Clinical Use and Utility of Amyloid Imaging J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Henryk Barthel; Osama Sabri
Currently, 3 amyloid PET tracers are approved and commercially available for clinical use. They allow for the accurate in vivo detection of amyloid plaques, one hallmark of Alzheimer disease. Here, we review the current knowledge on the clinical use and utility of amyloid imaging. Appropriate use criteria for the clinical application of amyloid imaging are established, and most currently available data point to their validity. Visual amyloid image analysis is highly standardized. Disclosure of amyloid imaging results is desired by many cognitively impaired subjects and seems to be safe once appropriate education is delivered to the disclosing clinicians. Regarding clinical utility, increasing evidence points to a change in diagnosis via amyloid imaging in about 30% of cases, to an increase in diagnostic confidence in about 60% of cases, to a change in patient management in about 60% of cases, and specifically to a change in medication in about 40% of cases. Also, amyloid imaging results seem to have a relevant impact on caregivers. Further, initial simulation studies point to a potential positive effect on patient outcome and to cost effectiveness of amyloid imaging. These features, however, will require confirmation in prospective clinical trials. More work is also required to determine the clinical utility of amyloid imaging specifically in subjects with mild cognitive impairment and in comparison with or in conjunction with other Alzheimer disease biomarkers. In summary, the clinical use of amyloid imaging is being studied, and the currently available data point to a relevant clinical utility of this imaging technique. Ongoing research will determine whether this accurate and noninvasive approach to amyloid plaque load detection will translate into a benefit to cognitively impaired subjects.
Current Concepts in 68Ga-DOTATATE Imaging of Neuroendocrine Neoplasms: Interpretation, Biodistribution, Dosimetry, and Molecular Strategies J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Lisa Bodei; Valentina Ambrosini; Ken Herrmann; Irvin Modlin
68Ga-DOTATATE PET/CT provides information on the location of somatostatin receptor–expressing tumors. Integrating this imaging data effectively in patient care requires the clinical history; the histopathology and biomarker information; and the grade, stage, and prior imaging results. Previous therapies and technical aspects of the study should be considered, given their ability to alter the interpretation of the images. This includes physiologic biodistribution of the radiotracer, as well as conditions that engender false-positive results. This article provides a guide to the performance and interpretation of 68Ga-DOTATATE PET/CT and describes its role in the diagnostic algorithm of neuroendocrine neoplasms and its overall utility in their management.
Metabolic Imaging of Infection J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Ismaheel Lawal; JanRijn Zeevaart; Thomas Ebenhan; Alfred Ankrah; Mariza Vorster; Hendrik G. Kruger; Thavendran Govender; Mike Sathekge
Metabolic imaging has come to occupy a prominent place in the diagnosis and management of microbial infection. Molecular probes available for infection imaging have undergone a rapid evolution starting with nonspecific agents that accumulate similarly in infection, sterile inflammation, and neoplastic tissue and then extending to more targeted probes that seek to identify specific microbial species. This focus review describes the metabolic and molecular imaging techniques currently available for clinical use in infection imaging and those that have demonstrated promising results in preclinical studies with the potential for clinical applications.
Nuclear Medicine Training in the United States J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 George M. Segall; Erin E. Grady; Joanna R. Fair; Munir V. Ghesani; Leonie Gordon
In the October issue of The Journal of Nuclear Medicine, the authors of the “Hot Topics” paper, “Nuclear Medicine Training: What Now?” suggested a path forward for training in nuclear medicine that “matches the needs of the evolving clinical specialty” by “combined, multispecialty training.” (1). The American Board of Nuclear Medicine (ABNM) also endorses combined, multispecialty training that maintains high standards for nuclear medicine education, prepares physicians for practice in a changing environment, and advances the specialty.
Curative Multicycle Radioimmunotherapy Monitored by Quantitative SPECT/CT-Based Theranostics, Using Bispecific Antibody Pretargeting Strategy in Colorectal Cancer J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Sarah M. Cheal; Edward K. Fung; Mitesh Patel; Hong Xu; Hong-fen Guo; Pat B. Zanzonico; Sebastien Monette; K. Dane Wittrup; Nai-Kong V. Cheung; Steven M. Larson
Radioimmunotherapy of solid tumors using antibody-targeted radionuclides has been limited by low therapeutic indices (TIs). We recently reported a novel 3-step pretargeted radioimmunotherapy (PRIT) strategy based on a glycoprotein A33 (GPA33)–targeting bispecific antibody and a small-molecule radioactive hapten, a complex of 177Lu and S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (177Lu-DOTA-Bn), that leads to high TIs for radiosensitive tissues such as blood (TI = 73) and kidney (TI = 12). We tested our hypothesis that a fractionated anti-GPA33 DOTA-PRIT regimen calibrated to deliver a radiation absorbed dose to tumor of more than 100 Gy would lead to a high probability of tumor cure while being well tolerated by nude mice bearing subcutaneous GPA33-positive SW1222 xenografts. Methods: We treated groups of nude mice bearing 7-d-old SW1222 xenografts with a fractionated 3-cycle anti-GPA33 DOTA-PRIT regimen (total administered 177Lu-DOTA-Bn activity, 167 MBq/mouse; estimated radiation absorbed dose to tumor, 110 Gy). In randomly selected mice undergoing treatment, serial SPECT/CT imaging was used to monitor treatment response and calculate radiation absorbed doses to tumor. Necropsy was done on surviving animals 100–200 d after treatment to determine frequency of cure and assess select normal tissues for treatment-related histopathologies. Results: Rapid exponential tumor progression was observed in control treatment groups (i.e., no treatment or 177Lu-DOTA-Bn only), leading to euthanasia due to excessive tumor burden, whereas 10 of 10 complete responses were observed for the DOTA-PRIT–treated animals within 30 d. Treatment was well tolerated, and 100% histologic cure was achieved in 9 of 9 assessable animals without detectable radiation damage to critical organs, including bone marrow and kidney. Radiation absorbed doses to tumor derived from SPECT/CT (102 Gy) and from biodistribution (110 Gy) agreed to within 6.9%. Of the total dose of approximately 100 Gy, the first dose contributes 30%, the second dose 60%, and the third dose 10%. Conclusion: In a GPA33-positive human colorectal cancer xenograft mouse model, we validated a SPECT/CT-based theranostic PRIT regimen that led to 100% complete responses and 100% cures without any treatment-related toxicities, based on high TIs for radiosensitive tissues. These studies support the view that anti-GPA33 DOTA-PRIT will be a potent radioimmunotherapy regimen for GPA33-positive colorectal cancer tumors in humans.
In Vivo Quantification of ERβ Expression by Pharmacokinetic Modeling: Studies with 18F-FHNP PET J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Inês F. Antunes; Antoon T.M. Willemsen; Jurgen W.A. Sijbesma; Ate S. Boerema; Aren van Waarde; Andor W.J.M. Glaudemans; Rudi A.J.O. Dierckx; Elisabeth G.E. de Vries; Geke A.P. Hospers; Erik F.J. de Vries
The estrogen receptor (ER) is a target for endocrine therapy in breast cancer patients. Individual quantification of ERα and ERβ expression, rather than total ER levels, might enable better prediction of the response to treatment. We recently developed the tracer 2-18F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol (18F-FHNP) for assessment of ERβ levels with PET. In the current study, we investigated several pharmacokinetic analysis methods to quantify changes in ERβ availability with 18F-FHNP PET. Methods: Male nude rats were subcutaneously inoculated in the shoulder with ERα/ERβ-expressing SKOV3 human ovarian cancer cells. Two weeks after tumor inoculation, a dynamic 18F-FHNP PET scan with arterial blood sampling was acquired from rats treated with vehicle or various concentrations of estradiol (nonspecific ER agonist) or genistein (ERβ-selective agonist). Different pharmacokinetic models were applied to quantify ERβ availability in the tumor. Results: Irreversible-uptake compartmental models fitted the kinetics of 18F-FHNP uptake better than reversible models. The irreversible 3-tissue-compartment model, which included both the parent and the metabolite input function, gave results comparable to those of the irreversible 2-tissue-compartment model with only a parent input function, indicating that radioactive metabolites contributed little to the tumor uptake. Patlak graphical analysis gave metabolic rates (Ki, the irreversible uptake rate constant) comparable to compartment modeling. The Ki values correlated well with ERβ expression but not with ERα, confirming that Ki is a suitable parameter to quantify ERβ expression. SUVs at 60 min after tracer injection also correlated (r2 = 0.47; P = 0.04) with ERβ expression. A reduction in 18F-FHNP tumor uptake and Ki values was observed in the presence of estradiol or genistein. Conclusion: 18F-FHNP PET enables assessment of ERβ availability in tumor-bearing rats. The most suitable parameter to quantify ERβ expression is the Ki. However, a simplified static imaging protocol for determining the SUVs can be applied to assess ERβ levels.
The Evolving Role of Succinate in Tumor Metabolism: An 18F-FDG–Based Study J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Philippe Garrigue; Aurore Bodin-Hullin; Laure Balasse; Samantha Fernandez; Wassim Essamet; Françoise Dignat-George; Karel Pacak; Benjamin Guillet; David Taïeb
In recent years, inherited and acquired mutations in the tricarboxylic acid (TCA) cycle enzymes have been reported in diverse cancers. Pheochromocytomas and paragangliomas often exhibit dysregulation of glucose metabolism, which is also driven by mutations in genes encoding the TCA cycle enzymes or by activation of hypoxia signaling. Pheochromocytomas and paragangliomas associated with succinate dehydrogenase (SDH) deficiency are characterized by high 18F-FDG avidity. This association is currently only partially explained. Therefore, we hypothesized that accumulation of succinate due to the TCA cycle defect could be the major connecting hub between SDH-mutated tumors and the 18F-FDG uptake profile. Methods: To test whether succinate modifies the 18F-FDG metabolic profile of tumors, we performed in vitro and in vivo (small-animal PET/CT imaging and autoradiography) experiments in the presence of succinate, fumarate, and phosphate-buffered saline (PBS) in different cell models. As a control, we also evaluated the impact of succinate on 18F-fluorocholine uptake and retention. Glucose transporter 1 (GLUT1) immunohistochemistry was performed to assess whether 18F-FDG uptake correlates with GLUT1 staining. Results: Intratumoral injection of succinate significantly increased 18F-FDG uptake at 24 h on small-animal PET/CT imaging and autoradiography. No effect of succinate was observed on cancer cells in vitro, but interestingly, we found that succinate caused increased 18F-FDG uptake by human umbilical vein endothelial cells in a concentration-dependent manner. No significant effect was observed after intratumoral injection of fumarate or PBS. Succinate, fumarate, and PBS have no effect on cell viability, regardless of cell lineage. Intramuscular injection of succinate also significantly increases 18F-FDG uptake by muscle when compared with either PBS or fumarate, highlighting the effect of succinate on connective tissues. No difference was observed between PBS and succinate on 18F-fluorocholine uptake in the tumor and muscle and on hind limb blood flow. GLUT1 expression quantification did not significantly differ between the study groups. Conclusion: The present study shows that succinate stimulates 18F-FDG uptake by endothelial cells, a finding that partially explains the 18F-FDG metabotype observed in tumors with SDH deficiency. Although this study is an 18F-FDG–based approach, it provides an impetus to better characterize the determinants of 18F-FDG uptake in various tumors and their surrounding microenvironment, with a special emphasis on the role of tumor-specific oncometabolites.
18F-FDG PET Response After Induction Chemotherapy Can Predict Who Will Benefit from Subsequent Esophagectomy After Chemoradiotherapy for Esophageal Adenocarcinoma J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Mian Xi; Zhongxing Liao; Wayne L. Hofstetter; Ritsuko Komaki; Linus Ho; Steven H. Lin
This study aimed to determine whether 18F-FDG PET response after induction chemotherapy before concurrent chemoradiotherapy can identify patients with esophageal adenocarcinoma who may benefit from subsequent esophagectomy. Methods: We identified and analyzed 220 patients with esophageal adenocarcinoma who had received induction chemotherapy before chemoradiotherapy, with or without surgery, with curative intent; all underwent 18F-FDG PET scanning before and after induction chemotherapy. 18F-FDG PET responders were defined as patients who achieved complete response (CR) after induction chemotherapy (maximum SUV ≤ 3.0). The predictive value of 18F-FDG PET response for patient outcomes was evaluated. Results: Overall, 86 patients had bimodality therapy (BMT; induction chemotherapy + chemoradiotherapy) and 134 had trimodality therapy (TMT; induction chemotherapy + chemoradiotherapy with surgery). Forty-eight patients (21.8%) achieved an 18F-FDG PET CR after induction chemotherapy. 18F-FDG PET CR was found to correlate with overall survival (OS) and progression-free survival (PFS) in BMT patients. For TMT patients, 18F-FDG PET CR predicted pathologic response (P = 0.003) but not survival. Among 18F-FDG PET nonresponders, TMT patients had significantly better survival than did BMT patients (P < 0.001). However, among 18F-FDG PET responders, BMT patients had OS (P = 0.201) and PFS (P = 0.269) similar to that of TMT patients. After propensity score-matched analysis, 18F-FDG PET responders treated with BMT versus TMT still had comparable OS and PFS, but TMT was associated with better locoregional control. Conclusion: 18F-FDG PET response to induction chemotherapy could be a useful imaging biomarker to identify patients with esophageal adenocarcinoma who could benefit from subsequent esophagectomy after chemoradiotherapy. Compared with BMT, TMT can significantly improve survival in 18F-FDG PET nonresponders. However, outcomes for 18F-FDG PET responders were similar after either treatment (BMT or TMT). Prospective validation of these findings is warranted.
Circulating Tumor DNA Reflects Tumor Metabolism Rather Than Tumor Burden in Chemotherapy-Naive Patients with Advanced Non–Small Cell Lung Cancer: 18F-FDG PET/CT Study J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Silvia Morbelli; Angela Alama; Giulia Ferrarazzo; Simona Coco; Carlo Genova; Erika Rijavec; Francesca Bongioanni; Federica Biello; Maria Giovanna Dal Bello; Giulia Barletta; Michela Massollo; Irene Vanni; Roberta Piva; Alberto Nieri; Matteo Bauckneht; Gianmario Sambuceti; Francesco Grossi
We aimed to evaluate the relationships between circulating tumor cells (CTCs) or plasma cell–free DNA (cfDNA) on one side and a comprehensive range of 18F-FDG PET/CT–derived parameters on the other side in chemotherapy-naive patients with advanced non–small cell lung cancer (NSCLC). Methods: From a group of 79 patients included in a trial evaluating the role of pretreatment circulating tumor markers as predictors of prognosis in chemotherapy-naive patients with advanced NSCLC, we recruited all those who underwent 18F-FDG PET/CT for clinical reasons at our institution before inclusion in the trial (and thus just before chemotherapy). For each patient, a peripheral blood sample was collected at baseline for the evaluation of CTCs and cfDNA. CTCs were isolated by size using a filtration-based device and then morphologically identified and enumerated; cfDNA was isolated from plasma and quantified by a quantitative polymerase chain reaction using human telomerase reverse transcriptase. The following 18F-FDG PET/CT–derived parameters were computed: maximum diameter of the primary lesion (T), of the largest lymph node (N), and of the largest metastatic lesion (M); SUVmax; SUVmean; size-incorporated SUVmax; metabolic tumor volume; and total lesion glycolysis. All parameters were independently measured for T, N, and M. The associations among CTCs, cfDNA, and 18F-FDG PET/CT–derived parameters were evaluated by multivariate-analysis. Patients were divided into 2 groups according to the presence of either limited metastatic involvement (M1a or M1b due to extrathoracic lymph nodes only) or disseminated metastatic disease. The presence or absence of metabolically active bone lesions was also recorded for each patient, and patient subgroups were compared. Results: Thirty-seven patients recruited in the trial matched our PET-based criteria (24 men; age, 64.5 ± 8.1 y). SUVmax for the largest metastatic lesion was the only variable independently associated with baseline cfDNA levels (P = 0.016). Higher levels of cfDNA were detected in the subgroup of patients with metabolically active bone lesions (P = 0.02), but no difference was highlighted when patients with more limited metastatic disease were compared with patients with disseminated metastatic disease. Conclusion: The correlation of cfDNA levels with tumor metabolism, but not with metabolic tumor volume at regional or distant levels, suggests that cfDNA may better reflect tumor biologic behavior or aggressiveness rather than tumor burden in metastatic NSCLC.
