High Tracer Uptake Research Articles

Uptake of positron emission tomography tracers reflects the tumor immune status in esophageal squamous cell carcinoma.

The relationship between the local immune status and cancer metabolism regarding 18F‐FDG and 18F‐FAMT uptake in esophageal squamous cell carcinoma (ESCC) remains unknown. The present study examined the correlations between tumor immune status, clinicopathological factors, and positron emission tomography (PET) tracer uptake in ESCC. Forty‐one ESCC patients who underwent 18F‐FDG PET and 18F‐FAMT PET before surgery were enrolled in the study. Immunohistochemistry was conducted for programmed death 1 (PD‐1), CD8, Ki‐67, CD34, GLUT1 (18F‐FDG transporter) and LAT1 (18F‐FAMT transporter). ESCC specimens with high tumoral PD‐L1 and high CD8‐positive lymphocytes were considered to have “hot tumor immune status.” High PD‐L1 expression (53.7%) was significantly associated with tumor/lymphatic/venous invasion (P = 0.028, 0.032 and 0.018), stage (P = 0.041), CD8‐positive lymphocytes (P < 0.001), GLUT1 (P < 0.001), LAT1 expression (P = 0.006), Ki‐67 labelling index (P = 0.009) and CD34‐positive vessel counts (P < 0.001). SUVmax of 18F‐FDG was significantly higher in high PD‐L1 cases than in low PD‐L1 cases (P = 0.009). SUVmax of 18F‐FAMT was significantly higher in high PD‐L1 (P < 0.001), high CD8 (P = 0.012) and hot tumor groups (P = 0.028) than in other groups. High SUVmax of 18F‐FAMT (≥4.15) was identified as the only predictor of hot tumor immune status. High PET tracer uptake was significantly associated with cancer aggressiveness and hot tumor immune status in ESCC. PET imaging may be an effective tool to predict tumor immune status in ESCC with respect to immune checkpoint inhibitor sensitivity.

18F-FDG PET-Based Imaging of Myocardial Inflammation Following Acute Myocardial Infarction in a Mouse Model.

Cellular inflammation is an integral part of the healing process following acute myocardial infarction and has been under intense investigation for both therapeutic and prognostic approaches. Monocytes and macrophages are metabolically highly active and show increased uptake rates of glucose and its analog, 18F-FDG. Yet, the specific allocation of the radioactivity to the inflammatory cells via positron emission tomography (PET) imaging requires the suppression of glucose metabolism in viable myocardium. In mice, the most important model organism in basic research, this can be achieved by the application of ketamine/xylazine (KX) for anesthesia instead of isoflurane. Yet, while the consensus exists that glucose metabolism is effectively suppressed, a strategy for reproducible image analysis is grossly lacking and causes uncertainty concerning data interpretation. We introduce a simple strategy for systematic image analysis, which is a prerequisite to evaluate therapies targeting myocardial inflammation. Mice underwent permanent occlusion of the left anterior descending artery (LAD), inducing an acute myocardial infarction (MI). Five days after MI induction, 10MBq 18F-FDG was injected intravenously and a static PET/CT scan under ketamine/xylazine anesthesia was performed. For image reconstruction, we used an algorithm based on three-dimensional ordered subsets expectation maximization (3D-OSEM) followed by three-dimensional ordinary Poisson maximum a priori (MAP) reconstruction. Using this approach, high focal tracer uptake was typically located in the border zone of the infarct by visual inspection. To precisely demarcate the border zone for reproducible volume of interest (VOI) positioning, our protocol relies on positioning VOIs around the whole left ventricle, the inferobasal wall and the anterolateral wall guided by anatomical landmarks. This strategy enables comparable data in mouse studies, which is an important prerequisite for using a PET-based assessment of myocardial inflammation as a prognostic tool in therapeutic applications.

Cetuximab PET delineated changes in cellular distribution of EGFR upon dasatinib treatment in triple negative breast cancer

BackgroundAt least 50% of triple negative breast cancer (TNBC) overexpress the epidermal growth factor receptor, EGFR, which paved the way for clinical trials investigating its blockade. Outcomes remained dismal stemming from mechanisms of resistance particularly the nuclear cycling of EGFR, which is enhanced by Src activation. Attenuation of Src reversed nuclear translocation, restoring EGFR to the cell surface. Herein, we hypothesize that changes in cellular distribution of EGFR upon Src inhibition with dasatinib can be annotated through the EGFR immunopositron emission tomography (immunoPET) radiotracer, [89Zr]Zr-cetuximab.MethodsNuclear and non-nuclear EGFR levels of dasatinib-treated vs. untreated MDA-MB-231 and MDA-MB-468 cells were analyzed via immunoblots. Both treated and untreated cells were exposed to [89Zr]Zr-cetuximab to assess binding at 4 °C and 37 °C. EGFR-positive MDA-MB-231, MDA-MB-468, and a patient-derived xenograft were treated with dasatinib or vehicle followed by cetuximab PET imaging to compare EGFR levels. After imaging, the treated mice were separated into two groups: one cohort continued with dasatinib with the addition of cetuximab while the other cohort received dasatinib alone. Correlations between the radiotracer uptake vs. changes in tumor growth and EGFR expression from immunoblots were analyzed.ResultsTreated cells displayed higher binding of [89Zr]Zr-cetuximab to the cell membrane at 4 °C and with greater internalized activity at 37 °C vs. untreated cells. In all tumor models, higher accumulation of the radiotracer in dasatinib-treated groups was observed compared to untreated tumors. Treated tumors displayed significantly decreased pSrc (Y416) with retained total Src levels compared to control. In MDA-MB-468 and PDX tumors, the analysis of cetuximab PET vs. changes in tumor volume showed an inverse relationship where high tracer uptake in the tumor demonstrated minimal tumor volume progression. Furthermore, combined cetuximab and dasatinib treatment showed better tumor regression compared to control and dasatinib-only-treated groups. No benefit was achieved in MDA-MB-231 xenografts with the addition of cetuximab, likely due to its KRAS-mutated status.ConclusionsCetuximab PET can monitor effects of dasatinib on EGFR cellular distribution and potentially inform treatment response in wild-type KRAS TNBC.

