Cholinergic PET imaging in infections and inflammation using <Superscript>11</Superscript>C-donepezil and <Superscript>18</Superscript>F-FEOBV

Introduction

Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated.

Methods

We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer.

Results

In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120–144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen.

Discussion

The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic mechanisms of immune modulation, but also clinical applications for diagnosing infections, inflammatory disorders, and cancer inflammation.

     

Comparison of <Superscript>68</Superscript>Ga-labelled PSMA-11 and <Superscript>11</Superscript>C-choline in the detection of prostate cancer metastases by PET/CT

Purpose

Prostate-specific membrane antigen (PSMA) is expressed ubiquitously on the membrane of most prostate tumors and its metastasis. While PET/CT using ¹¹C-choline was considered as the gold standard in the staging of prostate cancer, PET with radiolabelled PSMA ligands was introduced into the clinic in recent years. Our aim was to compare the PSMA ligand ⁶⁸Ga-PSMA-11 with ¹¹C-choline in patients with primary and recurrent prostate cancer.

Methods

123 patients underwent a whole-body PET/CT examination using ⁶⁸Ga-PSMA-11 and ¹¹C-choline. Suspicious lesions were evaluated visually and semiquantitatively (SUVavg). Out of these, 103 suffered from a confirmed biochemical relapse after prostatectomy and/or radiotherapy (mean PSA level of 4.5 ng/ml), while 20 patients underwent primary staging.

Results

In 67 patients with biochemical relapse, we detected 458 lymph nodes suspicious for metastasis. PET using ⁶⁸Ga-PSMA-11 showed a significantly higher uptake and detection rate than ¹¹C-choline PET. Also ⁶⁸Ga-PSMA-11 PET identified significantly more patients with suspicious lymph nodes as well as affected lymph nodes regions especially at low PSA levels. Bone lesions suspicious for prostate cancer metastasis were revealed in 36 patients’ biochemical relapse. Significantly more bone lesions were detected by ⁶⁸Ga-PSMA-11, but only 3 patients had only PSMA-positive bone lesions. Nevertheless, we detected also 29 suspicious lymph nodes and 8 bone lesions, which were only positive as per ¹¹C-choline PET. These findings led to crucial differences in the TNM classification and the identification of oligometastatic patients. In the patients who underwent initial staging, all primary tumors showed uptake of both tracers. Although significantly more suspicious lymph nodes and bone lesions were identified, only 2 patients presented with bone lesions only detected by ⁶⁸Ga-PSMA-11 PET.

Conclusion

Thus, PET using ⁶⁸Ga-PSMA-11 showed a higher detection rate than ¹¹C-choline PET for lymph nodes as well as bone lesions. However, we found lymph nodes and bone lesions which were not concordant applying both tracers.

     

The utility of PET/CT with <Superscript>68</Superscript>Ga-DOTATOC in sarcoidosis: comparison with <Superscript>67</Superscript>Ga-scintigraphy

Objective

This study was designed to compare the clinical efficacy of ⁶⁸Ga-DOTA-Tyr-octreotide (DOTATOC)-positron emission tomography (PET)/computed tomography (CT) with that of conventional ⁶⁷Ga-scintigraphy (GS), and to correlate quantitative parameters on DOTATOC-PET/CT with clinical data, in patients with sarcoidosis.

Methods

Twenty patients who were histologically and/or clinically diagnosed with sarcoidosis and underwent both DOTATOC-PET/CT and GS were analyzed in this study. The numbers of patients with positive findings for each organ were determined. The total numbers of involved nodal areas in the chest, as determined by DOTATOC-PET and gallium single-photon emission tomography (Ga-SPECT), were compared. The correlations between quantitative parameters on PET and clinical laboratory data were evaluated.

Results

DOTATOC-PET/CT was positive in 19 patients, being negative in only one patient with chronic inactive sarcoidosis, whereas GS was positive in 17 patients. DOTATOC-PET/CT visualized more lesions in lymph nodes, uvea, and muscles than did Ga-scintigraphy and identified more involved areas than did GS-SPECT (p < 0.0001). Whole-body active lesion volume showed a significant, but moderate correlation with angiotensin-converting enzyme level (ρ = 0.64, p = 0.0044).

