Decision support systems for imaging analysis and interpretation are rapidly being developed and will have an increasing impact on the practice of medicine. RENEX is a renal expert system to assist physicians evaluate suspected obstruction in patients undergoing mercaptoacetyltriglycine (MAG3) renography. RENEX uses quantitative parameters extracted from the dynamic renal scan data using QuantEM™II and heuristic rules in the form of a knowledge base gleaned from experts to determine if a kidney is obstructed; however, RENEX does not have access to and could not consider the clinical information available to diagnosticians interpreting these studies. We designed and implemented a methodology to incorporate clinical information into RENEX, implemented motion detection and evaluated this new comprehensive system (iRENEX) in a pilot group of 51 renal patients.
To reach a conclusion as to whether a kidney is obstructed, 56 new clinical rules were added to the previously reported 60 rules used to interpret quantitative MAG3 parameters. All the clinical rules were implemented after iRENEX reached a conclusion on obstruction based on the quantitative MAG3 parameters, and the evidence of obstruction was then modified by the new clinical rules. iRENEX consisted of a library to translate parameter values to certainty factors, a knowledge base with 116 heuristic interpretation rules, a forward chaining inference engine to determine obstruction and a justification engine. A clinical database was developed containing patient histories and imaging report data obtained from the hospital information system associated with the pertinent MAG3 studies. The system was fine-tuned and tested using a pilot group of 51 patients (21 men, mean age 58.2±17.1 years, 100 kidneys) deemed by an expert panel to have 61 unobstructed and 39 obstructed kidneys.
iRENEX, using only quantitative MAG3 data agreed with the expert panel in 87 % (34/39) of obstructed and 90 % (55/61) of unobstructed kidneys. iRENEX, using both quantitative and clinical data agreed with the expert panel in 95 % (37/39) of obstructed and 92 % (56/61) of unobstructed kidneys. The clinical information significantly (p<0.001) increased iRENEX certainty in detecting obstruction over using the quantitative data alone.
Our renal expert system for detecting renal obstruction has been substantially expanded to incorporate the clinical information available to physicians as well as advanced quality control features and was shown to interpret renal studies in a pilot group at a standardized expert level. These encouraging results warrant a prospective study in a large population of patients with and without renal obstruction to establish the diagnostic performance of iRENEX.
Decision support systems; Renal obstruction; Clinical data; 99mTc-MAG3 renography
In the treatment of patients with high-risk neuroblastoma, different doses of 131I-metaiodobenzylguanidine (131I-MIBG) are administered at different time points during treatment. Toxicity, mainly haematological (thrombocytopenia), from 131I-MIBG therapy is known to occur in extensively chemotherapy pretreated neuroblastoma patients. Up to now, acute toxicity from 131I-MIBG as initial treatment has never been studied in a large cohort. The aim of this retrospective study was to document acute toxicity related to upfront 131I-MIBG.
All neuroblastoma patients (stages 1–4 and 4S) treated upfront with 131I-MIBG at the Emma Children’s Hospital, Academic Medical Centre (1992 – 2008) were included in this retrospective analysis. The acute toxicity (during therapy) and short-term toxicity (1st month following therapy) of the first two 131I-MIBG therapies were studied.
Of 66 patients (34 boys, 32 girls; median age 2.2 years, range 0.1 – 9.4 years), 49 had stage 4 disease, 5 stage 4S, 6 stage 3, 1 stage 2 and 5 stage 1. The median first dose was 441 MBq/kg (range 157 – 804 MBq/kg). The median second dose was 328 MBq/kg (range 113 – 727 MBq/kg). The most frequently observed symptoms were nausea and vomiting (21 %, maximum grade II). The main toxicity was grade IV haematological, occurring only in stage 4 patients, after the first and second 131I-MIBG therapies: anaemia (5 % and 4 %, respectively), leucocytopenia (3 % and 4 %) and thrombocytopenia (2 % and 4 %). No stem cell rescue was needed.