Imaging CXCR4 expression in patients with suspected primary hyperaldosteronism

It is challenging to differentiate unilateral aldosterone-producing adenoma (APA) from bilateral idiopathic adrenal hyperplasia (IAH) and nonfunctional adrenal adenoma (NFA) in primary aldosteronism (PA). In a first primarily ex vivo study detection, CXC chemokine receptor type 4 (CXCR4) expression has been shown to be a valuable tool for the detection of APA. In this study, we aimed to clinically evaluate CXCR4 imaging with 68Ga-pentixafor PET/CT for detecting APA. We prospectively recruited 36 patients with clinical suspicion of PA. All patients underwent 68Ga-pentixafor PET/CT. Positive lesions were defined based on higher tracer uptake in adrenal nodular(s) shown on CT than the normal adrenal. These lesions were referred for adrenalectomy subsequently. All patients received clinical follow-up. Semi-quantitative analysis using maximum standardized uptake value (SUVmax), lesion-to-liver ratio (LLR), and lesion-to-contralateral ratio (LCR) has also been performed. PET/CT results were correlated with clinical presentation and follow-up. Thirty-nine adrenal lesions in 36 patients were found; 25 APA, 4 IAH, and 10 NFA according to histopathology and clinical assessment. Sensitivity, specificity, and accuracy of 68Ga-pentixafor PET/CT in distinguishing APA by visualization were 100%, 78.6%, and 92.3% respectively. The SUVmax of APA (21.34 ± 9.41, n = 25) was significantly higher than that of non-APA lesions (6.29 ± 2.10, n = 14, P < 0.0001). An optimal threshold of SUVmax = 11.18 was determined for predicting APA with a sensitivity of 88.0%, specificity of 100%, and an accuracy of 92.3%. A cutoff value for LCR of 2.12 yielded a sensitivity of 100% and a specificity of 92.9%, whereas a cutoff value for LLR of 2.36 reached at both 100% of sensitivity and specificity. All patients with (removed) positive lesions benefited from surgery. 68Ga-Pentixafor PET/CT may be used to non-invasively detect APA in PA patients.

Evaluation of Radiation dosimetry of 99mTc-HYNIC-PSMA and imaging in prostate cancer

This study aims to evaluate the radiation dosimetry of a new technetium-99m‒labelled small-molecule inhibitor of prostate-specific membrane antigen (HYNIC-Glu-Urea-A, 99mTc-HYNIC-PSMA) and its feasibility as a tumor-imaging agent in prostate cancer (PCa) patients. A total of 15 PCa patients were enrolled in this study. For the dosimetry study, 5 PCa patients received whole-body planar scans at 0.5 h, 1 h, 2 h, 4 h and 8 h after 99mTc-HYNIC-PSMA injection. The Dosimetry Toolkit (GE, Milwaukee) was used to process the data and segment the organs in the SPECT/CT images, which were then projected onto planar images. The organ-specific absorbed doses, total-body absorbed doses and 99mTc-HYNIC-PSMA effective doses of patients were calculated using OLINDA/EXM 1.1 software. Whole-body SPECT/CT images were also acquired from additional 10 prostate patients to investigate the feasibility of 99mTc-HYNIC-PSMA for imaging tumors by calculating the ratio of tumor-to-background tracer uptake at 2 h after 740 MBq administration. The total-body absorbed dose was 1.54E-03 ± 2.43E-04 mGy/MBq, and the effective dose was 3.72E-03 ± 4.5E-04 mSv/MBq. Compared to published studies of other similar PSMA tracers and 99mTc-targeted conventional tracers, the absorbed doses of 99mTc-HYNIC-PSMA in all organs showed that it could be used safely in the human body. In addition, 99mTc-HYNIC-PSMA showed high tracer uptake (with a tumor-to-background ratio of 9.42 ± 2.62) in the malignant lesions of PCa patients, making it a promising radiopharmaceutical imaging method for site-specific management of PCa.

Awake Craniotomy and Resection of a Left Frontal High-Grade Glioma: 2-Dimensional Operative Video

A 48-yr-old female patient presented in our outpatients' clinic after an episode of speech arrest and seizures a week earlier. On physical examination, there were no neurological deficits. Cranial magnetic resonance imaging (MRI) revealed a contrast-enhancing tumor of the superior and middle frontal gyrus. A 18F-fluoroethyl-tyrosine positron emission tomography (FET-PET) showed a high tracer uptake, and we suspected the lesion to be a high-grade glioma. The tumor was located next to the cortical motor and language areas. We performed a left frontal craniotomy while the patient was asleep, and then conducted cortical and subcortical stimulation under an awake condition. The patient was asked to move her right upper extremity and to name objects. Based on MRI navigation, we achieved a complete tumor resection. Postoperative imaging confirmed gross total resection, and final histopathology revealed an anaplastic astrocytoma isocitrate dehydrogenase (IDH) mut, 1p19q noncodeleted WHO°III. The patient was discharged home on the fifth postoperative day with a supplementary motor area syndrome and diminishing word-finding difficulties. We safely achieved gross total tumor resection in a highly eloquent localization through awake craniotomy with direct cortical and subcortical stimulation and electrophysiological monitoring. Awake craniotomy remains the gold standard for tumor resection in eloquent language areas in our clinics. We obtained informed consent from the patient.

