Combination of [68Ga]Ga-PSMA PET/CT and [18F]FDG PET/CT in demonstrating dedifferentiation in castration-resistant prostate cancer

Aim of the studyIn this study, we aimed to determine the factors affecting increased glucose metabolism, which is one of the dedifferentiation mechanisms, by using [¹⁸F]FDG and [⁶⁸Ga]Ga-PSMA PET/CT in patients with castration-resistant prostate cancer (CRPC).Materials and methodNinety-three patients with CRPC were included in the study. Gleason score (GS), and total PSA and free PSA levels of the patients were recorded. Patient- and organ-based evaluations were performed according to the lesion uptakes as follows: score 0: PSMA (-) FDG (-), score 1: PSMA (+) FDG (-), score 2: PSMA (+) FDG (+) (FDG < PSMA), score 3: PSMA (+) FDG (+) (FDG = PSMA), score 4: PSMA (+) FDG (+) (FDG > PSMA), and score 5: PSMA (-) FDG (+). scores 1 and 2 were classified as group 1, and scores 3 to 5 were classified as group 2.ResultsThe median age of our patients was 70 (51–88) years. Eighty-eight patients (94.6%) were PSMA-positive, 78 patients (83.8%) were FDG-positive, and 89 patients (95.6%) were or PSMA or FDG positive. When the two groups were compared in terms of patient-based parameters, the median age and GS were found to be significantly higher in group 2. ROC analyses revealed that age and GS were significant in predicting group 2.ConclusionSince glucose metabolism can increase in CRPC patients with advanced age and high GS, we recommend combining [¹⁸F]FDG PET/CT with [⁶⁸Ga]Ga-PSMA PET/CT in routine clinical practice in order to identify this patient subset and refer them to additional therapies.     

PET Imaging of Lung Inflammation with [18F]FEDAC, a Radioligand for Translocator Protein (18 kDa)

Purpose

The translocator protein (18 kDa) (TSPO) is highly expressed on the bronchial and bronchiole epithelium, submucosal glands in intrapulmonary bronchi, pneumocytes and alveolar macrophages in human lung. This study aimed to perform positron emission tomography (PET) imaging of lung inflammation with [¹⁸F]FEDAC, a specific TSPO radioligand, and to determine cellular sources enriching TSPO expression in the lung.

Methods

An acute lung injury model was prepared by intratracheal administration of lipopolysaccharide (LPS) to rat. Uptake of radioactivity in the rat lungs was measured with small-animal PET after injection of [¹⁸F]FEDAC. Presence of TSPO was examined in the lung tissue using Western blot and immunohistochemical assays.

Results

The uptake of [¹⁸F]FEDAC increased in the lung with the progress of inflammation by treatment with LPS. Pretreatment with a TSPO-selective ligand PK11195 showed a significant decrease in the lung uptake of [¹⁸F]FEDAC due to competitive binding to TSPO. TSPO expression was elevated in the inflamed lung section and its level responded to the [¹⁸F]FEDAC uptake and severity of inflammation. Increase of TSPO expression was mainly found in the neutrophils and macrophages of inflamed lungs.

Conclusion

From this study we conclude that PET with [¹⁸F]FEDAC may be a useful tool for imaging TSPO expression and evaluating progress of lung inflammation. Study on human lung using [¹⁸F]FEDAC-PET is promising.     

Accuracy of [18F]FDG PET/MRI for the Detection of Liver Metastases

Background

The aim of this study was to compare the diagnostic accuracy of [¹⁸F]FDG-PET/MRI with PET/CT for the detection of liver metastases.

Methods

32 patients with solid malignancies underwent [¹⁸F]FDG-PET/CT and subsequent PET/MRI of the liver. Two readers assessed both datasets regarding lesion characterization (benign, indeterminate, malignant), conspicuity and diagnostic confidence. An imaging follow-up (mean interval: 185±92 days) and/-or histopathological specimen served as standards of reference. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for both modalities. Accuracy was determined by calculating the area under the receiver operating characteristic (ROC) curve. Values of conspicuity and diagnostic confidence were compared using Wilcoxon-signed-rank test.