Test–Retest Variability in Lesion SUV and Lesion SUR in 18F-FDG PET: An Analysis of Data from Two Prospective Multicenter Trials J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Frank Hofheinz; Ivayla Apostolova; Liane Oehme; Jörg Kotzerke; Jörg van den Hoff
Quantitative assessment of radio- and chemotherapy response with 18F-FDG whole-body PET has attracted increasing interest in recent years. In most published work, SUV has been used for this purpose. In the context of therapy response assessment, the reliability of lesion SUVs, notably their test–retest stability, thus becomes crucial. However, a recent study demonstrated substantial test–retest variability (TRV) in SUVs. The purpose of the present study was to investigate whether the tumor-to-blood SUV ratio (SUR) can improve TRV in tracer uptake. Methods: 73 patients with advanced non–small cell lung cancer from the prospective multicenter trials ACRIN 6678 (n = 34) and MK-0646-008 (n = 39) were included in this study. All patients underwent two 18F-FDG PET/CT investigations on two different days (time difference, 3.6 ± 2.1 d; range, 1–7 d) before therapy. For each patient, up to 7 tumor lesions were evaluated. For each lesion, SUVmax and SUVpeak were determined. Blood SUV was determined as the mean value of a 3-dimensional aortic region of interest that was delineated on the attenuation CT image and transferred to the PET image. SURs were computed as the ratio of tumor SUV to blood SUV and were uptake time–corrected to 75 min after injection. TRV was quantified as 1.96 multiplied by the root-mean-square deviation of the fractional paired differences in SUV and SUR. The combined effect of blood normalization and uptake time correction was inspected by considering RTRV (TRVSUR/TRVSUV), a ratio reflecting the reduction in the TRV in SUR relative to SUV. RTRV was correlated with the group-averaged-value difference (δ) in CFmean (δCFmean) of the quantity δCF = |CF – 1|, where CF is the numeric factor that converts individual ratios of paired SUVs into corresponding SURs. This correlation analysis was performed by successively increasing a threshold value δCFmin and computing δCFmean and RTRV for the remaining subgroup of patients/lesions with δCF ≥ δCFmin. Results: The group-averaged TRVSUV and TRVSUR were 32.1 and 29.0, respectively, which correspond to a reduction of variability in SUR by an RTRV factor of 0.9 in comparison to SUV. This rather marginal improvement can be understood to be a consequence of the atypically low intrasubject variability in blood SUV and uptake time and the accordingly small δCF values in the investigated prospective study groups. In fact, subgroup analysis with increasing δCFmin thresholds revealed a pronounced negative correlation (Spearman ρ = −0.99, P < 0.001) between RTRV and δCFmean, where RTRV ≈ 0.4 in the δCFmin = 20% subgroup, corresponding to a more than 2-fold reduction of TRVSUR compared with TRVSUV. Conclusion: Variability in blood SUV and uptake time has been identified as a causal factor in the TRV in lesion SUV. Therefore, TRV in lesion uptake measurements can be reduced by replacing SUV with SUR as the uptake measure. The improvement becomes substantial for the level of variability in blood SUV and uptake time typically observed in the clinical context.
A Prospective Study Comparing 99mTc-Hydroxyethylene-Diphosphonate Planar Bone Scintigraphy and Whole-Body SPECT/CT with 18F-Fluoride PET/CT and 18F-Fluoride PET/MRI for Diagnosing Bone Metastases J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Johan Löfgren; Jann Mortensen; Sine H. Rasmussen; Claus Madsen; Annika Loft; Adam E. Hansen; Peter Oturai; Karl Erik Jensen; Mette Louise Mørk; Michala Reichkendler; Liselotte Højgaard; Barbara M. Fischer
We prospectively evaluated and compared the diagnostic performance of 99mTc-hydroxyethylene-diphosphonate (99mTc-HDP) planar bone scintigraphy (pBS), 99mTc-HDP SPECT/CT, 18F-NaF PET/CT, and 18F-NaF PET/MRI for the detection of bone metastases. Methods: One hundred seventeen patients with histologically proven malignancy referred for clinical pBS were prospectively enrolled. pBS and whole-body SPECT/CT were performed followed by 18F-NaF PET/CT within 9 d. 18F-NaF PET/MRI was also performed in 46 patients. Results: Bone metastases were confirmed in 16 patients and excluded in 101, which was lower than expected. The number of equivocal scans was significantly higher for pBS than for SPECT/CT and PET/CT (18 vs. 5 and 6, respectively; P = 0.004 and 0.01, respectively). When equivocal readings were excluded, no statistically significant difference in sensitivity, specificity, positive predictive value, negative predictive value, or overall accuracy were found when comparing the different imaging techniques. In the per-patient analysis, equivocal scans were either assumed positive for metastases (“pessimistic analysis”) or assumed negative for metastases (“optimistic analysis”). The percentages of misdiagnosed patients for the pessimistic analysis were 21%, 15%, 9%, and 7% for pBS, SPECT/CT, PET/CT, and PET/MRI, respectively. Corresponding figures for the optimistic analysis were 9%, 12%, 5%, and 7%. In those patients identified as having bone metastases according to the reference standard, SPECT/CT, 18F-NaF PET/CT, and PET/MRI detected additional lesions compared with pBS in 31%, 63%, and 71%, respectively. Conclusion: 18F-NaF PET/CT and whole-body SPECT/CT resulted in a significant reduction of equivocal readings compared with pBS, which implies an improved diagnostic confidence. However, the clinical benefit of using, for example, 18F-NaF PET/CT or PET/MRI as compared with SPECT/CT and pBS in this patient population with a relatively low prevalence of bone metastases (14%) is likely limited. This conclusion is influenced by the low prevalence of patients with osseous metastases. There may well be significant differences in the sensitivity of SPECT/CT, PET/CT, and PET/MRI compared with pBS, but a larger patient population or a patient population with a higher prevalence of bone metastases would have to be studied to demonstrate this.
Establishing 177Lu-PSMA-617 Radioligand Therapy in a Syngeneic Model of Murine Prostate Cancer J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Wolfgang P. Fendler; Andreea D. Stuparu; Susan Evans-Axelsson; Katharina Lückerath; Liu Wei; Woosuk Kim; Soumya Poddar; Jonathan Said; Caius G. Radu; Matthias Eiber; Johannes Czernin; Roger Slavik; Ken Herrmann
Clinical 177Lu-PSMA-617 radioligand therapy (RLT) is applied in advanced-stage prostate cancer. However, to the best of our knowledge murine models to study the biologic effects of various activity levels have not been established. The aim of this study was to optimize specific and total activity for 177Lu-PSMA-617 RLT in a syngeneic model of murine prostate cancer. Methods: Murine-reconstituted, oncogene-driven prostate cancer cells (0.1 × 106) (RM1), transduced to express human prostate-specific membrane antigen (PSMA), were injected into the left flank of C57Bl6 immunocompetent mice. RLT was performed by administering a single tail vein injection of 177Lu-PSMA-617 at different formulations for specific (60 MBq at high, 62 MBq/nmol; intermediate, 31 MBq/nmol; or low 15 MBq/nmol specific activity) or total activity (30, 60, or 120 MBq). Organ distribution was determined by ex vivo γ-counter measurement. DNA double-strand breaks were measured using anti–gamma-H2A.X (phospho S139) immunohistochemistry. Efficacy was assessed by serial CT tumor volumetry and 18F-FDG PET metabolic volume. Toxicity was evaluated 4 wk after the start of RLT. Results: Mean tumor-to-kidney ratios ± SEM were 19 ± 5, 10 ± 5, and 2 ± 0 for high, intermediate, and low (each n = 3) specific activity, respectively. Four of 6 (67%) mice treated with intermediate or high specific activity and none of 6 (0%) mice treated with low specific activity or formulation demonstrated significant DNA double-strand breaks (≥5% γ-H2A.X–positive cells). High when compared with intermediate or low specific activity resulted in a lower mean ± SEM tumor load by histopathology (vital tissue, 4 ± 2 vs. 8 ± 3 mm2; n = 3 vs. 6), day-4 18F-FDG PET (metabolic volume, 87 ± 23 vs. 118 ± 14 mm3; n = 6 vs. 12), and day-7 CT (volume, 323 ± 122 vs. 590 ± 46 mm3; n = 3 vs. 6; P = 0.039). 177Lu-PSMA-617 (120 MBq) with high specific activity induced superior tumor growth inhibition (P = 0.021, n = 5/group) without subacute hematologic toxicity (n = 3/group). Conclusion: 177Lu-PSMA-617 (120 MBq) and high specific activity resulted in the highest efficacy in a syngeneic model of murine prostate cancer. The model will be useful for studying the effects of PSMA-directed RLT combined with potentially synergistic pharmacologic approaches.
Most of the Intended Management Changes After 68Ga-DOTATATE PET/CT Are Implemented J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Jeremie Calais; Johannes Czernin; Matthias Eiber; Wolfgang P. Fendler; Jeannine Gartmann; Anthony P. Heaney; Andrew E. Hendifar; Joseph R. Pisegna; J. Randolph Hecht; Edward M. Wolin; Roger Slavik; Pawan Gupta; Andrew Quon; Christiaan Schiepers; Martin S. Allen-Auerbach; Ken Herrmann
In this prospective referring-physician–based survey, we investigated the definite clinical impact of 68Ga-DOTATATE PET/CT on managing patients with neuroendocrine tumors (NETs). Methods: We prospectively studied 130 patients with 68Ga-DOTATATE PET/CT referred for initial or subsequent management decisions (NCT02174679). Referring physicians completed one questionnaire before the scan (Q1) to indicate the treatment plan without PET/CT information, one immediately after review of the imaging report to denote intended management changes (Q2), and one 6 mo later (Q3) to verify whether intended changes were in fact implemented. To further validate the Q3 responses, a systematic electronic chart review was conducted. Results: All 3 questionnaires were completed by referring physicians for 96 of 130 patients (74%). 68Ga-DOTATATE PET/CT resulted in intended management changes (Q2) in 48 of 96 patients (50%). These changes were finally implemented (Q3) in 36 of 48 patients (75%). Q3 responses were confirmed in all patients with an available electronic chart (36/96; 38%). Conclusion: This prospective study confirmed a significant impact of 68Ga-DOTATATE PET/CT on the intended management of patients with NETs (50% of changes) and notably demonstrated a high implementation rate (75%) of these intended management changes.
18F-DCFPyL PET/CT in the Detection of Prostate Cancer at 60 and 120 Minutes: Detection Rate, Image Quality, Activity Kinetics, and Biodistribution J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Maurits Wondergem; Friso M. van der Zant; Remco J.J. Knol; Sergiy V. Lazarenko; Jan Pruim; Igle J. de Jong
There is increasing interest in PET/CT with prostate-specific membrane antigen (PSMA) tracers for imaging of prostate cancer because of the higher detection rates of prostate cancer lesions than with PET/CT with choline. For 68Ga-PSMA-11 tracers, late imaging at 180 min after injection instead of imaging at 45–60 min after injection improves the detection of prostate cancer lesions. For 18F-DCFPyL, improved detection rates have recently been reported in a small pilot study. In this study, we report the effects of PET/CT imaging at 120 min after injection of 18F-DCFPyL in comparison to images acquired at 60 min after injection in a larger clinical cohort of 66 consecutive patients with histopathologically proven prostate cancer. Methods: Images were acquired 60 and 120 min after injection of 18F-DCFPyL. We report the positive lesions specified for anatomic locations (prostate, seminal vesicles, local lymph nodes, distant lymph nodes, bone, and others) at both time points by visual analysis, the image quality at both time points, and a semiquantitative analysis of the tracer activity in both prostate cancer lesions as well as normal tissues at both time points. Results: Our data showed a significantly increasing uptake of 18F-DCFPyL between 60 and 120 min after injection in 203 lesions characteristic for prostate cancer (median, 10.78 vs. 12.86, P < 0.001, Wilcoxon signed-rank test). By visual analysis, 38.5% of all patients showed more lesions using images at 120 min after injection than using images at 60 min after injection, and in 9.2% a change in TNM staging was found. All lesions seen on images 60 min after injection were also visible on images 120 min after injection. A significantly better mean signal-to-noise ratio of 11.93 was found for images acquired 120 min after injection (P < 0.001, paired t test; signal-to-noise ratio at 60 min after injection, 11.15). Conclusion: 18F-DCFPyL PET/CT images at 120 min after injection yield a higher detection rate of prostate cancer characteristic lesions than images at 60 min after injection. Further studies are needed to elucidate the best imaging time point for 18F-DCFPyL.
Intraindividual Comparison of 18F-PSMA-1007 PET/CT, Multiparametric MRI, and Radical Prostatectomy Specimens in Patients with Primary Prostate Cancer: A Retrospective, Proof-of-Concept Study J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Claudia Kesch; Maria Vinsensia; Jan P. Radtke; Heinz P. Schlemmer; Martina Heller; Elena Ellert; Tim Holland-Letz; Stefan Duensing; Nils Grabe; Ali Afshar-Oromieh; Kathrin Wieczorek; Martin Schäfer; Oliver C. Neels; Jens Cardinale; Clemens Kratochwil; Markus Hohenfellner; Klaus Kopka; Uwe Haberkorn; Boris A. Hadaschik; Frederik L. Giesel
68Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT represents an advanced method for the staging of primary prostate cancer (PCa) and diagnosis of recurrent or metastatic PCa. However, because of the narrow availability of 68Ga the development of alternative tracers is of high interest. The objective of this study was to examine the value of the new PET tracer 18F-PSMA-1007 for the staging of local disease by comparing it with multiparametric MRI (mpMRI) and radical prostatectomy (RP) histopathology. Methods: In 2016, 18F-PSMA-1007 PET/CT was performed in 10 men with biopsy-confirmed high-risk PCa. Nine patients underwent mpMRI in the process of primary diagnosis. Consecutively, RP was performed in all 10 men. Agreement analysis was performed retrospectively. PSMA staining was added for representative sections in RP specimen slices. Localization and agreement analysis of 18F-PSMA-1007 PET/CT, mpMRI, and RP specimens was performed by dividing the prostate into 38 sections as described in the prostate imaging reporting and data system (PI-RADS) (version 2). Sensitivity, specificity, positive predictive values, negative predictive values (NPVs), and accuracy were calculated for total and near-total agreement. Results: 18F-PSMA-1007 PET/CT had an NPV of 68% and an accuracy of 75%, and mpMRI had an NPV of 88% and an accuracy of 73% for total agreement. Near-total agreement analysis resulted in an NPV of 91% and an accuracy of 93% for 18F-PSMA-1007 PET/CT and 91% and 87% for mpMRI, respectively. Retrospective combination of mpMRI and PET/CT had an accuracy of 81% for total and 93% for near-total agreement. Conclusion: Comparison with RP histopathology demonstrates that 18F-PSMA-1007 PET/CT is promising for accurate local staging of PCa.
