[Show abstract][Hide abstract] ABSTRACT: This paper summarises key themes and discussions from the 4th international workshop dedicated to the advancement of the technical, scientific and clinical applications of combined positron emission tomography (PET)/magnetic resonance imaging (MRI) systems that was held in Tübingen, Germany, from February 23 to 27, 2015. Specifically, we summarise the three days of invited presentations from active researchers in this and associated fields augmented by round table discussions and dialogue boards with specific topics. These include the use of PET/MRI in cardiovascular disease, paediatrics, oncology, neurology and multi-parametric imaging, the latter of which was suggested as a key promoting factor for the wider adoption of integrated PET/MRI. Discussions throughout the workshop and a poll taken on the final day demonstrated that attendees felt more strongly that PET/MRI has further advanced in both technical versatility and acceptance by clinical and research-driven users from the status quo of last year. Still, with only minimal evidence of progress made in exploiting the true complementary nature of the PET and MRI-based information, PET/MRI is still yet to achieve its potential. In that regard, the conclusion of last year's meeting "the real work has just started" still holds true.
Full-text · Article · Aug 2015 · Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Diffusion magnetic resonance imaging (MRI) and 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) positron emission tomography (PET) are used to interrogate malignant tumor microenvironment. It remains unclear whether there is a relationship between [(18)F]FDOPA uptake, diffusion MRI estimates of apparent diffusion coefficient (ADC), and mitotic activity in the context of recurrent malignant gliomas, where the tumor may be confounded by the effects of therapy. The purpose of the current study is to determine whether there is a correlation between these imaging techniques and mitotic activity in malignant gliomas.
We retrospectively examined 29 patients with recurrent malignant gliomas who underwent structural MRI, diffusion MRI, and [(18)F]FDOPA PET prior to surgical resection. Qualitative associations were noted, and quantitative voxel-wise and median measurement correlations between [(18)F]FDOPA PET, ADC, and mitotic index were performed.
Areas of high [(18)F]FDOPA uptake exhibited low ADC and areas of hyperintensity T2/fluid-attenuated inversion recovery (FLAIR) with low [(18)F]FDOPA uptake exhibited high ADC. There was a significant inverse voxel-wise correlation between [(18)F]FDOPA and ADC for all patients. Median [(18)F]FDOPA uptake and median ADC also showed a significant inverse correlation. Median [(18)F]FDOPA uptake was positively correlated, and median ADC was inversely correlated with mitotic index from resected tumor tissue.
A significant association may exist between [(18)F]FDOPA uptake, diffusion MRI, and mitotic activity in recurrent malignant gliomas.
No preview · Article · Dec 2014 · Molecular Imaging & Biology
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Patients with previously treated low-grade gliomas often present with T2 changes on MRI without contrast enhancement.
It is challenging to distinguish between progressive non-enhancing tumors and treatment effect. This study examines the value
of [18F]fluoro-L-dihydroxyphenylalanine (FDOPA) positron emission tomography (PET) to detect progressive tumor in this group of
patients. These findings are correlated with progression free survival (PFS) as well as overall survival (OS). METHODS: 93
patients with treated low-grade gliomas who presented with T2 changes on MRI without contrast enhancement underwent 18F-FDOPA PET (40F, 53M). 18F-FDOPA PET scans were analyzed semi-quantitatively (SUVmax, SUVmean, and their ratios to normal brain parenchyma) and visually
on a 5 point scale. ROC curve analysis was used to identify the best diagnostic indices. PET data were validated using histopathology
(22, 24%) and clinical follow-up (71, 76%). Predictive powers of 18F-FDOPA PET for PFS and OS were analyzed using Kaplan Meier survival statistics. RESULTS: Median time to progression was 14.1
months with 59 patients progressed (63%). Median time to death was 25.5 months with 27 patients deceased (29%). Both semi-quantitative
analysis using tumor to normal tissue ratios as well as visual methods are diagnostic of progressive tumor with accuracies
ranging 75%-79%. 18F-FDOPA PET provides significant predictions for PFS as well as OS with SUVmean/striatum ≤1.0 providing the best semi-quantitative
index (P = 0.01 for PFS, P = 0.005 for OS) and visual scale ≥0 (tumor 3 striatum) the best qualitative index (P = 0.01 for PFS, P = 0.001 for OS; median survival: 25.5 vs. 7.5 mo; P < 0.0001).