Results

The standard of reference revealed 113 liver lesions in 26 patients (malignant: n = 45; benign: n = 68). For PET/MRI a higher accuracy (PET/CT: 82.4%; PET/MRI: 96.1%; p<0.001) as well as sensitivity (67.8% vs. 92.2%, p<0.01) and NPV (82.0% vs. 95.1%, p<0.05) were observed. PET/MRI offered higher lesion conspicuity (PET/CT: 2.0±1.1 [median: 2; range 0–3]; PET/MRI: 2.8±0.5 [median: 3; range 0–3]; p<0.001) and diagnostic confidence (PET/CT: 2.0±0.8 [median: 2; range: 1–3]; PET/MRI 2.6±0.6 [median: 3; range: 1–3]; p<0.001). Furthermore, PET/MRI enabled the detection of additional PET-negative metastases (reader 1: 10; reader 2: 12).

Conclusions

PET/MRI offers higher diagnostic accuracy compared to PET/CT for the detection of liver metastases.     

Detection of apoptosis by PET/CT with the diethyl ester of [18F]ML-10 and fluorescence imaging with a dansyl analogue

The diethyl ester of [¹⁸F]ML-10 is a small molecule apoptotic PET probe for cancer studies. Here we report a novel multi-step synthesis of the diethyl ester of ML-10 in excellent yields via fluorination using Xtal-Fluor-E. In addition, a one-pot radiosynthesis of the diethyl ester of [¹⁸F]ML-10 from nucleophilic [¹⁸F]fluoride was completed in 23% radiochemical yield (decay corrected). The radiochemical purity of the product was ⩾99%. The diethyl ester of [¹⁸F]ML-10 was used in vivo to detect apoptosis in the testes of mice. In parallel studies, the dansyl-ML-10 diethyl ester was prepared and used to detect apoptotic cells in an in vitro cell based assay.     

An Intra-Individual Comparison of MRI, [18F]-FET and [18F]-FLT PET in Patients with High-Grade Gliomas

Objectives

Intra-individual spatial overlap analysis of tumor volumes assessed by MRI, the amino acid PET tracer [¹⁸F]-FET and the nucleoside PET tracer [¹⁸F]-FLT in high-grade gliomas (HGG).

Methods

MRI, [¹⁸F]-FET and [¹⁸F]-FLT PET data sets were retrospectively analyzed in 23 HGG patients. Morphologic tumor volumes on MRI (post-contrast T1 (cT1) and T2 images) were calculated using a semi-automatic image segmentation method. Metabolic tumor volumes for [¹⁸F]-FET and [¹⁸F]-FLT PETs were determined by image segmentation using a threshold-based volume of interest analysis. After co-registration with MRI the morphologic and metabolic tumor volumes were compared on an intra-individual basis in order to estimate spatial overlaps using the Spearman''s rank correlation coefficient and the Mann-Whitney U test.

Results

[¹⁸F]-FLT uptake was negative in tumors with no or only moderate contrast enhancement on MRI, detecting only 21 of 23 (91%) HGG. In addition, [¹⁸F]-FLT uptake was mainly restricted to cT1 tumor areas on MRI and [¹⁸F]-FLT volumes strongly correlated with cT1 volumes (r = 0.841, p<0.001). In contrast, [¹⁸F]-FET PET detected 22 of 23 (96%) HGG. [¹⁸F]-FET uptake beyond areas of cT1 was found in 61% of cases and [¹⁸F]-FET volumes showed only a moderate correlation with cT1 volumes (r = 0.573, p<0.001). Metabolic tumor volumes beyond cT1 tumor areas were significantly larger for [¹⁸F]-FET compared to [¹⁸F]-FLT tracer uptake (8.3 vs. 2.7 cm³, p<0.001).

Conclusion

In HGG [¹⁸F]-FET but not [¹⁸F]-FLT PET was able to detect metabolic active tumor tissue beyond contrast enhancing tumor on MRI. In contrast to [¹⁸F]-FET, blood-brain barrier breakdown seems to be a prerequisite for [¹⁸F]-FLT tracer uptake.     