Motion-Corrected Imaging of the Aortic Valve with 18F-NaF PET/CT and PET/MRI: A Feasibility Study J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Mhairi K. Doris; Mathieu Rubeaux; Tania Pawade; Yuka Otaki; Yibin Xie; Debiao Li; Balaji K. Tamarappoo; David E. Newby; Daniel S. Berman; Marc R. Dweck; Piotr J. Slomka; Damini Dey
We investigated whether motion correction of gated 18F-fluoride PET/CT and PET/MRI of the aortic valve could improve PET quantitation and image quality. Methods: A diffeomorphic, mass-preserving, anatomy-guided registration algorithm was used to align the PET images from 4 cardiac gates, preserving all counts, and apply them to the PET/MRI and PET/CT data of 6 patients with aortic stenosis. Measured signal-to-noise ratios (SNRs) and target-to-background ratios (TBRs) were compared with the standard method of using only the diastolic gate. Results: High-intensity aortic valve 18F-fluoride uptake was observed in all patients. After motion correction, SNR and TBR increased compared with the median diastolic gate (SNR, 51.61 vs. 21.0; TBR, 2.85 vs. 2.22) and the median summed data (SNR, 51.61 vs. 34.10; TBR, 2.85 vs. 1.95) (P = 0.028 for all). Furthermore, noise decreased from 0.105 (median, diastolic) to 0.042 (median, motion-corrected) (P = 0.028). Conclusion: Motion correction of hybrid 18F-fluoride PET markedly improves SNR, resulting in improved image quality.
Management Impact of Imaging Brain Vesicular Monoamine Transporter Type 2 in Clinically Uncertain Parkinsonian Syndrome with 18F-AV133 and PET J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Paschal K. Alexander; Yenni Lie; Gareth Jones; Chomalaven Sivaratnam; Svetlana Bozinvski; Rachel S. Mulligan; Kenneth Young; Victor L. Villemagne; Christopher C. Rowe
Idiopathic Parkinson disease is a common neurodegenerative disorder for which misdiagnosis occurs in up to 30% of patients after initial assessment and in 10%–15% even after long-term follow-up. Vesicular monoamine transporter type 2 (VMAT2) imaging with PET allows assessment of the integrity of the presynaptic dopaminergic pathway. We investigated the management impact of VMAT2 imaging in patients with clinically uncertain Parkinsonian syndromes. Methods: Forty-seven patients with clinically uncertain Parkinsonian syndromes (mean age ± SD, 56.9 ± 14.9 y; age range, 21–80 y) were referred from movement disorder specialists. All participants underwent a 20-min PET acquisition 2 h after injection of 250 MBq of 18F-AV-133, and the resulting images were quantitatively assessed. Clinical impact was recorded as high, moderate, or low based on diagnosis and management questionnaires completed by the referring specialists before and after release of the PET results. Management impact was high if there was a change in diagnostic category, moderate if there was a change in medication, and low if there was no change. Results: VMAT2 PET changed the diagnosis in 11 (23%) and medication in 25 (53%) participants. Management impact was high in 23%, moderate in 38%, and low in 39% of the participants. High diagnostic confidence increased from 11% of patients to 80% after the release of the scan results. Conclusion: 18F-AV-133 had substantial management impact in patients with clinically uncertain Parkinsonian syndromes. VMAT2 imaging with 18F-AV133 might improve diagnosis, prognosis, and appropriate use of medication, translating into better patient outcomes.
Diagnostic Performance of the Visual Reading of 123I-Ioflupane SPECT Images With or Without Quantification in Patients With Movement Disorders or Dementia J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Jan Booij; Jacob Dubroff; Daniel Pryma; Jian Yu; Rajan Agarwal; Paras Lakhani; Phillip H. Kuo
Visual interpretation of 123I-ioflupane SPECT images has high diagnostic accuracy for differentiating parkinsonian syndromes (PS), from essential tremor and probable dementia with Lewy bodies (DLB) from Alzheimer disease. In this study, we investigated the impact on accuracy and reader confidence offered by the addition of image quantification in comparison with visual interpretation alone. Methods: We collected 304 123I-ioflupane images from 3 trials that included subjects with a clinical diagnosis of PS, non-PS (mainly essential tremor), probable DLB, and non-DLB (mainly Alzheimer disease). Images were reconstructed with standardized parameters before striatal binding ratios were quantified against a normal database. Images were assessed by 5 nuclear medicine physicians who had limited prior experience with 123I-ioflupane interpretation. In 2 readings at least 1 mo apart, readers performed either a visual interpretation alone or a combined reading (i.e., visual plus quantitative data were available). Readers were asked to rate their confidence of image interpretation and judge scans as easy or difficult to read. Diagnostic accuracy was assessed by comparing image results with the standard of truth (i.e., diagnosis at follow-up) by measuring the positive percentage of agreement (equivalent to sensitivity) and the negative percentage of agreement (equivalent to specificity). The hypothesis that the results of the combined reading were not inferior to the results of the visual reading analysis was tested. Results: A comparison of the combined reading and the visual reading revealed a small, insignificant increase in the mean negative percentage of agreement (89.9% vs. 87.9%) and equivalent positive percentages of agreement (80.2% vs. 80.1%). Readers who initially performed a combined analysis had significantly greater accuracy (85.8% vs. 79.2%; P = 0.018), and their accuracy was close to that of the expert readers in the original studies (range, 83.3%–87.2%). Mean reader confidence in the interpretation of images showed a significant improvement when combined analysis was used (P < 0.0001). Conclusion: The addition of quantification allowed readers with limited experience in the interpretation of 123I-ioflupane SPECT scans to have diagnostic accuracy equivalent to that of the experienced readers in the initial studies. Also, the results of the combined reading were not inferior to the results of the visual reading analysis and offered an increase in reader confidence.
Does Antibiotic Treatment Affect the Diagnostic Accuracy of 18F-FDG PET/CT Studies in Patients with Suspected Infectious Processes? J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Olga Kagna; Marina Kurash; Nesrin Ghanem-Zoubi; Zohar Keidar; Ora Israel
18F-FDG PET/CT plays a significant role in the assessment of various infectious processes. Patients with suspected or known sites of infection are often referred for 18F-FDG imaging while already receiving antibiotic treatment. The current study assessed whether antibiotic therapy affected the detectability rate of infectious processes by 18F-FDG PET/CT. Methods: A 5-y retrospective study of all adult patients who underwent 18F-FDG PET/CT in search of a focal source of infection was performed. The presence, duration, and appropriateness of antibiotic treatment before 18F-FDG imaging were recorded. Diagnosis of an infectious process was based on microbiologic or pathologic data as well as on clinical and radiologic follow-up. Results: Two hundred seventeen patients underwent 243 PET/CT studies in search of a focal source of infection and were included in the study. Sixty-seven studies were excluded from further analysis because of a final noninfectious etiology or lack of further follow-up or details regarding the antibiotic treatment. The final study population included 176 18F-FDG PET/CT studies in 153 patients (107 men, 46 women; age range, 18–86 y). One hundred nineteen studies (68%) were performed in patients receiving antibiotic therapy for a range of 1–73 d. A diagnosis of infection was made in 107 true-positive cases (61%), including 63 studies (59%) in patients receiving appropriate antibiotic therapy started before the performance of the 18F-FDG PET/CT study. There were 52 true-negative (29%) and 17 false-positive (10%) 18F-FDG PET/CT studies. No false-negative results were found. Conclusion: 18F-FDG PET/CT correctly identified foci of increased uptake compatible with infection in most patients, including all patients receiving appropriate antimicrobial therapy, with no false-negative cases. On the basis of the current study results, the administration of antibiotics appears to have no clinically significant impact on the diagnostic accuracy of 18F-FDG PET/CT performed for evaluation of known or suspected infectious processes.
Integrating MRI and Chemokine Receptor CXCR4-Targeted PET for Detection of Leukocyte Infiltration in Complicated Urinary Tract Infections After Kidney Transplantation J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Thorsten Derlin; Faikah Gueler; Jan Hinrich Bräsen; Jessica Schmitz; Dagmar Hartung; Thomas R. Herrmann; Tobias L. Ross; Frank Wacker; Hans-Jürgen Wester; Marcus Hiss; Hermann Haller; Frank M. Bengel; Katja Hueper
Complicated urinary tract infections (UTIs) are frequent in immunosuppressed patients after kidney transplantation and may lead to allograft failure or urosepsis. Noninvasive detection of allograft involvement as well as localization of the primary site of infection are challenging. Therefore, we sought to determine whether molecularly targeted PET, combined with diffusion-weighted MRI, enables detection of leukocytes in renal allografts. Methods: Thirteen kidney transplant recipients with complicated UTIs underwent both PET with a specific CXCR4 ligand, 68Ga-pentixafor, and diffusion-weighted MRI. The spatial distribution and intensity of CXCR4 upregulation in renal allografts as determined by SUVs on PET and diffusion restriction as determined by apparent diffusion coefficients (ADCs) on MRI were analyzed and compared with urinalysis, clinical chemistry and bacteriology, and biopsy, if available. Results: Combined PET/MRI detected acute allograft infection in 9 patients and lower UTI/nonurologic infections in the remaining 4 patients. Leukocyte infiltration was identified by areas of CXCR4 upregulation compared with unaffected parenchyma in PET (SUVmean, 4.6 vs. 3.7; P < 0.01), corresponding to areas with increased cell density in MRI (ADCmin, 0.89 vs. 1.59 × 10−3 mm2/s, P < 0.01). Allograft CXCR4 signal was paralleled by CXCR4 upregulation in lymphoid organs. Histopathologic evaluation supported a correlation between CXCR4 signal and presence of leukocytes. Conclusion: Combined CXCR4-targeted PET/MRI with 68Ga-pentixafor may enable the noninvasive detection of leukocytes in renal allografts. This novel methodology may refine the characterization of infectious and inflammatory kidney diseases and may serve as a platform for future clinical studies targeting allograft infection.
PET-Guided Evaluation and Optimization of Internalized Antibody–Drug Conjugates Targeting Erythropoietin-Producing Hepatoma A2 Receptor J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Orit Jacobson; Qing Li; Haojun Chen; Gang Niu; Dale O. Kiesewetter; Lan Xu; Kimberly Cook; Gengcheng Yang; William Dall’Acqua; Ping Tsui; Li Peng; Xiaoyuan Chen
The erythropoietin-producing hepatoma A2 receptor (EphA2) is a tyrosine kinase overexpressed by tumor stroma and cancer cells. A high expression level of EphA2 predicts poor prognosis, correlating with disease progression and metastasis. Therefore, EphA2 is a relevant therapeutic target for human cancer. Antibodies, selectively bound to EphA2, can induce rapid receptor phosphorylation that results in antibody internalization and degradation. This internalization mechanism has been exploited with the development of antibody–drug conjugates (ADCs) for cancer chemotherapy. In this study, we used PET imaging to study the pharmacokinetics and tumor delivery of a panel of anti-EphA2 monoclonal antibodies (mAbs) with and without drug conjugates. Methods: A library of human anti-EphA2 mAbs were screened and evaluated for EphA2 internalization rate, binding affinity, epitope binding, and hydrophobicity. We chose 3 of these antibodies, denoted as 1C1, 3B10, and 2H7, which recognize different epitopes, for further evaluation. ADCs were generated by S239C mutation to give a ratio of 2 drug molecules per antibody. Native mAbs and ADCs were characterized, after conjugation to a DFO chelator and 89Zr radiolabeling, in assays including cell uptake, internalization, hydrophobicity, and in vivo imaging using PET. Results: All 3 mAbs had high affinities for EphA2 but exhibited different internalization rates following the order of 1C1 > 3B10 > 2H7. Internalization rate is only 1 factor that affects in vitro cell uptake and in vivo tumor accumulation. Interestingly, the hydrophobicity of the mAbs, which followed the order of 2H7 > 1C1 > 3B10, had a strong correlation with in vivo tumor uptake measured by PET, with the least hydrophobic antibody, 3B10, showing the highest tumor uptake. ADC significantly reduced the in vivo uptake of all 3 mAbs. Conclusion: Tumor uptake of mAb is a complex process that is affected by multiple parameters, including internalization, hydrophobicity, and chemical modification. Our results suggest that the addition of drug molecules to mAb increases the clearance of the mAb presumably due to the increased hydrophobicity. Understanding the complexity of antibody-based tumor delivery may help improve ADC engineering for better tumor targeting and reduced side effects.
Imaging B Cells in a Mouse Model of Multiple Sclerosis Using 64Cu-Rituximab PET J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Michelle L. James; Aileen Hoehne; Aaron T. Mayer; Kendra Lechtenberg; Monica Moreno; Gayatri Gowrishankar; Ohad Ilovich; Arutselvan Natarajan; Emily M. Johnson; Joujou Nguyen; Lisa Quach; May Han; Marion Buckwalter; Sudeep Chandra; Sanjiv S. Gambhir
B lymphocytes are a key pathologic feature of multiple sclerosis (MS) and are becoming an important therapeutic target for this condition. Currently, there is no approved technique to noninvasively visualize B cells in the central nervous system (CNS) to monitor MS disease progression and response to therapies. Here, we evaluated 64Cu-rituximab, a radiolabeled antibody specifically targeting the human B cell marker CD20, for its ability to image B cells in a mouse model of MS using PET. Methods: To model CNS infiltration by B cells, experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice that express human CD20 on B cells. EAE mice were given subcutaneous injections of myelin oligodendrocyte glycoprotein fragment1–125 emulsified in complete Freund adjuvant. Control mice received complete Freund adjuvant alone. PET imaging of EAE and control mice was performed 1, 4, and 19 h after 64Cu-rituximab administration. Mice were perfused and sacrificed after the final PET scan, and radioactivity in dissected tissues was measured with a γ-counter. CNS tissues from these mice were immunostained to quantify B cells or were further analyzed via digital autoradiography. Results: Lumbar spinal cord PET signal was significantly higher in EAE mice than in controls at all evaluated time points (e.g., 1 h after injection: 5.44 ± 0.37 vs. 3.33 ± 0.20 percentage injected dose [%ID]/g, P < 0.05). 64Cu-rituximab PET signal in brain regions ranged between 1.74 ± 0.11 and 2.93 ± 0.15 %ID/g for EAE mice, compared with 1.25 ± 0.08 and 2.24 ± 0.11 %ID/g for controls (P < 0.05 for all regions except striatum and thalamus at 1 h after injection). Similarly, ex vivo biodistribution results revealed notably higher 64Cu-rituximab uptake in the brain and spinal cord of huCD20tg EAE, and B220 immunostaining verified that increased 64Cu-rituximab uptake in CNS tissues corresponded with elevated B cells. Conclusion: B cells can be detected in the CNS of EAE mice using 64Cu-rituximab PET. Results from these studies warrant further investigation of 64Cu-rituximab in EAE models and consideration of use in MS patients to evaluate its potential for detecting and monitoring B cells in the progression and treatment of this disease. These results represent an initial step toward generating a platform to evaluate B cell–targeted therapeutics en route to the clinic.
