PET Acquisition Research Articles

Feasibility of Using FDG in the Stereotactic Ablative Setting for Tracked Dose Delivery With BgRT: Results from a Prospective Study of Serial Inter-Fraction PET/CTs

<h3>Purpose/Objective(s)</h3> Biology-guided radiotherapy (BgRT) is a new radiation modality that utilizes real-time limited time sampled FDG PET images of a tumor to deliver a dynamically tracked dose distribution. Since the delivered radiotherapy dose is dependent on the FDG distribution at each fraction, the ability to deliver the planned dose despite variations in daily FDG signal must be established. This study evaluates the predicted dose distribution for BgRT based on serial FDG scans obtained over a course of stereotactic ablative radiotherapy (SABR). <h3>Materials/Methods</h3> Six patients with 1 (n = 5) or 2 (n = 1) lung tumors at least 2 cm in diameter with SUV_max ≥ 6 treated with SABR (50 Gy in 5 fractions) were selected for this investigation. These patients received 3 PET/CT scans as part of an IRB approved prospective clinical trial: within 2 weeks of treatment start (PET1), between fractions 1 and 2 (PET2), and between fractions 4 and 5 (PET3). A simulation tool was developed to convert PET1 into a simulated BgRT planning PET image accounting for differences in system sensitivity, acquisition time, reconstruction method and geometry between the diagnostic PET/CT system and the BgRT machine. This same tool was used to convert PET2 and PET3 into simulated pre-scan PET images, short PET acquisitions made just prior to a BgRT delivery fraction to ensure the current FDG distribution is safe for treatment. BgRT plans designed to deliver 50 Gy in 5 fractions following RTOG 0813 dose constraints were developed for each of the 7 targets using the simulated planning PET images as input. Expected variations in the dynamically calculated dose delivery are presented as bounds on the dose-volume histogram (DVH). For each plan, the predicted DVH for fractions 2 and 5 was calculated from the simulated pre-scan PET images and compared to the bounded DVH of the BgRT plan. The pass %, defined as the percentage of points on the predicted DVH curves falling within the planned DVH bounds, was automatically calculated; the pass % must be ≥ 95% to proceed with BgRT delivery. <h3>Results</h3> All 7 BgRT plans met target coverage objectives and normal tissue constraints. The mean pass % for the 14 pre-scans was 98.6%, with 13 exceeding the 95% threshold required for BgRT. There was no statistically significant difference between pass % at fraction 2 versus fraction 5 (two-tailed paired t-test, <i>P</i> = 0.44). The pass % was 92.2% for 1 pre-scan. In this case, the target SUV_max had decreased by 55.5% of the baseline value. <h3>Conclusion</h3> This investigation provides initial evidence that FDG scans remain stable enough over a course of ablative radiotherapy to enable dynamically tracked dose delivery with BgRT. Significant changes in FDG biodistribution that would prevent dose from being delivered within the pre-approved bounds of the BgRT plan can be identified through analysis of a pre-scan PET image. A prospective clinical trial to confirm these results is in preparation. Clinical trial number NCT03493789.

Voxel-Based Analysis of [18F]-FDG Brain PET in Rats Using Data-Driven Normalization.

Introduction: [18F]-FDG PET is a widely used imaging modality that visualizes cellular glucose uptake and provides functional information on the metabolic state of different tissues in vivo. Various quantification methods can be used to evaluate glucose metabolism in the brain, including the cerebral metabolic rate of glucose (CMRglc) and standard uptake values (SUVs). Especially in the brain, these (semi-)quantitative measures can be affected by several physiological factors, such as blood glucose level, age, gender, and stress. Next to this inter- and intra-subject variability, the use of different PET acquisition protocols across studies has created a need for the standardization and harmonization of brain PET evaluation. In this study we present a framework for statistical voxel-based analysis of glucose uptake in the rat brain using histogram-based intensity normalization.Methods: [18F]-FDG PET images of 28 normal rat brains were coregistered and voxel-wisely averaged. Ratio images were generated by voxel-wisely dividing each of these images with the group average. The most prevalent value in the ratio image was used as normalization factor. The normalized PET images were voxel-wisely averaged to generate a normal rat brain atlas. The variability of voxel intensities across the normalized PET images was compared to images that were either normalized by whole brain normalization, or not normalized.To illustrate the added value of this normal rat brain atlas, 9 animals with a striatal hemorrhagic lesion and 9 control animals were intravenously injected with [18F]-FDG and the PET images of these animals were voxel-wisely compared to the normal atlas by group- and individual analyses.Results: The average coefficient of variation of the voxel intensities in the brain across normal [18F]-FDG PET images was 6.7% for the histogram-based normalized images, 11.6% for whole brain normalized images, and 31.2% when no normalization was applied. Statistical voxel-based analysis, using the normal template, indicated regions of significantly decreased glucose uptake at the site of the ICH lesion in the ICH animals, but not in control animals.Conclusion: In summary, histogram-based intensity normalization of [18F]-FDG uptake in the brain is a suitable data-driven approach for standardized voxel-based comparison of brain PET images.

FDG-PET/CT in Lymphoma: Where Do We Go Now?

