Acid Positron Emission Tomography Research Articles

Abstract 4157: Combining hyperpolarized magnetic resonance and positron emission tomography to interrogate prostate cancer metabolism

Abstract Background: There is an unmet clinical need for imaging biomarkers to distinguish indolent from aggressive prostate cancer (PCa). Many advanced and aggressive PCa patients receiving anti-androgens (enzalutamide) develop resistance. It is hypothesized that dysregulated cell metabolism is a key driver for PCa progression and therapy resistance. Two pathways commonly involved in PCa are glycolysis and fatty acid metabolism. Therefore, metabolic imaging and metabolomics were performed on enzalutamide sensitive/resistant, Androgen Receptor dependent (AR+) and AR independent (AR-) patient derived xenograft (PDX) tumors. To interrogate both pathways, [1-13C]-pyruvate hyperpolarized magnetic resonance spectroscopy (HP-MRS) and [18F]-fluorodeoxyglucose positron emission tomography (18F-FDG) for glycolysis, and [18F]-fluoro-pivalic acid positron emission tomography (18F-FPIA) for fatty acid metabolism were employed. 1H Nuclear Magnetic Resonance (NMR) spectroscopy and liquid chromatography with tandem mass spectrometry (LC-MS-MS) were employed for validation purposes. Methods: [1-13C]-labeled pyruvic acid was hyperpolarized using a DNP HyperSense polarizer following standard protocol. Anatomical MRI and 13C-MRS were obtained on different PCa PDX mouse models at two different time points using a Bruker 7T scanner. The PDX models included AR+ enzalutamide sensitive (183-A, 180-30), AR+ enzalutamide resistant (274-4), and AR- (144-4, 114-B). The time points imaged were before and after 7 days of treatment with enzalutamide. 1H-NMR spectroscopy was performed on extracted tissue. Simultaneously, 18F-FPIA-PET imaging were acquired on the same models on an Albira trimodal PET station. Results: The dynamic metabolic flux ratio, lactate-to-pyruvate (Lac/Pyr) was determined in vivo and used as a treatment response marker. The Lac/Pyr ratios were significantly higher in resistant tumors compared to sensitive tumors (p<0.01). The enzalutamide sensitive group had a lower Lac/Pyr ratio after treatment, while the enzalutamide resistant group had a higher Lac/Pyr ratio. After treatment, there was also a decrease in [18F]-FDG uptake, corresponding to the HP-MRS data. This was expected as both Pyruvate and [18F]-FDG interrogate the glycolytic pathway. As for the fatty acid metabolic imaging, PET imaging also revealed that [18F]-FPIA is transported into the tumors, and we are currently exploring how its uptake varies between AR (+/-) PCa-PDX tumors and enzalutamide resistant/sensitive models. Ex vivo NMR and mass spectrometry-based metabolomics validated the in vivo HP-MRS data with higher lactate levels in drug resistant tumors. Conclusion: Combining HP-MRS and PET presents an exciting opportunity to realize imaging-based personalized medicine in different AR (+/-) PCa-PDX preclinical models by interrogating glycolysis and fatty acid oxidation pathways. Citation Format: Muxin Wang, José S. Enriquez, Prasanta Dutta, Jenny Han, Peter Shepherd, Daniel Frigo, Federica Pisaneschi, Pratip K. Bhattacharya. Combining hyperpolarized magnetic resonance and positron emission tomography to interrogate prostate cancer metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4157.

Evaluating the Diagnostic Efficacy of 99mTc-Methionine Single-Photon Emission Computed Tomography-Computed Tomography: A Head-to-Head Comparison with 11C-Methionine Positron Emission Tomography-Magnetic Resonance Imaging in Glioma Patients.

Background: Amino acid positron emission tomography (PET) imaging plays a significant role in the diagnosis of gliomas and in differentiating tumor recurrence from necrosis. In this study, the authors have evaluated the diagnostic efficacy of [99mTc]Tc-methionine single-photon emission computed tomography-computed tomography (SPECT-CT) in comparison with [11C]methionine PET-magnetic resonance imaging (MRI) in delineating tumors. Methods: Thirty-one (primary: 16 and postoperative: 15) patients of confirmed (either MRI or histopathological proven) glioma underwent both [99mTc]Tc-methionine SPECT-CT and [11C]methionine PET-MRI. A comparative analysis was performed between SPECT, PET, and MR images to calculate the concordance between the modalities and to evaluate the diagnostic efficacy of the [99mTc]Tc-methionine SPECT. Results: [99mTc]Tc-methionine SPECT showed comparable uptake in the tumor lesions in comparison to [11C]methionine PET. A significant and strong positive correlation was observed between the volume of tumor (Vt) in PET and Vt MR (p < 0.004). Likewise, a significant and strong positive correlation was found between Vt SPECT and Vt MR. [99mTc]-methionine has a sensitivity and specificity of 91% and 75%, respectively, compared with 82% and 100% for [11C]methionine in postoperative cases to differentiate the tumor recurrence from necrosis. The sensitivity and specificity of [99mTc]Tc-methionine was 92% and 100%, respectively, compared with 92% and 67% for [11C]methionine in primary tumors. Conclusion: [99mTc]Tc-methionine SPECT-CT is as equally good as [11C]methionine for diagnosing and differentiating it from necrosis especially in high-grade glioma.