The main acute toxicity observed was haematological followed by nausea and vomiting. One patient developed posterior reversible encephalopathy syndrome during 131I-MIBG therapy, possibly related to 131I-MIBG. We consider 131I-MIBG therapy to be a safe treatment modality.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-013-2510-z) contains supplementary material, which is available to authorized users.
Neuroblastoma; 131I-MIBG therapy; Acute toxicity
The purpose of this study was to evaluate left ventricular (LV) mechanical dyssynchrony in patients with Wolff-Parkinson-White (WPW) syndrome pre- and post-radiofrequency catheter ablation (RFA) using phase analysis of gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI).
Forty-five WPW patients were enrolled and had gated SPECT MPI pre- and 2–3 days post-RFA. Electrophysiological study (EPS) was used to locate accessory pathways (APs) and categorize the patients according to the AP locations (septal, left and right free wall). Electrocardiography (ECG) was performed pre- and post-RFA to confirm successful elimination of the APs. Phase analysis of gated SPECT MPI was used to assess LV dyssynchrony pre- and post-RFA.
Among the 45 patients, 3 had gating errors, and thus 42 had SPECT phase analysis. Twenty-two patients (52.4 %) had baseline LV dyssynchrony. Baseline LV dyssynchrony was more prominent in the patients with septal APs than in the patients with left or right APs (p<0.05). RFA improved LV synchrony in the entire cohort and in the patients with septal APs (p<0.01).
Phase analysis of gated SPECT MPI demonstrated that LV mechanical dyssynchrony can be present in patients with WPW syndrome. Septal APs result in the greatest degree of LV mechanical dyssynchrony and afford the most benefit after RFA. This study supports further investigation in the relationship between electrical and mechanical activation using EPS and phase analysis of gated SPECT MPI.
Myocardial perfusion imaging; Phase analysis; LV dyssynchrony; Wolff-Parkinson-White syndrome; Radiofrequency catheter ablation
While evaluations of FDG PET-CT in adult patients with NPC have documented advantages and disadvantages of the technique compared with conventional imaging, to our knowledge, no such studies have been performed with pediatric patients. In this investigation, we studied the utility of FDG PET-CT in children with NPC.
Eighteen children with biopsy-proven NPC who underwent FDG PET-CT and MRI were studied (total 38 pairs of imagings). All baseline and follow-up FDG PET-CT and MRI studies were independently reviewed for restaging of disease.
The concordance between FDG PET-CT and MRI in T, N, and overall staging was 29%, 64%, and 43%, respectively. Compared with MRI, FDG PET-CT yielded lower T and overall staging and showed less cervical and retropharyngeal lymphadenopathy. The concordance between follow-up FDG PET-CT and MRI was 79% overall and 100% 9 months after therapy. In patients who achieved complete remission, FDG PET-CT showed disease clearance 3-6 months earlier than MRI. There were no false positive or false negative FDG PET-CT scans during follow-up.
FDG PET-CT may underestimate tumor extent and regional lymphadenopathy compared with MRI at the time of diagnosis, but it helps to detect metastasis and clarify ambiguous findings. FDG PET-CT is sensitive and specific for follow-up and enables earlier determination of disease remission. FDG PET-CT is a valuable imaging modality for the evaluation of and monitoring NPC in pediatric patients.
positron emission tomography; magnetic resonance imaging; nasopharyngeal carcinoma; child
Overactivity of the multidrug efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) is believed to play an important role in resistance to central nervous system drug treatment. (R)-[11C]verapamil (VPM) PET can be used to measure the function of P-gp at the BBB, but low brain uptake of VPM hampers the mapping of regional differences in cerebral P-gp function and expression. The aim of this study was to evaluate the dose-response relationship of two potent P-gp inhibitors and to investigate if increased brain uptake of VPM mediated by P-gp inhibition can be used to assess regional differences in P-gp activity.
Two groups of Sprague-Dawley rats (n=12) underwent single VPM PET scans at 120 min after administration of different doses of the P-gp inhibitors tariquidar and elacridar. In an additional 6 rats, paired VPM PET scans were performed before and after administration of 3 mg/kg tariquidar.