Simple SummaryWe focus on the role and current applications of 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography in the management of lymphoma patients through improved staging or treatment response assessment or through early PET-driven therapeutic strategies, leading the way to a novel area of personalized medicine, optimizing disease control and toxicity. We discuss the potential future directions of innovative metabolic metrics that are being developed, notably to assess response to new immunotherapy regimens and to provide an improved prognostic factor for predicting patients’ survival. Finally, we present new radiopharmaceuticals developed following the identification of pathways or specific receptors in lymphomas, providing great opportunities for molecular imaging in treatment evaluation and management.18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) is an essential part of the management of patients with lymphoma at staging and response evaluation. Efforts to standardize PET acquisition and reporting, including the 5-point Deauville scale, have enabled PET to become a surrogate for treatment success or failure in common lymphoma subtypes. This review summarizes the key clinical-trial evidence that supports PET-directed personalized approaches in lymphoma but also points out the potential place of innovative PET/CT metrics or new radiopharmaceuticals in the future.

Influence of 11C-MET PET acquisition time for differential diagnosis of human brain gliomas

The aim of this work was to study the effect of the reduced acquisition time of PET 11C-MET examination on the quality of primary brain tumors differential diagnosis. 57 patients with histologically verified diagnoses were recruited (glioblastoma n=20, anaplastic astrocytoma n=11, diffuse astrocytoma n=11, oligodendroglioma n=9 and anaplastic oligodendroglioma n=6). The scan time was varied in the range of 2-20 min. Our study demonstrated that in the case of intravenous administration of 11C-MET simultaneously with the start of scanning, the quality of primary gliomas differential diagnosis does not depend on the scan time. Therefor it becomes possible increasing the number of patients and reducing the acquisition time. The T/N60 ratio (T/N ratio measured in the first 60 seconds after 11C-MET intravenous injection) is equally successful parameter for glioma differential diagnosis as the traditional T/N ratio.

18F-DCFPyL PET Acquisition, Interpretation, and Reporting: Suggestions After Food and Drug Administration Approval.

¹⁸F-DCFPyL was recently approved by the FDA for evaluation prior to definitive therapy and for biochemical recurrence. Here we focus on the key data that justify the clinical use of ¹⁸F-DCFPyL, as well as those aspects of protocol implementation and image interpretation that are important to the nuclear medicine physicians and radiologists who will interpret ¹⁸F-DCFPyL PET/CT and PET/MR scans.

Use of dynamic reconstruction for parametric Patlak imaging in dynamic whole body PET

Dynamic whole body (DWB) PET acquisition protocols enable the use of whole body parametric imaging for clinical applications. In FDG imaging, accurate parametric images of Patlak K i can be complementary to regular standardised uptake value images and improve on current applications or enable new ones. In this study we consider DWB protocols implemented on clinical scanners with a limited axial field of view with the use of multiple whole body sweeps. These protocols result in temporal gaps in the dynamic data which produce noisier and potentially more biased parametric images, compared to single bed (SB) dynamic protocols. Dynamic reconstruction using the Patlak model has been previously proposed to overcome these limits and shown improved DWB parametric images of K i . In this work, we propose and make use of a spectral analysis based model for dynamic reconstruction and parametric imaging of Patlak K i . Both dynamic reconstruction methods were evaluated for DWB FDG protocols and compared against 3D reconstruction based parametric imaging from SB dynamic protocols. This work was conducted on simulated data and results were tested against real FDG dynamic data. We showed that dynamic reconstruction can achieve levels of parametric image noise and bias comparable to 3D reconstruction in SB dynamic studies, with the spectral model offering additional flexibility and further reduction of image noise. Comparisons were also made between step and shoot and continuous bed motion (CBM) protocols, which showed that CBM can achieve lower parametric image noise due to reduced acquisition temporal gaps. Finally, our results showed that dynamic reconstruction improved VOI parametric mean estimates but did not result to fully converged values before resulting in undesirable levels of noise. Additional regularisation methods need to be considered for DWB protocols to ensure both accurate quantification and acceptable noise levels for clinical applications.

Evaluation of [18F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies.