The clinical impact of amino acid positron emission tomography measurements in the treatment of primary malignant brain tumors

Despite the large-scale diagnostic and therapeutic progress of recent years, the heterogeneity and therapeutic management of adult primary malignant brain tumors pose a significant challenge to the attending physician. Based on the research and experience accumulated over the past two decades, the range of patients who can benefit the most from complex oncology treatment has been outlined, and it has been confirmed that a reliable complex diagnostic background is essential for adequate therapeutic management. However, after some necessary therapeutic steps, the "gold standard" magnetic resonance imaging (MRI) is not always able to accurately assess and diagnose post-therapeutic conditions. Thanks to the collaboration of the nuclear medicine and neuro-oncology professions, more and more types of radiotracer compounds are now available in more and more centers, including amino acid ligands and thus, positron emission tomography (PET) examinations with the radiopharmaceutical O-(2-[18F]fluoroethyl)-L-tyrosine. The metabolic state, as a kind of fourth dimension of imaging, is an essential part of adequate modern diagnostics. Combining advanced MRI techniques and PET-based (PET/CT, PET/MRI) measurements with a suitable tracer can place therapeutic decisions on a reliable basis. We present the clinical significance of amino acid-PET-based hybrid nuclear medicine imaging studies in the therapeutic management of these patients by reviewing the literature data on the practice of the method in Hungary and abroad and presenting the results of our retrospective summary research so far. Orv Hetil. 2023; 164(32): 1247-1255.

The role of optimal cut-off diagnosis in 11C-methionine PET for differentiation of intracranial brain tumor from non-neoplastic lesions before treatment

PurposeAmino acid positron emission tomography (PET) may provide additional information to computed tomography and magnetic resonance imaging for detecting the pretreatment diagnosis of intracranial lesions. The purpose of this study was to investigate the role of cutoff values of 11C-METPET, an amino acid PET tracer, in the differentiation of pretreatment brain tumors from non-neoplastic lesions. MethodsThis retrospective cohort study analyzed 101 pretreatment patients with a definitive diagnosis out of a total of 425 consecutive 11C-METPET imaging studies. The standardized uptake values (SUV) and the ratios of lesion to contralateral normal frontal-lobe gray matter uptake (L/N ratios) were measured. Cutoff values for the differential diagnosis of brain tumors from non-neoplastic lesions were determined using receiver operating characteristics curve (ROC) analysis. ResultsBased on the ROC analyses, the cutoffs were 3.33 for maximum SUV, 2.54 for mean SUV, 2.33 for peak SUV, 2.04 for Lmax/Nmean, and 2.23 for Lmax/Nmax. The sensitivity and specificity of these cutoffs were 69.2% and 82.6%, respectively, for maximum SUV, 64.1% and 91.3% for mean SUV, 69.2% and 91.3% for peak SUV, 70.5% and 91.3% for Lmax/Nmax and 75.6% and 82.6% for Lmax/Nmean. ConclusionIn differentiating intracranial brain tumor from non-neoplastic lesion with 11C-METPET, the use of optimal cutoff values indicates the high specificity, which means that positive result indicates the high likelihood of brain tumor. Considering the high specificity of 11C-METPET, more invasive examinations such as biopsy may be considered in positive cases.

P15.13.B Role and accuracy of FET-PET in gliomas, and its significance in the differential diagnosis among progression, pseudoprogression, and response to treatments

Abstract Background Lack of effective treatments for patients affected by gliomas emphasizes the need for innovative therapeutic approaches. Surgical resection plays a pivotal role in glioma treatment by improving both, progression-free survival (PFS) and overall survival (OS). Gliomas grow beyond contrast enhancement borders, reducing the ability of MRI to determine the tumor burden and predict metabolic change inside tumor. The most appropriate imaging tools to assess early response to treatment is still a matter of debate. In addition, lack of a quantifiable measure of non-enhancing disease progression, mistaking effect of radiation therapy, ischemic injury, or post-operative changes on MRI images can complicate the subject. With O-(2-18Ffluoroethyl)-L-tyrosine ([18F]) FET as a tracer, PET is known to visualize the amino acid uptake in gliomas and thus metabolically active tumor cells, and is a promising methodology providing new data to the currently used RANO criteria. We can distinguish treatment effects (e.g., radiation necrosis and pseudoprogression) as post treatment-related change (PTRC), from findings defined as “true glioma progression” (TPR). Material and Methods We retrospectively analysed data from 20 patients (15 males and 5 females, mean age 52 years, range 22-75) with diagnosis of glioma (WHO Grade 2: 6, Grade 3: 3, Grade 4:11) who underwent surgery and/or RT and were followed up by MRI and [18F]FET-PET/CT. PET/CT images were acquired by a dual time-point method: an early acquisition at 10 min (600sec acquisition duration) and a late acquisition at 50 min (650 sec acquisition duration) after the administration of 282,5±47,8 MBq [18F]FET. Images were visually analyzed. Moreover, a tumor/background ratio (T/B) was obtained by comparing SUV max in the tumoral ROI and SUV max in a mirrored contralateral ROI. Differences between these parameters in patients with recurrence and patients with response to treatments were evaluated by the Mann-Whitney test. Standard of reference was surgery or at least 9 months follow-up. Results On the basis of our standard of reference, 14 out of 20 patients had tumor recurrence, whereas 6 had PTRC. Visual analysis revealed no abnormal radiotracer accumulation in 4 patients. All these patients had PTRC. As far as semiquantitative analysis is concerned, statistically significant differences were found between tumor recurrence and PTRC for all analyzed indexes. Conclusion Although magnetic resonance imaging (MRI) is routinely used for serial evaluation of tumor burden in patients with glioma, amino acid positron emission tomography (PET) can be used for confirming the presence of metabolically active tumors. In the follow-up of patient affected by glioma, validation of response to treatments is a need issue, due to the reason that the wrong differentiation between TPR and PTRC could cause a wrong decision made by surgeon and patients.