Conclusions

PET/CT with DOTATOC may be superior to conventional GS in detecting sarcoidosis lesions, especially in lymph nodes, uvea, and muscles. Volumetric parameters in DOTATOC-PET/CT may be helpful in estimating the activity of sarcoidosis.

     

Comparison of choline influx from dynamic <Superscript>18</Superscript>F-Choline PET/CT and clinicopathological parameters in prostate cancer initial assessment

Aim

The aim of the study was to compare the kinetic analysis of ¹⁸F-labeled choline (FCH) uptake with static analysis and clinicopathological parameters in patients with newly diagnosed prostate cancer (PC).

Materials and methods

Sixty-one patients were included. PSA was performed few days before FCH PET/CT. Gleason scoring (GS) was collected from systematic sextant biopsies. FCH PET/CT consisted in a dual phase: early pelvic list-mode acquisition (from 0 to10 min post-injection) and late whole-body acquisition (60 min post-injection). PC volume of interest was drawn using an adaptative thresholding (40% of the maximal uptake) on the late acquisition and projected onto an early static frame of 10 min and each of the 20 reconstructed frames of 30 s. Kinetic analysis was performed using an imaging-derived plasma input function. Early kinetic parameter (K1 as influx) and static parameters (early SUVmean, late SUVmean, and retention index) were extracted and compared to clinicopathological parameters.

Results

K1 was significantly, but moderately correlated with early SUVmean (r?=?0.57, p?<?0.001) and late SUVmean (r?=?0.43, p?<?0.001). K1, early SUVmean, and late SUVmean were moderately correlated with PSA level (respectively, r?=?0.36, p?=?0.004; r?=?0.67, p?<?0.001; r?=?0.51, p?<?0.001). Concerning GS, K1 was higher for patients with GS?≥?4?+?3 than for patients with GS?<?4?+?3 (median value 0.409 vs 0.272 min^??1, p?<?0.001). No significant difference was observed for static parameters.

Conclusions

FCH influx index K1 seems to be related to GS and could be a non-invasive tool to gain further information concerning tumor aggressiveness.

     

Dual tracer tau PET imaging reveals different molecular targets for <Superscript>11</Superscript>C-THK5351 and <Superscript>11</Superscript>C-PBB3 in the Alzheimer brain

Purpose

Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (¹¹C-THK5351 and ¹¹C-PBB3) in a head-to-head, in vivo, multimodal design.

Methods

Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer’s disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer’s disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers ¹¹C-THK5351 and ¹¹C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer ¹¹C-AZD2184, a T1-MRI sequence, and neuropsychological assessment.

Results

The load and regional distribution of binding differed between ¹¹C-THK5351 and ¹¹C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of ¹¹C-PBB3, but not that of ¹¹C-THK5351, in the temporal lobe resembled that of ¹¹C-AZD2184, with strong correlations detected between ¹¹C-PBB3 and ¹¹C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with ¹¹C-THK5351 than with ¹¹C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with ¹¹C-THK5351 than with ¹¹C-PBB3 binding.

Conclusion

This research suggests different molecular targets for these tracers; while ¹¹C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of ¹¹C-THK5351 fitted the expected distribution of tau pathology in Alzheimer’s disease better and was more closely related to downstream disease markers.

     

Prospective head-to-head comparison of <Superscript>11</Superscript>C-choline-PET/MR and <Superscript>11</Superscript>C-choline-PET/CT for restaging of biochemical recurrent prostate cancer

Purpose

Whole-body integrated ¹¹C-choline PET/MR might provide advantages compared to ¹¹C-choline PET/CT for restaging of prostate cancer (PC) due to the high soft-tissue contrast and the use of multiparametric MRI, especially for detection of local recurrence and bone metastases.