Ordered subset expectation maximisation vs Bayesian penalised likelihood reconstruction algorithm in 18F-PSMA-1007 PET/CT

BackgroundThe aim of the study was to compare widely used ordered subset expectation maximisation (OSEM) algorithm with a new Bayesian penalised likelihood (BPL) Q.Clear algorithm in 18F-PSMA-1007 PET/CT.MethodsWe retrospectively assessed 25 18F-PSMA-1007 PET/CT scans with both OSEM and Q.Clear reconstructions available. Each scan was independently reported by two physicians both in OSEM and Q.Clear. SUVmax, SUVmean and tumour-to-background ratio (TBR) of each lesion were measured. Reports were also compared for their final conclusions and the number and localisation of lesions.ResultsIn both reconstructions the same 87 lesions were reported. Mean SUVmax, SUVmean and TBR were higher for Q.Clear than OSEM (7.01 vs 6.53 [p = 0.052], 4.16 vs 3.84 [p = 0.036] and 20.2 vs 16.8 [p < 0.00001], respectively). Small lesions (< 10 mm) had statistically significant higher SUVmax, SUVmean and TBR in Q.Clear than OSEM (5.37 vs 4.79 [p = 0.032], 3.08 vs 2.70 [p = 0.04] and 15.5 vs 12.5 [p = 0.00214], respectively). For lesions ≥ 10 mm, no significant differences were observed. Findings with higher tracer avidity (SUVmax ≥ 5) tended to have higher SUVmax, SUVmean and TBR values in Q.Clear (11.6 vs 10.3 [p = 0.00278], 7.0 vs 6.7 [p = 0.077] and 33.9 vs 26.7 [p < 0.00001, respectively). Mean background uptake did not differ significantly between Q.Clear and OSEM (0.42 vs 0.39, p = 0.07).ConclusionsIn 18F-PSMA-1007 PET/CT, Q.Clear SUVs and TBR tend to be higher (regardless of lesion localisation), especially for small and highly avid lesions. Increase in SUVs is also higher for lesions with high tracer uptake. Still, Q.Clear does not affect 18F-PSMA-1007 PET/CT specificity and sensitivity.

The Effect of Chirality on the Application of 5-[18F]Fluoro-Aminosuberic Acid ([18F]FASu) for Oxidative Stress Imaging.

The cystine transporter, system xC-, plays a crucial role in sustaining redox homeostasis and is reported to be overexpressed in several cancer subtypes. 5-[18F]Fluoroaminosuberic acid ([18F]FASu) is a novel positron emission tomography (PET) tracer, which exhibits specific uptake via system xC-. [18F]FASu synthesis by the commonly used Kryptofix 2.2.2/K2CO3-facilitated fluorination method results in four diastereomers, as a result of 2 chiral centers at positions 2- and 5- of the tracer. We recently reported the synthesis of the optically pure 2S-[18F]FASu from chiral precursors. Our preliminary results indicated preferential uptake of the 2S-isomer by tumor cells compared to 2R-[18F]FASu. Few studies have investigated the biodistribution of chiral 18F-labeled amino acids. The aim of this study was to evaluate the imaging utility and biodistribution of the 5-position diastereomers as well as the racemic (2S,5R/S-) mixture in three different tumor models. In vitro tracer uptake experiments and Western blotting were performed in breast cancer (MDA-MB-231), glioblastoma (U-87), and prostate (PC-3) cancer cell lines. PET imaging and biodistribution studies were conducted in xenograft-bearing immunocompromised Rag2M female mice. All three tracer conformations allowed for the visualization of tumor xenografts at 1 h (for U-87 and PC-3 tumors) or 2 h (in the case of MDA-MB-231 xenografts) post-injection, with the racemate (2S,5R/S-) displaying similar image contrast as compared to the 5- position diastereomers and the 2S,5S-[18F]FASu conformation exhibiting relatively higher contrast for imaging U-87 and PC-3 xenografts. Tumor uptake of the isomers was blocked by an excess of the non-radioactive standard, aminosuberic acid (ASu), confirming target specificity. All three isomers were excreted via the renal pathway. Biodistribution analyses showed that PC-3 tumors had the highest tracer uptake, and the accumulation (%ID/g) of the 2S,5R/S-, 2S,5S-, and 2S,5R- isomers was 9.19 ± 1.14, 8.00 ± 1.41, and 7.16 ± 2.13 at 1 h post-injection, respectively. This gave corresponding tumor-to-muscle ratios of 33.68 ± 9.52, 31.42 ± 4.54, and 25.33 ± 4.97, respectively. Our data suggest that pure 2S-[18F]FASu can be used to noninvasively image system xC- in a variety of cancers, either as the racemic mixture (2S,5R/S-) or optically pure form. Furthermore, this work shows potential utility of [18F]FASu for detection of glioblastoma and prostate cancer.