Diagnostic yield of simultaneous dynamic contrast-enhanced magnetic resonance perfusion measurements and [18F]FET PET in patients with suspected recurrent anaplastic astrocytoma and glioblastoma

PurposeBoth amino acid positron emission tomography (PET) and magnetic resonance imaging (MRI) blood volume (BV) measurements are used in suspected recurrent high-grade gliomas. We compared the separate and combined diagnostic yield of simultaneously acquired dynamic contrast-enhanced (DCE) perfusion MRI and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET in patients with anaplastic astrocytoma and glioblastoma following standard therapy.MethodsA total of 76 lesions in 60 hybrid [18F]FET PET/MRI scans with DCE MRI from patients with suspected recurrence of anaplastic astrocytoma and glioblastoma were included retrospectively. BV was measured from DCE MRI employing a 2-compartment exchange model (2CXM). Diagnostic performances of maximal tumour-to-background [18F]FET uptake (TBRmax), maximal BV (BVmax) and normalised BVmax (nBVmax) were determined by ROC analysis using 6-month histopathological (n = 28) or clinical/radiographical follow-up (n = 48) as reference. Sensitivity and specificity at optimal cut-offs were determined separately for enhancing and non-enhancing lesions.ResultsIn progressive lesions, all BV and [18F]FET metrics were higher than in non-progressive lesions. ROC analyses showed higher overall ROC AUCs for TBRmax than both BVmax and nBVmax in both lesion-wise (all lesions, p = 0.04) and in patient-wise analysis (p < 0.01). Combining TBRmax with BV metrics did not increase ROC AUC. Lesion-wise positive fraction/sensitivity/specificity at optimal cut-offs were 55%/91%/84% for TBRmax, 45%/77%/84% for BVmax and 59%/84%/72% for nBVmax. Combining TBRmax and best-performing BV cut-offs yielded lesion-wise sensitivity/specificity of 75/97%. The fraction of progressive lesions was 11% in concordant negative lesions, 33% in lesions only BV positive, 64% in lesions only [18F]FET positive and 97% in concordant positive lesions.ConclusionThe overall diagnostic accuracy of DCE BV imaging is good, but lower than that of [18F]FET PET. Adding DCE BV imaging did not improve the overall diagnostic accuracy of [18F]FET PET, but may improve specificity and allow better lesion-wise risk stratification than [18F]FET PET alone.

Exploratory Analysis of Serial 18F-fluciclovine PET-CT and Multiparametric MRI during Chemoradiation for Glioblastoma.