Materials and methods

Ninety-four patients with recurrent PC underwent a single-injection/dual-imaging protocol with contrast-enhanced PET/CT followed by fully diagnostic PET/MR. Imaging datasets were read separately by two reader teams (team 1 and 2) assessing the presence of local recurrence, lymph node and bone metastases in predefined regions using a five-point scale. Detection rates were calculated. The diagnostic performance of PET/CT vs. PET/MR was compared using ROC analysis. Inter-observer and inter-modality variability, radiation exposure, and mean imaging time were evaluated. Clinical follow-up, imaging, and/or histopathology served as standard of reference (SOR).

Results

Seventy-five patients qualified for the final image analysis. A total of 188 regions were regarded as positive: local recurrence in 37 patients, 87 regions with lymph node metastases, and 64 regions with bone metastases. Mean detection rate between both readers teams for PET/MR was 84.7% compared to 77.3% for PET/CT (p > 0.05). Local recurrence was identified significantly more often in PET/MR compared to PET/CT by team 1. Lymph node and bone metastases were identified significantly more often in PET/CT compared to PET/MR by both teams. However, this difference was not present in the subgroup of patients with PSA values ≤2 ng/ml.Inter-modality and inter-observer agreement (K > 0.6) was moderate to substantial for nearly all categories. Mean reduction of radiation exposure for PET/MR compared to PET/CT was 79.7% (range, 72.6–86.2%). Mean imaging time for PET/CT was substantially lower (18.4 ± 0.7 min) compared to PET/MR (50.4 ± 7.9 min).

Conclusions

¹¹C-choline PET/MR is a robust imaging modality for restaging biochemical recurrent PC and interpretations between different readers are consistent. It provides a higher diagnostic value for detecting local recurrence compared to PET/CT with the advantage of substantial dose reduction. Drawbacks of PET/MR are a substantially longer imaging time and a slight inferiority in detecting bone and lymph node metastases in patients with PSA values >2 ng/ml. Thus, we suggest the use of ¹¹C-choline PET/MR especially for patients with low (≤2 ng/ml) PSA values, whereas PET/CT is preferable in the subgroup with higher PSA values.

     

<Superscript>68</Superscript>Ga-PSMA PET/CT in the evaluation of bone metastases in prostate cancer

Purpose

The aims of this retrospective analysis were to compare ⁶⁸Ga-PSMA PET findings and low-dose CT findings (120 kV, 30 mA), and to obtain semiquantitative and quantitative ⁶⁸Ga-PSMA PET data in patients with prostate cancer (PC) bone metastases.

Methods

In total, 152 PET/CT scans from 140 patients were evaluated. Of these patients, 30 had previously untreated primary PC, and 110 had biochemical relapse after treatment of primary PC. All patients underwent dynamic PET/CT scanning of the pelvis and lower abdomen as well as whole-body PET/CT with ⁶⁸Ga-PSMA-11. The PET/CT scans were analysed qualitatively (visually), semiquantitatively (SUV), and quantitatively based on a two-tissue compartment model and a noncompartmental approach leading to the extraction of the fractal dimension. Differences were considered significant for p values <0.05.

Results

In total, 168 ⁶⁸Ga-PSMA-positive and 113 CT-positive skeletal lesions were detected in 37 patients (8 with primary PC, 29 with biochemical recurrence). Of these 168 lesions, 103 were both ⁶⁸Ga-PSMA PET-positive and CT-positive, 65 were only ⁶⁸Ga-PSMA-positive, and 10 were only CT-positive. The Yang test showed that there were significantly more ⁶⁸Ga-PSMA PET-positive lesions than CT-positive lesions. Association analysis showed that PSA plasma levels were significantly correlated with several ⁶⁸Ga-PSMA-11-associated parameters in bone metastases, including the degree of tracer uptake (SUV_average and SUV_max), its transport rate from plasma to the interstitial/intracellular compartment (K₁), its rate of binding to the PSMA receptor and its internalization (k₃), its influx rate (K_i), and its distribution heterogeneity.

Conclusion

⁶⁸Ga-PSMA PET/CT is a useful diagnostic tool in the detection of bone metastases in PC. ⁶⁸Ga-PSMA PET visualizes more bone metastases than low-dose CT. PSA plasma levels are significantly correlated with several ⁶⁸Ga-PSMA PET parameters.