Investigation of 6-[18F]-Fluoromaltose as a Novel PET Tracer for Imaging Bacterial Infection

Despite advances in the field of nuclear medicine, the imaging of bacterial infections has remained a challenge. The existing reagents suffer from poor sensitivity and specificity. In this study we investigate the potential of a novel PET (positron emission tomography) tracer that overcomes these limitations.

Methods

6-[¹⁸F]-fluoromaltose was synthesized. Its behavior in vitro was evaluated in bacterial and mammalian cultures. Detailed pharmacokinetic and biodistribution profiles for the tracer were obtained from a murine model.

Results

6-[¹⁸F]-fluoromaltose is taken up by multiple strains of pathogenic bacteria. It is not taken up by mammalian cancer cell lines. 6-[¹⁸F]-fluoromaltose is retained in infected muscles in a murine model of bacterial myositis. It does not accumulate in inflamed tissue.

Conclusion

We have shown that 6-[¹⁸F]-fluoromaltose can be used to image bacterial infection in vivo with high specificity. We believe that this class of agents will have a significant impact on the clinical management of patients.     

Development of a Novel PET Tracer [18F]AlF-NOTA-C6 Targeting MMP2 for Tumor Imaging

Background and Objective

The overexpression of gelatinases, that is, matrix metalloproteinase MMP2 and MMP9, has been associated with tumor progression, invasion, and metastasis. To image MMP2 in tumors, we developed a novel ligand termed [¹⁸F]AlF-NOTA-C6, with consideration that: c(KAHWGFTLD)NH₂ (herein, C6) is a selective gelatinase inhibitor; Cy5.5-C6 has been visualized in many in vivo tumor models; positron emission tomography (PET) has a higher detection sensitivity and a wider field of view than optical imaging; fluorine-18 (¹⁸F) is the optimal PET radioisotope, and the creation of a [¹⁸F]AlF-peptide complex is a simple procedure.

Methods

C6 was conjugated to the bifunctional chelator NOTA (1, 4, 7-triazacyclononanetriacetic acid) for radiolabeling [¹⁸F]AlF conjugation. The MMP2-binding characteristics and tumor-targeting efficacy of [¹⁸F]AlF-NOTA-C6 were tested in vitro and in vivo.

Results

The non-decay corrected yield of [¹⁸F]AlF-NOTA-C6 was 46.2–64.2%, and the radiochemical purity exceeded 95%. [¹⁸F]AlF-NOTA-C6 was favorably retained in SKOV3 and PC3 cells, determined by cell uptake. Using NOTA-C6 as a competitive ligand, the uptake of [¹⁸F]AlF-NOTA-C6 in SKOV3 cells decreased in a dose-dependent manner. In biodistribution and PET imaging studies, higher radioactivity concentrations were observed in tumors. Pre-injection of C6 caused a marked reduction in tumor tissue uptake. Immunohistochemistry showed MMP2 in tumor tissues.

Conclusions

[¹⁸F]AlF-NOTA-C6 was easy to synthesize and has substantial potential as an imaging agent that targets MMP2 in tumors.     

Imaging prostate derived tumors with PET and N-(3-[18F]fluoropropyl)putrescine

Because of the high uptake of polyamines by the prostate and by prostate derived tumors, polyamines have been considered as potential imaging agents for metastatic prostate cancer. We now report the successful PET imaging of the Dunning R3327H prostatic carcinoma with N-(3-[¹⁸F]fluoropropyl)-putrescine (FPP), a positron-labeled putrescine analog. Additionally, the biodistribution of FPP in tumor bearing Copenhagen male rats is analyzed. The tumor uptake of FPP was high, and the tumor-to-muscle ratios at 1,2,3 and 4.5 h post-injection were 7.2 ± 1.0, 5.61 ± 1.65, 4.62 ± 0.21 and 3.51 ± 0.91 respectively. The estimated radiation dose for FPP was calculated from rat biodistribution data. The radiation dose estimates suggest that the critical organ, following the administration of FPP, is the upper large intenstine which receives 0.3 rad/mCi administered.     