Simple SummaryGlioblastoma (GBM), the most common malignant adult primary brain tumour, has a prognosis of ~12–15 months. Poor prognosis is partly due to the inability to accurately define the extent of tumour infiltration; currently demarcated using magnetic resonance imaging (MRI) sequences (e.g., post-contrast T1-weighted (Gd-T1) and dynamic contrast-enhanced (DCE-MRI)). Anti-1-amino-3-18fluorine-fluorocyclobutane-1-carboxylic acid (18F-fluciclovine) positron emission tomography (PET) may depict GBM better than MRI. This prospective pilot study aimed to explore the relationship of 18F-fluciclovine PET, DCE-MRI and Gd-T1 in patients with GBM undergoing standard-of-care adjuvant chemoradiotherapy. A parallel mouse glioma model was used to investigate the relationship between 18F-fluciclovine PET, MRI and tumour biology. Clinical results showed that GBM volume on 18F-fluciclovine PET tended to be larger than Gd-T1 and DCE-MRI in patients with shorter overall survival (OS) but smaller in patients with longer OS. The preclinical study confirmed that 18F-fluciclovine uptake reflected biologically active tumour. Results suggest that 18F-fluciclovine PET may better define GBM infiltration than MRI.Anti-1-amino-3-18fluorine-fluorocyclobutane-1-carboxylic acid (18F-fluciclovine) positron emission tomography (PET) shows preferential glioma uptake but there is little data on how uptake correlates with post-contrast T1-weighted (Gd-T1) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) activity during adjuvant treatment. This pilot study aimed to compare 18F-fluciclovine PET, DCE-MRI and Gd-T1 in patients undergoing chemoradiotherapy for glioblastoma (GBM), and in a parallel pre-clinical GBM model, to investigate correlation between 18F-fluciclovine uptake, MRI findings, and tumour biology. 18F-fluciclovine-PET-computed tomography (PET-CT) and MRI including DCE-MRI were acquired before, during and after adjuvant chemoradiotherapy (60 Gy in 30 fractions with temozolomide) in GBM patients. MRI volumes were manually contoured; PET volumes were defined using semi-automatic thresholding. The similarity of the PET and DCE-MRI volumes outside the Gd-T1 volume boundary was measured using the Dice similarity coefficient (DSC). CT-2A tumour-bearing mice underwent MRI and 18F-fluciclovine PET-CT. Post-mortem mice brains underwent immunohistochemistry staining for ASCT2 (amino acid transporter), nestin (stemness) and Ki-67 (proliferation) to assess for biologically active tumour. 6 patients were recruited (GBM 1–6) and grouped according to overall survival (OS)—short survival (GBM-SS, median OS 249 days) and long survival (GBM-LS, median 903 days). For GBM-SS, PET tumour volumes were greater than DCE-MRI, in turn greater than Gd-T1. For GBM-LS, Gd-T1 and DCE-MRI were greater than PET. Tumour-specific 18F-fluciclovine uptake on pre-clinical PET-CT corresponded to immunostaining for Ki-67, nestin and ASCT2. Results suggest volumes of 18F-fluciclovine-PET activity beyond that depicted by DCE-MRI and Gd-T1 are associated with poorer prognosis in patients undergoing chemoradiotherapy for GBM. The pre-clinical model confirmed 18F-fluciclovine uptake reflected biologically active tumour.

In Vivo Quantitative Imaging of Glioma Heterogeneity Employing Positron Emission Tomography.

Simple SummaryDefining glioma heterogeneity represents a promising strategy to unravel the mechanisms behind therapy resistance and tumor recurrence. The current review provides a comprehensive overview of experimental and clinical data concerning the visualization and quantification of the tumor microenvironment heterogeneity using molecular imaging, with a special emphasis on positron emission tomography (PET).Glioblastoma is the most common primary brain tumor, highly aggressive by being proliferative, neovascularized and invasive, heavily infiltrated by immunosuppressive glioma-associated myeloid cells (GAMs), including glioma-associated microglia/macrophages (GAMM) and myeloid-derived suppressor cells (MDSCs). Quantifying GAMs by molecular imaging could support patient selection for GAMs-targeting immunotherapy, drug target engagement and further assessment of clinical response. Magnetic resonance imaging (MRI) and amino acid positron emission tomography (PET) are clinically established imaging methods informing on tumor size, localization and secondary phenomena but remain quite limited in defining tumor heterogeneity, a key feature of glioma resistance mechanisms. The combination of different imaging modalities improved the in vivo characterization of the tumor mass by defining functionally distinct tissues probably linked to tumor regression, progression and infiltration. In-depth image validation on tracer specificity, biological function and quantification is critical for clinical decision making. The current review provides a comprehensive overview of the relevant experimental and clinical data concerning the spatiotemporal relationship between tumor cells and GAMs using PET imaging, with a special interest in the combination of amino acid and translocator protein (TSPO) PET imaging to define heterogeneity and as therapy readouts.

A systematic review of amino acid PET in assessing treatment response to temozolomide in glioma.

The response assessment in neuro-oncology (RANO) criteria have been the gold standard for monitoring treatment response in glioblastoma (GBM) and differentiating tumor progression from pseudoprogression. While the RANO criteria have played a key role in detecting early tumor progression, their ability to identify pseudoprogression is limited by post-treatment damage to the blood-brain barrier (BBB), which often leads to contrast enhancement on MRI and correlates poorly to tumor status. Amino acid positron emission tomography (AA PET) is a rapidly growing imaging modality in neuro-oncology. While contrast-enhanced MRI relies on leaky vascularity or a compromised BBB for delivery of contrast agents, amino acid tracers can cross the BBB, making AA PET particularly well-suited for monitoring treatment response and diagnosing pseudoprogression. The authors performed a systematic review of PubMed, MEDLINE, and Embase through December 2021 with the search terms “temozolomide” OR “Temodar,” “glioma” OR “glioblastoma,” “PET,” and “amino acid.” There were 19 studies meeting inclusion criteria. Thirteen studies utilized [18F]FET, five utilized [11C]MET, and one utilized both. All studies used static AA PET parameters to evaluate TMZ treatment in glioma patients, with nine using dynamic tracer parameters in addition. Throughout these studies, AA PET demonstrated utility in TMZ treatment monitoring and predicting patient survival.