     

<Superscript>18</Superscript>F-FDG and <Superscript>18</Superscript>F-FLT PET/CT imaging in the characterization of mediastinal lymph nodes

Purpose

There is currently no single modality for accurate characterization of enlarged mediastinal lymph nodes into benign or malignant. Recently ¹⁸F-fluorothymidine (FLT) has been used as a proliferation marker. In this prospective study, we examined the role of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) and ¹⁸F-FLT PET/CT in categorizing mediastinal lymph nodes as benign or malignant.

Materials and methods

A total of 70 consecutive patients with mediastinal lymphadenopathy detected on computed tomography (CT) or chest radiograph underwent whole body ¹⁸F-FLT PET/CT and ¹⁸F-FDG PET/CT (within 1 week of each other). Lymph nodal tracer uptake was determined by calculation of standardized uptake value (SUV) with both the tracers. Results of PET/CT were compared with histopathology of the lymph nodes.

Results

Histopathology results showed thirty-seven patients with sarcoidosis, seven patients with tuberculosis, nine patients with non-small cell lung cancer, five patients with Hodgkin’s lymphoma and twelve patients with non-Hodgkin’s lymphoma. The mean FDG SUV_max of sarcoidosis, tuberculosis, Hodgkin’s and non-Hodgkin’s lymphoma was 12.7, 13.4, 8.2, and 8.8, respectively, and the mean FLT SUV_max was 6.0, 5.4, 4.4, and 3.8, respectively. It was not possible to characterize mediastinal lymphadenopathy as benign or malignant solely based on FDG SUV_max values (p > 0.05) or FLT SUV_max values (p > 0.05). There was no significant difference in FDG uptake (p > 0.9) or FLT uptake (p > 0.9) between sarcoidosis and tuberculosis. In lung cancer patients, the FDG SUV_max and FLT SUV_max of those lymph nodes with tumor infiltration on biopsy was 6.7 and 3.9, respectively, and those without nodal infiltration was 6.4 and 3.7, respectively, and both the tracers were not able to characterize the nodal status as malignant or benign (p > 0.05).

Conclusion

Though ¹⁸F-FLT PET/CT and ¹⁸F-FDG PET/CT reflect different aspects of biology, i.e., proliferation and metabolism, respectively, neither tracer could provide satisfactory categorization of benign and malignant lymph nodes. The results of this study clearly suggest that differentiation of mediastinal nodes into benign and malignant solely based on SUV_max values cannot be relied upon, especially in settings where tuberculosis and sarcoidosis are common.

     

Utility of <Superscript>18</Superscript>F-fluoroestradiol (<Superscript>18</Superscript>F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy

Background

Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. ¹⁸F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes ¹⁸F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen.

Methods

Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with ¹⁸F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with ¹⁸F-FES 1–5 days post administration of Z-endoxifen.

Results

Statistically significant changes (p?=?0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration.

Conclusion

F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy.

     

Incidental focal <Superscript>18</Superscript>F-FDG uptake in the frontal process of the maxilla on PET/CT: prevalence and clinical significance

Objective

We investigated the prevalence and clinical significance of incidental focal ¹⁸F-FDG uptake in the frontal process of the maxilla, mimicking malignancy on PET/CT.

Methods

From a total of 32,834 patients who underwent ¹⁸F-FDG PET/CT, patients with focal uptake in the frontal process of the maxilla were selected by a database search. For those patients, medical records including relevant imaging studies were reviewed.

Results

Thirty-nine patients (0.12 %) demonstrated focal uptake on PET/CT. On CT of PET/CT, all lesions showed ground-glass attenuation with or without bony expansion, consistent with fibrous dysplasia. When comparing previous PET/CT, follow-up PET/CT, and CT, a significant difference in degree of ¹⁸F-FDG uptake was noted, with no associated change in the size of maxillary lesions. There were no patients who had symptoms or signs related to maxillary lesions during follow-up.

Conclusion

Focal ¹⁸F-FDG uptake in the frontal process of the maxilla is a rare, incidental, and persistent finding with variable uptake and can represent a benign condition.