Novel radiosynthesis of PET HSV-tk gene reporter probes [18F]FHPG and [18F]FHBG employing dual Sep-Pak SPE techniques

Positron emission tomography (PET) herpes simplex virus thymidine kinase (HSV-tk) gene reporter probes 9-[(3-[(18)F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([(18)F]FHPG) and 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl)guanine ([(18)F]FHBG) were prepared by nucleophilic substitution of the appropriate tosylated precursors with [(18)F]KF/Kryptofix 2.2.2 followed by a quick deprotection reaction and purification with a simplified dual Silica Sep-Pak solid-phase extraction (SPE) method in 15-30% radiochemical yield.     

Early Assessment of the Efficacy of Temozolomide Chemotherapy in Experimental Glioblastoma Using [18F]FLT-PET Imaging

Addition of temozolomide (TMZ) to radiation therapy is the standard treatment for patients with glioblastoma (GBM). However, there is uncertainty regarding the effectiveness of TMZ. Considering the rapid evolution of the disease, methods to assess TMZ efficacy early during treatment would be of great benefit. Our aim was to monitor early effects of TMZ in a mouse model of GBM using positron emission tomography (PET) with 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT).

Methods

Human glioma cells sensitive to TMZ (Gli36dEGFR-1) were treated with sub-lethal doses of TMZ to obtain cells with lower sensitivity to TMZ (Gli36dEGFR-2), as measured by growth and clonogenic assays. Gli36dEGFR-1 and Gli36dEGFR-2 cells were subcutaneously (s.c.) or intracranially (i.c.) xenografted into nude mice. Mice were treated for 7 days with daily injection of 25 or 50 mg/kg TMZ. Treatment efficacy was measured using [¹⁸F]FLT-PET before treatment and after 2 days. Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) were used to determine tumor volumes before treatment and after 7 days.

Results

A significant difference was observed between TMZ and DMSO treated tumors in terms of variations of [¹⁸F]FLT T/B ratio as soon as day 2 in the i.c. as well as in the s.c. mouse model. Variations of [¹⁸F]FLT T/B uptake ratio between days 0 and 2 correlated with variations of tumor size between days 0 and 7 (s.c. model: n_tumor = 17 in n_mice = 11, P<0.01; i.c. model: n_tumor/mice = 9, P<0.01).

Conclusions

Our results indicate that [¹⁸F]FLT-PET may be useful for an early evaluation of the response of GBM to TMZ chemotherapy in patients with glioma.     

Incidental detection of a well-differentiated rectal adenocarcinoma by [18F]-Fluorocholine PET/CT in a patient with biochemical relapse of a prostate cancer

We report the case of a 70-year-old man who underwent an 18[F]-Fluorocholine ([18F]-FCH) positron emission tomography combined with computed tomography (PET/CT) after biochemical recurrence of prostate cancer previously treated by prostatectomy in 2012 (Gleason score 5 [2 + 3], PSA value before prostatectomy 19 ng/mL). Early acquisitions centered on the pelvis following the injection of 258 MBq of [18F]-FCH showed a rectal focused and intense uptake. The imaging performed 60 minutes after injection from the base of the skull to the upper third of the femur confirmed the presence of this focal uptake related on CT slices to a thickening of the rectal wall. Biopsies of the corresponding lesion allowed the diagnosis of well-differentiated rectal adenocarcinoma. The patient was directed to surgical resection, which was effective in September 2014. Pathology analysis was in favor of a well-differentiated rectal adenocarcinoma invaded the totality of the rectal wall. Fifteen lymph nodes were dissected and were benign. The tumor was classified as T3N0 (UICC 2010 classification). A contrast enhancement CT scan did not show any lesion compatible with rectal cancer metastasis. More and more incidental findings will occur in clinical PET/CT practice. If there are suspicious lesions of a different etiology than that announced in the request, nuclear medicine physicians must be aware of such issues in order to help clinicians to pursue further investigations like endoscopic biopsy for colorectal uptake. Finally, further studies must be performed to confirm the usefulness of [18F]-FCH PET/CT in colorectal cancer compared to [18F]-FDG PET/CT.     