Characterising 18F-fluciclovine uptake in breast cancer through the use of dynamic PET/CT imaging

Background18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades.MethodsThirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters.ResultsA reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation.Conclusions18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake.Clinical Trial RegistrationNCT03036943.

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of imaging in the management of progressive glioblastoma in adults.

These recommendations apply to adults with glioblastoma who have been previously treated with first-line radiation or chemoradiotherapy and who are suspected of experiencing tumor progression. In patients with previously treated glioblastoma, is standard contrast-enhanced magnetic resonance imaging including diffusion weighted imaging useful for diagnosing tumor progression and differentiating progression from treatment-related changes? Magnetic resonance imaging with and without gadolinium enhancement including diffusion weighted imaging is recommended as the imaging surveillance method to detect the progression of previously diagnosed glioblastoma. In patients with previously treated glioblastoma, does magnetic resonance spectroscopy add useful information for diagnosing tumor progression and differentiating progression from treatment-related changes beyond that derived from standard magnetic resonance imaging with and without gadolinium enhancement? Magnetic resonance spectroscopy is recommended as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma. In patients with previously treated glioblastoma, does magnetic resonance perfusion add useful information for diagnosing tumor progression and differentiating progression from treatment-related changes beyond that derived from standard magnetic resonance imaging with and without gadolinium enhancement? Magnetic resonance perfusion is suggested as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma. In patients with previously treated glioblastoma, does the addition of single-photon emission computed tomography (SPECT) provide additional useful information for diagnosing tumor progression and differentiating progression from treatment-related changes beyond that derived from standard magnetic resonance imaging with and without gadolinium enhancement? Single-photon emission computed tomography imaging is suggested as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma. In patients with previously treated glioblastoma, does 18F-fluorodeoxyglucose positron emission tomography add useful information for diagnosing tumor progression and differentiating progression from treatment-related changes beyond that derived from standard magnetic resonance imaging with and without gadolinium enhancement? The routine use of 18F-fluorodeoxyglucose positron emission tomography to identify progression of glioblastoma is not recommended. In patients with previously treated glioblastoma, does positron emission tomography with amino acid agents add useful information for diagnosing tumor progression and differentiating progression from treatment-related changes beyond that derived from standard magnetic resonance imaging with and without gadolinium enhancement? It is suggested that amino acid positron emission tomography be considered to assist in the differentiation of progressive glioblastoma from treatment related changes.

Dynamic 18F-FDopa PET Imaging for Newly Diagnosed Gliomas: Is a Semiquantitative Model Sufficient?

PurposeDynamic amino acid positron emission tomography (PET) has become essential in neuro-oncology, most notably for its prognostic value in the noninvasive prediction of isocitrate dehydrogenase (IDH) mutations in newly diagnosed gliomas. The 6-[18F]fluoro-l-DOPA (18F-FDOPA) kinetic model has an underlying complexity, while previous studies have predominantly used a semiquantitative dynamic analysis. Our study addresses whether a semiquantitative analysis can capture all the relevant information contained in time–activity curves for predicting the presence of IDH mutations compared to the more sophisticated graphical and compartmental models.MethodsThirty-seven tumour time–activity curves from 18F-FDOPA PET dynamic acquisitions of newly diagnosed gliomas (median age = 58.3 years, range = 20.3–79.9 years, 16 women, 16 IDH-wild type) were analyzed with a semiquantitative model based on classical parameters, with (SQ) or without (Ref SQ) a reference region, or on parameters of a fit function (SQ Fit), a graphical Logan model with input function (Logan) or reference region (Ref Logan), and a two-tissue compartmental model previously reported for 18F-FDOPA PET imaging of gliomas (2TCM). The overall predictive performance of each model was assessed with an area under the curve (AUC) comparison using multivariate analysis of all the parameters included in the model. Moreover, each extracted parameter was assessed in a univariate analysis by a receiver operating characteristic curve analysis.ResultsThe SQ model with an AUC of 0.733 for predicting IDH mutations showed comparable performance to the other models with AUCs of 0.752, 0.814, 0.693, 0.786, and 0.863, respectively corresponding to SQ Fit, Ref SQ, Logan, Ref Logan, and 2TCM (p ≥ 0.10 for the pairwise comparisons with other models). In the univariate analysis, the SQ time-to-peak parameter had the best diagnostic performance (75.7% accuracy) compared to all other individual parameters considered.ConclusionsThe SQ model circumvents the complexities of the 18F-FDOPA kinetic model and yields similar performance in predicting IDH mutations when compared to the other models, most notably the compartmental model. Our study provides supportive evidence for the routine clinical application of the SQ model for the dynamic analysis of 18F-FDOPA PET images in newly diagnosed gliomas.

Voxelwise Principal Component Analysis of Dynamic [S-Methyl-11C]Methionine PET Data in Glioma Patients.