Tau aggregates represent a key pathologic feature of Alzheimer’s disease and other neurodegenerative diseases. Recently, PET probes have been developed for in vivo detection of tau accumulation; however, they are limited because of off-target binding and a reduced ability to detect tau in non-Alzheimer’s disease tauopathies. The novel tau PET tracer, [18F]PI-2620, has a high binding affinity and specificity for aggregated tau; therefore, it was hypothesized to have desirable properties for the visualization of tau accumulation in Alzheimer’s disease and non-Alzheimer’s disease tauopathies. To assess the ability of [18F]PI-2620 to detect regional tau burden in non-Alzheimer’s disease tauopathies compared with Alzheimer’s disease, patients with progressive supranuclear palsy (n = 3), corticobasal syndrome (n = 2), corticobasal degeneration (n = 1) or Alzheimer’s disease (n = 8), and healthy controls (n = 7) were recruited. All participants underwent MRI, amyloid β assessment and [18F]PI-2620 PET (Image acquisition at 60–90 min post-injection). Cortical and subcortical tau accumulations were assessed by calculating standardized uptake value ratios using [18F]PI-2620 PET. For pathologic validation, tau pathology was assessed using tau immunohistochemistry and compared with [18F]PI-2620 retention in an autopsied case of corticobasal degeneration. In Alzheimer’s disease, focal retention of [18F]PI-2620 was evident in the temporal and parietal lobes, precuneus, and cingulate cortex. Standardized uptake value ratio analyses revealed that patients with non-Alzheimer’s disease tauopathies had elevated [18F]PI-2620 uptake only in the globus pallidus, as compared to patients with Alzheimer’s disease, but not healthy controls. A head-to-head comparison of [18F]PI-2620 and [18F]PM-PBB3, another tau PET probe for possibly visualizing the four-repeat tau pathogenesis in non-Alzheimer’s disease, revealed different retention patterns in one subject with progressive supranuclear palsy. Imaging-pathology correlation analysis of the autopsied patient with corticobasal degeneration revealed no significant correlation between [18F]PI-2620 retention in vivo. High [18F]PI-2620 uptake at 60–90 min post-injection in the globus pallidus may be a sign of neurodegeneration in four-repeat tauopathy, but not necessarily practical for diagnosis of non-Alzheimer’s disease tauopathies. Collectively, this tracer is a promising tool to detect Alzheimer’s disease-tau aggregation. However, late acquisition PET images of [18F]PI-2620 may have limited utility for reliable detection of four-repeat tauopathy because of lack of correlation between post-mortem tau pathology and different retention pattern than the non-Alzheimer’s disease-detectable tau radiotracer, [18F]PM-PBB3. A recent study reported that [18F]PI-2620 tracer kinetics curves in four-repeat tauopathies peak earlier (within 30 min) than Alzheimer’s disease; therefore, further studies are needed to determine appropriate PET acquisition times that depend on the respective interest regions and diseases.

An 89Zr-Labeled PSMA Tracer for PET/CT Imaging of Prostate Cancer Patients.

The short half-life of existing prostate-specific membrane antigen (PSMA) tracers limits their time for internalization into tumor cells after injection, which is an essential prerequisite for robust detection of tumor lesions with low PSMA expression on PET/CT scans. Because of its longer half-life, the 89Zr-labeled ligand 89Zr-PSMA-DFO allows acquisition of PET scans up to 6 d after injection, thereby overcoming the above limitation. We investigated whether 89Zr-PSMA-DFO allowed more sensitive detection of weak PSMA-positive prostate cancer lesions. Methods: We selected 14 prostate cancer patients with biochemical recurrence who exhibited no PSMA-positive lesions on a PET scan acquired with existing PSMA tracers (68Ga-PSMA-11, 18F-JK-PSMA-7). Within 5 wk after the negative scan result, we obtained a second PSMA PET scan using 89Zr-PSMA-DFO (117 ± 16 MBq, PET acquisition within 6 d of injection). Results:89Zr-PSMA-DFO detected 15 PSMA-positive lesions in 8 of 14 patients, who had a PET-negative reading of their initial PET scans with existing tracers. In these 8 patients, the new scans revealed localized recurrence of disease (3/8), metastases in lymph nodes (3/8), or lesions at distant sites (2/8). On the basis of these results, patients received lesion-targeted radiotherapies (5/8), androgen deprivation therapies (2/8), or no therapy (1/8). The plausibility of 14 of 15 lesions was supported by histology, clinical follow-up after radiotherapy, or subsequent imaging. Furthermore, comparison of the 15 89Zr-PSMA-DFO-positive lesions with their correlates on the original PET scan revealed that established tracers exhibited mild accumulation in 7 of 15 lesions; however, contrast-to-noise ratios were too low for robust detection of these lesions (contrast-to-noise ratios, 2.4 ± 3.7 for established tracers vs. 10.2 ± 8.5 for 89Zr-PSMA-DFO, P = 0.0014). The SUVmax of the 15 89Zr-PSMA-DFO-positive lesions (11.5 ± 5.8) was significantly higher than the SUVmax on the original PET scans (4.7 ± 2.8, P = 0.0001). Kidneys were the most exposed organ, with doses of 3.3 ± 0.7 mGy/MBq. The effective dose was 0.15 ± 0.04 mSv/MBq. Conclusion: In patients with weak PSMA expression, a longer period of time might be needed for ligand internalization than that offered by existing PSMA tracers to make lesions visible on PET/CT scans. Hence, 89Zr-PSMA-DFO might be of significant benefit to patients in whom the search for weak PSMA-positive lesions is challenging. Radiation exposure should be weighed against the potential benefit of metastasis-directed therapy or salvage radiotherapy, which we initiated in 36% (5/14) of our patients based on their 89Zr-PSMA-DFO PET scans.

Comprehensive mechanical &amp; metabolic imaging of abdominal aortic aneurysm with 4D flow/ FDG PET on an integrated PETMRI: a feasibility study

