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1.  Early reduction in tumour [18F]fluorothymidine (FLT) uptake in patients with non-small cell lung cancer (NSCLC) treated with radiotherapy alone 
Purpose
Changes in tumour 3′-deoxy-3′-[18F]fluorothymidine (FLT) uptake during concurrent chemo-radiotherapy in patients with non-small cell lung cancer (NSCLC) have been reported, at variable time points, in two pilot positron emission tomography (PET) studies. The aim of this study was to assess whether FLT changes occur early in response to radiotherapy (RT) without concurrent chemotherapy and whether such changes exceed test-retest variability.
Methods
Sixteen patients with NSCLC, scheduled to have radical RT, underwent FLT PET once/twice at baseline to assess reproducibility and/or after 5–11 RT fractions to evaluate response. Primary and nodal malignant lesions were manually delineated on CT and volume, mean and maximum standardized uptake values (SUVmean and SUVmax) estimated. Analysis included descriptive statistics and parameter fitting to a mixed-effects model accounting for patients having different numbers of evaluable lesions.
Results
In all, 35 FLT PET scans from 7 patients with a total of 18 lesions and 12 patients with a total of 30 lesions were evaluated for reproducibility and response, respectively. SUVmean reproducibility in primary tumours (SD 8.9 %) was better than SUVmax reproducibility (SD 12.6 %). In nodes, SUVmean and SUVmax reproducibilities (SD 18.0 and 17.2 %) were comparable but worse than for primary tumours. After 5–11 RT fractions, primary tumour SUVmean decreased significantly by 25 % (p = 0.0001) in the absence of significant volumetric change, whereas metastatic nodes decreased in volume by 31 % (p = 0.020) with a larger SUVmean decrease of 40 % (p < 0.0001). Similar changes were found for SUVmax.
Conclusion
Across this group of NSCLC patients, RT induced an early, significant decrease in lesion FLT uptake exceeding test-retest variability. This effect is variable between patients, appears distinct between primary and metastatic nodal lesions, and in primary tumours is lower than previously reported for concurrent chemo-RT at a similar time point. These results confirm the potential for FLT PET to report early on radiation response and to enhance the clinical development of novel drug-radiation combinations by providing an interpretable, early pharmacodynamic end point.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-013-2632-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s00259-013-2632-3
PMCID: PMC3955141  PMID: 24504503
[18F]Fluorothymidine PET; Non-small cell lung cancer; Radiotherapy; Early response monitoring
2.  Evaluation in vitro and in animals of a new 11C-labeled PET radioligand for metabotropic glutamate receptors 1 in brain 
Two allosteric modulators of the Group I metabotropic glutamate receptors (mGluR1 & mGluR5) were evaluated as positron emission tomography (PET) radioligands for mGluR1.
Methods
LY2428703, a full mGluR1 antagonist (IC50 = 8.9 nM) and partial mGluR5 antagonist (IC50 = 118 nM) and LSN2606428, a full mGluR1 and mGluR5 antagonist (IC50 = 35.3 nM and 10.2 nM, respectively) were successfully labeled with carbon-11 and evaluated as radioligands for mGluR1. A comprehensive assessment of the in vitro and in vivo pharmacology, Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) biodistribution, and rat PET imaging of LY2428703 was conducted. In contrast, LSN2606428 was only evaluated in vitro; further evaluation was stopped due to its unfavorable pharmacological properties and binding affinity.
Results
11C-LY2428703 showed promising characteristics, including: 1) high potency for binding to human mGluR1 (IC50 = 8.9 nM) with no significant affinity for other human mGlu receptors (mGluR2 through 8); 2) binding to brain displaceable by administration of an mGluR1 antagonist; 3) only one major radiometabolite in both plasma and brain, having negligible brain concentration (~3.5% of the total radioactivity in cerebellum) and no receptor affinity; 4) a large specific and displaceable signal in the mGluR1-rich cerebellum with no significant in vivo affinity for mGluR5, as shown with PET studies in rats; and 5) lack of substrate behavior for efflux transporters at the blood-brain barrier, as shown with PET studies conducted in wild-type and knock-out mice.