Simple SummaryRecent works on dynamic amino acid positron emission tomography (PET) imaging of gliomas have highlighted characteristic behaviors of time-activity curves (TACs) extracted from the whole tumor w.r.t. the grade, genotype, and outcome. However, gliomas are known to be highly heterogeneous tumors. Here, we aim at highlighting similar dynamic behaviors at the voxel level within the tumor volume in [S-methyl-11C]methionine PET data of 33 glioma patients using principal component analysis (PCA). The PCA model was derived from TACs of 20 patients and subsequently applied to 13 other patients in whom our approach was shown to outperform classical pharmacokinetic modeling to this end. Our parameter-free approach provides additional parametric maps from dynamic methionine PET scans with little modification of the routine protocol and no arterial sampling. This early methodological work paves the way for various clinical studies on glioma heterogeneity with applications for treatment planning and response evaluation.Recent works have demonstrated the added value of dynamic amino acid positron emission tomography (PET) for glioma grading and genotyping, biopsy targeting, and recurrence diagnosis. However, most of these studies are based on hand-crafted qualitative or semi-quantitative features extracted from the mean time activity curve within predefined volumes. Voxelwise dynamic PET data analysis could instead provide a better insight into intra-tumor heterogeneity of gliomas. In this work, we investigate the ability of principal component analysis (PCA) to extract relevant quantitative features from a large number of motion-corrected [S-methyl-11C]methionine ([11C]MET) PET frames. We first demonstrate the robustness of our methodology to noise by means of numerical simulations. We then build a PCA model from dynamic [11C]MET acquisitions of 20 glioma patients. In a distinct cohort of 13 glioma patients, we compare the parametric maps derived from our PCA model to these provided by the classical one-compartment pharmacokinetic model (1TCM). We show that our PCA model outperforms the 1TCM to distinguish characteristic dynamic uptake behaviors within the tumor while being less computationally expensive and not requiring arterial sampling. Such methodology could be valuable to assess the tumor aggressiveness locally with applications for treatment planning and response evaluation. This work further supports the added value of dynamic over static [11C]MET PET in gliomas.

Effects of 6 weeks of treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo-controlled, exploratory study.

To explore the early effects of dapagliflozin on myocardial function and metabolism in patients with type 2 diabetes without heart failure. Patients with type 2 diabetes on metformin treatment were randomized to double-blind, 6-week placebo or dapagliflozin 10 mg daily treatment. Investigations included cardiac function and structure with myocardial resonance imaging; cardiac oxygen consumption, perfusion and efficiency with [11 C]-acetate positron emission tomography (PET); and cardiac and hepatic fatty acid uptake with [18 F]-6-thia-heptadecanoic acid PET, analysed by ANCOVA as least square means with 95% confidence intervals. Evaluable patients (placebo: n = 24, dapagliflozin: n = 25; 53% males) had a mean age of 64.4 years, a body mass index of 30.2 kg/m2 and an HbA1c of 6.7%. Body weight and HbA1c were significantly decreased by dapagliflozin versus placebo. Dapagliflozin had no effect on myocardial efficiency, but external left ventricular (LV) work (-0.095 [-0.145, -0.043] J/g/min) and LV oxygen consumption were significantly reduced (-0.30 [-0.49, -0.12] J/g/min) by dapagliflozin, although the changes were not statistically significant versus changes in the placebo group. Change in left atrial maximal volume with dapagliflozin versus placebo was -3.19 (-6.32, -0.07) mL/m2 (p = .056). Peak global radial strain decreased with dapagliflozin versus placebo (-3.92% [-7.57%, -0.28%]; p = .035), while peak global longitudinal and circumferential strains were unchanged. Hepatic fatty acid uptake was increased by dapagliflozin versus placebo (0.024 [0.004, 0.044] μmol/g/min; p = .018), while cardiac uptake was unchanged. This exploratory study indicates reduced heart work but limited effects on myocardial function, efficiency and cardiac fatty acid uptake, while hepatic fatty acid uptake increased, after 6 weeks of treatment with dapagliflozin.

18F]FET PET Uptake Indicates High Tumor and Low Necrosis Content in Brain Metastasis.

Simple SummaryVarious types of cancers can lead to brain metastasis. Treatment strategies have improved substantially in the past decade, leading to longer survival in many cases, but also to new diagnostic challenges. Being able to locate those parts of a lesion suspicious for brain metastasis that contain the highest concentrations of viable tumor cells can be crucial, e.g., to obtain a precise diagnosis via targeted biopsies or to differentiate recurring tumor from dead tissue after treatment. Positron emission tomography (PET) imaging has the potential to provide this kind of information. However, studies relating PET findings to actual tissue properties are sparse. The aim of this study was to investigate the association of PET imaging with microscopic tissue properties in samples obtained neurosurgically from brain metastases. Our findings can improve the planning and yield of biopsies from brain metastases, and they may inform future studies aimed at improving the discrimination of recurring from dead tumor in treated brain metastases using PET.Amino acid positron emission tomography (PET) has been employed in the management of brain metastases. Yet, histopathological correlates of PET findings remain poorly understood. We investigated the relationship of O-(2-[18F]Fluoroethyl)-L-tyrosine ([18F]FET) PET, magnetic resonance imaging (MRI), and histology in brain metastases. Fifteen patients undergoing brain metastasis resection were included prospectively. Using intraoperative navigation, 39 targeted biopsies were obtained from parts of the metastases that were either PET-positive or negative and MRI-positive or negative. Tumor and necrosis content, proliferation index, lymphocyte infiltration, and vascularization were determined histopathologically. [18F]FET PET had higher specificity than MRI (66% vs. 56%) and increased sensitivity for tumor from 73% to 93% when combined with MRI. Tumor content per sample increased with PET uptake (rs = 0.3, p = 0.045), whereas necrosis content decreased (rs = −0.4, p = 0.014). PET-positive samples had more tumor (median: 75%; interquartile range: 10–97%; p = 0.016) than PET-negative samples. The other investigated histological properties were not correlated with [18F]FET PET intensity. Tumors were heterogeneous at the levels of imaging and histology. [18F]FET PET can be a valuable tool in the management of brain metastases. In biopsies, one should aim for PET hotspots to increase the chance for retrieval of samples with high tumor cell concentrations. Multiple biopsies should be performed to account for intra-tumor heterogeneity. PET could be useful for differentiating treatment-related changes (e.g., radiation necrosis) from tumor recurrence.