In Vivo Imaging of the Programmed Death Ligand 1 by 18F PET J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Dinko E. González Trotter; Xiangjun Meng; Paul McQuade; Daniel Rubins; Michael Klimas; Zhizhen Zeng; Brett M. Connolly; Patricia J. Miller; Stacey S. O’Malley; Shu-An Lin; Krista L. Getty; Laurence Fayadat-Dilman; Linda Liang; Elisabet Wahlberg; Olof Widmark; Caroline Ekblad; Fredrik Y. Frejd; Eric D. Hostetler; Jeffrey L. Evelhoch
Programmed death ligand 1 (PD-L1) is an immune regulatory ligand that binds to the T-cell immune check point programmed death 1. Tumor expression of PD-L1 is correlated with immune suppression and poor prognosis. It is also correlated with therapeutic efficacy of programmed death 1 and PD-L1 inhibitors. In vivo imaging may enable real-time follow-up of changing PD-L1 expression and heterogeneity evaluation of PD-L1 expression across tumors in the same subject. We have radiolabeled the PD-L1–binding Affibody molecule NOTA-ZPD-L1_1 with 18F and evaluated its in vitro and in vivo binding affinity, targeting, and specificity. Methods: The affinity of the PD-L1–binding Affibody ligand ZPD-L1_1 was evaluated by surface plasmon resonance. Labeling was accomplished by maleimide coupling of NOTA to a unique cysteine residue and chelation of 18F-AlF. In vivo studies were performed in PD-L1–positive, PD-L1–negative, and mixed tumor-bearing severe combined immunodeficiency mice. Tracer was injected via the tail vein, and dynamic PET scans were acquired for 90 min, followed by γ-counting biodistribution. Immunohistochemical staining with an antibody specific for anti–PD-L1 (22C3) was used to evaluate the tumor distribution of PD-L1. Immunohistochemistry results were then compared with ex vivo autoradiographic images obtained from adjacent tissue sections. Results: NOTA-ZPD-L1_1 was labeled, with a radiochemical yield of 15.1% ± 5.6%, radiochemical purity of 96.7% ± 2.0%, and specific activity of 14.6 ± 6.5 GBq/μmol. Surface plasmon resonance showed a NOTA-conjugated ligand binding affinity of 1 nM. PET imaging demonstrated rapid uptake of tracer in the PD-L1–positive tumor, whereas the PD-L1–negative control tumor showed little tracer retention. Tracer clearance from most organs and blood was quick, with biodistribution showing prominent kidney retention, low liver uptake, and a significant difference between PD-L1–positive (percentage injected dose per gram [%ID/g] = 2.56 ± 0.33) and –negative (%ID/g = 0.32 ± 0.05) tumors (P = 0.0006). Ex vivo autoradiography showed excellent spatial correlation with immunohistochemistry in mixed tumors. Conclusion: Our results show that Affibody ligands can be effective at targeting tumor PD-L1 in vivo, with good specificity and rapid clearance. Future studies will explore methods to reduce kidney activity retention and further increase tumor uptake.
A Modular Dual-Labeling Scaffold That Retains Agonistic Properties for Somatostatin Receptor Targeting J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Sukhen C. Ghosh; Melissa Rodriguez; Kendra S. Carmon; Julie Voss; Nathaniel L. Wilganowski; Agnes Schonbrunn; Ali Azhdarinia
Fluorescence-guided surgery is an emerging imaging technique that can enhance the ability of surgeons to detect tumors when compared with visual observation. To facilitate characterization, fluorescently labeled probes have been dual-labeled with a radionuclide to enable cross-validation with nuclear imaging. In this study, we selected the somatostatin receptor imaging agent DOTATOC as the foundation for developing a dual-labeled analog. We hypothesized that a customized dual-labeling approach with a multimodality chelation (MMC) scaffold would minimize steric effects of dye conjugation and retain agonist properties. Methods: An MMC conjugate (MMC-TOC) was synthesized on solid-phase and compared with an analog prepared using conventional methods (DA-TOC). Both analogs were conjugated to IRDye 800 using copper-free click chemistry. The resulting compounds, MMC(IR800)-TOC and DA(IR800)-TOC, were labeled with Cu and 64Cu and tested in vitro in somatostatin receptor subtype 2–overexpressing HEK-293 cells to assess agonist properties, and in AR42J rat pancreatic cancer cells to determine receptor binding characteristics. Multimodality imaging was performed in AR42J xenografts. Results: Cu-MMC(IR800)-TOC demonstrated higher potency for cyclic adenosine monophosphate inhibition (half maximal effective concentration [EC50]: 0.21 ± 0.18 vs. 1.38 ± 0.54 nM) and receptor internalization (EC50: 41.9 ± 29.8 vs. 455 ± 299 nM) than Cu-DA(IR800)-TOC. Radioactive uptake studies showed that blocking with octreotide caused a dose-dependent reduction in 64Cu-MMC(IR800)-TOC uptake whereas 64Cu-DA(IR800)-TOC was not affected. In vivo studies revealed higher tumor uptake for 64Cu-MMC(IR800)-TOC than 64Cu-DA(IR800)-TOC (5.2 ± 0.2 vs. 3.6 ± 0.4 percentage injected dose per gram). In vivo blocking studies with octreotide reduced tumor uptake of 64Cu-MMC(IR800)-TOC by 66%. Excretion of 64Cu-MMC(IR800)-TOC was primarily through the liver and spleen whereas 64Cu-DA(IR800)-TOC was cleared through the kidneys. Ex vivo analysis at 24 h confirmed PET/CT data by showing near-infrared fluorescence signal in tumors and a tumor-to-muscle ratio of 5.3 ± 0.8 as determined by γ-counting. Conclusion: The findings demonstrate that drug design affected receptor pharmacology and suggest that the MMC scaffold is a useful tool for the development of dual-labeled imaging agents.
New Fetal Radiation Doses for 18F-FDG Based on Human Data J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Paolo Zanotti-Fregonara; Michael G. Stabin
Current standard values of fetal dosimetry deriving from 18F-FDG injection in pregnant women are estimated from animal data. The present communication offers a revision of fetal dosimetry values calculated from recently published human data, in which fetal 18F-FDG uptake was directly observed in vivo. The final doses were obtained from the observed time-integrated activity coefficients and a new generation of anthropomorphic voxel-based pregnancy phantoms.
Evaluation of Sinus/Edge-Corrected Zero-Echo-Time–Based Attenuation Correction in Brain PET/MRI J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Jaewon Yang; Florian Wiesinger; Sandeep Kaushik; Dattesh Shanbhag; Thomas A. Hope; Peder E.Z. Larson; Youngho Seo
In brain PET/MRI, the major challenge of zero-echo-time (ZTE)–based attenuation correction (ZTAC) is the misclassification of air/tissue/bone mixtures or their boundaries. Our study aimed to evaluate a sinus/edge-corrected (SEC) ZTAC (ZTACSEC), relative to an uncorrected (UC) ZTAC (ZTACUC) and a CT atlas-based attenuation correction (ATAC). Methods: Whole-body 18F-FDG PET/MRI scans were obtained for 12 patients after PET/CT scans. Only data acquired at a bed station that included the head were used for this study. Using PET data from PET/MRI, we applied ZTACUC, ZTACSEC, ATAC, and reference CT-based attenuation correction (CTAC) to PET attenuation correction. For ZTACUC, the bias-corrected and normalized ZTE was converted to pseudo-CT with air (−1,000 HU for ZTE < 0.2), soft-tissue (42 HU for ZTE > 0.75), and bone (−2,000 × [ZTE − 1] + 42 HU for 0.2 ≤ ZTE ≤ 0.75). Afterward, in the pseudo-CT, sinus/edges were automatically estimated as a binary mask through morphologic processing and edge detection. In the binary mask, the overestimated values were rescaled below 42 HU for ZTACSEC. For ATAC, the atlas deformed to MR in-phase was segmented to air, inner air, soft tissue, and continuous bone. For the quantitative evaluation, PET mean uptake values were measured in twenty 1-mL volumes of interest distributed throughout brain tissues. The PET uptake was compared using a paired t test. An error histogram was used to show the distribution of voxel-based PET uptake differences. Results: Compared with CTAC, ZTACSEC achieved the overall PET quantification accuracy (0.2% ± 2.4%, P = 0.23) similar to CTAC, in comparison with ZTACUC (5.6% ± 3.5%, P < 0.01) and ATAC (−0.9% ± 5.0%, P = 0.03). Specifically, a substantial improvement with ZTACSEC (0.6% ± 2.7%, P < 0.01) was found in the cerebellum, in comparison with ZTACUC (8.1% ± 3.5%, P < 0.01) and ATAC (−4.1% ± 4.3%, P < 0.01). The histogram of voxel-based uptake differences demonstrated that ZTACSEC reduced the magnitude and variation of errors substantially, compared with ZTACUC and ATAC. Conclusion: ZTACSEC can provide an accurate PET quantification in brain PET/MRI, comparable to the accuracy achieved by CTAC, particularly in the cerebellum.
Metal Artifact Reduction of CT Scans to Improve PET/CT J Nucl. Med. (IF 6.646) Pub Date : 2017-11-01 Charlotte S. van der Vos; Anne I.J. Arens; James J. Hamill; Christian Hofmann; Vladimir Y. Panin; Antoi P.W. Meeuwis; Eric P. Visser; Lioe-Fee de Geus-Oei
In recent years, different metal artifact reduction methods have been developed for CT. These methods have only recently been introduced for PET/CT even though they could be beneficial for interpretation, segmentation, and quantification of the PET/CT images. In this study, phantom and patient scans were analyzed visually and quantitatively to measure the effect on PET images of iterative metal artifact reduction (iMAR) of CT data. Methods: The phantom consisted of 2 types of hip prostheses in a solution of 18F-FDG and water. 18F-FDG PET/CT scans of 14 patients with metal implants (either dental implants, hip prostheses, shoulder prostheses, or pedicle screws) and 68Ga-labeled prostate-specific membrane antigen (68Ga-PSMA) PET/CT scans of 7 patients with hip prostheses were scored by 2 experienced nuclear medicine physicians to analyze clinical relevance. For all patients, a lesion was located in the field of view of the metal implant. Phantom and patients were scanned in a PET/CT scanner. The standard low-dose CT scans were processed with the iMAR algorithm. The PET data were reconstructed using attenuation correction provided by both standard CT and iMAR-processed CT. Results: For the phantom scans, cold artifacts were visible on the PET image. There was a 30% deficit in 18F-FDG concentration, which was restored by iMAR processing, indicating that metal artifacts on CT images induce quantification errors in PET data. The iMAR algorithm was useful for most patients. When iMAR was used, the confidence in interpretation increased or stayed the same, with an average improvement of 28% ± 20% (scored on a scale of 0%–100% confidence). The SUV increase or decrease depended on the type of metal artifact. The mean difference in absolute values of SUVmean of the lesions was 3.5% ± 3.3%. Conclusion: The iMAR algorithm increases the confidence of the interpretation of the PET/CT scan and influences the SUV. The added value of iMAR depends on the indication for the PET/CT scan, location and size/type of the prosthesis, and location and extent of the disease.
Nuclear Medicine Training: What Now? J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 David Mankoff; Daniel A. Pryma
Although the multidisciplinary nature of nuclear medicine (NM) and clinical molecular imaging is a key strength of the specialty, the breadth of disciplines involved in the practice of NM creates challenges for education and training. The evolution of NM science and technology—and the practice of clinical molecular imaging and theranostics—has created a need for changes in the approach to specialty training. The broader U.S. community of imaging physicians has been slow to accept this change, in good part due to historical divides between the NM and nuclear radiology (NR) communities. In this Journal of Nuclear Medicine Hot Topics discussion, we review the historical pathways to training; discuss the training needs for the modern practice of NM, clinical molecular imaging, and radionuclide therapy; and suggest a path forward for an approach to training that matches the needs of the evolving clinical specialty.
18F-FDG PET/CT in Lymphoma: Has Imaging-Directed Personalized Medicine Become a Reality? J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Sally F. Barrington; Peter W.M. Johnson
PET/CT using 18F-FDG is an essential part of the management of patients with lymphoma. Efforts to standardize PET acquisition and reporting, including the 5-point Deauville scale, have enabled PET to become a surrogate for treatment success or failure in common lymphoma subtypes. This review summarizes the key clinical-trial evidence that supports PET-directed personalized approaches in lymphoma. PET-guided therapy has improved outcomes in Hodgkin lymphoma, using less chemotherapy and more selective radiotherapy. Attempts to intensify chemotherapy in aggressive non-Hodgkin lymphomas have, however, proved ineffective in patients treated with rituximab and chemotherapy. Trials are under way to determine whether PET can obviate consolidation radiotherapy in patients with diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma. More recently, PET has been reported to be a reliable predictor of outcome in follicular lymphoma requiring treatment, and prospective trials to test PET-guided therapy in this disease are anticipated.
PSMA Ligands for PET Imaging of Prostate Cancer J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Sarah M. Schwarzenboeck; Isabel Rauscher; Christina Bluemel; Wolfgang P. Fendler; Steven P. Rowe; Martin G. Pomper; Ali Asfhar-Oromieh; Ken Herrmann; Matthias Eiber
Targeting the prostate-specific membrane antigen (PSMA) with 68Ga-labeled and 18F-labeled PET agents has become increasingly important in recent years. Imaging of biochemically recurrent prostate cancer has been established as a widely accepted clinical indication for PSMA ligand PET/CT in many parts of the world because of the results of multiple, primarily retrospective, studies that indicate superior detection efficacy compared with standard-of-care imaging. For high-risk primary prostate cancer, evidence is growing that this modality significantly aids in the detection of otherwise occult nodal and bone metastases. For both clinical indications in recurrent as well as in primary prostate cancer, preliminary data demonstrate a substantial impact on clinical management. Emerging data imply that intraprostatic tumor localization, therapy stratification, and treatment monitoring of advanced disease in specific clinical situations might become future indications. Current criteria for image reporting of PSMA ligand PET are evolving given the expanding body of literature on physiologic and pathologic uptake patterns and pitfalls. This article intends to give an educational overview on the current status of PSMA ligand PET imaging, including imaging procedure and interpretation, clinical indications, diagnostic potential, and impact on treatment planning.
Pretargeted Imaging and Therapy J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Mohamed Altai; Rosemery Membreno; Brendon Cook; Vladimir Tolmachev; Brian M. Zeglis
In vivo pretargeting stands as a promising approach to harnessing the exquisite tumor-targeting properties of antibodies for nuclear imaging and therapy while simultaneously skirting their pharmacokinetic limitations. The core premise of pretargeting lies in administering the targeting vector and radioisotope separately and having the 2 components combine within the body. In this manner, pretargeting strategies decrease the circulation time of the radioactivity, reduce the uptake of the radionuclide in healthy nontarget tissues, and facilitate the use of short-lived radionuclides that would otherwise be incompatible with antibody-based vectors. In this short review, we seek to provide a brief yet informative survey of the 4 preeminent mechanistic approaches to pretargeting, strategies predicated on streptavidin and biotin, bispecific antibodies, complementary oligonucleotides, and bioorthogonal click chemistry.