P121918F-FDG perfusion-metabolism mismatch 3 days after acute myocardial infarction predicts worse outcome: molecular glucose steel phenomenon visualized by hybrid PET-MRI images

Abstract Background The disturbance of cardiac energy substrate metabolism has a decisive role in the pathogenesis of adverse cardiac remodeling and heart failure. Under normoxic conditions, the free fatty acid metabolism is the predominant pathway by providing the highest energy per substrate molecule. Severe myocardial hypoxia leads to a switch from beta-oxidation to glucose metabolism to increase the ATP production per oxygen molecule. This metabolic disorder appears as perfusion-metabolism mismatch in 18F-fluorodeoxyglucose (18F-FDG) PET images, as increased 18F-FDG uptake in the under-perfused hypoxic myocardial area. Purpose The aim of our study was to evaluate the simultaneous perfusion, metabolism and function of the ischemic heart by hybrid 18F-FDG-PET-cMRI with late enhancement images in a translation animal model of heart failure. Methods Under general anesthesia, closed chest reperfused acute myocardial infarction (AMI) was induced in 36 domestic pigs by 90 min occlusion of the mid left anterior descending artery with a percutaneous intracoronary balloon, followed by reperfusion. Three days and 1 month after AMI, after 12h fasting, 18F-FDG-PET-cMRI were performed by using standardized acquisition protocols (n=30). Cardiac functional parameter, such as ejection fraction (EF), end-diastolic volume (EDV), infarct size, and mean tracer uptake of the infarcted area were quantitatively assessed. Six animals were euthanized after the 3-day 18F-FDG-PET-cMRI images to elaborate the differences in gene expression patterns in animals with perfusion-metabolic mismatch by using next generation sequencing (NGS) and pathway network analyses. Results Eight (group Mismatch) of the 30 animals (group Match) with 1-month follow-up showed high 18F-FDG uptake in the infarcted area (perfusion-metabolism mismatch) at the 3-day 18F-FDG-PET-cMRI-LE images (Figure). The animals in the Mismatch group had significantly lower EF at 3 days (34±8.8 vs 42±3%) and at the 1-month follow-up (35.8±6 vs 43±6.6%) and larger infarct size at day 3 (26.6±6.6 vs 22.1±4.4%) and 1 month (28±5.4 vs 20.3±4.3%) with higher EDV at 1 month. Mean tracer uptake of the infarcted area was significantly reduced in the Mismatch group at 1 month (56±23.1 vs 64.7±13.2%). NGS revealed downregulation of the cholesterol metabolism pathway, and upregulation of carbohydrate derivative catabolism pathway with highly activated innate immune system and genes responsible for cytokine activation in the infarcted area 3 days post-AMI in the Mismatch group, which explains the paradox high 18F-FDG tracer uptake in the infarction zone. Accordingly, the high energy demand of the severe hypoxic area led to “glucose steel phenomenon” at the molecular level, subtracting the 18F-FDG from the normally perfused non-ischemic myocardial regions. Conclusions 18F-FDG-glucose perfusion-metabolism mismatch early after AMI visualized by hybrid 18F-FDG-PET-MRI images predict development of LV adverse remodeling. Acknowledgement/Funding Fibrotarget EU Grant Nr 602904

PET Imaging of Astrogliosis and Tau Facilitates Diagnosis of Parkinsonian Syndromes.

Neurodegenerative parkinsonian syndromes comprise a number of disorders that are characterized by similar clinical features but are separated on the basis of different pathologies, i.e., aggregates of α-synuclein or tau protein. Due to the overlap of signs and symptoms a precise differentiation is often difficult, especially early in the disease course. Enormous efforts have been taken to develop tau-selective PET imaging agents, but strong off-target binding to monoamine oxidase B (MAO-B) has been observed across first generation ligands. Nonetheless, astrogliosis-related MAO-B elevation is a common histopathological known feature of all parkinsonian syndromes and might be itself an interesting imaging target. Therefore, this study aimed to investigate the performance of [18F]-THK5351, a combined MAO-B and tau tracer for differential diagnosis of parkinsonian syndromes. [18F]-THK5351 PET was performed in 34 patients: six with Parkinson’s disease (PD), nine with multiple system atrophy with predominant parkinsonism (MSA-P), six with MSA with predominant cerebellar ataxia (MSA-C), and 13 with progressive supranuclear palsy (PSP) Richardson’s syndrome. Volume-of-interest-based quantification of standardized-uptake-values was conducted in different parkinsonian syndrome-related target regions. PET results were subjected to multinomial logistic regression to create a prediction model discriminating among groups. Furthermore, we correlated tracer uptake with clinical findings. Elevated [18F]-THK5351 uptake in midbrain and diencephalon differentiated PSP patients from PD and MSA-C. MSA-C patients were distinguishable by high tracer uptake in the pons and cerebellar deep white matter when compared to PSP and PD patients, whereas MSA-P patients tended to show higher tracer uptake in the lentiform nucleus. A multinomial logistic regression classified 33/34 patients into the correct clinical diagnosis group. Tracer uptake in the pons, cerebellar deep white matter, and striatum was closely associated with the presence of cerebellar and parkinsonian symptoms of MSA patients. The current study demonstrates that combined MAO-B and tau binding of THK5351 facilitates differential diagnosis of parkinsonian syndromes. Furthermore, our data indicate a correlation of MSA phenotype with [18F]-THK5351 uptake in certain brain regions, illustrating their relevance for the emergence of clinical symptoms and underlining the potential of THK5351 PET as a biomarker that correlates with pathological changes as well as with disease stage.