Contribution of perfusion to the 11 C-acetate signal in brown adipose tissue assessed by DCE-MRI and 68 Ga-DOTA PET in a rat model.

Determine if dynamic contrast enhanced (DCE) -MRI and/or 68 gallium 1,4,7,10-tetraazacyclododecane N, N', N″, N‴-tretraacetic acid (68 Ga-DOTA) positron emission tomography (PET) can assess perfusion in rat brown adipose tissue (BAT). Evaluate changes in perfusion between cold-stimulated and heat-inhibited BAT. Determine if the 11 C-acetate pharmacokinetic model can be constrained with perfusion information to improve assessment of BAT oxidative metabolism. Rats were split into three groups. In group 1 (N=6), DCE-MRI with gadobutrol was compared directly to 68 Ga-DOTA PET following exposure to 10°C for 48h. 11 C-Acetate PET was also performed to assess oxidation. In group 2 (N=4), only 68 Ga-DOTA PET was acquired following exposure to 10°C for 48h. Finally, in group 3 (N=10), perfusion was assessed with DCE-MRI in rats exposed to 10°C or 30°C for 48h, and oxidation was measured with 11 C-acetate. Perfusion was quantified with a two-compartment pharmacokinetic model, while oxidation was assessed by a four-compartment model. DCE-MRI and 68 Ga-DOTA PET provided similar perfusion measures, but a decrease in the perfusion signal was noted with longer imaging sessions. Exposure to 10°C or 30°C did not affect the perfusion measures, but the 11 C-acetate signal increased in BAT at 10°C. Without prior information about blood volume, the 11 C-acetate compartment model overestimated blood volume and underestimated oxidation in 10°C BAT. Precise assessment of oxidation via 11 C-acetate PET requires prior information about blood volume which can be obtained by DCE-MRI or 68 Ga-DOTA PET. Since perfusion can change rapidly, simultaneous PET-MRI would be preferred.

The Impact of 18F-DCFPyL PET-CT Imaging on Initial Staging, Radiation, and Systemic Therapy Treatment Recommendations for Veterans With Aggressive Prostate Cancer

PurposeOur purpose was to study the effect of 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) positron emission tomography (PET)-computed tomography (CT) on staging/treatment recommendations of previously untreated prostate cancer. We report here results of a prospective single center single arm imaging trial within Veterans Affairs (Greater Los Angeles): the frequency of patients upstaged to M1 disease (primary endpoint) and the frequency of patients with change in treatment recommendations (secondary endpoint). This is the first report of prostate-specific membrane antigen PET-CT exclusive to U.S. veterans. Methods and MaterialsVeterans with Gleason ≥4 + 3, clinical stage ≥T2c, or prostate-specific antigen >10 ng/mL were eligible. Patients underwent conventional imaging (99mTc-methyl diphosphonate bone scan or 18F-NaF PET-CT; and pelvic CT or pelvic magnetic resonance imaging) in addition to 18F-DCFPyL PET-CT. The effect of 18F-DCFPyL PET-CT on treatment change was determined by applying prespecified treatment recommendations based on National Comprehensive Cancer Network guidelines and modern clinical practice. ResultsOne hundred patients underwent 18F-DCFPyL PET-CT. Nineteen out of 84 (23%) patients initially thought to be nonmetastatic were upstaged to M1; 8/16 (50%) patients initially thought to have M1 disease were downstaged to M0. In total, 39/100 (39%) had a change in prespecified treatment recommendations, including change of radiation therapy volume/dose in 39/100 (39%) and starting abiraterone in 22/100 (22%). ConclusionsIncorporation of 18F-DCFPyL PET-CT into the initial conventional imaging workup for prostate cancer can substantially affect staging/treatment recommendations.

Relationship Between Tumor Immune Markers and Fluorine-18-α-Methyltyrosine ([18F]FAMT) Uptake in Patients with Lung Cancer.

3-[18F]Fluoro-α-methyl-L-tyrosine ([18F]FAMT) is an amino acid positron emission tomography (PET) tracer specific for cancer detection by assessment of tumor amino acid metabolism. Little is known on whether or not the uptake of [18F]FAMT within cancer cells is associated with the expression of programmed death ligand-1 (PD-L1), a predictor of anti-PD-1 antibody efficacy. We conducted a clinicopathological study to assess the expression of PD-L1 and the presence of tumor-infiltrating lymphocytes (TILs) in patients with non-small cell lung cancer (NSCLC) diagnosed by PET. A total of 75 patients with NSCLC who underwent [18F]FAMT and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET were enrolled in the study. Tumor specimens were stained by immunohistochemistry for glucose transporter 1 (Glut1), PD-L1 (using different antibody clones including E1L3N and 28-8), CD3, CD4, and CD8. The uptake of [18F]FAMT was correlated with clinicopathological variables. High uptake of [18F]FAMT was significantly associated with disease staging, initial treatment (surgical resection or chemotherapy), and the expression of PD-L1 (E1L3N). The value of the maximum standardized uptake value (SUVmax) for [18F]FAMT was significantly correlated with PD-L1 (E1L3N) expression, Glut1, and the SUVmax for [18F]FDG in patients with histological results of adenocarcinoma (AC) and advanced disease. A validation cohort for anti-PD-L1 using clone 28-8 showed a statistically significant correlation between SUVmax for [18F]FAMT and the expression of PD-L1 (28-8) and between the expression of PD-L1 (E1L3N) and PD-L1 (28-8). The uptake of [18F]FAMT on PET imaging was significantly correlated with PD-L1 expression in NSCLC, especially in patients with AC and advanced disease.

Amino Acid PET Imaging of Glioma

Gliomas are among the most lethal malignancies in the world with dismal outcomes for high-grade tumors. These lesions are difficult to completely characterize with conventional magnetic resonance imaging and amino acid positron emission tomography is a rapidly progressing area of research with widespread clinical use. Amino acid positron emission tomography allows for more accurate glioma characterization compared to traditional imaging techniques including grading of disease, delineation of tumor spread, identification of recurrent disease, and prognosis. While the summarized radiotracers share some diagnostic properties, each also has its own weaknesses and strengths. This article summarizes recent developments and clinical applications of the most widely used amino acid radiotracers. While none of these agents are FDA approved in the United States, they are considered standard of care in Europe and other parts of the world with > 10,000 studies being performed in some centers (Langen et al. in J Neurooncol 120(3):665–666, 2014).

Validation of R-2-[18F]Fluoropropionic Acid as a Potential Tracer for PET Imaging of Liver Cancer.

2-[18F]Fluoropropionic acid (RS-[18F]FPA) has shown potential value as a short-chain fatty acid positron emission tomography (PET) tracer for the detection of liver cancer. However, RS-[18F]FPA is a mixture of 2-R-[18F]fluoropropionic acid (R-[18F]FPA) and 2-S-[18F]fluoropropionic acid (S-[18F]FPA). The aim of this study is to validate the feasibility of R-[18F]FPA in preclinical PET imaging of liver cancer and to compare the use of R-[18F]FPA with that of RS-[18F]FPA and S-[18F]FPA. A comparative study of R-[18F]FPA, RS-[18F]FPA, S-[18F]FPA, and [18F]FDG micro-PET imaging was performed in HepG2 and SK-Hep-1 tumor-bearing mice. A comparison of R-[18F]FPA uptake with that of S-[18F]FPA by HepG2 and SK-Hep-1 cells was made at different time points. Additionally, in vivo blocking experiments in HepG2 and SK-Hep-1 tumor models were conducted with orlistat and 3-nitropropionic acid (3-NP). In vitro blocking experiments with orlistat or 3-NP were performed with HepG2 and SK-Hep-1 cells. The radioactivity uptake values of R-[18F]FPA were comparable to those of RS-[18F]FPA but were higher than those of S-[18F]FPA and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in HepG2 tumors. The radioactivity uptake values of R-[18F]FPA in large HepG2 tumors were lower than those of [18F]FDG (P < 0.05), while R-[18F]FPA PET was significantly superior to [18F]FDG PET in detecting small tumors (both SK-Hep-1 and HepG2 tumors). The in vivo PET imaging experiments showed that R-[18F]FPA uptake in HepG2 tumor-bearing mice was blocked by 19.3% and 31.8% after treatment with orlistat and 3-NP, respectively. The radioactivity uptake values of R-[18F]FPA in SK-Hep-1 tumor-bearing mice was blocked by 39.5% with orlistat. R-[18F]FPA seems to be more potential than S-[18F]FPA as an optically pure PET probe, with effective compensation for the deficiencies of [18F]FDG, particularly in PET imaging of small liver cancer. The uptake mechanism of [18F]FPA in liver cancer may be related to fatty acid synthesis and the tricarboxylic acid cycle. However, compared with the racemic RS-[18F]FPA, the possible advantages of R-enantiomer R-[18F]FPA still needs further research.