Imaging of Programmed Cell Death Ligand 1: Impact of Protein Concentration on Distribution of Anti-PD-L1 SPECT Agents in an Immunocompetent Murine Model of Melanoma J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Jessie R. Nedrow; Anders Josefsson; Sunju Park; Sagar Ranka; Sanchita Roy; George Sgouros
Programmed cell death ligand 1 (PD-L1) is part of an immune checkpoint system that is essential for preventing autoimmunity and cancer. Recent approaches in immunotherapy that target immune checkpoints have shown great promise in a variety of cancers, including metastatic melanoma. The use of targeted molecular imaging would help identify patients who will best respond to anti-PD-L1 treatment while potentially providing key information to limit immune-related adverse effects. Recently, we developed an antibody-based PD-L1–targeted SPECT agent—111In-diethylenetriaminepentaacetic acid (DTPA)-anti-PD-L1—to identify PD-L1–positive tumors in vivo. To best use such PD-L1–targeted imaging agents, it is important, as a first step, to understand how the signal is affected by different parameters. Methods: We evaluated the impact of protein concentration on the distribution of 111In-DTPA-anti-PD-L1 in a murine model of aggressive melanoma. Results: 111In-DTPA-anti-PD-L1 (dissociation constant, 0.6 ± 0.1 nM) demonstrated increased uptake in B16F10 tumors at protein concentrations equaling or exceeding 1 mg/kg at 24 h and 3 mg/kg at 72 h. At 24 h, the PD-L1–rich spleen and lungs demonstrated decreasing uptake with increasing protein concentration. At 72 h, uptake in the thymus was significantly increased at protein concentrations of 3 mg/kg or greater. Both time points demonstrated increased tracer amounts remaining in circulation as the amount of cold antibody was increased. Conclusion: These studies demonstrate that 111In-DTPA-anti-PD-L1 is capable of identifying tumors that overexpresses PD-L1 and monitoring the impact of PD-L1–rich organs on the distribution of anti-PD-L1 antibodies.
In Vivo Relationship Between Hypoxia and Angiogenesis in Human Glioblastoma: A Multimodal Imaging Study J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Keven Ferreira da Ponte; David Hassanein Berro; Solène Collet; Jean-Marc Constans; Evelyne Emery; Samuel Valable; Jean-Sébastien Guillamo
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena tumor hypoxia and angiogenesis, although few in vivo data exist in human brain tumors. This work aimed to study hypoxia and angiogenesis, in vivo and in situ, in patients admitted with GBM using multimodal imaging. Methods: Twenty-three GBM patients were assessed by 18F-fluoromisonidazole (18F-FMISO) PET and conventional and perfusion MRI before surgery. The level and location of hypoxia (18F-FMISO uptake, evaluated by tumor-to-blood [T/B] ratio), vascularization (cerebral blood volume [CBV]), and vascular permeability (contrast enhancement after gadolinium injection) were analyzed. The spatial relationship between tumor hypoxia and angiogenesis was assessed by an overlap analysis of the volume of 18F-FMISO uptake and the volumes of the high CBV regions and the contrast-enhancement regions. Results: A significant correlation was found between hypoxia and hypervascularization, especially for their maximum values (volume of maximal tumor hypoxia vs. relative CBV: r = 0.61, P = 0.002) and their volumes (hypoxia vs. hypervascularization: r = 0.91, P < 0.001). A large proportion of the high CBVs collocated with hypoxia (81.3%) and with contrast enhancement (46.5%). Conclusion: These results support the hypothesis of a tight association between hypoxia and angiogenesis. Our results suggest that there is insufficient tumor oxygenation in human GBM, despite increased tumor vascularization.
18F-Fluoromisonidazole Kinetic Modeling for Characterization of Tumor Perfusion and Hypoxia in Response to Antiangiogenic Therapy J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Milan Grkovski; Sally-Ann Emmas; Sean D. Carlin
Multiparametric imaging of tumor perfusion and hypoxia with dynamic 18F-fluoromisonidazole (18F-FMISO) PET may allow for an improved response assessment to antiangiogenic therapies. Cediranib (AZD2171) is a potent inhibitor of tyrosine kinase activity associated with vascular endothelial growth factor receptors 1, 2, and 3, currently in phase II/III clinical trials. Serial dynamic 18F-FMISO PET was performed to investigate changes in tumor biomarkers of perfusion and hypoxia after cediranib treatment. Methods: Twenty-one rats bearing HT29 colorectal xenograft tumors were randomized into a vehicle-treated control group (0.5% methylcellulose daily for 2 d [5 rats] or 7 d [4 rats]) and a cediranib-treated test group (3 mg/kg daily for 2 or 7 d; 6 rats in both groups). All rats were imaged before and after treatment, using a 90-min dynamic PET acquisition after administration of 42.1 ± 3.9 MBq of 18F-FMISO by tail vein injection. Tumor volumes were delineated manually, and the input function was image-derived (abdominal aorta). Kinetic modeling was performed using an irreversible 1-plasma 2-tissue compartmental model to estimate the kinetic rate constants K1, K1/k2, and k3—surrogates for perfusion, 18F-FMISO distribution volume, and hypoxia-mediated entrapment, respectively. Tumor-to-blood ratios (TBRs) were calculated on the last dynamic frame (80–90 min). Tumors were assessed ex vivo by digital autoradiography and immunofluorescence for microscopic visualization of perfusion (pimonidazole) and hypoxia (Hoechst 33342). Results: Cediranib treatment resulted in significant reduction of mean voxelwise 18F-FMISO TBR, K1, and K1/k2 in both the 2-d and the 7-d groups (P < 0.05). The k3 parameter was increased in both groups but reached significance only in the 2-d group. In the vehicle-treated groups, no significant change in TBR, K1, K1/k2, or k3 was observed (P > 0.2). Ex vivo tumor analysis confirmed the presence of hypoxic tumor regions that nevertheless exhibited relatively lower 18F-FMISO uptake. Conclusion: 18F-FMISO kinetic modeling reveals a more detailed response to antiangiogenic treatment than a single static image is able to reveal. The reduced mean K1 reflects a reduction in tumor vascular perfusion, whereas the increased k3 reflects a rise in hypoxia-mediated entrapment of the radiotracer. However, if only late static images are analyzed, the observed reduction in 18F-FMISO uptake after treatment with cediranib may be mistakenly interpreted as a global decrease, rather than an increase, in tumor hypoxia. These findings support the use of 18F-FMISO kinetic modeling to more accurately characterize the response to treatments that have a direct effect on tumor vascularization and perfusion.
Improved Detection of Transosseous Meningiomas Using 68Ga-DOTATATE PET/CT Compared with Contrast-Enhanced MRI J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Wolfgang G. Kunz; Lisa M. Jungblut; Philipp M. Kazmierczak; Franziska J. Vettermann; Andreas Bollenbacher; Jörg C. Tonn; Christian Schichor; Axel Rominger; Nathalie L. Albert; Peter Bartenstein; Maximilian F. Reiser; Clemens C. Cyran
68Ga-DOTATATE PET/CT enables detection of meningioma tissue based on somatostatin receptor 2 expression. Transosseous extension of intracranial meningiomas is known to be an important risk factor for tumor recurrence and patient mortality. We analyzed the diagnostic performance of 68Ga-DOTATATE PET/CT and contrast-enhanced MRI (CE-MRI) for the detection of osseous infiltration using qualitative and quantitative imaging parameters. Methods: In this institutional review board–approved retrospective study, subjects were selected from 327 consecutive 68Ga-DOTATATE PET/CT examinations for evaluation of confirmed or suspected meningioma. Inclusion criteria were CE-MRI within 30 d and pathology-confirmed meningioma diagnosis with inclusion or exclusion of transosseous extension as the standard of reference. Imaging was analyzed by two readers. Tracer uptake values and meningioma volumes were determined. χ2, Mann–Whitney U, Wilcoxon signed rank, and McNemar tests, as well as receiver-operating-characteristic analyses, were performed to compare variables and diagnostic performance. Results: Eighty-two patients fulfilled the inclusion criteria. Patients with transosseous extension of meningioma (n = 67) showed significantly larger lesions (median, 12.8 vs. 3.3 mL; P < 0.001) and significantly higher tracer uptake values (median SUVmax, 14.2 vs. 7.6; P = 0.011) than patients with extraosseous meningiomas (n = 15). 68Ga-DOTATATE PET/CT in comparison to CE-MRI performed at a higher sensitivity (98.5% vs. 53.7%) while maintaining high specificity (86.7% vs. 93.3%) in the detection of osseous involvement (P < 0.001). In receiver-operating-characteristic analysis, PET/CT assessment performed better than CE-MRI (area under the curve, 0.932 vs. 0.773). PET/CT- and CE-MRI–based volume estimation yielded comparable results for extraosseous meningiomas (P = 0.132) and the extraosseous part of transosseous meningiomas (P = 0.636), whereas the volume of the intraosseous part was assessed as significantly larger by PET/CT (P < 0.001). Conclusion: 68Ga-DOTATATE PET/CT enables improved detection of the transosseous extension of intracranial meningiomas compared with CE-MRI.
Alternative Means of Estimating 131I Maximum Permissible Activity to Treat Thyroid Cancer J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Kenneth J. Nichols; William Robeson; Miyuki Yoshida-Hay; Pat B. Zanzonico; Fritzgerald Leveque; Kuldeep K. Bhargava; Gene G. Tronco; Christopher J. Palestro
To protect bone marrow from overirradiation, the maximum permissible activity (MPA) of 131I to treat thyroid cancer is that which limits the absorbed dose to blood (as a surrogate of marrow) to less than 200 cGy. The conventional approach (method 1) requires repeated γ-camera whole-body measurements along with blood samples. We sought to determine whether reliable MPA values can be obtained by simplified procedures. Methods: Data acquired over multiple time points were examined retrospectively for 65 thyroid cancer patients, referred to determine 131I uptake and MPA for initial treatment after thyroidectomy (n = 39), including 17 patients with compromised renal function and 22 patients with known (n = 16) or suspected (n = 6) metastases. The total absorbed dose to blood (DTotal) was the sum of mean whole-body γ-ray dose component (Dγ) from uncollimated γ-camera measurements and dose due to β emissions (Dβ) from blood samples. Method 2 estimated DTotal from Dβ alone, method 3 estimated DTotal from Dγ alone, and method 4 estimated DTotal from a single 48-h γ-camera measurement. MPA was computed as 200 cGy/DTotal for each DTotal estimate. Results: Method 2 had the strongest correlation with conventional method 1 (r = 0.98) and values similar to method 1 (21.0 ± 13.7 cGy/GBq vs. 21.0 ± 14.1 cGy/GBq, P = 0.11), whereas method 3 had a weaker (P = 0.001) correlation (r = 0.94) and method 4 had the weakest (P < 0.0001) correlation (r = 0.69) and lower dose (16.3 ± 14.8 cGy/GBq, P < 0.0001). Consequently, correlation with method 1 MPA was strongest for method 2 MPA (r = 0.99) and weakest for method 4 (r = 0. 75). Method 2 and method 1 values agreed equally well regardless of whether patients had been treated with 131I previously or had abnormal renal function. Conclusion: Because MPA based on blood measurements alone is comparable to MPA obtained with combined body counting and blood sampling, blood measurements alone are sufficient for determining MPA.
Reader Training for the Restaging of Biochemically Recurrent Prostate Cancer Using 18F-Fluciclovine PET/CT J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Matthew P. Miller; Lale Kostakoglu; Daniel Pryma; Jian Qin Yu; Albert Chau; Eric Perlman; Bonnie Clarke; Donald Rosen; Penelope Ward
18F-Fluciclovine is a novel PET/CT tracer. This blinded image evaluation (BIE) sought to demonstrate that, after limited training, readers naïve to 18F-fluciclovine could interpret 18F-fluciclovine images from subjects with biochemically recurrent prostate cancer with acceptable diagnostic performance and reproducibility. The primary objectives were to establish individual readers’ diagnostic performance and the overall interpretation (2/3 reader concordance) compared with standard-of-truth data (histopathology or clinical follow-up) and to evaluate interreader reproducibility. Secondary objectives included comparison to the expert reader and assessment of intrareader reproducibility. Methods: 18F-Fluciclovine PET/CT images (n = 121) and corresponding standard‐of‐truth data were collected from 110 subjects at Emory University using a single-time-point static acquisition starting 5 min after injection of approximately 370 MBq of 18F-fluciclovine. Three readers were trained using standardized interpretation methodology and subsequently evaluated the images in a blinded manner. Analyses were conducted at the lesion, region (prostate, including bed and seminal vesicle, or extraprostatic, including all lymph nodes, bone, or soft-tissue metastasis), and subject level. Results: Lesion-level overall positive predictive value was 70.5%. The readers’ positive predictive value and negative predictive value were broadly consistent with each other and with the onsite read. Sensitivity was highest for readers 1 and 2 (68.5% and 63.9%, respectively) whereas specificity was highest for reader 3 (83.6%). Overall, prostate-level sensitivity was high (91.4%), but specificity was moderate (48.7%). Interreader agreement was 94.7%, 74.4%, and 70.3% for the lesion, prostate, and extraprostatic levels, respectively, with associated Fleiss’ κ-values of 0.54, 0.50, and 0.57. Intrareader agreement was 97.8%, 96.9%, and 99.1% at the lesion level; 100%, 100%, and 91.7% in the prostate region; and 83.3%, 75.0%, and 83.3% in the extraprostatic region for readers 1, 2, and 3, respectively. Concordance between the BIE and the onsite reader exceeded 75% for each reader at the lesion, region, and subject levels. Conclusion: Specific training in the use of standardized interpretation methodology for assessment of 18F-fluciclovine PET/CT images enables naïve readers to achieve acceptable diagnostic performance and reproducibility when staging recurrent prostate cancer.
Assessing Bone Marrow Activity in Patients with Myelofibrosis: Results of a Pilot Study of 18F-FLT PET J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Laetitia Vercellino; Matthieu John Ouvrier; Emmanuelle Barré; Bruno Cassinat; Virginie de Beco; Christine Dosquet; Sylvie Chevret; Véronique Meignin; Christine Chomienne; Marie-Elisabeth Toubert; Pascal Merlet; Jean-Jacques Kiladjian
An emerging noninvasive approach to assess tissue proliferation uses the PET tracer 3′-deoxy-3′-18F-fluorothymidine (18F-FLT). To evaluate the diagnostic value of this technique in myelofibrosis, 18F-FLT PET imaging results were compared with bone marrow histology and bone marrow scintigraphy (BMS), the gold standard techniques in this clinical situation. Methods: Fifteen patients with histology-proven myelofibrosis were included consecutively in the study. Tracers’ distributions were assessed using a visual grading assessment score of the uptake in the axial skeleton, proximal and distal limbs, liver, and spleen. This visual score was used to define patterns of tracer distribution and to compare the information provided either by PET or by BMS. A semiquantitative analysis with determination of SUVmax in the same localizations was performed for 18F-FLT PET. Results: The histology grade of fibrosis correlated with the SUVmax in the axial skeleton (spine and iliac crests) and proximal limbs. 18F-FLT uptake in these areas was much lower in patients with grade 3 fibrosis than in patients with grade 1 or 2 fibrosis. 18F-FLT PET showed the same distribution of uptake as BMS in 13 of 14 patients (1 patient did not undergo BMS). In 1 patient, 18F-FLT PET clearly showed an intense abnormal splenic uptake, whereas spleen uptake was inconclusive with BMS. Conclusion: 18F-FLT PET appears to be a reliable and convenient technique to assess hematopoietic activity in bone marrow. It yields results close to those observed with BMS. In our study population, 18F-FLT uptake in the axial skeleton and proximal limbs assessed by SUVmax correlated with the grade of fibrosis. Thus, 18F-FLT PET may be a useful tool to measure the severity of myelofibrosis, and to monitor noninvasively the patients’ status during follow-up. Finally, 18F-FLT PET may be foreseen as an alternative to BMS.