P14.27 The significance of multicentric noncontrast-enhancing lesions distant from surgically resected glioblastoma: Case series of 3 patients

Abstract BACKGROUND Glioblastoma is the most malignant primary brain tumor. The tumor location and multiplicity plays an important role in surgical and further treatment. The incidence of multiple lesions at the time of diagnosis was known as 1–20%, which showed a poor prognostic factor. Most researches has focused on multiple contrast-enhancing lesions, however, multicentric non-enhancing lesions distant from glioblastoma has been rarely evaluated. The authors reported the case series of the patient who showed multicentric non contrast-enhancing lesions without connection to histologically-proven glioblastoma. MATERIAL AND METHODS Multicentric non contrast-enhancing lesions were defined as areas of FLAIR hyperintensity and mass effect without post-contrast enhancement, separated from the histologically-proven glioblastoma in a newly diagnosed disease. Three patients who showed distant non-enhancing lesions with appearance of a multicentric low-grade glioma were included in this study. The typical enhancing lesions were surgically resected and standard chemo-radiotherapy was followed in all patients. RESULTS All patients were male and their age was 38, 60 and 65 years old respectively. Multicentric tumor location was as follows: Case 1, left frontal lobe with non-enhancing lesion in left parahippocampal gyrus; Case 2, left parietal with non-enhancing lesion in left anteromedial temporal lobe; Case 3, left thalamus with non-enhancing lesions in both basal frontal and right temporal lobe. Pathologically, the resected enhancing tumor revealed glioblastoma in 2 patients and diffuse midline glioma in 1. All tumors were IDH-wild type. The resected enhanced lesion showed no progression but all non-enhancing lesions developed contrast-enhancing tumors at 3, 13 and 17 months after initial treatment, with high tracer uptake on 18FDG-PET or 18FDOPA-PET. Despite multidisciplinary treatment, two patients died from disease progression at 30 and 32 months after diagnosis and one patient is still alive with overall survival of 15 months. CONCLUSION The appearance of multicentric non-enhancing lesions distant from a typically enhancing tumor showed an uncommon finding in glioblastoma and poor prognostic features. These lesions progress faster than expected for a low-grade glioma. These lesions should be distinguished from typical low-grade glioma and should be considered more advanced lesions than their appearances suggest.

Abstract 1146: [18F]FPyGal: A novel ß-galactosidase specific PET tracer for in vivo imaging of tumor senescence

Abstract Senescence influences treatment outcome in cancer. Therefore it is of great interest to develop a diagnostic tool to detect senescent cells in cancer patients. Here we describe the evaluation of the PET tracer FPyGal for non-invasive imaging of ß-galactosidase as a surrogate marker for senescence. In vitro, we induced senescence in HCT116 cells by doxorubicin, in a liver progenitor cell line by p53-reactivation and in two liver carcinoma cell lines by a ribosomal checkpoint inhibitor (RCI). The cells were then incubated with FPyGal and tracer uptake was determined in a gamma-counter. For in vivo testing, the described cell lines were injected s.c. in mice. The tumor bearing mice were then treated appropriately to induce senescence. PET/MR scans were performed after i.v. injection of FPyGal for assessment of tracer uptake in the tumors. Ex vivo autoradiographies and X-Gal stainings were prepared to correlate intratumoral distribution of ⇓-galactosidase activity and tracer uptake. After toxicology studies, a pilot first-in-man study was performed in a cancer patient treated with Alisertib. Compared to the respective control cells, in vitro tracer uptake was significantly increased in all four cellular models tested. The strongest increase was observed in one of the liver carcinoma cell lines with a &amp;gt;3-fold increase in senescent cells. FPyGal tracer uptake increased in control HCT116 tumors from 1.1 to 1.7%ID/cc in senescent cells in in vivo PET/MRI studies and in the HRas model from 0.9 to 1.5 %ID/cc. In one of the liver tumor models we could observe a 2-fold increase in treated mice. Ex vivo ⇓-galactosidase staining and IHC of tumor tissue confirmed induction of senescence. Autoradiography and X-Gal staining showed an intratumoral correlation of ⇓-gal activity and FPyGal uptake. The compound passed the toxicology tests. A first patient study revealed high and heterogeneous tracer uptake in a liver metastasis. FPyGal shows increased in vitro and in vivo uptake in senescent cells and tumors. No toxicity of the compound could be detected and a first-in-man study showed promising results. Clinical trials including histological cross-validation are currently being prepared. Citation Format: Marcel A. Krueger, Jonathan M. Cotton, Benyuan Zhou, Katharina Wolter, Johannes Schwenck, Anna Kuehn, Kerstin Fuchs, Andreas Maurer, Christian La Fougere, Lars Zender, Bernd J. Pichler. [18F]FPyGal: A novel ß-galactosidase specific PET tracer for in vivo imaging of tumor senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1146.