CONCLUSION: In patients with previously treated low-grade gliomas presenting with only T2 changes on MRI, 18F-FDOPA PET is predictive of PFS as well as OS. Both semi-quantitative analyses using tumor to normal tissue ratio, as well
as a visual score provide good predictors.
[Show abstract][Hide abstract] ABSTRACT: Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers.
Full-text · Article · Oct 2014 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
High-grade gliomas (HGGs) are the most common malignant primary tumors of the central nervous system. PET probes of amino acid transport such as O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET), 3,4-dihydroxy-6-(18)F-fluoro-l-phenylalanine ((18)F-DOPA), and (11)C-methionine ((11)C-MET) detect primary and recurrent tumors with a high accuracy. (18)F-FET is predominantly used in Europe, whereas amino acid transport imaging is infrequently done in the United States. The aim of this study was to determine whether (18)F-FET and (18)F-DOPA PET/CT provide comparable information in HGG.
Thirty (18)F-FET and (18)F-DOPA PET/CT scans were obtained before surgery or biopsy in 27 patients with high clinical suspicion for primary or recurrent HGG (5 primary, 22 recurrent tumors). (18)F-FET and (18)F-DOPA PET/CT images were compared visually and semiquantitatively (maximum standardized uptake value [SUV(max)], mean SUV [SUV(mean)]). Background (SUV(max) and SUV(mean)) and tumor-to-background ratios (TBRs) were calculated for both PET probes. The degree of (18)F-DOPA uptake in the basal ganglia (SUV(mean)) was also assessed.
Visual analysis revealed no difference in tumor uptake pattern between the 2 PET probes. The SUV(mean) and SUV(max) for (18)F-FET were higher than those of (18)F-DOPA (4.0 ± 2.0 and 4.9 ± 2.3 vs. 3.5 ± 1.6 and 4.3 ± 2.0, respectively; all P < 0.001). TBRs for SUV(mean) but not for SUV(max) were significantly higher for (18)F-FET than (18)F-DOPA (TBR SUV(mean): 3.8 ± 1.7 vs. 3.4 ± 1.2, P = 0.004; TBR SUV(max): 3.3 ± 1.6 and 3.0 ± 1.1, respectively; P = 0.086). (18)F-DOPA uptake by the basal ganglia was present (SUV(mean), 2.6 ± 0.7) but did not affect tumor visualization.
Whereas visual analysis revealed no significant differences in uptake pattern for (18)F-FET and (18)F-DOPA in patients with primary or recurrent HGG, both SUVs and TBRs for SUV(mean) were significantly higher for (18)F-FET. However, regarding tumor delineation, both tracers performed equally well and seem equally feasible for imaging of primary and recurrent HGG. These findings suggest that both PET probes can be used based on availability in multicenter trials.
Full-text · Article · Aug 2014 · Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
Absolute quantitation of myocardial blood flow (MBF) by PET is an established method of analyzing coronary artery disease (CAD) but subject to the various shortcomings of available radiotracers. Flurpiridaz F 18 is a novel PET radiotracer that exhibits properties of an ideal tracer.
A new absolute perfusion quantitation method with flurpiridaz was developed, taking advantage of the early kinetics and high first-pass extraction by the myocardium of this radiotracer, and the first-in-human measurements of MBF performed in 7 healthy subjects and 8 patients with documented CAD. PET images with time-activity curves were acquired at rest and during adenosine stress.