SSTR-Mediated Imaging in Breast Cancer: Is There a Role for Radiolabeled Somatostatin Receptor Antagonists? J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Simone U. Dalm; Joost Haeck; Gabriela N. Doeswijk; Erik de Blois; Marion de Jong; Carolien H.M. van Deurzen
Recent studies have shown enhanced tumor targeting by novel somatostatin receptor (SSTR) antagonists compared with clinically widely used agonists. However, these results have been obtained mostly in neuroendocrine tumors, and only limited data are available for cancer types with lower SSTR expression, including breast cancer (BC). To date, two studies have reported higher binding of the antagonist than the agonist in BC, but in both studies only a limited number of cases were evaluated. In this preclinical study, we further investigated whether the application of an SSTR antagonist can improve SSTR-mediated BC imaging in a large panel of BC specimens. We also generated an in vivo BC mouse model and performed SPECT/MRI and biodistribution studies. Methods: Binding of 111In-DOTA-Tyr3-octreotate (SSTR agonist) and 111In-DOTA-JR11 (SSTR antagonist) to 40 human BC specimens was compared using in vitro autoradiography. SSTR2 immunostaining was performed to confirm SSTR2 expression of the tumor cells. Furthermore, binding of the radiolabeled SSTR agonist and antagonist was analyzed in tissue material from 6 patient-derived xenografts. One patient-derived xenograft, the estrogen receptor–positive model T126, was chosen to generate in vivo mouse models containing orthotopic breast tumors for in vivo SPECT/MRI and biodistribution studies after injection with 177Lu-DOTA-Tyr3-octreotate or 177Lu-DOTA-JR11. Results: 111In-DOTA-JR11 binding to human BC tissue was significantly higher than 111In-DOTA-Tyr3-octreotate binding (P < 0.001). The median ratio of antagonist binding versus agonist binding was 3.39 (interquartile range, 2–5). SSTR2 immunostaining confirmed SSTR2 expression on the tumor cells. SPECT/MRI of the mouse model found better tumor visualization with the antagonist. This result was in line with the significantly higher tumor uptake of the radiolabeled antagonist than of the agonist as measured in biodistribution studies 285 min after radiotracer injection (percentage injected dose per gram of tissue: 1.92 ± 0.43 vs. 0.90 ± 0.17; P = 0.002). Conclusion: SSTR antagonists are promising candidates for BC imaging.
68Ga-PSMA-11 PET/CT Interobserver Agreement for Prostate Cancer Assessments: An International Multicenter Prospective Study J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Wolfgang Peter Fendler; Jeremie Calais; Martin Allen-Auerbach; Christina Bluemel; Nina Eberhardt; Louise Emmett; Pawan Gupta; Markus Hartenbach; Thomas A. Hope; Shozo Okamoto; Christian Helmut Pfob; Thorsten D. Pöppel; Christoph Rischpler; Sarah Schwarzenböck; Vanessa Stebner; Marcus Unterrainer; Helle D. Zacho; Tobias Maurer; Christian Gratzke; Alexander Crispin; Johannes Czernin; Ken Herrmann; Matthias Eiber
The interobserver agreement for 68Ga-PSMA-11 PET/CT study interpretations in patients with prostate cancer is unknown. Methods: 68Ga-PSMA-11 PET/CT was performed in 50 patients with prostate cancer for biochemical recurrence (n = 25), primary diagnosis (n = 10), biochemical persistence after primary therapy (n = 5), or staging of known metastatic disease (n = 10). Images were reviewed by 16 observers who used a standardized approach for interpretation of local (T), nodal (N), bone (Mb), or visceral (Mc) involvement. Observers were classified as having a low (<30 prior 68Ga-PSMA-11 PET/CT studies; n = 5), intermediate (30–300 studies; n = 5), or high level of experience (>300 studies; n = 6). Histopathology (n = 25, 50%), post–external-beam radiation therapy prostate-specific antigen response (n = 15, 30%), or follow-up PET/CT (n = 10, 20%) served as a standard of reference. Observer groups were compared by overall agreement (% patients matching the standard of reference) and Fleiss' κ with mean and corresponding 95% confidence interval (CI). Results: Agreement among all observers was substantial for T (κ = 0.62; 95% CI, 0.59–0.64) and N (κ = 0.74; 95% CI, 0.71–0.76) staging and almost perfect for Mb (κ = 0.88; 95% CI, 0.86–0.91) staging. Level of experience positively correlated with agreement for T (κ = 0.73/0.66/0.50 for high/intermediate/low experience, respectively), N (κ = 0.80/0.76/0.64, respectively), and Mc staging (κ = 0.61/0.46/0.36, respectively). Interobserver agreement for Mb was almost perfect irrespective of prior experience (κ = 0.87/0.91/0.88, respectively). Observers with low experience, when compared with intermediate and high experience, demonstrated significantly lower median overall agreement (54% vs. 66% and 76%, P = 0.041) and specificity for T staging (73% vs. 88% and 93%, P = 0.032). Conclusion: The interpretation of 68Ga-PSMA-11 PET/CT for prostate cancer staging is highly consistent among observers with high levels of experience, especially for nodal and bone assessments. Initial training on at least 30 patient cases is recommended to ensure acceptable performance.
Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Clemens Kratochwil; Frank Bruchertseifer; Hendrik Rathke; Marcus Bronzel; Christos Apostolidis; Wilko Weichert; Uwe Haberkorn; Frederik L. Giesel; Alfred Morgenstern
The aim of this study was to develop a treatment protocol for 225Ac-PSMA-617 α-radiation therapy in advanced-stage, metastatic castration-resistant prostate cancer patients with prostate-specific membrane antigen (PSMA)–positive tumor phenotype. Methods: A dosimetry estimate was calculated on the basis of time–activity curves derived from serially obtained 177Lu-PSMA-617 scans extrapolated to the physical half-life of 225Ac, assuming instant decay of unstable daughter nuclides. Salvage therapies empirically conducted with 50 (n = 4), 100 (n = 4), 150 (n = 2), and 200 kBq/kg (n = 4) of 225Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. Eight of 14 patients received further cycles in either 2- or 4-mo intervals with identical or deescalated activities. Results: Dosimetry estimates for 1 MBq of 225Ac-PSMA-617 assuming a relative biologic effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys, and 0.05 Sv for red marrow that are composed of 99.4% α, 0.5% β, and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100 kBq/kg per cycle. At 100 kBq/kg, the duration of prostate-specific antigen decline was less than 4 mo, but if therapy was repeated every 2 mo patients experienced additive antitumor effects. Treatment activities of 50 kBq/kg were without toxicity but induced insufficient antitumor response in these high-tumor-burden patients. Remarkable antitumor activity by means of objective radiologic response or tumor marker decline was observed in 9 of 11 evaluable patients. Conclusion: For advanced-stage patients, a treatment activity of 100 kBq/kg of 225Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.
Exploring New Multimodal Quantitative Imaging Indices for the Assessment of Osseous Tumor Burden in Prostate Cancer Using 68Ga-PSMA PET/CT J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Marie Bieth; Markus Krönke; Robert Tauber; Marielena Dahlbender; Margitta Retz; Stephan G. Nekolla; Bjoern Menze; Tobias Maurer; Matthias Eiber; Markus Schwaiger
PET combined with CT and prostate-specific membrane antigen (PSMA) ligands has gained significant interest for staging prostate cancer (PC). In this study, we propose 2 multimodal quantitative indices as imaging biomarkers for the assessment of osseous tumor burden using 68Ga-PSMA PET/CT and present preliminary clinical data. Methods: We defined 2 bone PET indices (BPIs) that incorporate anatomic information from CT and functional information from 68Ga-PSMA PET: BPIVOL is the percentage of bone volume affected by tumor and BPISUV additionally considers the level of PSMA expression. We describe a semiautomatic computation method based on segmentation of bones in CT and of lesions in PET. Data from 45 patients with castration-resistant PC and bone metastases during 223Ra-dichloride were retrospectively analyzed. We evaluated the computational stability and reproducibility of the proposed indices and explored their relation to the prostate-specific antigen blood value, the bone scan index (BSI), and disease classification using PERCIST. Results: On the technical side, BPIVOL and BPISUV showed an interobserver maximum difference of 3.5%, and their computation took only a few minutes. On the clinical side, BPIVOL and BPISUV showed significant correlations with BSI (r = 0.76 and 0.74, respectively, P < 0.001) and prostate-specific antigen values (r = 0.57 and 0.54, respectively, P < 0.01). When the proposed indices were compared against expert rating using PERCIST, BPIVOL and BPISUV showed better agreement than BSI, indicating their potential for objective response evaluation. Conclusion: We propose the evaluation of BPIVOL and BPISUV as imaging biomarkers for 68Ga-PSMA PET/CT in a prospective study exploring their potential for outcome prediction in patients with bone metastases from PC.
Evaluation of the Effect of Fingolimod Treatment on Microglial Activation Using Serial PET Imaging in Multiple Sclerosis J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Marcus Sucksdorff; Eero Rissanen; Jouni Tuisku; Salla Nuutinen; Teemu Paavilainen; Johanna Rokka; Juha Rinne; Laura Airas
Traditionally, multiple sclerosis (MS) has been considered a white matter disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial activation, also takes place outside the plaque areas, that is, in areas of normal-appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using 18-kDa translocator protein (TSPO)–binding radioligands and PET. It is unknown whether fingolimod affects microglial activation in MS. The aim of this study was to investigate whether serial PET can be used to evaluate the effect of fingolimod treatment on microglial activation. Methods: Ten relapsing-remitting MS patients were studied using the TSPO radioligand 11C-(R)-PK11195. Imaging was performed at baseline and after 8 and 24 wk of fingolimod treatment. Eight healthy individuals were imaged for comparison. Microglial activation was evaluated as distribution volume ratio of 11C‐(R)-PK11195. Results: The patients had MS for an average of 7.9 ± 4.3 y (mean ± SD), their total relapses averaged 4 ± 2.4, and their Expanded Disability Status Scale was 2.7 ± 0.5. The patients were switched to fingolimod because of safety reasons or therapy escalation. The mean washout period before the initiation of fingolimod was 2.3 ± 1.1 mo. The patients were clinically stable on fingolimod. At baseline, microglial activation was significantly higher in the combined NAWM and GM areas of MS patients than in healthy controls (P = 0.021). 11C‐(R)-PK11195 binding was reduced (−12.31%) within the combined T2 lesion area after 6 mo of fingolimod treatment (P = 0.040) but not in the areas of NAWM or GM. Conclusion: Fingolimod treatment reduced microglial/macrophage activation at the site of focal inflammatory lesions, presumably by preventing leukocyte trafficking from the periphery. It did not affect the widespread, diffuse microglial activation in the NAWM and GM. The study opens new vistas for designing future therapeutic studies in MS that use the evaluation of microglial activation as an imaging outcome measure.
Doxorubicin Effect on Myocardial Metabolism as a Prerequisite for Subsequent Development of Cardiac Toxicity: A Translational 18F-FDG PET/CT Observation J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Matteo Bauckneht; Giulia Ferrarazzo; Francesco Fiz; Silvia Morbelli; Matteo Sarocchi; Fabio Pastorino; Alberto Ghidella; Elena Pomposelli; Maurizio Miglino; Pietro Ameri; Laura Emionite; Flavia Ticconi; Eleonora Arboscello; Ambra Buschiazzo; Elena Augusta Massimelli; Salvatore Fiordoro; Anna Borra; Vanessa Cossu; Annalisa Bozzano; Adalberto Ibatici; Mirco Ponzoni; Paolo Spallarossa; Andrea Gallamini; Paolo Bruzzi; Gianmario Sambuceti; Cecilia Marini
The present translational study aimed to verify whether serial 18F-FDG PET/CT predicts doxorubicin cardiotoxicity. Methods: Fifteen athymic mice were treated intravenously with saline (n = 5) or with 5 or 7.5 mg of doxorubicin per kilogram (n = 5 each) and underwent dynamic small-animal PET beforehand and afterward to estimate left ventricular (LV) metabolic rate of glucose (MRGlu). Thereafter, we retrospectively identified 69 patients who had been successfully treated with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine for Hodgkin disease (HD) and had undergone 4 consecutive 18F-FDG PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean SUV. All patients were subsequently interviewed by telephone (median follow-up, 30 mo); 36 of them agreed to undergo electrocardiography and transthoracic echocardiography. Results: In mice, LV MRGlu was 17.9 ± 4.4 nmol × min−1 × g−1 at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min−1 × g−1, P < 0.05 vs. controls) and high-dose subgroups (37.2 ± 7.8 nmol × min−1 × g−1, P < 0.01 vs. controls, P < 0.05 vs. standard-dose). In HD patients, LV SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New-onset cardiac abnormalities appeared in 11 of 36 patients (31%). In these subjects, pretherapy LV SUV was markedly lower with respect to the remaining patients (1.53 ± 0.9 vs. 3.34 ± 2.54, respectively, P < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Conclusion: Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baseline 18F-FDG uptake. These results imply that low myocardial 18F-FDG uptake before the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity, suggesting that prospective clinical trials are warranted to test this hypothesis.
High-Contrast PET Imaging of Vasopressin V1B Receptors with a Novel Radioligand, 11C-TASP699 J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Kazumi Koga; Yuji Nagai; Masayuki Hanyu; Mitsukane Yoshinaga; Shigeyuki Chaki; Norikazu Ohtake; Satoshi Ozaki; Ming-Rong Zhang; Tetsuya Suhara; Makoto Higuchi
Vasopressin 1B receptors (V1BRs) are abundantly expressed in the pituitary, and in vivo PET of V1BRs was recently enabled by our development of a specific radioligand, 11C-TASP0434299, derivatized from pyridopyrimidin-4-one. Here, we identified a novel pyridopyrimidin-4-one analog, N-tert-butyl-2-[2-(6-11C-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]acetamide (11C-TASP0410699, hereafter referred to as 11C-TASP699), as a potent V1BR radioligand producing a higher image contrast for the target than 11C-TASP0434299. Methods: In vitro properties of TASP699 were assessed by assaying its affinity for human V1BR and its selectivity for off-target molecules. Radioactive uptake in the pituitary was analyzed using PET in rhesus monkeys after intravenous administration of 11C-TASP699. Serial doses of a selective V1BR antagonist, 2-[2-(3-chloro-4-fluorophenyl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]-N-isopropylacetamide hydrochloride (TASP0390325), were administered before the radioligand injection. Autoradiographic labeling of monkey pituitary slices with 11C-TASP699 was conducted with or without nonradioactive V1BR antagonists. Results: The half maximal inhibitory concentration (IC50) of TASP699 for human V1BRs (0.165 nM) was lower than that of TASP0434299 (0.526 nM), whereas its IC50 values for off-target molecules exceeded 1 μM. PET imaging in monkeys demonstrated that the peak pituitary uptake of 11C-TASP699 was almost equivalent to that of 11C-TASP0434299 and that pretreatment with TASP0390325 inhibited the retention of 11C-TASP699 in a dose-dependent manner, inducing nearly full occupancy at 0.3 mg/kg. Specific radioligand binding was determined as a specific–to–nondisplaceable uptake ratio at equilibrium using radioactivity retentions at 60 min in baseline and blocking studies. This ratio for 11C-TASP699 was approximately 2.5-fold greater than that of 11C-TASP0434299. A reversed-phase high-performance liquid chromatography study identified the parent and polar radiometabolites. Affinities of 2 predicted metabolite candidates for V1BRs were more than 10 times weaker than that of the parent. Intense autoradiographic labeling of the anterior pituitary with 11C-TASP699 was inhibited with TASP0390325 in a concentration-dependent manner. Conclusion: 11C-TASP699 yielded PET images of pituitary V1BRs with a higher contrast than 11C-TASP0434299, supporting the applicability of 11C-TASP699 in the assessment of neuropsychiatric diseases and dose findings for test drugs in clinical trials.