Radiation Dosimetry and Biodistribution of 18F-PSMA-11 for PET Imaging of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer. Many PSMA analog radiotracers for PET/CT prostate cancer staging have been developed, such as 68Ga-PSMA-11. This radiotracer has achieved good results in multiple clinical trials, but because of the superior imaging characteristics of 18F-fluoride, 18F-PSMA-11 was developed. The aim of this study was to evaluate the administration safety and radiation dosimetry of 18F-PSMA-11. Methods: Six patients (aged 62-68 y; mean, 66 ± 2 y) with suspected prostate cancer recurrence after previous treatment were administered 2 MBq of 18F-PSMA-11 per kilogram of body weight and then underwent low-dose PET/CT imaging at 0, 20, 50, 90, and 300 min after injection. To evaluate the safety of administration, vital parameters were monitored. To assess toxicity, full blood count and biochemical parameters were determined. According to the latest International Commission on Radiological Protection recommendations, radiation dosimetry analysis was performed using IDAC-Dose 2.1. For blood activity measurement, small samples of venous blood were collected at various time points after injection. The unbound 18F-fluoride fraction was determined in plasma at 20, 50, and 90 min after administration to evaluate the defluorination rate of 18F-PSMA-11. Results: After injection, 18F-PSMA-11 cleared rapidly from the blood. At 5 h after injection, 29.0% ± 5.9% of the activity was excreted in urine. The free 18F fraction in plasma increased from 9.7% ± 1.0% 20 min after injection to 22.2% ± 1.5% 90 min after injection. The highest tracer uptake was observed in kidneys, bladder, spleen, and liver. No study drug-related adverse events were observed. The calculated mean effective dose was 12.8 ± 0.6 μSv/MBq. Conclusion:18F-PSMA-11 can be safely administered and results in a mean effective dose of 12.8 ± 0.6 μSv/MBq. Therefore, the total radiation dose is lower than for other PSMA PET agents and in the same range as 18F-DCFPyL.

Topography of 11C-Pittsburgh compound B uptake in Alzheimer's disease: a voxel-based investigation of cortical and white matter regions.

Objective:To compare results of positron emission tomography (PET) with carbon-11-labeled Pittsburgh compound B (11C-PIB) obtained with cerebellar or global brain uptake for voxel intensity normalization, describe the cortical sites with highest tracer uptake in subjects with mild Alzheimer’s disease (AD), and explore possible group differences in 11C-PIB binding to white matter.Methods: 11C-PIB PET scans were acquired from subjects with AD (n=17) and healthy elderly controls (n=19). Voxel-based analysis was performed with statistical parametric mapping (SPM).Results:Cerebellar normalization showed higher 11C-PIB uptake in the AD group relative to controls throughout the cerebral cortex, involving the lateral temporal, orbitofrontal, and superior parietal cortices. With global uptake normalization, greatest cortical binding was detected in the orbitofrontal cortex; decreased 11C-PIB uptake in white matter was found in the posterior hippocampal region, corpus callosum, pons, and internal capsule.Conclusion:The present case-control voxelwise 11C-PIB PET comparison highlighted the regional distribution of amyloid deposition in the cerebral cortex of mildly demented AD patients. Tracer uptake was highest in the orbitofrontal cortex. Decreased 11C-PIB uptake in white-matter regions in this patient population may be a marker of white-matter damage in AD.

18F-FLT PET/MRI for bone marrow failure syndrome-initial experience

BackgroundBone marrow failure syndrome (BMFS) is a heterogeneous group of disorders associated with single- or multiple-lineage cytopenia and failure of normal hematopoiesis. We assessed the feasibility of integrated PET/MRI with 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) to assess the pathophysiology of whole-body bone marrow for the diagnosis and monitoring of BMFS. Twenty-five consecutive patients with BMFS underwent a pre-treatment 18F-FLT PET/MRI scan. They included 7 patients with aplastic anemia (AA), 16 with myelodysplastic syndrome (MDS), and 2 with myeloproliferative neoplasms (MPNs), primary myelofibrosis (MF), and secondary [post-essential thrombocythemia (post-ET)] MF. Two of the seven AA patients underwent a post-treatment scan. Eight of the 16 MDS patients who exhibited decreased 18F-FLT uptake in the pelvis were considered to have hypoplastic MDS (hypo-MDS). 18F-FLT PET and diffusion-weighted imaging (DWI) were visually and quantitatively evaluated.ResultsThe 18F-FLT uptake in the ilium was strongly correlated with bone marrow cellularity based on biopsy samples (ρ = 0.85). AA patients exhibited heterogeneously decreased uptake of 18F-FLT according to disease severity. Multiple 18F-FLT foci were observed in the proximal extremities, and they were in the central skeleton in severe AA patients. Post-treatment 18F-FLT PET scans of severe AA patients reflected the response of hematopoietic activity to treatment. MDS patients had marked 18F-FLT uptake in the central skeleton and proximal extremities, whereas hypo-MDS patients had heterogeneously decreased uptake, similar to that of non-severe AA patients. 18F-FLT PET and DWI were unable to predict the progression to leukemia for both MDS and hypo-MDS patients. A primary MF patient had slightly decreased 18F-FLT uptake in the central skeleton, but marked expansion of bone marrow activity to the distal extremities and high uptake of tracer in the extremely enlarged spleen (extramedullary hematopoiesis). In contrast, a secondary (post-ET) MF patient demonstrated marked bone marrow uptake, reflecting the hypercellular marrow with fibrosis. DWI revealed diffusely high signal intensities in both the primary and secondary MF patients.Conclusion18F-FLT PET can be used to noninvasively assess whole-body bone marrow proliferative activity and DWI may reflect the different aspects of bone marrow pathophysiology from 18F-FLT PET. 18F-FLT PET/MRI is useful for the diagnosis and monitoring of BMFS, except for the differentiation between non-severe AA and hypo-MDS, and the prediction of progression to leukemia.