[18F]FLT and [18F]FDG PET for Non-invasive Treatment Monitoring of the Nicotinamide Phosphoribosyltransferase Inhibitor APO866 in Human Xenografts

Introduction

APO866 is a new anti-tumor compound inhibiting nicotinamide phosphoribosyltransferase (NAMPT). APO866 has an anti-tumor effect in several pre-clinical tumor models and is currently in several clinical phase II studies. 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of this study was non-invasively to study effect of APO866 treatment on [18F]FLT and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake.

Methods

In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) was studied at various time points after APO866 treatment. Baseline [18F]FLT or [18F]FDG scans were made before treatment and repeated after 24 hours, 48 hours and 7 days. Tumor volume was followed with computed tomography (CT). Tracer uptake was quantified using small animal PET/CT. One hour after iv injection of tracer, static PET scans were performed. Imaging results were compared with Ki67 immunohistochemistry.

Results

Tumors treated with APO866 had volumes that were 114% (24 h), 128% (48 h) and 130% (Day 7) relative to baseline volumes at Day 0. In the control group tumor volumes were 118% (24 h), 145% (48 h) and 339% (Day 7) relative to baseline volumes Day 0. Tumor volume between the treatment and control group was significantly different at Day 7 (P = 0.001). Compared to baseline, [18F]FLT SUVmax was significantly different at 24 h (P<0.001), 48 h (P<0.001) and Day 7 (P<0.001) in the APO866 group. Compared to baseline, [18F]FDG SUVmax was significantly different at Day 7 (P = 0.005) in the APO866 group.

Conclusions

APO866 treatment caused a significant decrease in [18F]FLT uptake 24 and 48 hours after treatment initiation. The early reductions in tumor cell proliferation preceded decrease in tumor volume. The results show the possibility to use [18F]FLT and [18F]FDG to image treatment effect early following treatment with APO866 in future clinical studies.     

Hypoxia Imaging Using PET and SPECT: The Effects of Anesthetic and Carrier Gas on [64Cu]-ATSM, [99mTc]-HL91 and [18F]-FMISO Tumor Hypoxia Accumulation

Background

Preclinical imaging requires anaesthesia to reduce motion-related artefacts. For direct translational relevance, anaesthesia must not significantly alter experimental outcome. This study reports on the effects of both anaesthetic and carrier gas upon the uptake of [⁶⁴Cu]-CuATSM, [^99mTc]-HL91 and [¹⁸F]-FMISO in a preclinical model of tumor hypoxia.

Methodology/Principal Findings

The effect of carrier gas and anaesthetic was studied in 6 groups of CaNT-bearing CBA mice using [⁶⁴Cu]-CuATSM, [^99mTc]-HL91 or [¹⁸F]-FMISO. Mice were anaesthetised with isoflurane in air, isoflurane in pure oxygen, with ketamine/xylazine or hypnorm/hypnovel whilst breathing air, or in the awake state whilst breathing air or pure oxygen. PET or SPECT imaging was performed after which the mice were killed for organ/tumor tracer quantitation. Tumor hypoxia was confirmed. Arterial blood gas analysis was performed for the different anaesthetic regimes. The results demonstrate marked influences on tumor uptake of both carrier gas and anaesthetic, and show differences between [^99mTc]-HL91, [¹⁸F]-FMISO and [⁶⁴Cu]-CuATSM. [^99mTc]-HL91 tumor uptake was only altered significantly by administration of 100% oxygen. The latter was not the case for [¹⁸F]-FMISO and [⁶⁴Cu]-CuATSM. Tumor-to-muscle ratio (TMR) for both compounds was reduced significantly when either oxygen or anaesthetics (isoflurane in air, ketamine/xylazine or hypnorm/hypnovel) were introduced. For [¹⁸F]-FMISO no further decrease was measured when both isoflurane and oxygen were administered, [⁶⁴Cu]-CuATSM did show an additional significant decrease in TMR. When using the same anaesthetic regimes, the extent of TMR reduction was less pronounced for [⁶⁴Cu]-CuATSM than for [¹⁸F]-FMISO (40–60% versus 70% reduction as compared to awake animals breathing air).