     

<Superscript>18</Superscript>F-FDG uptake by rectal cancer is similar in mucinous and nonmucinous histological subtypes

Purpose

PET/CT has been considered limited for the evaluation of mucinous colorectal tumors due to low ¹⁸F-FDG uptake. The aim of our study was to compare PET/CT variables in mucinous (MC) and nonmucinous (NMC) rectal adenocarcinomas.

Methods

Consecutive patients with cT2-4N0-2M0 rectal cancer included in a prospective clinical trial were reviewed. PET/CT was performed for primary baseline staging. Visual and quantitative analysis included SUVmax and SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG). PET/CT parameters were compared according to histological subtypes.

Results

Overall, 73 patients were included (18 mucinous and 55 nonmucinous). SUVmax values were similar between MC and NMC (19.7 vs. 16.6; p = 0.5). MTV and TLG values were greater in the MC group (103.9 vs. 54.1; p = 0.007 and 892.5 vs. 358.8; p = 0.020) due to larger tumor volumes of MC.

Conclusions

Metabolic parameters at baseline PET/CT for patients with rectal cancer are similar in mucinous and nonmucinous histological subtypes.

     

A Single Intraperitoneal Injection of Endotoxin Changes Glial Cells in Rats as Revealed by Positron Emission Tomography Using [<Superscript>11</Superscript>C]PK11195

Purpose

Intracranial administration of lipopolysaccharide (LPS) is known to elicit a rapid innate immune response, activate glial cells in the brain, and induce depression-like behavior. However, no study has focused on the changes in glial cells induced by intraperitoneal injection of LPS in vivo.

Methods

Ten adult male Fischer F344 rats underwent [¹¹C]PK11195 PET before and 2 days after intraperitoneal injection of LPS to evaluate the changes in glial cells. The difference in standardized uptake values (SUV) of [¹¹C]PK11195 between before and after injection was determined.

Results

There was a cluster of brain regions that showed significant reductions in SUV. This cluster included the bilateral striata and bilateral frontal regions, especially the somatosensory areas.

Conclusions

Changes in activity of glial cells induced by the intraperitoneal injection of LPS were detected in vivo by [¹¹C]PK11195 PET. Intraperitoneal injection of LPS is known to induce depression, and further studies with [¹¹C]PK11195 PET would clarify the relationships between neuroinflammation and depression.

     

Synthesis and preclinical evaluation of an Al<Superscript>18</Superscript>F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand

Purpose

The aim of this study was to synthesize and preclinically evaluate an ¹⁸F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.

Methods

Several conditions for the labeling of ¹⁸F-PSMA-11 via ¹⁸F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.

Results

Quantitative labeling yields could be achieved with >97 % radiochemical purity. The ¹⁸F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4?±?3.3 %ID/g and 0.795?±?0.260 %ID/g, respectively; p?<?4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv.

Conclusion

¹⁸F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible.

     

Evaluation of ECG-gated [<Superscript>11</Superscript>C]acetate PET for measuring left ventricular volumes,mass, and myocardial external efficiency

Background

Noninvasive estimation of myocardial external efficiency (MEE) requires measurements of left ventricular (LV) oxygen consumption with [¹¹C]acetate PET in addition to LV stroke volume and mass with cardiovascular magnetic resonance (CMR). Measuring LV geometry directly from ECG-gated [¹¹C]acetate PET might enable MEE evaluation from a single PET scan. Therefore, we sought to establish the accuracy of measuring LV volumes, mass, and MEE directly from ECG-gated [¹¹C]acetate PET.

Methods

Thirty-five subjects with aortic valve stenosis underwent ECG-gated [¹¹C]acetate PET and CMR. List mode PET data were rebinned into 16-bin ECG-gated uptake images before measuring LV volumes and mass using commercial software and compared to CMR. Dynamic datasets were used for calculation of mean LV oxygen consumption and MEE.

Results

LV mass, volumes, and ejection fraction measured by CMR and PET correlated strongly (r = 0.86-0.92, P < .001 for all), but were underestimated by PET (P < .001 for all except ESV P = .79). PET-based MEE, corrected for bias, correlated fairly with PET/CMR-based MEE (r = 0.60, P < .001, bias ?3 ± 21%, P = .56). PET-based MEE bias was strongly associated with LV wall thickness.