Performance evaluation of a small animal PET scanner a high level of multiplexing and charge-signal transmission

Small animal positron emission tomography (PET) is a noninvasive imaging modality that enables in vivo imaging and quantification of the biological processes of small experimental animals. We have developed a small animal PET that utilizes a high-resolution multiplexed readout and charge signal transmission (CST) method. The small animal PET was composed of six detector blocks consisting of SiPMs and LYSO arrays. Six detector blocks were mounted on a PET gantry having an inner diameter of 76 mm, outer diameter of 112 mm, and axial length of 40.8 mm. The charge signals of SiPM output were transmitted to the input of multiplexed readout using 4 m flexible flat cables. The multiplexed readout was composed of six main boards, each of which included 36 detector boards, to reduce the number of readout channels by a factor of 36, with a multiplexing ratio of 144:4. The performance of the small animal PET was evaluated using NEMA NU 4-2008 standards, and its imaging capability was demonstrated by in vivo mouse imaging studies. The average energy and time resolutions were 13.2% ± 0.3% and 3.8 ns, respectively. The spatial resolution at the center of the transaxial FOV was 1.1 mm, and the peak sensitivity at the center of the axial FOV was 1.5%. The peak noise equivalent count (NEC) rate and scatter fraction were 21.1 kcps at 18.2 MBq and 21%, respectively. The acquired images demonstrated high quality tracer uptake patterns of small experimental animals. The results of performance evaluation and animal imaging indicate that the small animal PET developed in this study can provide high-quality small animal imaging with cost-effectiveness and compactness.

Evaluation of aortic 18F-NaF tracer uptake using PET/CT as a predictor of aortic calcification in postmenopausal women: A longitudinal study.

IntroductionAortic calcification as detected by computed tomography is associated with arterial stiffening and is an important predictor of cardiovascular morbidity and mortality. Uptake of 18F-sodium fluoride (18F-NaF) in the aortic wall reflects metabolically active areas of calcification. The aim of this study was to determine if 18F-NaF uptake in the aorta is associated with calcification and progression of calcification as detected by computed tomography.MethodsTwenty-one postmenopausal women (mean age 62 ± 6 years) underwent assessment of aortic 18F-NaF uptake using positron emission tomography/computer tomography at baseline and a repeat computed tomography scan after a mean follow-up of 3.8 ± 1.3 years. Tracer uptake was quantified by calculating the target-to-background (TBR) ratios at baseline and follow-up. Calcification was assessed at baseline and follow-up using computed tomography.ResultsOver the follow-up period, aortic calcium volume increased from 0.46 ± 0.62 to 0.71 ± 0.93 cm3 (P < 0.05). However, the change in calcium volume did not correlate with baseline TBR either unadjusted (r = 0.00, P = 1.00) or adjusted for age and baseline calcium volume (beta coefficient = −0.18, P = 0.42). TBR at baseline did not differ between participants with (n = 16) compared to those without (n = 5) progression in calcium volume (2.43 ± 0.46 vs. 2.31 ± 0.38, P = 0.58). In aortic segments identified to have the highest tracer uptake at baseline, calcium volume did not significantly change over the follow-up period (P = 0.41).ConclusionIn a cohort of postmenopausal women, 18F-NaF uptake as measured by TBR in the lumbar aorta did not predict progression of aortic calcification as detected by computed tomography over a four-year follow-up.

The role of bone SPECT/CT in patients with persistent or recurrent lumbar pain following lumbar spine stabilization surgery.

Despite recent advances in lumbar spine stabilization surgery (LSSS), a high number of patients continue to complain of persistent/recurrent lumbar pain after LSSS. Conventional imaging (plain radiography, CT and MRI) is commonly performed to assess potential lumbar pain generators, but findings are equivocal in approximately 20% of patients. The purpose of this study was to assess the diagnostic performance of 99mTc-HDP bone SPECT/CT in identifying potential pain generators in patients with persistent/recurrent lumbar pain after LSSS but in whom conventional diagnostic imaging is inconclusive. A total of 187 patients (median age 56years, 70 men) with persistent/recurrent lumbar pain following LSSS with inconclusive conventional imaging (plain radiography, CT and/or MRI) underwent 99mTc-HDP bone SPECT/CT and were included in the study. Tracer uptake on SPECT/CT, as an indicator of ongoing or altered osteoblastic activity, was assessed in the lumbar spine stabilization segment(s) and in adjacent segments. Uptake intensity was graded as (1) high (the same as or more than iliac crest uptake), (2) mild (the same as or more than nondiseased vertebral uptake but less than iliac crest uptake), or (3) negative (normal scan). Mild and high uptake were regarded as positive. In 160 of the 187 patients (85.6%), SPECT/CT showed positive mild or high tracer uptake in the LSSS region. More than half of the patients had abnormal tracer uptake in the stabilized segments (56.7%) and/or in the adjacent segments (55.6%). Although positive stabilized segment findings were commonly seen at <2years (70.3%) and the rate decreased with time after LSSS, they were seen at >6years after surgery in 38.2% of patients. In 51.4% of patients, abnormal activity was seen in the adjacent segments <2years after LSSS, suggesting early/accelerated degeneration after surgery. The proportion of patients with abnormal activity in the adjacent segments increased to 67.3% at >6years after LSSS (p< 0.05). Positive SPECT/CT findings in the stabilized segments were more frequent in patients with three or more stabilized segments (p< 0.05), but were not more frequent in the adjacent segments. Overall, positive SPECT/CT guided therapy in 64% of patients, which included facet joint/nerve root injections or re-do surgery at active sites and/or adjacent sites. Bone SPECT/CT is a sensitive diagnostic tool for identifying altered osteoblastic activity, which might be a pain generator in patients with persistent/recurrent pain after lumbar surgery especially when conventional imaging is inconclusive.