Molecular Imaging of Human Embryonic Stem Cells Stably Expressing Human PET Reporter Genes After Zinc Finger Nuclease–Mediated Genome Editing J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Esther Wolfs; Bryan Holvoet; Laura Ordovas; Natacha Breuls; Nicky Helsen; Matthias Schönberger; Susanna Raitano; Tom Struys; Bert Vanbilloen; Cindy Casteels; Maurilio Sampaolesi; Koen Van Laere; Ivo Lambrichts; Catherine M. Verfaillie; Christophe M. Deroose
Molecular imaging is indispensable for determining the fate and persistence of engrafted stem cells. Standard strategies for transgene induction involve the use of viral vectors prone to silencing and insertional mutagenesis or the use of nonhuman genes. Methods: We used zinc finger nucleases to induce stable expression of human imaging reporter genes into the safe-harbor locus adeno-associated virus integration site 1 in human embryonic stem cells. Plasmids were generated carrying reporter genes for fluorescence, bioluminescence imaging, and human PET reporter genes. Results: In vitro assays confirmed their functionality, and embryonic stem cells retained differentiation capacity. Teratoma formation assays were performed, and tumors were imaged over time with PET and bioluminescence imaging. Conclusion: This study demonstrates the application of genome editing for targeted integration of human imaging reporter genes in human embryonic stem cells for long-term molecular imaging.
18F-Tetrafluoroborate, a PET Probe for Imaging Sodium/Iodide Symporter Expression: Whole-Body Biodistribution, Safety, and Radiation Dosimetry in Thyroid Cancer Patients J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Jim O’Doherty; Maite Jauregui-Osoro; Teresa Brothwood; Teresa Szyszko; Paul K. Marsden; Michael J. O’Doherty; Gary J.R. Cook; Philip J. Blower; Val Lewington
We report the safety, biodistribution, and internal radiation dosimetry, in humans with thyroid cancer, of 18F-tetrafluoroborate (18F-TFB), a novel PET radioligand for imaging the human sodium/iodide symporter (hNIS). Methods: Serial whole-body PET scans of 5 subjects with recently diagnosed thyroid cancer were acquired before surgery for up to 4 h after injection of 184 ± 15 MBq of 18F-TFB. Activity was determined in whole blood, plasma, and urine. Mean organ-absorbed doses and effective doses were calculated via quantitative image analysis and using OLINDA/EXM software. Results: Images showed a high uptake of 18F-TFB in known areas of high hNIS expression (thyroid, salivary glands, and stomach). Excretion was predominantly renal. No adverse effects in relation to safety of the radiopharmaceutical were observed. The effective dose was 0.0326 ± 0.0018 mSv/MBq. The critical tissues/organs receiving the highest mean sex-averaged absorbed doses were the thyroid (0.135 ± 0.079 mSv/MBq), stomach (0.069 ± 0.022 mSv/MBq), and salivary glands (parotids, 0.031 ± 0.011 mSv/MBq; submandibular, 0.061 ± 0.031 mSv/MBq). Other organs of interest were the bladder (0.102 ± 0.046 mSv/MBq) and kidneys (0.029 ± 0.009 mSv/MBq). Conclusion: Imaging using 18F-TFB imparts a radiation exposure similar in magnitude to many other 18F-labeled radiotracers. 18F-TFB shows a biodistribution similar to 99mTc-pertechnetate, a known nonorganified hNIS tracer, and is pharmacologically and radiobiologically safe in humans. Phase 2 trials for 18F-TFB as an hNIS imaging agent are warranted.
Three-Dimensional Dosimetry for Radiation Safety Estimates from Intrathecal Administration J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Jacob Y. Hesterman; Susan D. Kost; Robert W. Holt; Howard Dobson; Ajay Verma; P. David Mozley
Intrathecal administration is of growing interest for drug delivery, and its utility is being increasingly investigated through imaging. In this work, the 3-dimensional Voxel-Based Internal Dosimetry Application (VIDA) and 4D Extended Cardiac Torso Phantom (XCAT) were extended to provide radiation safety estimates specific to intrathecal administration. Methods: The 3-dimensional VIDA dosimetry application Monte Carlo simulation was run using a modified XCAT phantom with additional and edited cerebrospinal fluid (CSF) regions to produce voxel-level absorbed dose per unit cumulated activity maps for 9 selected source regions. Simulation validation was performed to compare absorbed dose estimates for common organs in a preexisting dosimetry tool (OLINDA/EXM). Dynamic planar imaging data were acquired in 6 healthy subjects using administered volumes of 5 or 15 mL (n = 3 each) of 185 MBq of 99mTc-diethylenetriaminepentaacetic acid. Absorbed dose was estimated for each subject using the intrathecal-specific dosimetry application. Results: Simulation results were within 6% of OLINDA estimates for common organs. Absorbed dose estimates were highest (0.3–0.8 mGy/MBq) in the lumbar CSF space. A whole-body effective dose estimate of 0.003 mSv/MBq was observed. An administered volume dependency was observed with a 15-mL volume, resulting in lower absorbed dose estimates for several intrathecal and nonintrathecal regions. Conclusion: The intrathecal-specific VIDA implementation enables tailored dosimetry estimation for regions most relevant in intrathecal administration. Absorbed doses are highly localized to CSF and spinal regions and should be taken into consideration when designing intrathecal imaging studies. A potentially interesting relationship was observed between absorbed dose and administered volume, which merits further investigation.
Specific Imaging of Bacterial Infection Using 6″-18F-Fluoromaltotriose: A Second-Generation PET Tracer Targeting the Maltodextrin Transporter in Bacteria J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Gayatri Gowrishankar; Jonathan Hardy; Mirwais Wardak; Mohammad Namavari; Robert E. Reeves; Evgenios Neofytou; Ananth Srinivasan; Joseph C. Wu; Christopher H. Contag; Sanjiv Sam Gambhir
6″-18F-fluoromaltotriose is a PET tracer that can potentially be used to image and localize most bacterial infections, much like 18F-FDG has been used to image and localize most cancers. However, unlike 18F-FDG, 6″-18F-fluoromaltotriose is not taken up by inflammatory lesions and appears to be specific to bacterial infections by targeting the maltodextrin transporter that is expressed in gram-positive and gram-negative strains of bacteria. Methods: 6″-18F-fluoromaltotriose was synthesized with high radiochemical purity and evaluated in several clinically relevant bacterial strains in cultures and in living mice. Results: 6″-18F-fluoromaltotriose was taken up in both gram-positive and gram-negative bacterial strains. 6″-18F-fluoromaltotriose was also able to detect Pseudomonas aeruginosa in a clinically relevant mouse model of wound infection. The utility of 6″-18F-fluoromaltotriose to help monitor antibiotic therapies was also evaluated in rats. Conclusion: 6″-18F-fluoromaltotriose is a promising new tracer that has significant diagnostic utility, with the potential to change the clinical management of patients with infectious diseases of bacterial origin.
Imaging Macrophage Accumulation in a Murine Model of Chronic Pancreatitis with 125I-Iodo-DPA-713 SPECT/CT J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Catherine A. Foss; Liansheng Liu; Ronnie C. Mease; Haofan Wang; Pankaj Pasricha; Martin G. Pomper
Pancreatitis remains a diagnostic challenge in patients with mild to moderate disease, with current imaging modalities being inadequate. Given the prominent macrophage infiltration in chronic pancreatitis, we hypothesized that 125I-iodo-DPA-713, a small-molecule radiotracer that specifically targets macrophages, could be used with SPECT/CT to image pancreatic inflammation in a relevant experimental model. Methods: Chronic pancreatitis was induced with cerulein in C57BL/6 mice, which were contrasted with saline-injected control mice. The animals were imaged at 7 wk after induction using N,N-diethyl-2-(2-(3-125I-iodo-4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide (125I-iodo-DPA-713) SPECT/CT or 18F-FDG PET/CT. The biodistribution of 125I-iodo-DPA-713 was determined under the same conditions, and a pair of mice was imaged using a fluorescent analog of 125I-iodo-DPA-713, DPA-713-IRDye800CW, for correlative histology. Results: Pancreatic 125I-iodo-DPA-713 uptake was significantly higher in treated mice than control mice (5.17% ± 1.18% vs. 2.41% ± 0.34% injected dose/g, P = 0.02), as corroborated by imaging. Mice imaged with 18F-FDG PET/CT showed cerulein-enhanced pancreatic uptake in addition to a moderate signal from healthy pancreas. Near-infrared fluorescence imaging with DPA-713-IRDye800CW showed strong pancreatic uptake, focal liver uptake, and gastrointestinal uptake in the treated mice, whereas the control mice showed only urinary excretion. Ex vivo fluorescence microscopy revealed a large influx of macrophages in the pancreas colocalizing with the retained fluorescent probe in the treated but not the control mice. Conclusion: These data support the application of both 125I-iodo-DPA-713 SPECT/CT and DPA-713-IRDye800CW near-infrared fluorescence to delineate pancreatic, liver, or intestinal inflammation in living mice.
Quantitative Evaluation of 2 Scatter-Correction Techniques for 18F-FDG Brain PET/MRI in Regard to MR-Based Attenuation Correction J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Jarmo Teuho; Virva Saunavaara; Tuula Tolvanen; Terhi Tuokkola; Antti Karlsson; Jouni Tuisku; Mika Teräs
In PET, corrections for photon scatter and attenuation are essential for visual and quantitative consistency. MR attenuation correction (MRAC) is generally conducted by image segmentation and assignment of discrete attenuation coefficients, which offer limited accuracy compared with CT attenuation correction. Potential inaccuracies in MRAC may affect scatter correction, because the attenuation image (μ-map) is used in single scatter simulation (SSS) to calculate the scatter estimate. We assessed the impact of MRAC to scatter correction using 2 scatter-correction techniques and 3 μ-maps for MRAC. Methods: The tail-fitted SSS (TF-SSS) and a Monte Carlo–based single scatter simulation (MC-SSS) algorithm implementations on the Philips Ingenuity TF PET/MR were used with 1 CT-based and 2 MR-based μ-maps. Data from 7 subjects were used in the clinical evaluation, and a phantom study using an anatomic brain phantom was conducted. Scatter-correction sinograms were evaluated for each scatter correction method and μ-map. Absolute image quantification was investigated with the phantom data. Quantitative assessment of PET images was performed by volume-of-interest and ratio image analysis. Results: MRAC did not result in large differences in scatter algorithm performance, especially with TF-SSS. Scatter sinograms and scatter fractions did not reveal large differences regardless of the μ-map used. TF-SSS showed slightly higher absolute quantification. The differences in volume-of-interest analysis between TF-SSS and MC-SSS were 3% at maximum in the phantom and 4% in the patient study. Both algorithms showed excellent correlation with each other with no visual differences between PET images. MC-SSS showed a slight dependency on the μ-map used, with a difference of 2% on average and 4% at maximum when a μ-map without bone was used. Conclusion: The effect of different MR-based μ-maps on the performance of scatter correction was minimal in non–time-of-flight 18F-FDG PET/MR brain imaging. The SSS algorithm was not affected significantly by MRAC. The performance of the MC-SSS algorithm is comparable but not superior to TF-SSS, warranting further investigations of algorithm optimization and performance with different radiotracers and time-of-flight imaging.
Simulation of Tracer Dose Reduction in 18F-FDG PET/MRI: Effects on Oncologic Reading, Image Quality, and Artifacts J Nucl. Med. (IF 6.646) Pub Date : 2017-10-01 Ferdinand Seith; Holger Schmidt; Julia Kunz; Thomas Küstner; Sergios Gatidis; Konstantin Nikolaou; Christian la Fougère; Nina Schwenzer
The aim of our study was to evaluate the effect of stepwise-reduced doses on objective and subjective image parameters and on oncologic readings in whole-body 18F-FDG PET/MRI. Methods: We retrospectively simulated the stepwise reduction of 18F-FDG doses of 19 patients (mean age ± SD, 50.9 ± 11.7 y; mean body mass index ± SD, 22.8 ± 3.2 kg/m2) who received a whole-body PET/MRI examination from 3 to 0.5 MBq/kg of body weight (kgBW) in intervals of 0.25. Objective imaging parameters were assessed by measuring the SUV and coefficient of variation in different regions (aorta, liver, spleen, kidney, small bowel, lumbar vertebra, psoas muscle, urinary bladder) as well as the noise-equivalent counting rates in each bed position. Subjective image quality was evaluated with a masked reading of each simulated PET compared with the dose of 2 MBq/kgBW. Oncologic reading was performed first according to PERCIST in each dose and second by defining malignant lesions in doses of 2 MBq/kgBW and the maximum dose image (gold standard). The diagnostic confidence of each lesion was measured using a Likert scale. Results: With decreasing doses, regions in the mid abdomen showed a stronger decrease of SUVmean and noise-equivalent counting rates than regions in the upper abdomen (SUVmean, −45% and −15% on average in the small bowel and the liver, respectively). The coefficient of variation showed a nonlinear increase, pronounced below 1.5 MBq/kgBW. Subjective image quality was stable over a range between 1.25 and 2.75 MBq/kgBW compared with 2 MBq/kgBW. However, large photopenic areas in the mid abdomen were observed in 2 patients. In the PERCIST reading, target lesions were above the liver threshold with a stable SUVpeak in all cases down to 2 MBq/kgBW. Eighty-six of 90 lesions were identified correctly with a dose of 2 MBq/kgBW; Likert scores did not differ significantly. Conclusion: A reduction of doses in 18F-FDG PET/MRI might be possible down to 2 MBq/kgBW in oncologic whole-body examinations. The image quality in the mid abdomen seems to be more affected by lower doses than in the upper abdomen, and in single cases large photopenic areas can occur. Therefore, we do not recommend reducing doses below 3 MBq/kgBW in adults at this time.
PET/MRI for Oncologic Brain Imaging: A Comparison of Standard MR-Based Attenuation Corrections with a Model-Based Approach for the Siemens mMR PET/MR System J Nucl. Med. (IF 6.646) Pub Date : 2017-09-01 Ivo Rausch; Lucas Rischka; Claes N. Ladefoged; Julia Furtner; Matthias Fenchel; Andreas Hahn; Rupert Lanzenberger; Marius E. Mayerhoefer; Tatjana Traub-Weidinger; Thomas Beyer
The aim of this study was to compare attenuation-correction (AC) approaches for PET/MRI in clinical neurooncology. Methods: Forty-nine PET/MRI brain scans were included: brain tumor studies using 18F-fluoro-ethyl-tyrosine (18F-FET) (n = 31) and 68Ga-DOTANOC (n = 7) and studies of healthy subjects using 18F-FDG (n = 11). For each subject, MR-based AC maps (MR-AC) were acquired using the standard DIXON- and ultrashort echo time (UTE)–based approaches. A third MR-AC was calculated using a model-based, postprocessing approach to account for bone attenuation values (BD, noncommercial prototype software by Siemens Healthcare). As a reference, AC maps were derived from patient-specific CT images (CTref). PET data were reconstructed using standard settings after AC with all 4 AC methods. We report changes in diagnosis for all brain tumor patients and the following relative differences values (RDs [%]), with regards to AC-CTref: for 18F-FET (A)—SUVs as well as volumes of interest (VOIs) defined by a 70% threshold of all segmented lesions and lesion-to-background ratios; for 68Ga-DOTANOC (B)—SUVs as well as VOIs defined by a 50% threshold for all lesions and the pituitary gland; and for 18F-FDG (C)—RD of SUVs of the whole brain and 10 anatomic regions segmented on MR images. Results: For brain tumor imaging (A and B), the standard PET-based diagnosis was not affected by any of the 3 MR-AC methods. For A, the average RDs of SUVmean were −10%, −4%, and −3% and of the VOIs 1%, 2%, and 7% for DIXON, UTE, and BD, respectively. Lesion-to-background ratios for all MR-AC methods were similar to that of CTref. For B, average RDs of SUVmean were −11%, −11%, and −3% and of the VOIs 1%, −4%, and −3%, respectively. In the case of 18F-FDG PET/MRI (C), RDs for the whole brain were −11%, −8%, and −5% for DIXON, UTE, and BD, respectively. Conclusion: The diagnostic reading of PET/MR patients with brain tumors did not change with the chosen AC method. Quantitative accuracy of SUVs was clinically acceptable for UTE- and BD-AC for group A, whereas for group B BD was in accordance with CTref. Nevertheless, for the quantification of individual lesions large deviations to CTref can be observed independent of the MR-AC method used.