Inhibitor administration resulted in an up to 11-fold increase in VPM brain distribution volumes (DV) with ED50 values of 3.0±0.2 and 1.2±0.1 mg/kg for tariquidar and elacridar, respectively. In paired PET scans, 3 mg/kg tariquidar resulted in regionally different enhancement of brain activity distribution, with lowest DV in cerebellum and highest DV in thalamus.
Our data show that tariquidar and elacridar are able to increase VPM brain distribution in rat brain up to 11-fold over baseline at maximum effective doses, with elacridar being about 3 times more potent than tariquidar. Regional differences in tariquidar-induced modulation of VPM brain uptake point to regional differences in cerebral P-gp function and expression in rat brain.
small animal PET; (R)–[11C]verapamil; tariquidar; elacridar; P-glycoprotein, blood-brain barrier, regional
One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. Aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [11C]tariquidar and [11C]elacridar with the Pgp substrate radiotracer (R)-[11C]verapamil to discriminate tumours expressing low and high levels of Pgp using small-animal PET imaging in a murine breast cancer model.
Murine mammary carcinoma cells (EMT6) were continuously exposed to doxorubicin to generate a Pgp overexpressing, doxorubicin-resistant cell line (EMT6AR1.0 cells). Both cell lines were subcutaneously injected in female athymic nude mice. One week after implantation, animals underwent PET scans with [11C]tariquidar (n=7), [11C]elacridar (n=6) and (R)-[11C]verapamil (n=7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was studied by Western blotting.
[11C]Tariquidar showed significantly higher retention in Pgp overexpressing EMT6AR1.0 compared with EMT6 tumours (mean area under the time-activity curve in scan 1 from time 0 to 60 min, AUC0-60±SD: 38.8±2.2 min vs. 25.0±5.3 min, p=0.016, Wilcoxon matched pairs test). [11C]Elacridar and (R)-[11C]verapamil were not able to discriminate Pgp expression in tumour models. Following administration of unlabelled tariquidar, both EMT6Ar1.0 and EMT6 tumours showed increases in tumoural uptake of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil.
Among the tested radiotracers, [11C]tariquidar performed best in discriminating high from low Pgp expressing tumours. Therefore [11C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels of solid tumours.
Multidrug resistance; P-glycoprotein; positron emission tomography; [11C]tariquidar; [11C]elacridar; (R)-[11C]verapamil
In patients with localised neuroblastoma without adverse genetic aberrations, observational treatment is justified. Therapy is required when organ or respiratory functions have become compromised. As the outcome is good, side effects of treatment should be prevented. The aim of this retrospective study was to evaluate response and outcome in patients treated with 131I-metaiodobenzylguanidine (MIBG) for unresectable localised neuroblastoma, with compromised organ functions.
Patients with localised neuroblastoma [median age 1.6 years (0–5.5 years)] diagnosed between 1989 and 2008 were included in this retrospective study (n = 21). Primary tumours were unresectable and there was a compromised organ or respiratory function. Diagnosis and staging were performed according to the International Neuroblastoma Staging System. Fixed doses of 131I-MIBG therapy (50–200 mCi) were given. The median number of infusions was two (range one to seven). Response was graded according to the International Neuroblastoma Response Criteria.
Of the 21 patients, 14 did not need any chemotherapy. Patients were treated with 131I-MIBG therapy and, in most cases, with additional surgery and/or chemotherapy. Sixteen achieved complete response (CR), three very good partial response (VGPR), one partial response (PR) and one progressive disease (PD). Two patients died of PD after having achieved CR initially and due to surgical complications a few months after resection. Ten-year overall survival and event-free survival were 90.5 %. The median follow-up was 8.5 years (range 0.4–19.6 years).
131I-MIBG therapy is an effective treatment modality for unresectable localised neuroblastoma with compromised organ functions. However, this was a small and heterogeneous cohort and further studies are needed.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-013-2455-2) contains supplementary material, which is available to authorized users.