Matched-pair, 86Y/90Y-labeled, bivalent RGD/bombesin antagonist, [RGD-Glu-[DO3A]-6-Ahx-RM2], as a potential theranostic agent for prostate cancer

IntroductionIn this study, we describe development of a true matched-pair theranostic agent that is able to target the αVβ3 integrin and the gastrin releasing peptide receptor (GRPR). We herein describe methods to metallate and characterize the new conjugate and to validate its biological efficacy by in vitro and in vivo methods. MethodsWe have previously described the development of [RGD-Glu-6Ahx-RM2] (where RGD: Arg-Gly-Asp; Glu: glutamic acid; 6-Ahx: 6-amino hexanoic acid; RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2)) that has been conjugated to a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) bifunctional chelating agent (BFCA) to afford [RGD-Glu-[DO3A]-6-Ahx-RM2] peptide. In this study, we have radiolabeled [RGD-Glu-[DO3A]-6-Ahx-RM2] peptide with 86Y or 90Y. Natural-metallated (natY) conjugates were assessed for binding affinity for the αVβ3 integrin or GRPR in human glioblastoma U87-MG and prostate PC-3 cell lines, respectively. The effective stability of the new tracers was also evaluated prior to in vivo evaluation in normal CF-1 mice and SCID mice bearing xenografted tumors. ResultsCompetitive displacement binding assays in PC-3 cells showed high binding affinity for the GRPR (IC50, 5.65 ± 0.00 nM). On the other hand, competitive displacement binding assays in U87-MG cells revealed only moderate binding to the αVβ3 integrin (IC50, 346 ± 5.30 nM). Biodistribution studies in PC-3 tumor-bearing mice [RGD-Glu-[[90Y]Y-DO3A]-6-Ahx-RM2] showed high tumor uptake (8.70 ± 0.35%ID/g at 1 h post-intravenous injection) and retention of tracer (5.28 ± 0.12%ID/g) at 24 h post-intravenous injection. Micro-positron emission tomography (microPET) in PC-3 tumor-bearing mice using [RGD-Glu-[[86Y]Y-DO3A]-6-Ahx-RM2] correlated well with biodistribution investigations over the various time points that were studied. ConclusionsThe [RGD-Glu-[[86Y]Y-DO3A]-6-Ahx-RM2] and [RGD-Glu-[[90Y]Y-DO3A]-6-Ahx-RM2] matched-pair conjugates described herein exhibit favorable microPET and pharmacokinetic profiles and merit further investigations for molecular imaging and/or therapeutic evaluation in larger animal models and potentially humans. Advances in knowledge and implications for patient careThe theranostic, heterobivalent, agents described herein perform comparably with other mono- and multivalent conjugates we have reported and offer the potential of improved sensitivity for detecting prostate cancer cells that might exhibit differing profiles of receptor expression on tumor cells in human patients.

Data-driven gating in PET: Influence of respiratory signal noise on motion resolution.

Data-driven gating (DDG) approaches for positron emission tomography (PET) are interesting alternatives to conventional hardware-based gating methods. In DDG, the measured PET data themselves are utilized to calculate a respiratory signal, that is, subsequently used for gating purposes. The success of gating is then highly dependent on the statistical quality of the PET data. In this study, we investigate how this quality determines signal noise and thus motion resolution in clinical PET scans using a center-of-mass-based (COM) DDG approach, specifically with regard to motion management of target structures in future radiotherapy planning applications. PET list mode datasets acquired in one bed position of 19 different radiotherapy patients undergoing pretreatment [18 F]FDG PET/CT or [18 F]FDG PET/MRI were included into this retrospective study. All scans were performed over a region with organs (myocardium, kidneys) or tumor lesions of high tracer uptake and under free breathing. Aside from the original list mode data, datasets with progressively decreasing PET statistics were generated. From these, COM DDG signals were derived for subsequent amplitude-based gating of the original list mode file. The apparent respiratory shift d from end-expiration to end-inspiration was determined from the gated images and expressed as a function of signal-to-noise ratio SNR of the determined gating signals. This relation was tested against additional 25 [18 F]FDG PET/MRI list mode datasets where high-precision MR navigator-like respiratory signals were available as reference signal for respiratory gating of PET data, and data from a dedicated thorax phantom scan. All original 19 high-quality list mode datasets demonstrated the same behavior in terms of motion resolution when reducing the amount of list mode events for DDG signal generation. Ratios and directions of respiratory shifts between end-respiratory gates and the respective nongated image were constant over all statistic levels. Motion resolution d/dmax could be modeled as d/dmax=1-e-1.52(SNR-1)0.52, with dmax as the actual respiratory shift. Determining dmax from d and SNR in the 25 test datasets and the phantom scan demonstrated no significant differences to the MR navigator-derived shift values and the predefined shift, respectively. The SNR can serve as a general metric to assess the success of COM-based DDG, even in different scanners and patients. The derived formula for motion resolution can be used to estimate the actual motion extent reasonably well in cases of limited PET raw data statistics. This may be of interest for individualized radiotherapy treatment planning procedures of target structures subjected to respiratory motion.