Conclusion
11C-LY2428703, a new PET radioligand for mGluR1 quantification, displayed promising characteristics both in vitro and in vivo in rodents.
doi:10.1007/s00259-012-2269-7
PMCID: PMC3537910  PMID: 23135321
mGlu1 receptors; PET; brain
4.  Stress-induced myocardial ischemia is associated with early post-stress left ventricular mechanical dyssynchrony as assessed by phase analysis of 201Tl gated SPECT myocardial perfusion imaging 
Purpose
In 201Tl SPECT myocardial perfusion imaging (MPI) data are acquired shortly after the stress injection to assess early post-stress left ventricle (LV) function. The purpose of this study was to use 201Tl SPECT MPI to investigate whether stress-induced myocardial ischemia is associated with LV mechanical dyssynchrony.
Methods
Enrolled in the study were 75 patients who were referred for dipyridamole stress and rest 201Tl gated SPECT MPI. The early post-stress scan was started 5 min after injection, and followed by the rest scan 4 h later. The patients were divided into three groups: ischemia group (N=25, summed stress score, SSS, ≥5, summed rest score, SRS, <5), infarct group (N=16, SSS ≥5, SRS ≥5) and normal group (N=34, SSS <5, SRS <5). LV dyssynchrony parameters were calculated by phase analysis, and compared between the stress and rest images.
Results
In the ischemia group, LV dyssynchrony was significantly larger during stress than during rest. On the contrary, LV dyssynchrony during stress was significantly smaller than during rest in the normal and infarct groups. LV dyssynchrony during rest was significantly larger in the infarct group than in the normal and ischemia groups. There were no significant differences in LV dyssynchrony during rest between the normal and ischemia groups.
Conclusion
Stress-induced myocardial ischemia caused dyssynchronous contraction in the ischemic region, leading to a deterioration in LV synchrony. Normal myocardium had more synchronous contraction during stress. The different dyssynchrony pattern between ischemic and normal myocardium early post-stress may aid the diagnosis of coronary artery disease using 201Tl gated SPECT MPI.
doi:10.1007/s00259-012-2208-7
PMCID: PMC3717145  PMID: 22875446
Thallium-201; Gated SPECT; Left-ventricular dyssynchrony; Myocardial ischemia
5.  Regadenoson in Europe: first-year experience of regadenoson stress combined with submaximal exercise in patients undergoing myocardial perfusion scintigraphy 
Purpose
Regadenoson was approved for clinical use in Europe in 2011. Since then, it has become the default form of stress at our institution. We have assessed the side-effect profile and tolerability of regadenoson in patients undergoing clinically indicated myocardial perfusion scintigraphy between July 2011 and July 2012.
Methods
Clinical, stress and imaging data were recorded prospectively. Symptoms during stress were recorded and defined as mild, moderate or severe. An adverse event was defined as any symptom that persisted for more than 30 min or that required investigation or treatment.
Results
Of 1,764 consecutive patients, 1,581 (90 %) received regadenoson combined with submaximal exercise unless contraindicated. Symptoms were common (63 %) but transient and well-tolerated. The severity of symptoms was recorded in most patients as mild (84 %). Dyspnoea (36 %) and chest discomfort (12 %) were the commonest side effects. Adverse events were reported in eight patients (0.5 %), thought to be vasovagal in seven of these. All patients recovered fully without sequelae. There were no deaths, myocardial infarction or hospital admissions. Regadenoson stress was performed in 206 patients (12 %) with asthma or chronic obstructive pulmonary disease (COPD) without bronchospasm or any other major side effect.
Conclusion
We studied the symptom profile of regadenoson in the largest European cohort to date. Regadenoson combined with submaximal exercise was well tolerated, notably also in patients with asthma or COPD. The majority of regadenoson-related adverse events were vasovagal episodes without sequelae.
doi:10.1007/s00259-013-2619-0
PMCID: PMC3913852  PMID: 24265072
Myocardial perfusion scintigraphy; Regadenoson; Side effects; Safety; Tolerability
6.  Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2 
European journal of nuclear medicine and molecular imaging  2008;35(8):10.1007/s00259-008-0738-9.
Purpose
Fluoropyrimidines like 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-thymine (FMAU) and 3′-deoxy-3′-fluorothymidine (FLT) accumulate in tumors and are being used as positron emission tomography tumor-imaging tracers. Proliferating tissues with high thymidine kinase 1 (TK1) activity retain FLT; however, the mechanism of selective accumulation of FMAU in tumors and certain other tissues requires further study.