Neuroblastoma; 131I-MIBG therapy; Localised; Unresectable
In patients with unilateral internal carotid or middle cerebral artery (ICA or MCA) occlusive disease, the degree of crossed cerebellar hypoperfusion that is evident within a few months after the onset of stroke may reflect cerebral metabolic rate of oxygen in the affected cerebral hemisphere relative to that in the contralateral cerebral hemisphere. The aim of the present study was to determine whether the ratio of blood flow asymmetry in the cerebellar hemisphere to blood flow asymmetry in the cerebral hemisphere on positron emission tomography (PET) and single photon emission computed tomography (SPECT) correlates with oxygen extraction fraction (OEF) asymmetry in the cerebral hemisphere on PET in patients with chronic unilateral ICA or MCA occlusive disease and whether this blood flow ratio on SPECT detects misery perfusion in the affected cerebral hemisphere in such patients.
Brain blood flow and OEF were assessed using 15O-PET and N-isopropyl-p-[123I]iodoamphetamine (123I-IMP) SPECT, respectively. All images were anatomically standardized using SPM2. A region of interest (ROI) was automatically placed in the bilateral MCA territories and in the bilateral cerebellar hemispheres using a three-dimensional stereotaxic ROI template, and affected-to-contralateral asymmetry in the MCA territory or contralateral-to-affected asymmetry in the cerebellar hemisphere was calculated. Sixty-three patients with reduced blood flow in the affected cerebral hemisphere on 123I-IMP SPECT were enrolled in this study.
A significant correlation was observed between MCA ROI asymmetry of PET OEF and the ratio of cerebellar hemisphere asymmetry of blood flow to MCA ROI asymmetry of blood flow on PET (r = 0.381, p = 0.0019) or SPECT (r = 0.459, p = 0.0001). The correlation coefficient was higher when reanalyzed in a subgroup of 43 patients undergoing a PET study within 3 months after the last ischemic event (r = 0.541, p = 0.0001 for PET; r = 0.609, p < 0.0001 for SPECT). The blood flow ratio on brain perfusion SPECT in all patients provided 100 % sensitivity and 58 % specificity, with 43 % positive and 100 % negative predictive values for detecting abnormally elevated MCA ROI asymmetry of PET OEF.
The ratio of blood flow asymmetry in the cerebellar hemisphere to blood flow asymmetry in the cerebral hemisphere on PET and SPECT correlates with PET OEF asymmetry in the cerebral hemisphere, and this blood flow ratio on SPECT detects misery perfusion in the affected cerebral hemisphere.
Crossed cerebellar hypoperfusion; Misery perfusion; Oxygen extraction fraction; PET; SPECT
Translocator protein (TSPO) is a biomarker of neuroinflammation that can be imaged by PET using [11C]-(R)PK11195. We sought to characterize the [11C]-(R)PK11195 kinetics in gliomas of different histotypes and grades, and to compare two reference tissue input functions (supervised cluster analysis versus cerebellar grey matter) for the estimation of [11C]-(R)PK11195 binding in gliomas and surrounding brain structures.
Twenty-three glioma patients and ten age-matched controls underwent structural MRI and dynamic [11C]-(R)PK11195 PET scans. Tissue time–activity curves (TACs) were extracted from tumour regions as well as grey matter (GM) and white matter (WM) of the brains. Parametric maps of binding potential (BPND) were generated with the simplified reference tissue model using the two input functions, and were compared with each other. TSPO expression was assessed in tumour tissue sections by immunohistochemistry.
Three types of regional kinetics were observed in individual tumour TACs: GM-like kinetics (n = 6, clearance of the tracer similar to that in cerebellar GM), WM-like kinetics (n = 8, clearance of the tracer similar to that in cerebral WM) and a form of mixed kinetics (n = 9, intermediate rate of clearance). Such kinetic patterns differed between low-grade astrocytomas (WM-like kinetics) and oligodendrogliomas (GM-like and mixed kinetics), but were independent of tumour grade. There was good agreement between parametric maps of BPND derived from the two input functions in all controls and 10 of 23 glioma patients. In 13 of the 23 patients, BPND values derived from the supervised cluster input were systematically smaller than those using the cerebellar input. Immunohistochemistry confirmed that TSPO expression increased with tumour grade.