Conclusions

Although analysis-related improvements in accuracy are recommended, LV geometry estimated from ECG-gated [¹¹C]acetate PET correlate excellently with CMR and can indeed be used to evaluate MEE.

     

<Superscript>18</Superscript>F-Florbetaben PET beta-amyloid binding expressed in Centiloids

Purpose

The Centiloid (CL) method enables quantitative values from Aβ-amyloid (Aβ) imaging to be expressed in a universal unit providing pathological, diagnostic and prognostic thresholds in clinical practice and research and allowing integration of multiple tracers and methods. The method was developed for ¹¹C-PiB scans with zero CL set as the average in young normal subjects and 100 CL the average in subjects with mild Alzheimer’s disease (AD). The method allows derivation of equations to convert the uptake value of any tracer into the same standard CL units but first requires head-to-head comparison with ¹¹C-PiB results. We derived the equation to express ¹⁸F-florbetaben (FBB) binding in CL units.

Methods

Paired PiB and FBB PET scans were obtained in 35 subjects. including ten young normal subjects aged under 45 years (33 ± 8 years). FBB images were acquired from 90 to 110 min after injection. Spatially normalized images were analysed using the standard CL method (SPM8 coregistration of PET data to MRI data and the MNI-152 atlas) and standard CL regions (cortex and whole cerebellum downloaded from http://www.gaain.org).

Results

FBB binding was strongly correlated with PiB binding (R ² = 0.96, SUVR_FBB = 0.61 × SUVR_PiB + 0.39). The equation to derive CL values from FBB SUVR was CL units = 153.4 × SUVR_FBB ? 154.9. The CL value in the young normal subjects was ?1.08 ± 6.81 for FBB scans compared to ?0.32 ± 3.48 for PiB scans, giving a variance ratio of 1.96 (SD_{FBB CL}/SD_{PiB CL}).

Conclusions

¹⁸F-FBB binding is strongly correlated with PiB binding and FBB results can now be expressed in CL units.

     

Biphasic <Superscript>68</Superscript>Ga-PSMA-HBED-CC-PET/CT in patients with recurrent and high-risk prostate carcinoma

Purpose

Binding of ⁶⁸Ga-PSMA-HBED-CC (⁶⁸Ga-PSMA) at prostate cancer (PC) cells increases over time. A biphasic protocol may help separating benign from tumor lesions. The aim of this study was the retrospective evaluation of a diagnostic incremental value of a dual-time point (biphasic) ⁶⁸Ga-PSMA-PET/CT in patients with prostate cancer.

Methods

Retrospective analysis of 35 consecutive patients (49–78 years, median 71) with newly diagnosed PC (12/35) or recurrence of PC (23/35). PET/CT (Gemini TF16, Philips) was acquired 1 h and 3 h p. i. of 140–392 MBq (300 MBq median) ⁶⁸Ga-PSMA, followed by a diagnostic contrast CT. PET findings were correlated with histology or unequivocal CT findings. Semiquantitative PET data (SUVmax, SUV mean) were acquired and target-to-background-ratios (T/B-ratio) were calculated for benign and malign lesions for both time points. Size of lymph nodes (LN) on diagnostic CT was recorded. Statistical analysis was performed for assessment of significant changes of semiquantitative PET-parameters over time and for correlation of size and uptake of lymph nodes.

Results

One hundred and four lesions were evaluated. Sixty lesions were referenced by histology or unequivocal CT findings, including eight (13.3 %) histopathologically benign lymph nodes, 12 (20 %) histopathologically lymph node metastases, 12 (20 %) primary tumors, three (5 %) local recurrences, and 25 (41.7 %) bone metastases. Forty-four lesions were axillary LN with normal CT-appearance. Benign lesions had significantly lower SUVmax and T/B-ratios compared with malignant findings. Malign lesions showed a significant increase of both parameters over time compared to benign findings. There was no correlation between LN size and SUVmax. The sensitivity, specificity, the positive predictive value and negative predictive value of PET/CT regarding pelvic LN was 94 %, 99 %, 89 %, and 99.5 %, respectively.