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): NIHR Biomedical Research Centre, University College London Hospitals. Background A number of non-invasive imaging derived parameters have been implicated in the development and progression of abdominal aortic aneurysm, although the mechanism, and relationships of many of these are yet to be precisely determined. Mechanical parameters can now be studied using 4D phase contrast magnetic resonance (PCMR), and inflammatory cellular activity can be detected with FDG PET. Purpose It may be postulated that inflammation of the aortic wall may be the intermediary at the tissue level linking mechanical wall shear stress (WSS) to aneurysm progression. It may be feasible to study 4D PCMR and FDG PET at the same patient visit on a PETMRI platform, with the potential to enhance temporal and spatial co-registration and improving the understanding of any relationship between these two parameters. Our study aims to assess feasibility of studying these on an integrated PETMRI system. Methods 7 patients with known aortic aneurysm were recruited in a vascular ultrasound screening follow up clinic. During a single visit following 6 hours fasting, all patients underwent FDG injection and 60 minutes uptake period. With quiet breathing, list mode PET acquisition and concurrent 4D PCMR was acquired using stacks of spiral acquisition, with ECG trace information for retrospective gating. Images from the 4D PCMR and FDG PET were assessed qualitatively for image quality and visual matching. Results All 7 patients completed the study. Overall image quality was adequate to good. There is qualitatively a good concordance with impression of positive correlation between wall shear stress and inflammatory signal (see attached image). Conclusion We have demonstrated feasibility of combined assessment of mechanical and metabolic imaging parameters using an integrated PETMRI system. Initial findings show there to be a broad concordance of wall shear stress and inflammatory signal in the abdominal aneurysm.

Survival Outcome with Routine Clinical Use of 82Rb PET/CT Myocardial Blood Flow (MBF) Quantification

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): NIHR Biomedical Research Centre, University College London Hospitals Background The prognostic value of 82Rb PET/CT derived myocardial blood flow (MBF) is increasingly recognised in both general and specific cardiovascular populations. Purpose This study investigates the prognostic potential of MBF in a large cohort of patients undergoing routine 82Rb PET/CT examination. Methods 1148 consecutive patients (687 males, mean age 64 +/- 12 years) whom had been referred for 82Rb PET/CT examination in a single centre were included in this study. All patients completed a stress 82Rb PET/CT with adenosine infusion, paired with a rest study. Dynamic PET acquisitions were performed in both. Cardiovascular risk factors were documented as per clinical routine. Images were checked for quality and analysed using a proprietary software by an experienced operator to derive MBF parameters. Overall survival was recorded following the study. Results Median follow-up period was 71 +/- 28 months. Mean survival was 121 (95% CI: 118-124) months. On univariate analysis, global myocardial flow reserve &amp;lt;1.77 was associated with a higher all-cause mortality (p &amp;lt; 0.001). Other parameters including higher age (&amp;gt; =76 years), lower BMI (&amp;lt;21), qualitative abnormality on the myocardial perfusion scan (MPS), low hyperaemic ejection fraction on the gated studies (stress &amp;lt; 37 and rest &amp;lt; 34). Patients being on cardiac glycosides and diuretics were also significant predictor of poor prognosis (p &amp;lt; 0.001) on univariate analysis, presumably reflecting underlying arrhythmia and heart failure. A multivariate Cox regression analysis (step-wise Forward Wald), comprising of the above significant univariate markers, highlighted global myocardial flow reserve (HR: 2.6, 95%CI: 1.8-3.6, p &amp;lt; 0.001), age (HR: 2.8, 95%CI: 2.0-3.9, p &amp;lt; 0.001),, BMI (HR: 2.7, 95%CI: 1.7-4.1, p &amp;lt; 0.001),, ejection fraction (stress - HR: 3.3, 95%CI: 2.3-4.8, p &amp;lt; 0.001), MPS (HR: 1.5, 95%CI: 1.1-2.1, p = 0.024), and patients on diuretics (HR: 1.8, 95%CI: 1.2-2.5, p = 0.003) were independent predictors of overall survival (overall model: p &amp;lt; 0.001) Discussion We show that high volume routinely derived MBF in patients undergoing 82Rb PET/CT is a strong predictor of mortality and independent of other risk factors. This has important clinical implication for measuring not only interventional treatment but also measuring the effect of lifestyle and medical strategies.

Kinds of pet chosen and manner of pet acquisition during COVID 19 in Serbia

In mid-March 2020, a state of emergency was declared in Serbia in order to prevent the spread of COVID 19. Many activities of Serbian citizens were limited or completely stopped. Citizens had to spend most of their time confined in their homes. However, some still wanted and managed to acquire pets. Therefore, the aim of this study was to examine which kinds of pets (dogs, cats and non-traditional animals) the residents of Serbia acquired during the first year of the COVID 19 pandemic and in which manner (purchase, adoption or gift). If the pets were acquired by adoption, the participants were asked from what sources they adopted them. Finally, how the characteristics of the owner and their household influenced the adoption of pets was examined. A total of 566 pet owners who acquired pets in the pre-COVID 19 and COVID 19 periods participated in the research. The COVID pandemic reduced the number of pet owners 2.7-fold in 2020 compared to 2019. Dogs were the most favourite pets acquired before (43%) and during (43%) the pandemic. During the pandemic, 61% of pets were acquired by adoption and the percentage of dogs, cats and non-traditional pets adopted directly from previous owners increased by 32%, 13% and 12%, respectively. The probability of acquiring pets by adoption was significantly increased by the presence of people older than 65 in the household (OR=2.56; P=0.02), the absence of children up to 5 years of age (OR=0.17; P<0.001) in the household, lower monthly incomes (OR=0.47; P<0.001), the greater available free time of the owner (OR=2.09; P<0.001), and the period of adoption (OR=2.42; P<0.001).

Performance of nanoScan PET/CT and PET/MR for quantitative imaging of 18F and 89Zr as compared with ex vivo biodistribution in tumor-bearing mice

IntroductionThe assessment of ex vivo biodistribution is the preferred method for quantification of radiotracers biodistribution in preclinical models, but is not in line with current ethics on animal research. PET imaging allows for noninvasive longitudinal evaluation of tracer distribution in the same animals, but systemic comparison with ex vivo biodistribution is lacking. Our aim was to evaluate the potential of preclinical PET imaging for accurate tracer quantification, especially in tumor models.MethodsNEMA NU 4-2008 phantoms were filled with 11C, 68Ga, 18F, or 89Zr solutions and scanned in Mediso nanoPET/CT and PET/MR scanners until decay. N87 tumor-bearing mice were i.v. injected with either [18F]FDG (~ 14 MBq), kept 50 min under anesthesia followed by imaging for 20 min, or with [89Zr]Zr-DFO-NCS-trastuzumab (~ 5 MBq) and imaged 3 days post-injection for 45 min. After PET acquisition, animals were killed and organs of interest were collected and measured in a γ-counter to determine tracer uptake levels. PET data were reconstructed using TeraTomo reconstruction algorithm with attenuation and scatter correction and regions of interest were drawn using Vivoquant software. PET imaging and ex vivo biodistribution were compared using Bland–Altman plots.ResultsIn phantoms, the highest recovery coefficient, thus the smallest partial volume effect, was obtained with 18F for both PET/CT and PET/MR. Recovery was slightly lower for 11C and 89Zr, while the lowest recovery was obtained with 68Ga in both scanners. In vivo, tumor uptake of the 18F- or 89Zr-labeled tracer proved to be similar irrespective whether quantified by either PET/CT and PET/MR or ex vivo biodistribution with average PET/ex vivo ratios of 0.8–0.9 and a deviation of 10% or less. Both methods appeared less congruent in the quantification of tracer uptake in healthy organs such as brain, kidney, and liver, and depended on the organ evaluated and the radionuclide used.ConclusionsOur study suggests that PET quantification of 18F- and 89Zr-labeled tracers is reliable for the evaluation of tumor uptake in preclinical models and a valuable alternative technique for ex vivo biodistribution. However, PET and ex vivo quantification require fully described experimental and analytical procedures for reliability and reproducibility.

Innovative procedure for measuring left ventricular ejection fraction from 18F-FDG first-pass ultra-sensitive digital PET/CT images: evaluation with an anthropomorphic heart phantom

BackgroundLeft ventricular ejection fraction (LVEF) is usually measured by cine-cardiac magnetic resonance imaging (MRI), planar and single-photon emission-computerized tomography (SPECT) equilibrium radionuclide angiocardiography (ERNA), and echocardiography. It would be clinically useful to measure LVEF from first-pass positron-emission tomography/computed tomography (PET/CT) radionuclide angiography, but this approach has been limited by fast radiotracer diffusion. Ultra-sensitive digital PET systems can produce high-quality images within 3-s acquisition times. This study determined whether digital PET/CT accurately measured LVEF in an anthropomorphic heart phantom under conditions mimicking radiotracer first-pass into the cardiac cavities.MethodsHeart phantoms in end-diastole and end-systole were 3D-printed from a patient’s MRI dataset. Reference left ventricle end-diastole volume (EDV), end-systole volume (ESV), and LVEF were determined by phantom weights before/after water filling. PET/CT (3-s acquisitions), MRI, and planar and SPECT ERNA were performed. EDV, ESV, and/or LVEF were measured by manual and automated cardiac cavity delineation, using clinical segmentation softwares. LVEF was also measured from PET images converted to 2D “pseudo-planar” images along the short axis and horizontal long axis. LVEF was also calculated for planar ERNA images. All LVEF, ESV and EDV values were compared to the reference values assessed by weighing.ResultsManually calculated 3D-PET-CT-based EDV, ESV, and LVEF were close to MRI and reference values. Automated calculations on the 3D-PET-CT dataset were unreliable, suggesting that the SPECT-based tool used for this calculation is not well adapted for PET acquisitions. Manual and automated LVEF estimations from “pseudo-planar” PET images were very close/identical to MRI and reference values.ConclusionsFirst-pass “pseudo-planar” PET may be a promising method for estimating LVEF, easy to use in clinical practice. Processing 3D PET images is also a valid method but to date suffers from a lack of well-suited software for automated LV segmentation.

Brown Adipose Tissue Volume and Distribution in Premenopausal and Postmenopausal Women

Introduction The loss of ovarian function and the accompanying decrease in estradiol during menopause has an impact on the metabolic activity of many tissues and organs, resulting in a reduction in resting energy expenditure. In rodents, ovariectomy or the absence of the estrogen receptor α suppresses brown adipose tissue (BAT) thermogenesis. It is therefore hypothesized that a reduction in BAT volume and thermogenesis may contribute to the reduction in resting energy expenditure in postmenopausal women. Objective The primary aim was to investigate the impact of estrogen on BAT volume and its distribution across the various depots in pre- and postmenopausal women. Methods A cohort of 22 premenopausal (33 years, 95% CI: 29 to 37 years) and 22 postmenopausal women (63 years, 95% CI: 60 to 67 years) took part in a 3-hr cold exposure using a liquid-conditioned suit perfused with 18°C water. During cold exposure, an i.v. bolus of [11C]-acetate and [18F]FDG were given sequentially, with each injection followed by a 30 min list-mode dynamic PET acquisition to quantify BAT oxidative metabolism and glucose uptake, respectively. Finally, a whole-body static PET acquisition was performed to quantify the whole-body biodistribution of glucose and estimate BAT volume and the distribution of this BAT volume across the various depots. BAT volume was determined according to the following criteria: [18F]FDG ≥ 2 SUVmean and a radiodensity between -10 and -250 HU. Results There was significant variability in BAT volume and its distribution in both pre- and postmenopausal women. Premenopausal women had greater total BAT volume (53 mL, 95% CI: 34 to 72 mL) compared to postmenopausal women (21 mL, 95% CI: 8 to 34 mL, P = 0.006), although both groups included individuals with undetectable BAT. In premenopausal women, 65% of BAT was localized in the supraclavicular depot (95% CI: 57 to 73%) and 9% in the paravertebral depot (95% CI: 5 to 13%), with the remaining depots (e.g. cervical, axillary, mediastinal, and perirenal) accounting for 25% (95% CI: 16 to 34%). In postmenopausal women, 45% of BAT was localized in the supraclavicular depot (95% CI: 24 to 66%) while the paravertebral depot represented 32% (95% CI: 12 to 52%) of total BAT. The remaining 23% (95% CI: 5 to 41 %) was distributed among the other depots. Thus, in postmenopausal women, there was a 20% reduction in the relative contribution of supraclavicular depots to the total volume and a 23% increase in the relative contribution of paravertebral depots to the total BAT volume compared to premenopausal women. Conclusion Here we show that total BAT volume is lower in postmenopausal women and results in a redistribution of BAT. However, there was tremendous variability in both BAT volume and distribution in both premenopausal and postmenopausal women. Further, it is difficult to distinguish the effects of estrogen from the effect of age or adiposity in the observed differences between our two cohorts.

Relationship Between Brown Adipose Tissue and Shivering in Cold‐Exposed Humans

Background An inverse relationship between brown adipose tissue (BAT) volume and shivering intensity has previously been reported in humans. Considering its small volume in adult humans, this inverse relationship may be explained by the regional distribution of BAT. It has been postulated that the paraspinal depot may be critical to heating the spinal cord to maintain neural conductivity under cold stimulation. However, this local heating may also suppress the drive to shiver, a phenomenon previously shown in guinea pigs. Objective The research objective was to determine whether the presence of paraspinal BAT can modulate the intensity and pattern of shivering in lean, healthy, adult humans. Hypothesis We propose that paraspinal BAT thermogenesis can supress shivering intensity and modulate the shivering pattern. Methodology The present data includes 23 young women who completed a 3h mild cold exposure protocol, using a liquid-conditioned suit perfused with water at 18°C. During cold exposure, participants remained supine in a PET/CT scanner. An i.v. bolus of [11C]-acetate and [18F]FDG were given sequentially, with each injection followed by a 30 min list-mode dynamic PET acquisition to quantify depot-specific BAT oxidative metabolism and glucose uptake, respectively. Finally, a whole-body static PET acquisition was performed to quantify the total BAT volume and distribution. Surface electromyography (sEMG) was used to characterize shivering activity in 8 different muscles. Shivering intensity and shivering pattern were determined using custom-designed EMG algorithms. In brief, the two distinct shivering patterns (continuous vs burst shivering) are distinguished according to differences in frequency of occurrence (4-8 Hz for continuous vs. 0.1-0.2 Hz for bursts) and intensity [2-5% maximal voluntary contraction (MVC) for continuous vs. 7-15% MVC for bursts]. Results Total BAT volume was estimated at 53 mL (95% CI: 34 to 72 mL) with paraspinal BAT volume accounting for 9% (95% CI: 5 to 13%) of total BAT. Mean shivering intensity under this cold stimulus was 3.0 % MVC (95% CI: 2.0 to 3.8 %). Shivering bursts occurred at a frequency of 2.8 bursts/min (95% CI: 2.3 to 3.2 bursts/min), eliciting a shivering intensity of 9.6 % MVC (95% CI: 5.9 to 13.3 % MVC), while the more continuous low-intensity shivering was maintained at 3.0 % MVC (95% CI: 1.6 to 4.4% MVC). Pearson correlations revealed no associations between total BAT volume, shivering intensity or shivering pattern. Similarly, paraspinal BAT volume was not associated with any shivering outcomes. Conclusion The role of BAT in humans is still not clearly elucidated. Here we showed that in premenopausal women, neither total BAT volume nor paraspinal BAT are associated with shivering intensity or shivering pattern. Further studies are required to determine whether BAT plays a more regionalized role, unique to each depot, or more globally on whole-body energy metabolism.

First-in-Human PET Imaging and Estimated Radiation Dosimetry of l-[5-11C]-Glutamine in Patients with Metastatic Colorectal Cancer.

Altered metabolism is a hallmark of cancer. In addition to glucose, glutamine is an important nutrient for cellular growth and proliferation. Noninvasive imaging via PET may help facilitate precision treatment of cancer through patient selection and monitoring of treatment response. l-[5-11C]-glutamine (11C-glutamine) is a PET tracer designed to study glutamine uptake and metabolism. The aim of this first-in-human study was to evaluate the radiologic safety and biodistribution of 11C-glutamine for oncologic PET imaging. Methods: Nine patients with confirmed metastatic colorectal cancer underwent PET/CT imaging. Patients received 337.97 ± 44.08 MBq of 11C-glutamine. Dynamic PET acquisitions that were centered over the abdomen or thorax were initiated simultaneously with intravenous tracer administration. After the dynamic acquisition, a whole-body PET/CT scan was acquired. Volume-of-interest analyses were performed to obtain estimates of organ-based absorbed doses of radiation. Results:11C-glutamine was well tolerated in all patients, with no observed safety concerns. The organs with the highest radiation exposure included the bladder, pancreas, and liver. The estimated effective dose was 4.46E-03 ± 7.67E-04 mSv/MBq. Accumulation of 11C-glutamine was elevated and visualized in lung, brain, bone, and liver metastases, suggesting utility for cancer imaging. Conclusion: PET using 11C-glutamine appears safe for human use and allows noninvasive visualization of metastatic colon cancer lesions in multiple organs. Further studies are needed to elucidate its potential for other cancers and for monitoring response to treatment.

Total-body 18F-FDG PET/CT scan in oncology patients: how fast could it be?

The aim of the study was to determine a faster PET acquisition protocol for a total-body PET/CT scanner by assessing the image quality that is equivalent to a conventional digital PET/CT scanner from both a phantom and a clinical perspective. A phantom study using a NEMA/IEC NU-2 body phantom was first performed in both a total-body PET/CT (uEXPLORER) and a routine digital PET/CT (uMI 780), with a hot sphere to background activity concentration ratio of 4:1. The contrast recovery coefficient (CRC), background variability (BV), and recovery coefficient (RC: RCmax and RCmean) were assessed in the uEXPLORER with different scanning durations and reconstruction protocols, which were compared to those acquired from the uMI 780 with clinical acquisition settings. The coefficient of variation (COV) of the uMI 780 with clinical settings was calculated and used as a threshold reference to determine the optimized scanning duration and reconstruction protocol for the uEXPLORER. The obtained protocol from the phantom study was subsequently tested and validated in 30 oncology patients. Images acquired from the uMI 780 with 2-3min per bed position were referred as G780 and served as the reference for comparison. All PET raw data from the uEXPLORER were reconstructed using the data-cutting technique to simulate a 30-s, 45-s, or 60-s acquisition duration, respectively. The iterations were 2 and 3 for the uEXPLORER, referred as G30s_3i, G45s_2i, G45s_3i, G60s_2i, and G60s_3i, respectively. A 5-point Likert scale was used in the qualitative analysis to assess the image quality. The image quality was also evaluated by the liver COV, the lesion target-to-background ratio (TBR), and the lesion signal-to-noise ratio (SNR). In the phantom study, CRC, BV, RCmax, and RCmean in the uEXPLORER with different scanning durations and reconstruction iterations were compared with those in the uMI 780 with clinical settings. A minor fluctuation was found among different scanning durations. COV of the uMI 780 with clinical settings was 11.6%, and a protocol with a 30-45-s scanning duration and 2 or 3 iterations for the uEXPLORER was found to provide an equivalent image quality as the uMI 780. An almost perfect agreement was shown with a kappa value of 0.875. The qualitative score of the G30s_3i in the uEXPLORER was inferior to the G780 reference (p = 0.001); however, the scores of other groups in the uEXPLORER with a 45-s and above acquisition time were higher than the G780 in the uMI 780. In quantitative analysis, the delay time between the two scans in the two orders was not significantly different. There was no significant difference of the liver COV between the G780 and G30s_3i (p = 0.162). A total of 33 lesions were analyzed in the clinical patient study. There was no significant difference in lesion TBR between the reference G780 and the G45s_2i obtained from the uEXPLORER (p = 0.072), while the latter showed a higher lesion SNR value compared to that in uMI 780 with clinical settings (p < 0.001). This study showed that a fast PET protocol with a 30-45-s acquisition time in the total-body uEXPLORER PET/CT can provide an equivalent image quality as the conventional digital uMI 780 PET/CT with longer clinical acquisition settings.

Kinetic and Static Analysis of Poly-(Adenosine Diphosphate-Ribose) Polymerase-1-Targeted 18F-Fluorthanatrace PET Images of Ovarian Cancer.

The poly-(adenosine diphosphate-ribose) polymerase (PARP) family of proteins participates in numerous functions, most notably the DNA damage response. Cancer vulnerability to DNA damage has led to development of several PARP inhibitors (PARPi). This class of drugs has demonstrated therapeutic efficacy in ovarian, breast, and prostate cancers, but with variable response. Consequently, clinics need to select patients likely to benefit from these targeted therapies. In vivo imaging of 18F-fluorthanatrace uptake has been shown to correspond to PARP-1 expression in tissue. This study characterized the pharmacokinetics of 18F-fluorthanatrace and tested kinetic and static models to guide metric selection in future studies assessing 18F-fluorthanatrace as a biomarker of response to PARPi therapy. Methods: Fourteen prospectively enrolled ovarian cancer patients were injected with 18F-fluorthanatrace and imaged dynamically for 60 min after injection followed by up to 2 whole-body scans, with venous blood activity and metabolite measurements. SUVmax and SUVpeak were extracted from dynamic images and whole-body scans. Kinetic parameter estimates and SUVs were assessed for correlations with tissue PARP-1 immunofluorescence (n = 7). Simulations of population kinetic parameters enabled estimation of measurement bias and precision in parameter estimates. Results:18F-fluorthanatrace blood clearance was variable, but labeled metabolite profiles were similar across patients, supporting use of a population parent fraction curve. The total distribution volume from a reversible 2-tissue-compartment model and Logan reference tissue distribution volume ratio (DVR) from the first hour of PET acquisition correlated with tumor PARP-1 expression by immunofluorescence (r = 0.76 and 0.83, respectively; P < 0.05). DVR bias and precision estimates were 6.4% and 29.1%, respectively. SUVmax and SUVpeak acquired from images with midpoints of 57.5, 110 ± 3, and 199 ± 4 min highly correlated with PARP-1 expression (mean ± SD, r ≥ 0.79; P < 0.05). Conclusion: Tumor SUVmax and SUVpeak at 55-60 min after injection and later and DVR from at least 60 min appear to be robust noninvasive measures of PARP-1 binding. 18F-fluorthanatrace uptake in ovarian cancer was best described by models of reversible binding. However, pharmacokinetic patterns of tracer uptake were somewhat variable, especially at later time points.

Inhibition of Glucose-6-Phosphate Dehydrogenase Activity Attenuates Right Ventricle Pressure and Hypertrophy Elicited by VEGFR Inhibitor + Hypoxia.

Pulmonary hypertension (PH) is a disease of hyperplasia of pulmonary vascular cells. The pentose phosphate pathway (PPP)-a fundamental glucose metabolism pathway-is vital for cell growth. Because treatment of PH is inadequate, our goal was to determine whether inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, prevents maladaptive gene expression that promotes smooth muscle cell (SMC) growth, reduces pulmonary artery remodeling, and normalizes hemodynamics in experimental models of PH. PH was induced in mice by exposure to 10% oxygen (Hx) or weekly injection of vascular endothelial growth factor receptor blocker [Sugen5416 (SU); 20 mg kg-1] during exposure to hypoxia (Hx + SU). A novel G6PD inhibitor (N-[(3β,5α)-17-oxoandrostan-3-yl]sulfamide; 1.5 mg kg-1) was injected daily during exposure to Hx. We measured right ventricle (RV) pressure and left ventricle pressure-volume relationships and gene expression in lungs of normoxic, Hx, and Hx + SU and G6PD inhibitor-treated mice. RV systolic and end-diastolic pressures were higher in Hx and Hx + SU than normoxic control mice. Hx and Hx + SU decreased expression of epigenetic modifiers (writers and erasers), increased hypomethylation of the DNA, and induced aberrant gene expression in lungs. G6PD inhibition decreased maladaptive expression of genes and SMC growth, reduced pulmonary vascular remodeling, and decreased right ventricle pressures compared with untreated PH groups. Pharmacologic inhibition of G6PD activity, by normalizing activity of epigenetic modifiers and DNA methylation, efficaciously reduces RV pressure overload in Hx and Hx + SU mice and preclinical models of PH and appears to be a safe pharmacotherapeutic strategy. SIGNIFICANCE STATEMENT: The results of this study demonstrated that inhibition of a metabolic enzyme efficaciously reduces pulmonary hypertension. For the first time, this study shows that a novel inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the fundamental pentose phosphate pathway, modulates DNA methylation and alleviates pulmonary artery remodeling and dilates pulmonary artery to reduce pulmonary hypertension.

Equivalent tumor detection for early and late FAPI-46 PET acquisition

IntroductionPositron emission tomography (PET) using small ligands of the fibroblast activation protein (FAP) was recently introduced. However, optimal uptake time has not been defined yet. Here, we systematically compare early (~ 10 min p.i.) and late (~ 60 min p.i.) FAPI-46 imaging in patients with various types of cancer.MethodsThis is a retrospective single-institutional study. Imaging was performed at the Essen University Hospital, Germany. A total of 69 patients who underwent dual time-point imaging for either restaging (n = 52, 75%) or staging (n = 17, 25%) of cancer were included. Patients underwent PET with two acquisitions: early (mean 11 min, SD 4) and late (mean 66 min, SD 9). Mean injected activity was 148 MBq (SD 33).ResultsIn total, 400 lesions were detected in 69 patients. Two of 400 (0.5%) lesions were only seen in early time-point imaging but not in late time-point imaging. On a per-patient level, there was no significant difference between SUVmax of hottest tumor lesions (Wilcoxon: P = 0.73). Organ uptake demonstrated significant early to late decrease in SUVmean (average ∆SUVmean: − 0.48, − 0.14, − 0.27 for gluteus, liver, and mediastinum, respectively; Wilcoxon: P < 0.001). On a per-lesion basis, a slight increase of SUVmax was observed (average ∆SUVmax: + 0.4, Wilcoxon: P = 0.03).ConclusionIn conclusion, early (~ 10 min p.i.) versus late (~ 60 min p.i.) FAPI-46 imaging resulted in equivalent lesion uptake and tumor detection. For improved feasibility and scan volume, we implement early FAPI-46 PET in future clinical and research protocols.