Amino Acid Positron Emission Tomography Research Articles

Phantom test procedures for a new neuro-oncological amino acid PET tracer: [18F]fluciclovine.

Amino acid positron emission tomography (PET) examinations using anti-1-amino-3-[18F]-fluorocyclobutane-1-carboxylic acid ([18F]FACBC) were allowed for routine clinical use in July 2024. However, phantom test procedures for [18F]FACBC reconstruction parameters have not yet been established. The present study aimed to establish new phantom test procedures for [18F]FACBC brain PET imaging to determine optimal reconstruction parameters. Background (BG) activity as well as hot sphere and target-to-background ratios (TBRs) of [18F]FACBC were estimated based on brain activity and tumor-to-normal tissue ratios (TNR) in a Japanese clinical trial of [18F]FACBC. Phantom experiments proceeded under [18F]FACBC or L-[methyl-11C]-methionine ([11C]MET) conditions. The number of iterations and the Gaussian filter parameters were determined from the reconstruction parameters %contrastmean and coefficients of variation (CVs) in ordered subset expectation maximization (OSEM) and time-of-flight (TOF) with or without point-spread-function (PSF) correction. The amounts of activity in the hot spheres and BG were 1.1 and 5.5kBq/mL, respectively, and the TBR was 5.0 at the start of acquisition. The %contrastmean of all hot spheres was higher with [18F]FACBC than [11C]MET, and %contrastmean converged between 4 and 6 iterations in hot spheres with diameters < 10mm. We used four iterations for OSEM + TOF and five for OSEM + TOF + PSF correction for [18F]FACBC and [11C]MET images. The CV was higher for [18F]FACBC than [11C]MET. The optimal sizes of Gaussian filters for OSEM + TOF and OSEM + TOF + PSF correction of image reconstruction were 5mm for [18F]FACBC, and 4 and 3mm, respectively, for [11C]MET images. We estimated phantom activity and TBR based on brain activity in a Japanese clinical trial and established new phantom test procedures for [18F]FACBC. We recommend that the optimal reconstruction parameters for [18F]FACBC should be set to the same number of iterations as [11C]MET and that the FWHM of Gaussian filter should have a few mm higher than [11C]MET to reduce image noise from brain normal tissue.

Implementation of PET/CT in radiation oncology—a patterns-of-care analysis of the German Society of Nuclear Medicine and the German Society of Radiation Oncology

BackgroundThe use of positron-emission tomography (PET)/computed tomography (CT) in radiation therapy (RT) has increased. Radiation oncologists (RadOncs) have access to PET/CT with a variety of tracers for different tumor entities and use it for target volume definition. The German Society of Nuclear Medicine (DGN) and the German Society of Radiation Oncology (DEGRO) aimed to identify current patterns of care in order to improve interdisciplinary collaboration.MethodsWe created an online survey on participating RadOncs’ use of PET tracers for different tumor entities and how they affect RT indication, dose prescription, and target volume definition. Further topics were reimbursement of PET/CT and organizational information (fixed timeslots and use of PET with an immobilization device [planning/RT-PET]). The survey contained 31 questions in German language (yes/no questions, multiple choice [MC] questions, multiple select [MS] questions, and free-text entry options). The survey was distributed twice via the DEGRO member mailing list.ResultsDuring the survey period (May 22–August 7, 2023) a total of 156 RadOncs (13% of respondents) answered the survey. Among these, 59% reported access to diagnostic PET/CT within their organization/clinic and 24% have fixed timeslots for their patients. 37% of survey participants can perform RT-PET and 29% have the option of providing a dedicated RT technician for planning PET. Besides [18F]-fluorodeoxyglucose (FDG; mainly used in lung cancer: 95%), diagnostic prostate-specific membrane antigen (PSMA)-PET/CT for RT of prostate cancer is routinely used by 44% of participants (by 64% in salvage RT). Use of amino acid PET in brain tumors and somatostatin receptor PET in meningioma is low (19 and 25%, respectively). Scans are reimbursed through private (75%) or compulsory (55%) health insurance or as part of indications approved by the German Joint Federal Committee (Gemeinsamer Bundesausschuss; 59%). 98% of RadOncs agree that PET impacts target volume definition and 62% think that it impacts RT dose prescription.DiscussionThis is the first nationwide survey on the role of PET/CT for RT planning among RadOncs in Germany. We find high acceptance of PET results for treatment decisions and target volume definition. Planning PET comes with logistic challenges for different healthcare settings (e.g., private practices vs. university hospitals). The decision to request PET/CT is often based on the possibility of reimbursement.ConclusionPET/CT has become an important tool for RadOncs, with several indications. However, access is still limited at several sites, especially for dedicated RT-PET. This study aims to improve interdisciplinary cooperation and adequate implementation of current guidelines for the treatment of various tumor entities.