The three types of [11C]-(R)PK11195 kinetics in gliomas are determined in part by tracer delivery, and indicated that kinetic analysis is a valuable tool in the study of gliomas with the potential for in vivo discrimination between low-grade astrocytomas and oligodendrogliomas. Supervised cluster and cerebellar input functions produced consistent BPND estimates in approximately half of the gliomas investigated, but had a systematic difference in the remainder. The cerebellar input is preferred based on theoretical and practical considerations.
Translocator protein; [11C]-(R)PK11195; Kinetic analysis; Reference tissue; Glioma; PET
In patients with a small heart, defined as an end-systolic volume (ESV) of ≤20 mL calculated using the Quantitative Gated SPECT (QGS) program, underestimation of ESV and overestimation of ejection fraction (EF) using gated myocardial perfusion imaging are considered errors caused by inappropriate delineation of the left ventricle (LV). The aim of this study was to develop a new method for delineation of the LV and to evaluate it in studies using a digital phantom, normal subjects and patients.
The active shape-based method for LV delineation, EXINI heart (ExH), was adjusted to more accurately process small hearts. In small hearts, due to the partial volume effect and the short distance to the opposite ventricular wall, the endocardial and the epicardial surfaces are shifted in the epicardial direction depending on the midventricular volume. The adjusted method was evaluated using digital XCAT phantoms with Monte Carlo simulation (8 virtual patients), a Japanese multicentre normal database (69 patients) and consecutive Japanese patients (116 patients). The LV volumes, EF and diastolic parameters derived from ExH and QGS were compared.
The digital phantom studies showed a mean ESV of 87 % ± 9 % of the true volume calculated using ExH and 22 % ± 18 % calculated using QGS. In the normal database, QGS gave higher EFs in women than in men (71.4 ± 6.0 % vs. 67.2 ± 6.0 %, p = 0.0058), but ExH gave comparable EFs (70.7 ± 4.9 % and 71.4 ± 5 % in men and women, respectively, p = ns). QGS gave higher EFs in subjects with a small heart than in those with a normal-sized heart (74.5 ± 5.1 % vs. 66.1 ± 4.9 %), but ExH gave comparable values (70.0 ± 5.9 % vs. 71.6 ± 4.2 %, respectively, p = ns). In consecutive patients, the average EFs with QGS in patients with ESV >20 mL, 11–20 mL and ≤10 mL were 57.9 %, 71.9 % and 83.2 %, but with ExH the differences among these groups were smaller (65.2 %, 67.8 % and 71.5 %, respectively).
The volume-dependent edge correction algorithm was able to effectively reduce the effects on ESV and EF of a small heart. The uniform normal values might be applicable to both men and women and to both small and normal-sized hearts.
Myocardial perfusion imaging; Small heart; Left ventricular function; Software algorithm; Normal values
To evaluate the impact of dosimetry based on MAA SPECT/CT for the prediction of response, toxicity and survival, and for treatment planning in patients with hepatocellular carcinoma (HCC) treated with 90Y-loaded glass microspheres (TheraSphere®).
TheraSphere® was administered to 71 patients with inoperable HCC. MAA SPECT/CT quantitative analysis was used for the calculation of the tumour dose (TD), healthy injected liver dose (HILD), and total injected liver dose. Response was evaluated at 3 months using EASL criteria. Time to progression (TTP) and overall survival (OS) were evaluated using the Kaplan-Meier method. Factors potentially associated with liver toxicity were combined to construct a liver toxicity score (LTS).
