 expression in tumors. Methods: In vitro binding assays with ¹⁸F-BMS-986192 were performed in human tumor cell lines with different total cellular and membrane PD-L1 protein expression levels. Subsequently, PET imaging was executed in immunodeficient mice xenografted with these cell lines. Mice were treated with interferon gamma (IFN) intraperitoneally for 3 days or with the mitogen-activated protein kinase kinase (MEK1/2) inhibitor selumetinib by oral gavage for 24 hours. Thereafter ¹⁸F-BMS-986192 was administered intravenously, followed by a 60-minute dynamic PET scan. Tracer uptake was expressed as percentage injected dose per gram tissue (%ID/g). Tissues were collected to evaluate ex vivo tracer biodistribution and to perform flow cytometric, Western blot, and immunohistochemical tumor analyses. Results: ¹⁸F-BMS-986192 uptake reflected PD-L1 membrane levels in tumor cell lines, and tumor tracer uptake in mice was associated with PD-L1 expression measured immunohistochemically. In vitro IFN treatment increased PD-L1 expression in the tumor cell lines and caused up to 12-fold increase in tracer binding. In vivo, IFN did neither affect PD-L1 tumor expression measured immunohistochemically nor ¹⁸F-BMS-986192 tumor uptake. In vitro, selumetinib downregulated cellular and membrane levels of PD-L1 of tumor cells by 50% as measured by Western blotting and flow cytometry. In mice, selumetinib lowered cellular, but not membrane PD-L1 levels of tumors and consequently no treatment-induced change in ¹⁸F-BMS-986192 tumor uptake was observed. Conclusion: ¹⁸F-BMS-986192 PET imaging allows detection of membrane-expressed PD-L1, as soon as 60 minutes after tracer injection. The tracer can discriminate a range of tumor cell PD-L1 membrane expression levels.

Purpose: This study is designed to assess the safety and therapeutic response to ¹⁷⁷Lu-EB-PSMA treatment with escalating doses in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: With institutional review board approval and informed consent, patients were randomly divided into three groups: Group A (n = 10) were treated with 1.18 ± 0.09 GBq/dose of ¹⁷⁷Lu-EB-PSMA. Group B (n = 10) were treated with 2.12 ± 0.19 GBq/dose of ¹⁷⁷Lu-EB-PSMA. Group C (n = 8) were treated with 3.52 ± 0.58 GBq/dose of ¹⁷⁷Lu-EB-PSMA. Eligible patients received up to three cycles of ¹⁷⁷Lu-EB-PSMA therapy, at eight-week intervals. Results: Due to disease progression or bone marrow suppression, 4 out of 10, 5 out of 10, and 5 out of 10 patients completed three cycles therapy as planned in Groups A, B, and C, respectively. The prostate-specific antigen (PSA) response was correlated with treatment dose, with PSA disease control rates in Group B (70%) and C (75%) being higher than that in Group A (10%) (P = 0.007), but no correlation between Group B and Group C was found. ⁶⁸Ga-PSMA PET/CT showed response in all the treatment groups, however, there was no significant difference between the three groups. Hematologic toxicity study found that platelets in Group B and Group C decreased more than those in Group A, and that Grade 4 thrombocytopenia occurred in 2 (25.0%) patients in Group C. No serious nephritic or hepatic side effects were observed. Conclusion: This study demonstrates that 2.12 GBq/dose of ¹⁷⁷Lu-EB-PSMA seems to be safe and adequate in tumor treatment. Further investigations with increased number of patients are warranted.