Conclusions

In contrast to benign tissues, the uptake of proven tumor lesions increases on ⁶⁸Ga-PSMA-PET/CT over time. A biphasic PET-study may lead to a better detection of tumor lesions in unequivocal findings.

     

The <Superscript>68</Superscript>Ga/<Superscript>177</Superscript>Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUV<Subscript>max</Subscript> values and absorbed dose estimates

Introduction

A targeted theragnostic approach based on increased expression of prostate-specific membrane antigen (PSMA) on PC cells is an attractive treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC).

Methods

Ten consecutive mCRPC patients were selected for ¹⁷⁷Lu-PSMA617 therapy on the basis of PSMA-targeted ⁶⁸Ga-PSMA-HBED-CC PET/CT diagnosis showing extensive and progressive tumour load. Following dosimetry along with the first therapy cycle restaging (⁶⁸Ga-PSMA-HBED-CC and ¹⁸F-NaF PET/CT) was performed after 2 and 3 therapy cycles (each 6.1?±?0.3 GBq, range 5.4–6.5 GBq) given intravenously over 30 minutes, 9?±?1 weeks apart. PET/CT scans were compared to ¹⁷⁷Lu-PSMA617 24-hour whole-body scans and contrast-enhanced dual-phase CT. Detailed comparison of SUVmax values and absorbed tumour doses was performed.

Results

¹⁷⁷Lu-PSMA617 dosimetry indicated high tumour doses for skeletal (3.4?±?1.9 Gy/GBq; range 1.1–7.2 Gy/GBq), lymph node (2.6?±?0.4 Gy/GBq; range 2.3–2.9 Gy/GBq) as well as liver (2.4?±?0.8 Gy/GBq; range 1.7–3.3 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 18?±?0.3 GBq. Three patients showed partial remission, three mixed response, one stable and three progressive disease. Decreased ¹⁷⁷Lu-PSMA617 and ⁶⁸Ga-PSMA-HBED-CC uptake (mean SUVmax values 20.2 before and 15.0 after 2 cycles and 11.5 after 3 cycles, p?<?0.05) was found in 41/54 skeletal lesions, 12/13 lymph node metastases, 3/5 visceral metastases and 4/4 primary PC lesions.

Conclusion

Due to substantial individual variance, dosimetry is mandatory for a patient-specific approach following ¹⁷⁷Lu-PSMA617 therapy. Higher activities and/or shorter treatment intervals should be applied in a larger prospective study.

     

Prospective evaluation of <Superscript>18</Superscript>F-FACBC PET/CT and PET/MRI versus multiparametric MRI in intermediate- to high-risk prostate cancer patients (FLUCIPRO trial)

Purpose

The purpose of this study was to evaluate ¹⁸F-FACBC PET/CT, PET/MRI, and multiparametric MRI (mpMRI) in detection of primary prostate cancer (PCa).

Methods

Twenty-six men with histologically confirmed PCa underwent PET/CT immediately after injection of 369 ± 10 MBq ¹⁸F-FACBC (fluciclovine) followed by PET/MRI started 55 ± 7 min from injection. Maximum standardized uptake values (SUV_max) were measured for both hybrid PET acquisitions. A separate mpMRI was acquired within a week of the PET scans. Logan plots were used to calculate volume of distribution (V_T). The presence of PCa was estimated in 12 regions with radical prostatectomy findings as ground truth. For each imaging modality, area under the curve (AUC) for detection of PCa was determined to predict diagnostic performance. The clinical trial registration number is NCT02002455.

Results

In the visual analysis, 164/312 (53%) regions contained PCa, and 41 tumor foci were identified. PET/CT demonstrated the highest sensitivity at 87% while its specificity was low at 56%. The AUC of both PET/MRI and mpMRI significantly (p < 0.01) outperformed that of PET/CT while no differences were detected between PET/MRI and mpMRI. SUV_max and V_T of Gleason score (GS) >3 + 4 tumors were significantly (p < 0.05) higher than those for GS 3 + 3 and benign hyperplasia. A total of 442 lymph nodes were evaluable for staging, and PET/CT and PET/MRI demonstrated true-positive findings in only 1/7 patients with metastatic lymph nodes.

Conclusions

Quantitative ¹⁸F-FACBC imaging significantly correlated with GS but failed to outperform MRI in lesion detection. ¹⁸F-FACBC may assist in targeted biopsies in the setting of hybrid imaging with MRI.

     

Prediction of all-cause death using <Superscript>11</Superscript>C-hydroxyephedrine positron emission tomography in Japanese patients with left ventricular dysfunction

Objectives

The aim of this study was to determine whether ¹¹C-hydroxyephedrine (¹¹C-HED) can predict adverse events including all-cause death in Japanese patients with left ventricular (LV) dysfunction.

Background

Although ¹¹C-HED PET has been used to assess cardiac sympathetic innervation in various disease conditions, data on their prognostic value are limited.

Methods

Sixty patients (mean LVEF, 42 ± 14 %) with LV dysfunction (42 ischemic and 18 non-ischemic heart disease) underwent ¹¹C-HED PET. Myocardial retention was calculated for ¹¹C-HED PET as a measure of cardiac sympathetic neuronal integrity. Statistical analysis was performed using Cox proportional hazards regression and log-rank test.

Results

Thirteen deaths (7 cardiac and 6 non-cardiac deaths) occurred during a mean follow-up period of 33 ± 23 months. The patients with death were associated with significantly lower ¹¹C-HED retention (7.1 ± 2.1 vs 9.0 ± 2.4, p = 0.015) than those without death. The hazard ratio for global ¹¹C-HED retention per unit (/min) was 0.762 (p = 0.039), which remained significant in multivariate analysis. When the patients were divided into the high (≥8.5) and low (<8.5) ¹¹C-HED retention groups, the low ¹¹C-HED retention group was associated with significantly poorer survival than the high ¹¹C-HED retention group (p = 0.004).

Conclusion

The low global ¹¹C-HED retention is a marker of poor overall survival in patients with LV dysfunction in this study.

     

<Superscript>89</Superscript>Zr-Onartuzumab PET imaging of c-MET receptor dynamics

Purpose

c-MET and its ligand hepatocyte growth factor are often dysregulated in human cancers. Dynamic changes in c-MET expression occur and might predict drug efficacy or emergence of resistance. Noninvasive visualization of c-MET dynamics could therefore potentially guide c-MET-directed therapies. We investigated the feasibility of ⁸⁹Zr-labelled one-armed c-MET antibody onartuzumab PET for detecting relevant changes in c-MET levels induced by c-MET-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib resistance or heat shock protein-90 (HSP90) inhibitor NVP-AUY-922 treatment in human non-small-cell lung cancer (NSCLC) xenografts.

Methods

In vitro membrane c-MET levels were determined by flow cytometry. HCC827ErlRes, an erlotinib-resistant clone with c-MET upregulation, was generated from the exon-19 EGFR-mutant human NSCLC cell line HCC827. Mice bearing HCC827 and HCC827ErlRes tumours in opposite flanks underwent ⁸⁹Zr-onartuzumab PET scans. The HCC827-xenografted mice underwent ⁸⁹Zr-onartuzumab PET scans before treatment and while receiving biweekly intraperitoneal injections of 100 mg/kg NVP-AUY-922 or vehicle. Ex vivo, tumour c-MET immunohistochemistry was correlated with the imaging results.

Results

In vitro, membrane c-MET was upregulated in HCC827ErlRes tumours by 213?±?44% in relation to the level in HCC827 tumours, while c-MET was downregulated by 69?±?9% in HCC827 tumours following treatment with NVP-AUY-922. In vivo, ⁸⁹Zr-onartuzumab uptake was 26% higher (P?<?0.05) in erlotinib-resistant HCC827ErlRes than in HCC827 xenografts, while HCC827 tumour uptake was 33% lower (P?<?0.001) following NVP-AUY-922 treatment.

Conclusion

The results show that ⁸⁹Zr-onartuzumab PET effectively discriminates relevant changes in c-MET levels and could potentially be used clinically to monitor c-MET status.