The response rate was 78.8 %. Median TD were 342 Gy for responding lesions and 191 Gy for nonresponding lesions (p < 0.001). With a threshold TD of 205 Gy, MAA SPECT/CT predicted response with a sensitivity of 100 % and overall accuracy of 90 %. Based on TD and HILD, 17 patients underwent treatment intensification resulting in a good response rate (76.4 %), without increased grade III liver toxicity. The median TTP and OS were 5.5 months (2–9.5 months) and 11.5 months (2–31 months), respectively, in patients with TD <205 Gy and 13 months (10–16 months) and 23.2 months (17.5–28.5 months), respectively, in those with TD >205 Gy (p = 0.0015 and not significant). Among patients with portal vein thrombosis (PVT) (n = 33), the median TTP and OS were 4.5 months (2–7 months) and 5 months (2–8 months), respectively, in patients with TD <205 Gy and 10 months (6–15.2 months) and 21.5 months (12–28.5 months), respectively, in those with TD >205 Gy (p = 0.039 and 0.005). The median OS was 24.5 months (18–28.5 months) in PVT patients with TD >205 Gy and good PVT targeting on MAA SPECT/CT. The LTS was able to detect severe liver toxicity (n = 6) with a sensitivity of 83 % and overall accuracy of 97 %.
Dosimetry based on MAA SPECT/CT was able to accurately predict response and survival in patients treated with glass microspheres. This method can be used to adapt the injected activity without increasing liver toxicity, thus defining a new concept of boosted selective internal radiation therapy (B-SIRT). This new concept and LTS enable fully personalized treatment planning with glass microspheres to be achieved.
Radioembolization; Microspheres; Dosimetry; Liver; Radionuclide therapy
Position emission tomography imaging of angiogenesis may provide non-invasive insights into the corresponding molecular processes and may be applied for individualized treatment planning of antiangiogenic therapies. At the moment, most strategies are focusing on the development of radiolabelled proteins and antibody formats targeting VEGF and its receptor or the ED-B domain of a fibronectin isoform as well as radiolabelled matrix metalloproteinase inhibitors or αvβ3 integrin antagonists. Great efforts are being made to develop suitable tracers for different target structures. All of the major strategies focusing on the development of radiolabelled compounds for use with positron emission tomography are summarized in this review. However, because the most intensive work is concentrated on the development of radiolabelled RGD peptides for imaging αvβ3 expression, which has successfully made its way from bench to bedside, these developments are especially emphasized.
Angiogenesis; Vascular endothelial growth factor; Fibronectin ED-B domain; Integrin αvβ3; Matrix metalloproteinase; Imaging; Positron emission tomography
We prospectively evaluated whether a strategy using point spread function (PSF) reconstruction for both diagnostic and quantitative analysis in non-small cell lung cancer (NSCLC) patients meets the European Association of Nuclear Medicine (EANM) guidelines for harmonization of quantitative values.
The NEMA NU-2 phantom was used to determine the optimal filter to apply to PSF-reconstructed images in order to obtain recovery coefficients (RCs) fulfilling the EANM guidelines for tumour positron emission tomography (PET) imaging (PSFEANM). PET data of 52 consecutive NSCLC patients were reconstructed with unfiltered PSF reconstruction (PSFallpass), PSFEANM and with a conventional ordered subset expectation maximization (OSEM) algorithm known to meet EANM guidelines. To mimic a situation in which a patient would undergo pre- and post-therapy PET scans on different generation PET systems, standardized uptake values (SUVs) for OSEM reconstruction were compared to SUVs for PSFEANM and PSFallpass reconstruction.
Overall, in 195 lesions, Bland-Altman analysis demonstrated that the mean ratio between PSFEANM and OSEM data was 1.03 [95 % confidence interval (CI) 0.94–1.12] and 1.02 (95 % CI 0.90–1.14) for SUVmax and SUVmean, respectively. No difference was noticed when analysing lesions based on their size and location or on patient body habitus and image noise. Ten patients (84 lesions) underwent two PET scans for response monitoring. Using the European Organization for Research and Treatment of Cancer (EORTC) criteria, there was an almost perfect agreement between OSEMPET1/OSEMPET2 (current standard) and OSEMPET1/PSFEANM-PET2 or PSFEANM-PET1/OSEMPET2 with kappa values of 0.95 (95 % CI 0.91–1.00) and 0.99 (95 % CI 0.96–1.00), respectively. The use of PSFallpass either for pre- or post-treatment (i.e. OSEMPET1/PSFallpass-PET2 or PSFallpass-PET1/OSEMPET2) showed considerably less agreement with kappa values of 0.75 (95 % CI 0.67–0.83) and 0.86 (95 % CI 0.78–0.94), respectively.