Challenges, limitations, and pitfalls of PET and advanced MRI in patients with brain tumors: A report of the PET/RANO group.

Brain tumor diagnostics have significantly evolved with the use of positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques. In addition to anatomical MRI, these modalities may provide valuable information for several clinical applications such as differential diagnosis, delineation of tumor extent, prognostication, differentiation between tumor relapse and treatment-related changes, and the evaluation of response to anticancer therapy. In particular, joint recommendations of the Response Assessment in Neuro-Oncology (RANO) Group, the European Association of Neuro-oncology, and major European and American Nuclear Medicine societies highlighted that the additional clinical value of radiolabeled amino acids compared to anatomical MRI alone is outstanding and that its widespread clinical use should be supported. For advanced MRI and its steadily increasing use in clinical practice, the Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition provided more recently an updated acquisition protocol for the widely used dynamic susceptibility contrast perfusion MRI. Besides amino acid PET and perfusion MRI, other PET tracers and advanced MRI techniques (e.g. MR spectroscopy) are of considerable clinical interest and are increasingly integrated into everyday clinical practice. Nevertheless, these modalities have shortcomings which should be considered in clinical routine. This comprehensive review provides an overview of potential challenges, limitations, and pitfalls associated with PET imaging and advanced MRI techniques in patients with gliomas or brain metastases. Despite these issues, PET imaging and advanced MRI techniques continue to play an indispensable role in brain tumor management. Acknowledging and mitigating these challenges through interdisciplinary collaboration, standardized protocols, and continuous innovation will further enhance the utility of these modalities in guiding optimal patient care.

Enhancing predictability of IDH mutation status in glioma patients at initial diagnosis: a comparative analysis of radiomics from MRI, [18F]FET PET, and TSPO PET

PurposeAccording to the World Health Organization classification for tumors of the central nervous system, mutation status of the isocitrate dehydrogenase (IDH) genes has become a major diagnostic discriminator for gliomas. Therefore, imaging-based prediction of IDH mutation status is of high interest for individual patient management. We compared and evaluated the diagnostic value of radiomics derived from dual positron emission tomography (PET) and magnetic resonance imaging (MRI) data to predict the IDH mutation status non-invasively.MethodsEighty-seven glioma patients at initial diagnosis who underwent PET targeting the translocator protein (TSPO) using [18F]GE-180, dynamic amino acid PET using [18F]FET, and T1-/T2-weighted MRI scans were examined. In addition to calculating tumor-to-background ratio (TBR) images for all modalities, parametric images quantifying dynamic [18F]FET PET information were generated. Radiomic features were extracted from TBR and parametric images. The area under the receiver operating characteristic curve (AUC) was employed to assess the performance of logistic regression (LR) classifiers. To report robust estimates, nested cross-validation with five folds and 50 repeats was applied.ResultsTBRGE-180 features extracted from TSPO-positive volumes had the highest predictive power among TBR images (AUC 0.88, with age as co-factor 0.94). Dynamic [18F]FET PET reached a similarly high performance (0.94, with age 0.96). The highest LR coefficients in multimodal analyses included TBRGE-180 features, parameters from kinetic and early static [18F]FET PET images, age, and the features from TBRT2 images such as the kurtosis (0.97).ConclusionThe findings suggest that incorporating TBRGE-180 features along with kinetic information from dynamic [18F]FET PET, kurtosis from TBRT2, and age can yield very high predictability of IDH mutation status, thus potentially improving early patient management.

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.

Exploring the mechanism of 18F-fluorodopa uptake in recurrent high-grade gliomas: A comprehensive histomolecular-positron emission tomography analysis.

Dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-FDOPA) positron emission tomography (PET) is a valuable tool for managing high-grade gliomas (HGGs), but there is a lack of literature on its relationship with glioma subtypes since the 2021 reclassification of brain tumors. There is also debate surrounding the mechanism of 18F-FDOPA uptake, particularly after chemoradiation therapy. This study aimed to investigate the correlation between 18F-FDOPA uptake and histomolecular characteristics, particularly L-amino acid transporter 1 (LAT1) expression, in recurrent gliomas, and examine their impact on survival in HGGs. Thirty-nine patients with recurrent HGGs (14 isocitrate dehydrogenase [IDH]-mutant, 25 IDH-wildtype) who underwent a brain 18F-FDOPA PET/computed tomography (CT) or PET/magnetic resonance imaging (MRI) followed by surgical resection of the 18F-FDOPA-avid lesion within 6 months, were retrospectively reviewed. PET results were compared with histological examination and for SCL7A5/LAT1 immunostaining. The study also examined the relationship between PET parameters, LAT1 expression, and survival outcomes. Astrocytoma IDH-mutant G4 had higher 18F-FDOPA uptake than glioblastoma IDH-wildtype G4 (maximum tumor-to-normal brain ratio [TBRmax] 5 [3.4-9] vs. 3.8 [2.8-5.9], p = 0.02). IDH-mutant gliomas had higher LAT1 expression than IDH-wildtype gliomas (100 [14-273] vs. 15.5 [0-137], p < 0.05) as well as higher TBRmax (5 [2.4-9] vs. 3.8 [2.8-6], p < 0.05). In survival analysis, LAT1 score >100 was a predictor for longer progression-free survival in IDH-mutant HGGs. To our knowledge, our study is the first to suggest a link between LAT1 expression and IDH mutation status. We showed that higher TBRmax was associated with higher LAT1 expression and IDH mutation status. Further studies are needed to better understand the mechanisms underlying amino acid PET tracers uptake, especially in the post-radiation and chemotherapy settings.

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.

Imaging-Based Patterns of Failure following Re-Irradiation for Recurrent/Progressive High-Grade Glioma.

Re-irradiation (ReRT) is an effective treatment modality in appropriately selected patients with recurrent/progressive high-grade glioma (HGG). The literature is limited regarding recurrence patterns following ReRT, which was investigated in the current study. Patients with available radiation (RT) contours, dosimetry, and imaging-based evidence of recurrence were included in the retrospective study. All patients were treated with fractionated focal conformal RT. Recurrence was detected on imaging with magnetic resonance imaging (MRI) and/ or amino-acid positron emission tomography (PET), which was co-registered with the RT planning dataset. Failure patterns were classified as central, marginal, and distant if >80%, 20-80%, or <20% of the recurrence volumes were within 95% isodose lines, respectively. Thirty-seven patients were included in the current analysis. A total of 92% of patients had undergone surgery before ReRT, and 84% received chemotherapy. The median time to recurrence was 9 months. Central, marginal, and distant failures were seen in 27 (73%), 4 (11%), and 6 (16%) patients, respectively. None of the patient-, disease-, or treatment-related factors were significantly different across different recurrence patterns. Failures are seen predominantly within the high-dose region following ReRT in recurrent/ progressive HGG.

The Role of Molecular Imaging in Patients with Brain Metastases: A Literature Review.

Over the last several years, molecular imaging has gained a primary role in the evaluation of patients with brain metastases (BM). Therefore, the "Response Assessment in Neuro-Oncology" (RANO) group recommends amino acid radiotracers for the assessment of BM. Our review summarizes the current use of positron emission tomography (PET) radiotracers in patients with BM, ranging from present to future perspectives with new PET radiotracers, including the role of radiomics and potential theranostics approaches. A comprehensive search of PubMed results was conducted. All studies published in English up to and including December 2022 were reviewed. Current evidence confirms the important role of amino acid PET radiotracers for the delineation of BM extension, for the assessment of response to therapy, and particularly for the differentiation between tumor progression and radionecrosis. The newer radiotracers explore non-invasively different biological tumor processes, although more consistent findings in larger clinical trials are necessary to confirm preliminary results. Our review illustrates the role of molecular imaging in patients with BM. Along with magnetic resonance imaging (MRI), the gold standard for diagnosis of BM, PET is a useful complementary technique for processes that otherwise cannot be obtained from anatomical MRI alone.

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.

The impact of tumor metabolic activity assessed by 18F-FET amino acid PET imaging in particle radiotherapy of high-grade glioma patients.

BackgroundSelective uptake of (18)F-fluoro-ethyl-tyrosine (18F-FET) is used in high-grade glioma (HGG) to assess tumor metabolic activity via positron emission tomography (PET). We aim to investigate its value for target volume definition, as a prognosticator, and associations with whole-blood transcriptome liquid biopsy (WBT lbx) for which we recently reported feasibility to mirror tumor characteristics and response to particle irradiation in recurrent HGG (rHGG).Methods 18F-FET-PET data from n = 43 patients with primary glioblastoma (pGBM) and n = 33 patients with rHGG were assessed. pGBM patients were irradiated with photons and sequential proton/carbon boost, and rHGG patients were treated with carbon re-irradiation (CIR). WBT (Illumina HumanHT-12 Expression BeadChips) lbx was available for n = 9 patients from the rHGG cohort. PET isocontours (40%–70% SUVmax, 10% steps) and MRI-based treatment volumes (MRIvol) were compared using the conformity index (CI) (pGBM, n = 16; rHGG, n = 27). Associations with WBT lbx data were tested on gene expression level and inferred pathways activity scores (PROGENy) and from transcriptome estimated cell fractions (CIBERSORT, xCell).ResultsIn pGBM, median SUVmax was higher in PET acquired pre-radiotherapy (4.1, range (R) 1.5–7.8; n = 20) vs. during radiotherapy (3.3, R 1.5–5.7, n = 23; p = 0.03) and in non-resected (4.7, R 2.9–7.9; n = 11) vs. resected tumors (3.3, R 1.5–7.8, n = 32; p = 0.01). In rHGG, a trend toward higher SUVmax values in grade IV tumors was observed (p = 0.13). Median MRIvol was 32.34 (R 8.75–108.77) cm3 in pGBM (n = 16) and 20.77 (R 0.63–128.44) cm3 in rHGG patients (n = 27). The highest median CI was observed for 40% (pGBM, 0.31) and 50% (rHGG, 0.43, all tumors) isodose, with 70% (40%) isodose in grade III (IV) rHGG tumors (median CI, 0.38 and 0.49). High SUVmax was linked to shorter survival in pGBM (>3.3, p = 0.001, OR 6.0 [2.1–17.4]) and rHGG (>2.8, p = 0.02, OR 4.1 [1.2–13.9]). SUVmax showed associations with inferred monocyte fractions, hypoxia, and TGFbeta pathway activity and links to immune checkpoint gene expression from WBT lbx.ConclusionThe benefits of 18F-FET-PET imaging on gross tumor volume (GTV) definition for particle radiotherapy warrant further evaluation. SUVmax might assist in prognostic stratification of HGG patients for particle radiotherapy, highlights heterogeneity in rHGG, and is positively associated with unfavorable signatures in peripheral whole-blood transcriptomes.

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.

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.

Joint EANM/SIOPE/RAPNO practice guidelines/SNMMI procedure standards for imaging of paediatric gliomas using PET with radiolabelled amino acids and [18F]FDG: version 1.0

Positron emission tomography (PET) has been widely used in paediatric oncology. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is the most commonly used radiopharmaceutical for PET imaging. For oncological brain imaging, different amino acid PET radiopharmaceuticals have been introduced in the last years. The purpose of this document is to provide imaging specialists and clinicians guidelines for indication, acquisition, and interpretation of [18F]FDG and radiolabelled amino acid PET in paediatric patients affected by brain gliomas. There is no high level of evidence for all recommendations suggested in this paper. These recommendations represent instead the consensus opinion of experienced leaders in the field. Further studies are needed to reach evidence-based recommendations for the applications of [18F]FDG and radiolabelled amino acid PET in paediatric neuro-oncology. These recommendations are not intended to be a substitute for national and international legal or regulatory provisions and should be considered in the context of good practice in nuclear medicine. The present guidelines/standards were developed collaboratively by the EANM and SNMMI with the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group and the Response Assessment in Paediatric Neuro-Oncology (RAPNO) working group. They summarize also the views of the Neuroimaging and Oncology and Theranostics Committees of the EANM and reflect recommendations for which the EANM and other societies cannot be held responsible.

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.