Conclusions/Significance

The use of anaesthesia can have profound effects on the experimental outcome. More importantly, all tested anaesthetics reduced tumor-hypoxia uptake. Anaesthesia cannot be avoided in preclinical studies but great care has to be taken in preclinical models of hypoxia as anaesthesia effects cannot be generalised across applications, nor disease states.     

Limits of [18F]-FLT PET as a Biomarker of Proliferation in Oncology

Background

Non-invasive imaging biomarkers of cellular proliferation hold great promise for quantifying response to personalized medicine in oncology. An emerging approach to assess tumor proliferation utilizes the positron emission tomography (PET) tracer 3’-deoxy-3’[¹⁸F]-fluorothymidine, [¹⁸F]-FLT. Though several studies have associated serial changes in [¹⁸F]-FLT-PET with elements of therapeutic response, the degree to which [¹⁸F]-FLT-PET quantitatively reflects proliferative index has been continuously debated for more that a decade. The goal of this study was to elucidate quantitative relationships between [¹⁸F]-FLT-PET and cellular metrics of proliferation in treatment naïve human cell line xenografts commonly employed in cancer research.

Methods and Findings

[¹⁸F]-FLT-PET was conducted in human cancer xenograft-bearing mice. Quantitative relationships between PET, thymidine kinase 1 (TK1) protein levels and immunostaining for proliferation markers (Ki67, TK1, PCNA) were evaluated using imaging-matched tumor specimens. Overall, we determined that [¹⁸F]-FLT-PET reflects TK1 protein levels, yet the cell cycle specificity of TK1 expression and the extent to which tumors utilize thymidine salvage for DNA synthesis decouple [¹⁸F]-FLT-PET data from standard estimates of proliferative index.

Conclusions

Our findings illustrate that [¹⁸F]-FLT-PET reflects tumor proliferation as a function of thymidine salvage pathway utilization. Unlike more general proliferation markers, such as Ki67, [¹⁸F]-FLT PET reflects proliferative indices to variable and potentially unreliable extents. [¹⁸F]-FLT-PET cannot discriminate moderately proliferative, thymidine salvage-driven tumors from those of high proliferative index that rely primarily upon de novo thymidine synthesis. Accordingly, the magnitude of [¹⁸F]-FLT uptake should not be considered a surrogate of proliferative index. These data rationalize the diversity of [¹⁸F]-FLT-PET correlative results previously reported and suggest future best-practices when [¹⁸F]-FLT-PET is employed in oncology.     

Prostate cancer PET bioprobes: synthesis of [18F]-radiolabeled hydroxyflutamide derivatives

Approximately 80-90% of prostate cancers are androgen dependent at initial diagnosis. The androgen receptor (AR) is present in most advanced prostate cancer specimens and is believed to have a critical role in its development. Today, treatment of prostate cancer is done by inhibition of AR using antiandrogens such as flutamide (pro-drug of hydroxyflutamide), nilutamide, and bicalutamide. However, there is currently no noninvasive imaging modalities to detect, guide, and monitor specific treatment of AR-positive prostate cancer. (R)-3-Bromo-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-propanamide [18F]-1 and N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide [18F]-2, derivatives of hydroxyflutamide, were synthesized as a fluorine-containing imaging agent candidates. A three-step fluorine-18 radiosynthesis route was developed, and the compounds were successfully labeled with a 10+/-3% decay corrected radiochemical yield, 95% radiochemical purity, and a specific activity of 1500+/-200 Ci/mmol end of bombardment (n = 10). These labeled biprobes not only may enable for the future quantitative molecular imaging of AR-positive prostate cancer using positron emission tomography but may also allow for image-guided treatment of prostate cancer.     