Methods
Retention of [3H]FLT and [3H]FMAU was measured in prostate cancer cell lines PC3, LNCaP, DU145, and the breast cancer cell line MD-MBA-231, and the tracer metabolites were analyzed by high-performance liquid chromatography (HPLC). FMAU retention, thymidine kinase 2 (TK2) activity, and mitochondrial mass were determined in cells stressed by depleted cell culture medium or by treating with oxidative, reductive, and energy stress, or specific adenosine monophosphate-activated protein kinase activator, or eIF2 inhibitor. TK1 and TK2 activities and mitochondrial mass were determined by FLT phosphorylation, 1-β-D-arabinofuranosylthymine (Ara-T) phosphorylation, and flow cytometry, respectively.
Results
FMAU retention in rapidly proliferating cancer cell lines was five to ten times lower than FLT after 10 min incubation. HPLC analysis of the cellular extracts showed that phosphorylated tracers are the main retained metabolites. Nutritional stress decreased TK1 activity and FLT retention but increased retained FMAU. TK2 inhibition decreased FMAU retention and phosphorylation with negligible effects on FLT. Oxidative, reductive, or energy stress increased FMAU retention and correlated with mitochondrial mass (r2= 0.88, p=0.006). FMAU phosphorylation correlated with increased TK2 activity (r2=0.87, p=0.0002).
Conclusion
FMAU is preferably phosphorylated by TK2 and can track TK2 activity and mitochondrial mass in cellular stress. FMAU may provide an early marker of treatment effects.
doi:10.1007/s00259-008-0738-9
PMCID: PMC3826914  PMID: 18265975
FMAU; Positron emission tomography; Thymidine kinase 2; Stress; Cancer
7.  Detection and quantification of focal uptake in head and neck tumours: 18F-FDG PET/MR versus PET/CT 
Purpose
Our objectives were to assess the quality of PET images and coregistered anatomic images obtained with PET/MR, to evaluate the detection of focal uptake and SUV, and to compare these findings with those of PET/CT in patients with head and neck tumours.
Methods
The study group comprised 32 consecutive patients with malignant head and neck tumours who underwent whole-body 18F-FDG PET/MR and PET/CT. PET images were reconstructed using the attenuation correction sequence for PET/MR and CT for PET/CT. Two experienced observers evaluated the anonymized data. They evaluated image and fusion quality, lesion conspicuity, anatomic location, number and size of categorized (benign versus assumed malignant) lesions with focal uptake. Region of interest (ROI) analysis was performed to determine SUVs of lesions and organs for both modalities. Statistical analysis considered data clustering due to multiple lesions per patient.
Results
PET/MR coregistration and image fusion was feasible in all patients. The analysis included 66 malignant lesions (tumours, metastatic lymph nodes and distant metastases), 136 benign lesions and 470 organ ROIs. There was no statistically significant difference between PET/MR and PET/CT regarding rating scores for image quality, fusion quality, lesion conspicuity or anatomic location, number of detected lesions and number of patients with and without malignant lesions. A high correlation was observed for SUVmean and SUVmax measured on PET/MR and PET/CT for malignant lesions, benign lesions and organs (ρ = 0.787 to 0.877, p < 0.001). SUVmean and SUVmax measured on PET/MR were significantly lower than on PET/CT for malignant tumours, metastatic neck nodes, benign lesions, bone marrow, and liver (p < 0.05). The main factor affecting the difference between SUVs in malignant lesions was tumour size (p < 0.01).
Conclusion
In patients with head and neck tumours, PET/MR showed equivalent performance to PET/CT in terms of qualitative results. Comparison of SUVs revealed an excellent correlation for measurements on both modalities, but underestimation of SUVs measured on PET/MR as compared to PET/CT.
doi:10.1007/s00259-013-2580-y
PMCID: PMC3913851  PMID: 24108458
PET/MR; PET/CT; Hybrid imaging; Head and neck tumours; SUV
9.  Is nano too big? 
doi:10.1007/s00259-013-2574-9
PMCID: PMC3843741  PMID: 24092264
10.  Comparison of PET imaging with a 68Ga-labelled PSMA ligand and 18F-choline-based PET/CT for the diagnosis of recurrent prostate cancer 
Purpose
Positron emission tomography (PET) with choline tracers has found widespread use for the diagnosis of prostate cancer (PC). However, choline metabolism is not increased in a considerable number of cases, whereas prostate-specific membrane antigen (PSMA) is overexpressed in most PCs. Therefore, a 68Ga-labelled PSMA ligand could be superior to choline tracers by obtaining a high contrast. The aim of this study was to compare such a novel tracer with standard choline-based PET/CT.
Methods
Thirty-seven patients with biochemical relapse of PC [mean prostate-specific antigen (PSA) 11.1 ± 24.1 ng/ml, range 0.01–116] were retrospectively analysed after 18F-fluoromethylcholine and 68Ga-PSMA PET/CT within a time window of 30 days. Radiotracer uptake that was visually considered as PC was semi-quantitatively analysed by measuring the maximum standardized uptake values (SUVmax) of the scans acquired 1 h after injection of 68Ga-PSMA complex solution (median 132 MBq, range 59–263 MBq) and 18F-fluoromethylcholine (median 237 MBq, range 114–374 MBq), respectively. In addition, tumour to background ratios were calculated.
Results
A total of 78 lesions characteristic for PC were detected in 32 patients using 68Ga-PSMA PET/CT and 56 lesions were detected in 26 patients using choline PET/CT. The higher detection rate in 68Ga-PSMA PET/CT was statistically significant (p = 0.04). In five patients no lesion was found with both methods. All lesions detected by 18F-fluoromethylcholine PET/CT were also seen by 68Ga-PSMA PET/CT. In 68Ga-PSMA PET/CT SUVmax was clearly (>10 %) higher in 62 of 78 lesions (79.1 %) and the tumour to background ratio was clearly (>10 %) higher in 74 of 78 lesions (94.9 %) when compared to 18F-fluoromethylcholine PET/CT.
Conclusion
68Ga-PSMA PET/CT can detect lesions characteristic for PC with improved contrast when compared to standard 18F-fluoromethylcholine PET/CT, especially at low PSA levels.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-013-2525-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00259-013-2525-5
PMCID: PMC3843747  PMID: 24072344
Prostate cancer; PET/CT; Positron emission tomography; PSMA; Choline
11.  iRENEX: a clinically informed decision support system for the interpretation of 99mTc-MAG3 scans to detect renal obstruction 
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s00259-012-2151-7
PMCID: PMC3688257  PMID: 22644714
Decision support systems; Renal obstruction; Clinical data; 99mTc-MAG3 renography
12.  Areas of normal pulmonary parenchyma on HRCT exhibit increased FDG PET signal in IPF patients 
Purpose
Patients with idiopathic pulmonary fibrosis (IPF) show increased PET signal at sites of morphological abnormality on high-resolution computed tomography (HRCT). The purpose of this investigation was to investigate the PET signal at sites of normal-appearing lung on HRCT in IPF.
Methods
Consecutive IPF patients (22 men, 3 women) were prospectively recruited. The patients underwent 18F-FDG PET/HRCT. The pulmonary imaging findings in the IPF patients were compared to the findings in a control population. Pulmonary uptake of 18F-FDG (mean SUV) was quantified at sites of morphologically normal parenchyma on HRCT. SUVs were also corrected for tissue fraction (TF). The mean SUV in IPF patients was compared with that in 25 controls (patients with lymphoma in remission or suspected paraneoplastic syndrome with normal PET/CT appearances).
Results
The pulmonary SUV (mean ± SD) uncorrected for TF in the controls was 0.48 ± 0.14 and 0.78 ± 0.24 taken from normal lung regions in IPF patients (p < 0.001). The TF-corrected mean SUV in the controls was 2.24 ± 0.29 and 3.24 ± 0.84 in IPF patients (p < 0.001).
Conclusion
IPF patients have increased pulmonary uptake of 18F-FDG on PET in areas of lung with a normal morphological appearance on HRCT. This may have implications for determining disease mechanisms and treatment monitoring.
doi:10.1007/s00259-013-2514-8
PMCID: PMC3890564  PMID: 23942907
Idiopathic pulmonary fibrosis; PET/CT
13.  Toxicity of upfront 131I-metaiodobenzylguanidine (131I-MIBG) therapy in newly diagnosed neuroblastoma patients: a retrospective analysis 
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s00259-013-2510-z
PMCID: PMC3788185  PMID: 23921531
Neuroblastoma; 131I-MIBG therapy; Acute toxicity
14.  LV dyssynchrony as assessed by phase analysis of gated SPECT myocardial perfusion imaging in patients with Wolff-Parkinson-White syndrome 
Purpose
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).
Methods
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.
Results
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).
Conclusion
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.
doi:10.1007/s00259-012-2101-4
PMCID: PMC3732446  PMID: 22532253
Myocardial perfusion imaging; Phase analysis; LV dyssynchrony; Wolff-Parkinson-White syndrome; Radiofrequency catheter ablation
15.  Positron emission tomography-computed tomography for staging and follow-up of pediatric nasopharyngeal carcinoma 
Purpose
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s00259-012-2091-2
PMCID: PMC3531235  PMID: 22532252
positron emission tomography; magnetic resonance imaging; nasopharyngeal carcinoma; child
16.  Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[11C]verapamil PET 
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s00259-009-1332-5
PMCID: PMC3690672  PMID: 20016890
small animal PET; (R)–[11C]verapamil; tariquidar; elacridar; P-glycoprotein, blood-brain barrier, regional
17.  A comparative small-animal PET evaluation of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil for detection of P-glycoprotein expressing murine breast cancer 
Purpose
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.
Methods
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.
Results
[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.
Conclusions
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.
doi:10.1007/s00259-011-1941-7
PMCID: PMC3684861  PMID: 21983837
Multidrug resistance; P-glycoprotein; positron emission tomography; [11C]tariquidar; [11C]elacridar; (R)-[11C]verapamil
18.  The role of 131I-metaiodobenzylguanidine (MIBG) therapy in unresectable and compromising localised neuroblastoma 
Purpose
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1007/s00259-013-2455-2
PMCID: PMC3779309  PMID: 23740371
Neuroblastoma; 131I-MIBG therapy; Localised; Unresectable
19.  Detection of misery perfusion in the cerebral hemisphere with chronic unilateral major cerebral artery steno-occlusive disease using crossed cerebellar hypoperfusion: comparison of brain SPECT and PET imaging 
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s00259-013-2463-2
PMCID: PMC3779315  PMID: 23740375
Crossed cerebellar hypoperfusion; Misery perfusion; Oxygen extraction fraction; PET; SPECT
20.  [11C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches 
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s00259-013-2447-2
PMCID: PMC3738844  PMID: 23715902
Translocator protein; [11C]-(R)PK11195; Kinetic analysis; Reference tissue; Glioma; PET
21.  Improved quantification of small hearts for gated myocardial perfusion imaging 
Purpose
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1007/s00259-013-2431-x
PMCID: PMC3699706  PMID: 23632963
Myocardial perfusion imaging; Small heart; Left ventricular function; Software algorithm; Normal values
22.  Boosted selective internal radiation therapy with 90Y-loaded glass microspheres (B-SIRT) for hepatocellular carcinoma patients: a new personalized promising concept 
Purpose
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®).
Methods
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).
Results
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 %.
Conclusion
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.
doi:10.1007/s00259-013-2395-x
PMCID: PMC3679421  PMID: 23613103
Radioembolization; Microspheres; Dosimetry; Liver; Radionuclide therapy
23.  Positron emission tomography tracers for imaging angiogenesis 
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.
doi:10.1007/s00259-010-1503-4
PMCID: PMC3629959  PMID: 20559632
Angiogenesis; Vascular endothelial growth factor; Fibronectin ED-B domain; Integrin αvβ3; Matrix metalloproteinase; Imaging; Positron emission tomography
24.  Harmonizing SUVs in multicentre trials when using different generation PET systems: prospective validation in non-small cell lung cancer patients 
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s00259-013-2391-1
PMCID: PMC3679414  PMID: 23564036
PET; Multicentre trials; PSF; NSCLC; SUV; Tumour imaging
25.  18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma 
Purpose
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.
Methods
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.
Results
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).
Conclusion
[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.
doi:10.1007/s00259-011-1980-0
PMCID: PMC3617488  PMID: 22170321
Exendin-4; GLP-1R; Insulinoma; 18F; PET

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