Protocol-optimized images and compliance with EANM guidelines allowed for a reliable pre- and post-therapy evaluation when using different generation PET systems. These data obtained in NSCLC patients could be extrapolated to other solid tumours.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-013-2391-1) contains supplementary material, which is available to authorized users.
PET; Multicentre trials; PSF; NSCLC; SUV; Tumour imaging
Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic β-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic β-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging.
We prepared 18F radioligands for GLP-1R by the reaction of [18F]FBEM, a maleimide prosthetic group, with [Cys0] and [Cys40] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice.
The [18F]FBEM-[Cysx]-exendin-4 analogs were obtained in good yield (34.3±3.4%, n=11), based on the starting compound [18F]FBEM), and had a specific activity of 45.51±16.28 GBq/μmol (1.23±0.44 Ci/μmol, n=7) at the end of synthesis. The C-terminal isomer, [18F]FBEM-[Cys40]-exendin-4, had higher affinity for INS-1 tumor cells (IC50 1.11±0.057 nM) and higher tumor uptake (25.25±3.39 %ID/g at 1 h) than the N-terminal isomer, [18F]FBEM-[Cys0]-exendin-4 (IC50 2.99±0.06 nM, uptake 7.20±1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cysx]-exendin-4 (p<0.05).
[18F]FBEM-[Cys40]-exendin-4 and [18F]FBEM-[Cys0]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors exhibited by [18F]FBEM-[Cys40]-exendin-4 suggests that this compound would be the better tracer for imaging GLP-1R.
Exendin-4; GLP-1R; Insulinoma; 18F; PET
The αvβ3 integrin represents a potential target for noninvasive imaging of angiogenesis. The purpose of this study was to evaluate a novel one-step labeled integrin αvβ3 targeting PET probe, 18F-AlF-NOTA-PRGD2, for angiogenesis imaging in a myocardial infract/reperfusion (MI/R) animal model.
Male SD rats underwent 45 min transient left coronary artery occlusion followed by reperfusion. The myocardial infarction was confirmed by ECG, 18F-FDG imaging and cardiac ultrasound. In vivo PET imaging were used to determine myocardial uptake of 18F-AlF-NOTA-PRGD2 at different time points following reperfusion. The control peptide RAD was labeled with a similar procedure and used to confirm the specificity. Ex vivo autoradiographic analysis and CD31/CD61 double immunofluoresence staining were performed to validate the PET results.
Myocardial origin of the 18F-AlF-NOTA-PRGD2 accumulation was confirmed by 18F-FDG and autoradiography. PET imaging demonstrated increased focal accumulation of 18F-AlF-NOTA-PRGD2 in the infarcted area started at day 3 (0.28 ± 0.03 %ID/g, p < 0.05), peaked between 1 and 3 weeks (0.59 ± 0.16 and 0.55 ± 0.13 %ID/g, respectively). The focal accumulation decreased but still kept at a higher level than the sham group after 4 months of reperfusion (0.31 ± 0.01 %ID/g, p < 0.05). Pretreatment with unlabeled RGD peptide significantly decreased tracer uptake, indicating integrin specificity of this tracer. At 1 week after MI/R, uptake of the control tracer 18F-AlF-NOTA-RAD that does not bind to integrin, in the infarcted area, was only 0.21 ± 0.01 %ID/g. Autoradiographic imaging showed the same trend of uptake in myocardial infarction area. The time course of focal tracer uptake was consistent with the pattern of vascular density and integrin β3 expression as measured by CD31 and CD61 immunostaining analysis.
PET imaging using one-step labeled 18F-AlF-NOTA-PRGD2 allows noninvasive visualization of ischemia-reperfusion induced myocardial angiogenesis longitudinally. The favorable in vivo kinetics and easy production method of this integrin targeted PET tracer facilitates its future clinical translation for lesion evaluation and therapy response monitoring in patients with occlusive cardiovascular diseases.