Studies of a Next-Generation Silicon-Photomultiplier–Based Time-of-Flight PET/CT System J Nucl. Med. (IF 6.646) Pub Date : 2017-09-01 David F.C. Hsu; Ezgi Ilan; William T. Peterson; Jorge Uribe; Mark Lubberink; Craig S. Levin
This article presents system performance studies for the Discovery MI PET/CT system, a new time-of-flight system based on silicon photomultipliers. System performance and clinical imaging were compared between this next-generation system and other commercially available PET/CT and PET/MR systems, as well as between different reconstruction algorithms. Methods: Spatial resolution, sensitivity, noise-equivalent counting rate, scatter fraction, counting rate accuracy, and image quality were characterized with the National Electrical Manufacturers Association NU-2 2012 standards. Energy resolution and coincidence time resolution were measured. Tests were conducted independently on two Discovery MI scanners installed at Stanford University and Uppsala University, and the results were averaged. Back-to-back patient scans were also performed between the Discovery MI, Discovery 690 PET/CT, and SIGNA PET/MR systems. Clinical images were reconstructed using both ordered-subset expectation maximization and Q.Clear (block-sequential regularized expectation maximization with point-spread function modeling) and were examined qualitatively. Results: The averaged full widths at half maximum (FWHMs) of the radial/tangential/axial spatial resolution reconstructed with filtered backprojection at 1, 10, and 20 cm from the system center were, respectively, 4.10/4.19/4.48 mm, 5.47/4.49/6.01 mm, and 7.53/4.90/6.10 mm. The averaged sensitivity was 13.7 cps/kBq at the center of the field of view. The averaged peak noise-equivalent counting rate was 193.4 kcps at 21.9 kBq/mL, with a scatter fraction of 40.6%. The averaged contrast recovery coefficients for the image-quality phantom were 53.7, 64.0, 73.1, 82.7, 86.8, and 90.7 for the 10-, 13-, 17-, 22-, 28-, and 37-mm-diameter spheres, respectively. The average photopeak energy resolution was 9.40% FWHM, and the average coincidence time resolution was 375.4 ps FWHM. Clinical image comparisons between the PET/CT systems demonstrated the high quality of the Discovery MI. Comparisons between the Discovery MI and SIGNA showed a similar spatial resolution and overall imaging performance. Lastly, the results indicated significantly enhanced image quality and contrast-to-noise performance for Q.Clear, compared with ordered-subset expectation maximization. Conclusion: Excellent performance was achieved with the Discovery MI, including 375 ps FWHM coincidence time resolution and sensitivity of 14 cps/kBq. Comparisons between reconstruction algorithms and other multimodal silicon photomultiplier and non–silicon photomultiplier PET detector system designs indicated that performance can be substantially enhanced with this next-generation system.
18F-FDG PET/CT Optimizes Treatment in Staphylococcus Aureus Bacteremia and Is Associated with Reduced Mortality J Nucl. Med. (IF 6.646) Pub Date : 2017-09-01 Marvin A.H. Berrevoets; Ilse J.E. Kouijzer; Erik H.J.G. Aarntzen; Marcel J.R. Janssen; Lioe-Fee De Geus-Oei; Heiman F.L. Wertheim; Bart-Jan Kullberg; Jaap Ten Oever; Wim J.G. Oyen; Chantal P. Bleeker-Rovers
Metastatic infection is an important complication of Staphylococcus aureus bacteremia (SAB). Early diagnosis of metastatic infection is crucial, because specific treatment is required. However, metastatic infection can be asymptomatic and difficult to detect. In this study, we investigated the role of 18F-FDG PET/CT in patients with SAB for detection of metastatic infection and its consequences for treatment and outcome. Methods: All patients with SAB at Radboud University Medical Center were included between January 2013 and April 2016. Clinical data and results of 18F-FDG PET/CT and other imaging techniques, including echocardiography, were collected. Primary outcomes were newly diagnosed metastatic infection by 18F-FDG PET/CT, subsequent treatment modifications, and patient outcome. Results: A total of 184 patients were included, and 18F-FDG PET/CT was performed in 105 patients, of whom 99 had a high-risk bacteremia. 18F-FDG PET/CT detected metastatic infectious foci in 73.7% of these high-risk patients. In 71.2% of patients with metastatic infection, no signs and symptoms suggesting metastatic complications were present before 18F-FDG PET/CT was performed. 18F-FDG PET/CT led to a total of 104 treatment modifications in 74 patients. Three-month mortality was higher in high-risk bacteremia patients without 18F-FDG PET/CT performed than in those in whom 18F-FDG PET/CT was performed (32.7% vs. 12.4%, P = 0.003). In multivariate analysis, 18F-FDG PET/CT was the only factor independently associated with reduced mortality (P = 0.005; odds ratio, 0.204; 95% confidence interval, 0.066–0.624). A higher comorbidity score was independently associated with increased mortality (P = 0.003; odds ratio, 1.254; 95% confidence interval, 1.078–1.457). Conclusion: 18F-FDG PET/CT is a valuable technique for early detection of metastatic infectious foci, often leading to treatment modification. Performing 18F-FDG PET/CT is associated with significantly reduced 3-mo mortality.
Biodistribution and Radiation Dosimetry for the Tau Tracer 18F-THK-5351 in Healthy Human Subjects J Nucl. Med. (IF 6.646) Pub Date : 2017-09-01 Ing-Tsung Hsiao; Kun-Ju Lin; Kuo-Lun Huang; Chin-Chang Huang; Han-Shiuan Chen; Shiaw-Pyng Wey; Tzu-Chen Yen; Nobuyuki Okamura; Jung-Lung Hsu
18F-THK-5351 is a novel radiotracer that demonstrates high binding selectivity and affinity for tau pathology and exhibits better pharmacokinetics in the living brain than previous THK tau probes. The aim of the present study was to estimate the radiation dose of 18F-THK-5351 in humans and to compare the clinical radiation dosimetry results to estimations published previously with preclinical data. Methods: Serial whole-body PET/CT imaging was performed for 240 min on 12 healthy volunteers after injecting 18F-THK-5351 (mean administered activity, 377.8 ± 14.0 MBq; range, 340–397 MBq). The bladder and gallbladder were delineated on PET images, and the other organs were delineated on CT images. Voided urine activity was recorded. The decay-corrected and normalized 18F-THK-5351 activity of 15 source-organ regions as a function of time was entered into the OLINDA/EXM software to calculate the effective dose for each subject following the medical internal radiation dosimetry schema. Results: Overall, the 18F-THK-5351 injection was well tolerated. The highest mean initial uptake at 10 min after injection was in the liver (11.4% ± 2.0%), lung (5.7% ± 2.1%), intestine (3.4% ± 0.8%), and kidney (1.4% ± 0.3%). The highest mean absorbed dose of radiation was in the gallbladder wall (242.2 ± 105.2 μGy/MBq), upper large intestine (90.0 ± 15.8 μGy/MBq), small intestine (79.5 ± 13.8 μGy/MBq), and liver (55.8 ± 6.1 μGy/MBq). The resultant whole-body effective dose was 22.7 ± 1.3 μSv/MBq. Conclusion: Our results suggest that a routine injection of 370 MBq of 18F-THK-5351 would lead to an estimated effective dose of 8.4 mSv; hence, 18F-THK-5351 has a radiation burden similar to that of other commonly used clinical tracers. Our findings in humans were compatible with recently published preclinical dosimetry data extrapolated from mice.
Alteration of Monoamine Receptor Activity and Glucose Metabolism in Pediatric Patients with Anticonvulsant-Induced Cognitive Impairment J Nucl. Med. (IF 6.646) Pub Date : 2017-09-01 Yuankai Zhu; Jianhua Feng; Jianfeng Ji; Haifeng Hou; Lin Chen; Shuang Wu; Qing Liu; Qiong Yao; Peizhen Du; Kai Zhang; Qing Chen; Zexin Chen; Hong Zhang; Mei Tian
A landmark study from the Institute of Medicine reported that the assessment of cognitive difficulties in children with epilepsy is timely and imperative. Anticonvulsant-induced cognitive impairment could influence the quality of life more than seizure itself in patients. Although the monoaminergic system is involved in the regulation of cognitive process, its role in anticonvulsant-induced cognitive impairment remains unclear. Methods: To explore in vivo monoamine receptor binding activity in patients with anticonvulsant-induced cognitive impairment, each patient underwent PET imaging with both monoamine receptor binding agent 11C-N-methylspiperone and glucose metabolic agent 18F-FDG. Tests of intelligence quotient (IQ), including verbal IQ (VIQ), performance IQ (PIQ), and full-scale IQ (FSIQ), were performed in each patient. Results: Compared with the patients with monotherapy, patients with polytherapy had significantly lower VIQ, PIQ, and FSIQ (P < 0.01 in each comparison), as well as significantly lower monoamine receptor activities detected in the caudate nucleus, prefrontal cortex, dorsal anterior cingulate cortex, and amygdale (P < 0.05 in each comparison). However, regarding the glucose metabolism, there was no significant difference found in patients with monotherapy or polytherapy (P > 0.05). Conclusion: Monoamine receptor PET imaging could be a promising in vivo imaging biomarker for mapping anticonvulsant-induced cognitive impairment.
Validation of the Semiquantitative Static SUVR Method for 18F-AV45 PET by Pharmacokinetic Modeling with an Arterial Input Function J Nucl. Med. (IF 6.646) Pub Date : 2017-09-01 Julie Ottoy; Jeroen Verhaeghe; Ellis Niemantsverdriet; Leonie Wyffels; Charisse Somers; Ellen De Roeck; Hanne Struyfs; Femke Soetewey; Steven Deleye; Tobi Van den Bossche; Sara Van Mossevelde; Sarah Ceyssens; Jan Versijpt; Sigrid Stroobants; Sebastiaan Engelborghs; Steven Staelens
Increased brain uptake of 18F-AV45 visualized by PET is a key biomarker for Alzheimer disease (AD). The SUV ratio (SUVR) is widely used for quantification, but is subject to variability based on choice of reference region and changes in cerebral blood flow. Here we validate the SUVR method against the gold standard volume of distribution (VT) to assess cross-sectional differences in plaque load. Methods: Dynamic 60-min 18F-AV45 (291 ± 67 MBq) and 1-min 15O-H2O (370 MBq) scans were obtained in 35 age-matched elderly subjects, including 10 probable AD, 15 amnestic mild cognitive impairment (aMCI), and 10 cognitively healthy controls (HCs). 18F-AV45 VT was determined from 2-tissue-compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50–60 min after injection, using either cerebellar gray matter (SUVRCB) or whole subcortical white matter (SUVRWM) as the reference. Additionally, whole cerebellum, pons, centrum semiovale, and a composite region were examined as alternative references. Blood flow was quantified by 15O-H2O SUV. Data are presented as mean ± SEM. Results: There was rapid metabolization of 18F-AV45, with only 35% of unchanged parent remaining at 10 min. Compared with VT, differences in cortical Aβ load between aMCI and AD were overestimated by SUVRWM (+4% ± 2%) and underestimated by SUVRCB (−10% ± 2%). VT correlated better with SUVRWM (Pearson r: from 0.63 for posterior cingulate to 0.89 for precuneus, P < 0.0001) than with SUVRCB (Pearson r: from 0.51 for temporal lobe [P = 0.002] to 0.82 for precuneus [P < 0.0001]) in all tested regions. Correlation results for the alternative references were in between those for CB and WM. 15O-H2O data showed that blood flow was decreased in AD compared with aMCI in cortical regions (−5% ± 1%) and in the reference regions (CB, −9% ± 8%; WM, −8% ± 8%). Conclusion: Increased brain uptake of 18F-AV45 assessed by the simplified static SUVR protocol does not truly reflect Aβ load. However, SUVRWM is better correlated with VT and more closely reflects VT differences between aMCI and AD than SUVRCB.
11C-PBR28 and 18F-PBR111 Detect White Matter Inflammatory Heterogeneity in Multiple Sclerosis J Nucl. Med. (IF 6.646) Pub Date : 2017-09-01 Gourab Datta; Alessandro Colasanti; Nicola Kalk; David Owen; Gregory Scott; Eugenii A. Rabiner; Roger N. Gunn; Anne Lingford-Hughes; Omar Malik; Olga Ciccarelli; Richard Nicholas; Lei Nei; Marco Battaglini; Nicola D. Stefano; Paul M. Matthews
The objective of this study was to assess microglial activation in lesions and in normal-appearing white matter (NAWM) of multiple sclerosis (MS) patients using PET. Methods: Thirty-four MS patients (7 with secondary progressive MS [SPMS], 27 with relapsing remitting MS [RRMS]) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO) binding status, underwent PET scanning with TSPO radioligands (11C-PBR28 or 18F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudoreference region). White matter lesions (WMLs) were classified as “active” (DVR highest in the lesion), “peripherally active” (perilesional DVR highest), “inactive” (DVR highest in surrounding NAWM), or “undifferentiated” (similar DVR across lesion, perilesional and NAWM volumes). Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4 × 10−11). A higher proportion of lesions were inactive in patients with SPMS (35%) than RRMS (23%), but active lesions were found in all patients, including those on highly efficacious treatments. Conclusion: TSPO radioligand uptake was increased in the brains of MS patients relative to healthy controls with 2 TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. Their independent prognostic significance needs further investigation.
Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET J Nucl. Med. (IF 6.646) Pub Date : 2017-09-01 Mony J. de Leon; Yi Li; Nobuyuki Okamura; Wai H. Tsui; Les A. Saint-Louis; Lidia Glodzik; Ricardo S. Osorio; Juan Fortea; Tracy Butler; Elizabeth Pirraglia; Silvia Fossati; Hee-Jin Kim; Roxana O. Carare; Maiken Nedergaard; Helene Benveniste; Henry Rusinek
Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer disease (AD) comes primarily from rodent models. However, unlike rodents, in which predominant extracranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Dynamic PET with 18F‐THK5117, a tracer for tau pathology, was used to estimate the ventricular CSF time–activity as a biomarker for CSF clearance. We tested 3 hypotheses: extracranial CSF is detected at the superior turbinates; CSF clearance is reduced in AD; and CSF clearance is inversely associated with amyloid deposition. Methods: Fifteen subjects, 8 with AD and 7 normal control volunteers, were examined with 18F‐THK5117. Ten subjects additionally underwent 11C-Pittsburgh compound B (11C-PiB) PET scanning, and 8 were 11C-PiB–positive. Ventricular time–activity curves of 18F‐THK5117 were used to identify highly correlated time–activity curves from extracranial voxels. Results: For all subjects, the greatest density of CSF-positive extracranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinate CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET-measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.
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