In healthy subjects, regional MBF between coronary artery territories did not differ significantly, leading to a mean global MBF of 0.73 mL/min/g at rest and 2.53 mL/min/g during stress, with a mean global myocardial flow reserve (MFR) of 3.70. CAD vascular territories with <50% stenosis demonstrated a mean MBF of 0.73 at rest and 2.02 during stress, leading to a mean MFR of 2.97. CAD vascular territories with ≥50% stenosis exhibited a mean MBF of 0.86 at rest and 1.43 during stress, leading to a mean MFR of 1.86. Differences in stress MBF and MFR between normal and CAD territories, as well as between <50% and ≥50% stenosis vascular territories, were significant (P < 0.01).
Absolute quantitation of MBF in humans with the novel PET radiotracer flurpiridaz is feasible over a wide range of cardiac flow in the presence or absence of stress-inducible myocardial ischemia. The significant decrease in stress MBF and ensuing MFR in CAD territories allows a clear distinction between vascular territories exhibiting stress-inducible myocardial ischemia and those with normal perfusion.
Preview · Article · Jul 2014 · Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: Various single or multi-modality therapeutic options are available to treat pain of bone metastasis in patients with prostate cancer. Different radionuclides that emit β-rays such as (153)Samarium and (89)Strontium and achieve palliation are commercially available. In contrast to β-emitters, (223)Radium as a α-emitter has a short path-length. The advantage of the α-emitter is thus a highly localized biological effect that is caused by radiation induced DNA double-strand breaks and subsequent cell killing and/or limited effectiveness of cellular repair mechanisms. Due to the limited range of the α-particles the bone surface to red bone marrow dose ratio is also lower for (223)Radium which is expressed in a lower myelotoxicity. The α emitter (223)Radium dichloride is the first radiopharmaceutical that significantly prolongs life in castrate resistant prostate cancer patients with wide-spread bone metastatic disease. In a phase III, randomized, double-blind, placebo-controlled study 921 patients with castration-resistant prostate cancer and bone metastases were randomly assigned. The analysis confirmed the (223)Radium survival benefit compared to the placebo (median, 14.9 mo vs 11.3 mo; P < 0.001). In addition, the treatment results in pain palliation and thus, improved quality of life and a delay of skeletal related events. At the same time the toxicity profile of (223)Radium was favourable. Since May 2013, (223)Radium dichloride (Xofigo(®)) is approved by the US Food and Drug Administration.
[Show abstract][Hide abstract] ABSTRACT: Various integrated PET/MR imaging systems have recently been developed to provide improved clinical assessments of cancers in tissues that may be anatomically better characterized with MR imaging than with CT, to explore whether the combined anatomic and functional capabilities of MR imaging together with the molecular PET information provide new insights into disease phenotypes and biology, and to reduce radiation exposure to vulnerable populations such as children and women of child-bearing age. The following review summarizes the published studies and informs about the potential diagnostic advantages of this new technology.
Preview · Article · May 2014 · Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: The contrast recovery coefficients (CRC) were evaluated for five different small animal PET scanners: GE Explore Vista, Genisys4, MiniPET-2, nanoScan PC and Siemens Inveon. The NEMA NU-4 2008 performance test with the suggested image quality phantom (NU4IQ) does not allow the determination of the CRC values for the hot regions in the phantom. This drawback of NU4IQ phantom motivated us to develop a new method for this purpose. The method includes special acquisition and reconstruction protocols using the original phantom, and results in an artificially merged image enabling the evaluation of CRC values. An advantageous feature of this method is that it stops the cold wall effect from distorting the CRC calculation. Our suggested protocol results in a set of CRC values contributing to the characterization of small animal PET scanners. GATE simulations were also performed to validate the new method and verify the evaluated CRC values. We also demonstrated that the numerical values of this parameter depend on the actual object contrast of the hot region(s) and this mainly comes from the spillover effect. This effect was also studied while analysing the background activity level around the hot rods. We revealed that the calculated background mean values depended on the target contrast in a scanner specific manner. Performing the artificially merged imaging procedure and additional simulations using the micro hollow sphere (MHS) phantom geometry, we also proved that the inactive wall around the hot spheres can have a remarkable impact on the calculated CRC. In conclusion, we have shown that the proposed artificial merging procedure and the commonly used NU4IQ phantom prescribed by the NEMA NU-4 can easily deliver reliable CRC data otherwise unavailable for the NU4IQ phantom in the conventional protocol or the MHS phantom.