PET imaging; angiogenesis; myocardial infarction; integrin; RGD peptide
17-DMAG, a heat shock protein 90 (Hsp90) inhibitor, has been intensively investigated for cancer therapy and is undergoing clinical trials. Human epidermal growth factor receptor 2 (HER-2) is one of the client proteins of Hsp90 and its expression is decreased upon 17-DMAG treatment. In this study, we aimed to non-invasively monitor the HER-2 response to 17-DMAG treatment in xenografted mice.
The sensitivity of human ovarian cancer SKOV-3 cells to 17-DMAG in vitro was measured by MTT assay. HER-2 expression of SKOV-3 cells was determined by flow cytometry. Nude mice bearing SKOV-3 tumors were treated with 17-DMAG and the therapeutic efficacy was evaluated by tumor size measurement. Both treated and control mice were imaged with microPET using 64Cu-DOTA-trastuzumab and 18F-FDG. Biodistribution studies, immunofluorescence staining were performed to validate the microPET results.
SKOV-3 cells are sensitive to 17-DMAG treatment, in a dose dependent manner, with an IC50 value of 68.7 nM after 72 h incubation. The tumor growth curve supported the inhibition effect of 17-DMAG on SKOV-3 tumors. Quantitative microPET imaging showed that 64Cu-DOTA-trastuzumab had prominent tumor activity accumulation in untreated SKOV-3 tumors, which was significantly reduced in 17-DMAG treated tumors. There was no uptake difference detected by FDG PET. Immunofluorescence staining confirmed the significant reduction in tumor HER-2 level upon 17-DMAG treatment.
The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using 64Cu-DOTA-trastuzumab. This approach may be valuable in monitoring the therapeutic response in HER-2-positive cancer patients under 17-DMAG treatment.
Human epidermal growth factor receptor (HER-2); Positron emission tomography (PET); Heat shock protein 90 (Hsp90); 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG); Trastuzumab
Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists 90Y-DOTATOC ([90Y-DOTA0,Tyr3]-octreotide) or 177Lu-DOTATATE ([177Lu-DOTA0,Tyr3,Thr8]-octreotide or [177Lu-DOTA0,Tyr3]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving 177Lu-DOTATATE or 90Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts’ opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency.
Peptide receptor radionuclide therapy; PRRNT; PRRNT, neuroendocrine tumours, guideline/s, renal protection
To prepare and evaluate a new radiotracer for molecular imaging of cell surface receptors for epidermal growth factor (EGF).
Cys tagged EGF (cEGF) was labeled with 18F by coupling the free thiol group of the Cys tag with N-[2-(4-[18F]fluorobenzamido)ethyl]maleimide ([18F]FBEM) to form [18F]FBEM-cEGF. Cell uptake, internalization and efflux of [18F]FBEM-cEGF were tested in human head and neck squamous carcinoma UM-SCC1 cells. In vivo tumor targeting and pharmacokinetics of the radiotracers were evaluated in UM-SCC1 tumor-bearing athymic nude mice by static and dynamic microPET imaging. Ex vivo biodistribution assays were performed to confirm the noninvasive imaging results.
The radiolabeling yield for [18F]FBEM-cEGF was over 60%, based on starting [18F]FBEM. [18F]FBEM-cEGF exhibited rapid blood clearance through both hepatobiliary and renal excretion. UM-SCC1 tumors were clearly visualized and showed modest tracer uptake of 2.60 ± 0.59 %ID/g at 30 min post injection. Significantly higher tumor uptake of [18F]FBEM-cEGF (5.99 ± 1.61 %ID/g at 30 min p.i., p < 0.01) and tumor/non-tumor ratio were achieved by co-injection of 50 μg of unlabeled EGF. Decreased liver uptake of [18F]FBEM-cEGF was observed when unlabeled EGF was co-administered.
With optimized liver blocking, [18F]FBEM-cEGF has the potential to be used in a non-invasive and quantitative manner for detection of malignant lesions and evaluation of EGFR activity.
PET; [18F]FBEM-cEGF; HNSCC; EGFR