Early detection of response to experimental chemotherapeutic Top216 with [18F]FLT and [18F]FDG PET in human ovary cancer xenografts in mice

Background

3′-deoxy-3′-[¹⁸F]fluorothymidine (¹⁸F-FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use ¹⁸F-FLT positron emission tomography (PET) to study treatment responses to a new anti-cancer compound. To do so, we studied early anti-proliferative effects of the experimental chemotherapy Top216 non-invasively by PET.

Methodology/Principal Findings

In vivo uptake of ¹⁸F-FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after Top216 treatment (50 mg/kg i.v. at 0 and 48 hours) was initiated. Baseline ¹⁸F-FLT scans were made before either Top216 (n = 7–10) or vehicle (n = 5–7) was injected and repeated after 2 and 6 hours and 1 and 5 days of treatment. A parallel study was made with 2′-deoxy-2′-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) (n = 8). Tracer uptake was quantified using small animal PET/CT. Imaging results were validated by tumor volume changes and gene-expression of Ki67 and TK1. Top216 (50 mg/kg 0 and 48 hours) inhibited the growth of the A2780 tumor compared to the control group (P<0.001). ¹⁸F-FLT uptake decreased significantly at 2 hours (−52%; P<0.001), 6 hours (−49%; P = 0.002) and Day 1 (−47%; P<0.001) after Top216 treatment. At Day 5 ¹⁸F-FLT uptake was comparable to uptake in the control group. Uptake of ¹⁸F-FLT was unchanged in the control group during the experiment. In the treatment group, uptake of ¹⁸F-FDG was significantly decreased at 6 hours (−21%; P = 0.003), Day 1 (−29%; P<0.001) and Day 5 (−19%; P = 0.05) compared to baseline.

Conclusions/Significance

One injection with Top216 initiated a fast and significant decrease in cell-proliferation assessable by ¹⁸F-FLT after 2 hours. The early reductions in tumor cell proliferation preceded changes in tumor size. Our data indicate that ¹⁸F-FLT PET is promising for the early non-invasive assessment of chemotherapy effects in both drug development and for tailoring therapy in patients.     

Myocardial Metastases on 6-[18F] fluoro-L-DOPA PET/CT: A Retrospective Analysis of 116 Serotonin Producing Neuroendocrine Tumour Patients

Purpose

This study evaluates the prevalence of cardiac metastases in patients with serotonin producing neuroendocrine tumours (NET), examined with ¹⁸F-FDOPA PET/CT, and the relationship of these metastases to the presence of carcinoid heart disease (CHD) based on echocardiography.

Background

CHD occurs in patients with serotonin producing NET. The diagnostic method of choice remains echocardiography. The precise prevalence of cardiac metastases is unknown given the limitations of standard technologies. Nuclear medicine modalities have the potential to visualize metastases of NET.

Methods

All patients who underwent ¹⁸F-FDOPA PET/CT because of serotonin producing NET between November 2009 and May 2012 were retrospectively analyzed. The presence of cardiac metastasis was defined as myocardial tracer accumulation higher than the surrounding physiological myocardial uptake. Laboratory tests and transthoracic echocardiography (TTE) results were digitally collected.

Results

116 patients (62 male) underwent ¹⁸F-FDOPA PET/CT, mean age was 61±13 years. TTE was performed in 79 patients. Cardiac metastases were present in 15 patients, of which 10 patients also underwent TTE. One patient had both cardiac metastasis (only on ¹⁸F-FDOPA PET/CT) and echocardiographic signs of CHD. There were no differences in echocardiographic parameters for CHD between patients with and without cardiac metastases. TTE in none of the 79 patients showed cardiac metastases.

Conclusion

The prevalence of cardiac metastases detected with ¹⁸F-FDOPA PET/CT in this study is 13%. ¹⁸F-FDOPA PET/CT can visualize cardiac metastases in serotonin producing NET patients. There appears to be no relationship between the presence of cardiac metastases and TTE parameters of CHD.