No preview · Article · May 2014 · Physics in Medicine and Biology
[Show abstract][Hide abstract] ABSTRACT: We have developed an efficient, streamlined, cost-effective approach to obtain Investigational New Drug (IND) approvals from the Food and Drug Administration (FDA) for positron emission tomography (PET) imaging probes (while the FDA uses the terminology PET drugs, we are using “PET imaging probes,” “PET probes,” or “probes” as the descriptive terms). The required application and supporting data for the INDs were collected in a collaborative effort involving appropriate scientific disciplines. This path to INDs was successfully used to translate three [18 F]fluoro-arabinofuranosylcytosine (FAC) analog PET probes to phase 1 clinical trials. In doing this, a mechanism has been established to fulfill the FDA regulatory requirements for translating promising PET imaging probes from preclinical research into human clinical trials in an efficient and cost-effective manner.
Electronic supplementary material
The online version of this article (doi:10.1007/s11307-014-0735-2) contains supplementary material, which is available to authorized users.
Full-text · Article · Apr 2014 · Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging
[Show abstract][Hide abstract] ABSTRACT: This study compares the value of 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-FDOPA) PET and MRI in assessing outcome during antiangiogenic treatment in patients with recurrent high-grade gliomas.
Thirty patients were prospectively studied with 18F-FDOPA PET scans immediately before, and two and six weeks after start of bevacizumab therapy. 18F-FDOPA metabolic tumor volumes (MTV) as well as max and mean SUVs within this MTV were obtained. MRI treatment response was assessed at 6 weeks. The predictive ability of 18F-FDOPA PET and MRI response assessment were evaluated with regard to progression-free survival (PFS) and overall survival (OS).
30, 28, and 24 18F-FDOPA PET scans at baseline, 2 weeks, and 6 weeks, were available for analysis, respectively. 18F-FDOPA PET SUVs as well as their changes through therapy were not predictive of outcome. However, metabolic tumor volume (MTV) parameters such as MTV changes were highly prognostic. Interestingly, absolute MTV at the first follow up scan provides the most significant prediction for increased OS (P < 0.0001) as well as PFS (P = 0.001). This surprising result was scrutinized with cross-validation and simulation analysis. Responders based on 18F-FDOPA PET data survived 3.5 times longer (12.1 vs. 3.5 months median OS, P < 0.001) than non-responders (17 vs. 11 patients, respectively). In comparison, responders based on MRI data lived 1.5 times longer (11.4 vs 7.7 mo, P = 0.03) than non-responders (22 vs. 7 patients, respectively).
18F-FDOPA PET identifies treatment responders to antiangiogenic therapy as early as two weeks after treatment initiation.
Full-text · Article · Mar 2014 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: This workshop was held a year after the initial positron emission tomography/magnetic resonance (PET/MR) workshop in Tübingen, which was recently reported in this journal. The discussions at the 2013 workshop, however, differed substantially from those of the initial workshop, attesting to the progress of combined PET/MR as an innovative imaging modality. Discussions were focused on the search for truly novel, unique clinical and research applications as well as technical issues such as reliable and accurate approaches for attenuation and scatter correction of PET emission data. The workshop provided hands-on experience with PET and MR imaging. In addition, structured and moderated open discussion sessions, including six dialogue boards and two roundtable discussions, provided input from current and future PET/MR imaging users. This summary provides a snapshot of the current achievements and challenges for PET/MR.
Full-text · Article · Mar 2014 · Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging