L-2-hydroxyglutarate remodeling of the epigenome and epitranscriptome creates a metabolic vulnerability in kidney cancer models.

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule L-2-hdroxyglutarate (L-2HG) is elevated in the most common histology of renal cancer. Similar to other oncometabolites, L-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that L-2HG remodels amino acid metabolism in renal cancer cells through the combined effects on histone methylation and RNA N6-methyladenosine (m6A). The combined effects of L-2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high L-2HG kidney cancers demonstrates reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high L-2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors.

Evidence of neuroinflammation in fibromyalgia syndrome: a [ 18 F]DPA-714 positron emission tomography study.

ABSTRACT: This observational study aimed to determine whether individuals with fibromyalgia (FM) exhibit higher levels of neuroinflammation than healthy controls (HCs), as measured with positron emission tomography using [ 18 F]DPA-714, a second-generation radioligand for the translocator protein (TSPO). Fifteen women with FM and 10 HCs underwent neuroimaging. Distribution volume (V T ) was calculated for in 28 regions of interest (ROIs) using Logan graphical analysis and compared between groups using multiple linear regressions. Group (FM vs HC) was the main predictor of interest and TSPO binding status (high- vs mixed-affinity) was added as a covariate. The FM group had higher V T in the right postcentral gyrus ( b = 0.477, P = 0.033), right occipital gray matter (GM; b = 0.438, P = 0.039), and the right temporal GM ( b = 0.466, P = 0.042). The FM group also had lower V T than HCs in the left isthmus of the cingulate gyrus ( b = -0.553, P = 0.014). In the subgroup of high-affinity binders, the FM group had higher V T in the bilateral precuneus, postcentral gyrus, parietal GM, occipital GM, and supramarginal gyrus. Group differences in the right parietal GM were associated with decreased quality of life, higher pain severity and interference, and cognitive problems. In support of our hypothesis, we found increased radioligand binding (V T ) in the FM group compared with HCs in several brain regions regardless of participants' TSPO binding status. The ROIs overlapped with prior reports of increased TSPO binding in FM. Overall, increasing evidence supports the hypothesis that FM involves microglia-mediated neuroinflammation in the brain.

Prediction of MCI-to-AD progression with atrophy-weighted standard uptake value ratios of 18 F-Florbetapir PET.

Accurate prediction of MCI-to-AD progression is an important yet challenging task. We introduce a new quantitative parameter: the atrophy-weighted standard uptake value ratio (awSUVR), defined as the PET SUVR divided by the hippocampal volume measured with MR, and evaluate whether it may provide better prediction of the MCI-to-AD progression. MATERIALS AND METHODS: We used ADNI data to evaluate the prediction performances of the awSUVR against SUVR. 571, 363 and 252 18-F-Florbetaipir scans were selected based on criteria of conversion at the third, fifth and seventh year after the PET scans, respectively. Corresponding MR scans were segmented with Freesurfer and applied on PET for SUVR and awSUVR computation. We also searched for the optimal combination of target and reference regions. In addition to evaluating the overall prediction performances, we also evaluated the prediction for APOE4 carriers and non-carriers. For the scans with false predictions, we used 18-F-Flortaucipir scans to investigate the potential source of error. RESULTS: awSUVR provides more accurate prediction than the SUVR in all three progression criteria. The 5-year prediction accuracy/sensitivity/specificity is 90/81/93% for awSUVR and 86/81/88% for SUV. awSUVR also yields good 3- and 7-year prediction accuracy/sensitivity/specificity of 91/57/96 and 92/89/93, respectively. APOE4 carriers generally are slightly more difficult to predict for the progression. False negative prediction is found to either due to a near-cutoff mis-classification or potentially non-AD dementia pathology. False positive prediction is mainly due to the slightly delayed progression than the expected progression time. CONCLUSION: We demonstrated with ADNI data that 18-F-Florbetapir SUVR weighted with hippocampus volume may provide good prediction power with over 90% accuracy in MCI-to-AD progression.

Investigating Tau and Amyloid Tracer Skull Binding in Studies of Alzheimer Disease.

Off-target binding of [18F]flortaucipir (FTP) can complicate quantitative PET analyses. An underdiscussed off-target region is the skull. Here, we characterize how often FTP skull binding occurs, its influence on estimates of Alzheimer disease pathology, its potential drivers, and whether skull uptake is a stable feature across time and tracers. Methods: In 313 cognitively normal and mildly impaired participants, CT scans were used to define a skull mask. This mask was used to quantify FTP skull uptake. Skull uptake of the amyloid-ß PET tracers [18F]florbetapir and [11C]Pittsburgh compound B (n = 152) was also assessed. Gaussian mixture modeling defined abnormal levels of skull binding for each tracer. We examined the relationship of continuous bone uptake to known off-target binding in the basal ganglia and choroid plexus as well as skull density measured from the CT. Finally, we examined the confounding effect of skull binding on pathologic quantification. Results: We found that 50 of 313 (∼16%) FTP scans had high levels of skull signal. Most were female (n = 41, 82%), and in women, lower skull density was related to higher FTP skull signal. Visual reads by a neuroradiologist revealed a significant relationship with hyperostosis; however, only 21% of women with high skull binding were diagnosed with hyperostosis. FTP skull signal did not substantially correlate with other known off-target regions. Skull uptake was consistent over longitudinal FTP scans and across tracers. In amyloid-ß-negative, but not -positive, individuals, FTP skull binding impacted quantitative estimates in temporal regions. Conclusion: FTP skull binding is a stable, participant-specific phenomenon and is unrelated to known off-target regions. Effects were found primarily in women and were partially related to lower bone density. The presence of [11C]Pittsburgh compound B skull binding suggests that defluorination does not fully explain FTP skull signal. As signal in skull bone can impact quantitative analyses and differs across sex, it should be explicitly addressed in studies of aging and Alzheimer disease.

Image Quantification for TSPO PET with a Novel Image-Derived Input Function Method.

There is a growing interest in using 18F-DPA-714 PET to study neuroinflammation and microglial activation through imaging the 18-kDa translocator protein (TSPO). Although quantification of 18F-DPA-714 binding can be achieved through kinetic modeling analysis with an arterial input function (AIF) measured with blood sampling procedures, the invasiveness of such procedures has been an obstacle for wide application. To address these challenges, we developed an image-derived input function (IDIF) that noninvasively estimates the arterial input function from the images acquired for 18F-DPA-714 quantification. Methods: The method entails three fully automatic steps to extract the IDIF, including a segmentation of voxels with highest likelihood of being the arterial blood over the carotid artery, a model-based matrix factorization to extract the arterial blood signal, and a scaling optimization procedure to scale the extracted arterial blood signal into the activity concentration unit. Two cohorts of human subjects were used to evaluate the extracted IDIF. In the first cohort of five subjects, arterial blood sampling was performed, and the calculated IDIF was validated against the measured AIF through the comparison of distribution volumes from AIF (VT,AIF) and IDIF (VT,IDIF). In the second cohort, PET studies from twenty-eight healthy controls without arterial blood sampling were used to compare VT,IDIF with VT,REF measured using a reference region-based analysis to evaluate whether it can distinguish high-affinity (HAB) and mixed-affinity (MAB) binders. Results: In the arterial blood-sampling cohort, VT derived from IDIF was found to be an accurate surrogate of the VT from AIF. The bias of VT, IDIF was −5.8 ± 7.8% when compared to VT,AIF, and the linear mixed effect model showed a high correlation between VT,AIF and VT, IDIF (p < 0.001). In the nonblood-sampling cohort, VT, IDIF showed a significance difference between the HAB and MAB healthy controls. VT, IDIF and standard uptake values (SUV) showed superior results in distinguishing HAB from MAB subjects than VT,REF. Conclusions: A novel IDIF method for 18F-DPA-714 PET quantification was developed and evaluated in this study. This IDIF provides a noninvasive alternative measurement of VT to quantify the TSPO binding of 18F-DPA-714 in the human brain through dynamic PET scans.

A Path to Qualification of PET/MRI Scanners for Multicenter Brain Imaging Studies: Evaluation of MRI-Based Attenuation Correction Methods Using a Patient Phantom.

PET/MRI scanners cannot be qualified in the manner adopted for hybrid PET/CT devices. The main hurdle with qualification in PET/MRI is that attenuation correction (AC) cannot be adequately measured in conventional PET phantoms because of the difficulty in converting the MR images of the physical structures (e.g., plastic) into electron density maps. Over the last decade, a plethora of novel MRI-based algorithms has been developed to more accurately derive the attenuation properties of the human head, including the skull. Although promising, none of these techniques has yet emerged as an optimal and universally adopted strategy for AC in PET/MRI. In this work, we propose a path for PET/MRI qualification for multicenter brain imaging studies. Specifically, our solution is to separate the head AC from the other factors that affect PET data quantification and use a patient as a phantom to assess the former. The emission data collected on the integrated PET/MRI scanner to be qualified should be reconstructed using both MRI- and CT-based AC methods, and whole-brain qualitative and quantitative (both voxelwise and regional) analyses should be performed. The MRI-based approach will be considered satisfactory if the PET quantification bias is within the acceptance criteria specified here. We have implemented this approach successfully across 2 PET/MRI scanner manufacturers at 2 sites.

Applications of PET/MRI in Abdominopelvic Oncology.

With PET/MRI, the strengths of PET and MRI are combined to allow simultaneous image acquisition and near-perfect image coregistration. MRI is increasingly being used for staging and restaging of abdominopelvic oncologic lesions, including prostate, hepatobiliary, pancreatic, neuroendocrine, cervical, and rectal cancers. Fluorine 18-fluorodeoxyglucose PET/CT has long been considered a cornerstone of oncologic imaging, and the development of multiple targeted radiotracers has led to increased research on and use of these agents in clinical practice. Thus, simultaneously performed PET/MRI enables the acquisition of complementary imaging information, with distinct advantages over PET/CT and MR image acquisitions. The authors provide an overview of PET/MRI, including descriptions of the major differences between PET/MRI and PET/CT, as well as case examples and treatment protocols for patients with commonly encountered malignancies in the abdomen and pelvis. Online supplemental material is available for this article. ©RSNA, 2021.

Racial Differences in Alzheimer's Disease Specialist Encounters Are Associated with Usage of Molecular Imaging and Dementia Medications: An Enterprise-Wide Analysis Using i2b2.

BACKGROUND: African Americans are at increased risk for Alzheimer's disease (AD) but barriers to optimal clinical care are unclear. OBJECTIVE: To comprehensively evaluate potential racial differences in the diagnosis and treatment of AD in an academic medical center. METHODS: We used the clinical informatics tool, i2b2, to analyze all patient encounters for AD or mild cognitive impairment (MCI) in the University of Alabama at Birmingham Health System over a three-year period, examining neuroimaging rates and dementia-related medication use by race and clinic site using ratio tests on contingency tables of stratified patient counts. RESULTS: Enterprise-wide, African Americans were not underrepresented among outpatients seen for AD/MCI. However, there were differences in the clinic setting where visits occurred, with African Americans overrepresented in Geriatrics and primary care clinics and underrepresented in Memory Disorders specialty clinics. There were no racial differences in the rates at which any clinic ordered PET neuroimaging tests or dementia-related medications. However, unsurprisingly, specialty clinics ordered both PET neuroimaging and dementia-related medications at a higher rate than primary care clinics, and overall across the medical enterprise, African Americans were statistically less likely to have PET neuroimaging or dementia-related medications ordered. CONCLUSION: African Americans with AD/MCI were not underrepresented at this academic medical center but were somewhat less likely to have PET neuroimaging or to be on dementia-related medications, potentially in part from underrepresentation in the specialty clinics where these orders are more likely. The reasons for this underrepresentation in specialty clinics are likely multifactorial and important to better understand.

Production of [89 Zr]Oxinate4 and cell radiolabeling for human use.

[89 Zr]Oxinate4 is a Positron Emission Tomography (PET) tracer for cell radiolabeling that can enable imaging techniques to help better understand cell trafficking in various diseases. Although several groups have synthetized this compound for use in preclinical studies, there is no available data regarding the production of [89 Zr]Oxinate4 for human use. In this report, we describe the detailed production of [89 Zr]Oxinate4 under USP <823> and autologous leukocyte radiolabeling under USP <797>. The final product presented high radiochemical purity and stability at 24 h post synthesis (>99%) and passed in all quality control assays required for clinical use. [89 Zr]Oxinate4 did not compromise the white blood cells viability and did not show considerable cellular efflux up to 3 h post labeling. The translation of this technique into human use can provide insight into several disease mechanisms since [89 Zr]Oxinate4 has the potential to label any cell subset of interest.

Real-Time Gain Control of PET Detectors and Evaluation With Challenging Radionuclides.

Accurate gain control of PET detectors is a prerequisite for quantitative accuracy. A shift in the 511 keV peak position can lead to errors in scatter correction, degrading quantitation. The PET detectors in a PET/MR scanner are subject to thermal transients due to eddy currents induced during gradient-intensive MRI sequences. Since the gain of silicon photomultiplier-based detectors changes with temperature, good gain control is particularly challenging. In this paper we describe a method that utilizes information from the entire singles spectrum to create a real-time gain control method that maintains gain of PET detectors stable within approximately ±0.5% (±2.5 keV) with varying levels of scatter and in the presence of significant thermal transients. We describe the methods used to combine information about multiple peaks and how this algorithm is implemented in a way that permits real-time processing on a field-programmable gate array. Simulations demonstrate rapid response time and stability. A method ("virtual scatter filter") is also described that extracts unscattered photopeak events from phantom data and demonstrates the accuracy of the photopeak for various radionuclides that emit energies in addition to the pure 511 keV annihilation peak. Radionuclides 52 Mn, 55 Co, 64 Cu, 89 Zr, 90 Y, and 124 I are included in the study for their various forms of spectral contamination.

Synchronous Malignancies Identified by 18F-fluciclovine Positron Emission Tomography for Prostate Cancer: Case Series and Mini-Review.

Positron emission tomography using the fluorine-18 (18F) fluciclovine radiotracer has been approved for use in recurrent prostate cancer and is a useful tool for clinical decision making. However, 18F-fluciclovine is not specific for prostate cancer tumor cells, and false-positive results have been reported. In the present study, we have reported our experience with synchronous malignancies identified using 18F-fluciclovine and reviewed other reported cases, with a special emphasis on highlighting the clinical decisions that led to the correct diagnosis.

Dynamic 18F-FDOPA-PET/MRI for the preoperative evaluation of gliomas: correlation with stereotactic histopathology.

BACKGROUND: MRI alone has limited accuracy for delineating tumor margins and poorly predicts the aggressiveness of gliomas, especially when tumors do not enhance. This study evaluated simultaneous 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (FDOPA)-PET/MRI to define tumor volumes compared to MRI alone more accurately, assessed its role in patient management, and correlated PET findings with histopathology. METHODS: Ten patients with known or suspected gliomas underwent standard of care surgical resection and/or stereotactic biopsy. FDOPA-PET/MRI was performed prior to surgery, allowing for precise co-registration of PET, MR, and biopsies. The biopsy sites were modeled as 5-mm spheres, and the local FDOPA uptake at each site was determined. Correlations were performed between measures of tumor histopathology, and static and dynamic PET values: standardized uptake values (SUVs), tumor to brain ratios, metabolic tumor volumes, and tracer kinetics at volumes of interest (VOIs) and biopsy sites. RESULTS: Tumor FDOPA-PET uptake was visualized in 8 patients. In 2 patients, tracer uptake was similar to normal brain reference with no histological findings of malignancy. Eight biopsy sites confirmed for glioma had FDOPA uptake without T1 contrast enhancement. The PET parameters were highly correlated only with the cell proliferation marker, Ki-67 (SUVmax: r = 0.985, P = .002). In this study, no statistically significant difference between high-grade and low-grade tumors was demonstrated. The dynamic PET analysis of VOIs and biopsy sites showed decreasing time-activity curves patterns. FDOPA-PET imaging directly influenced patient management. CONCLUSIONS: Simultaneous FDOPA-PET/MRI allowed for more accurate visualization and delineation of gliomas, enabling more appropriate patient management and simplified validation of PET findings with histopathology.

Feasibility of Dose Escalating [18F]fluciclovine Positron Emission Tomography Positive Pelvic Lymph Nodes During Moderately Hypofractionated Radiation Therapy for High-Risk Prostate Cancer.

PURPOSE: The aim of this study was to report the treatment planning feasibility of dose escalation to suspicious lymph nodes (LNs) for a series of men who underwent pretreatment [18F]fluciclovine positron emission tomography (PET)/magnetic resonance imaging (MRI). METHODS AND MATERIALS: Cases of men with prostate cancer who enrolled in a clinical trial of pretreatment [18F]fluciclovine PET who had suspicious LNs were selected. Pelvic LNs <1 cm were defined as positive based on [18F]fluciclovine-PET if their maximum standardized uptake value (SUVmax) was ≥1.3-fold greater than the reference blood pool SUVmean, and LNs ≥1 cm were defined as positive if the SUV was greater than the reference SUV bone marrow reference. For each case, a radiation treatment plan was generated to deliver 70 Gy to the prostate and proximal seminal vesicles, 60.2 Gy to the PET-positive LNs, and 50.4 Gy to the elective nodal regions, simultaneously in 28 fractions of 2.5 Gy, 2.15 Gy, and 1.8 Gy, respectively. Treatment planning goals were defined a priori. The resulting target volume and organ-at-risk dosimetry were compared with the original treatment plan. RESULTS: Four cases were identified, with between 1 and 5 [18F]fluciclovine PET-positive LNs each. Goals for the prostate and elective nodal target volumes were successfully met in all cases. The goal of covering more than 90% of the positive LN planning target volume by the prescription dose of 60.2 Gy was met in 3 of the 4 cases. This goal was not met in 1 case, but 100% of clinical target volume was covered by 60.2 Gy. The primary organ-at-risk tradeoff was that a small volume (0.5-8.2 cm3) of small bowel would receive ≥54 Gy in each case. CONCLUSIONS: These preliminary results suggest that [18F]fluciclovine PET/MRI directed dose escalation of suspicious pelvic LNs is likely feasible in the setting of definitive radiation therapy. The potential clinical benefit of dose escalating [18F]fluciclovine PET-positive LNs should be investigated in a prospective clinical trial.

Current and Future Imaging Methods for Evaluating Response to Immunotherapy in Neuro-Oncology.

Imaging plays a central role in evaluating responses to therapy in neuro-oncology patients. The advancing clinical use of immunotherapies has demonstrated that treatment-related inflammatory responses mimic tumor growth via conventional imaging, thus spurring the development of new imaging approaches to adequately distinguish between pseudoprogression and progressive disease. To this end, an increasing number of advanced imaging techniques are being evaluated in preclinical and clinical studies. These novel molecular imaging approaches will serve to complement conventional response assessments during immunotherapy. The goal of these techniques is to provide definitive metrics of tumor response at earlier time points to inform treatment decisions, which has the potential to improve patient outcomes. This review summarizes the available immunotherapy regimens, clinical response criteria, current state-of-the-art imaging approaches, and groundbreaking strategies for future implementation to evaluate the anti-tumor and immune responses to immunotherapy in neuro-oncology applications.

ACR-ACNM Practice Parameter for the Performance of Fluorine-18 Fluciclovine-PET/CT for Recurrent Prostate Cancer.

The American College of Radiology (ACR) and American College of Nuclear Medicine (ACNM) collaborated to develop a clinical practice document for the performance of fluciclovine positron-emission tomography (PET) / computed tomography (CT) in the evaluation of patients with suspected prostate cancer recurrence based on the elevation of prostate-specific antigen (PSA) level (biochemical recurrence) after prior therapy. Prostate cancer is the third leading cause of cancer death in the United States. Up to 50% of patients diagnosed with prostate cancer will develop biochemical failure after initial therapy. The differentiation of local from extraprostatic recurrence plays a critical role in patient management. The use of functional imaging targeting features of cancer metabolism has proven highly useful in this regard. Amino acid transport is upregulated in prostate cancer. Fluciclovine (anti-1-amino-3-F-18-fluorocyclobutane-1-carboxylic acid, FACBC, Axumin™) is an artificial amino acid PET tracer which demonstrates utility in the diagnosis of recurrent prostate cancer with significant added value to conventional imaging.

PET/MR Imaging in Head and Neck Cancer: Current Applications and Future Directions.

Clinical PET/MR imaging is being implemented at institutions worldwide as part of the standard-of-care imaging for select oncology patients. This article focuses on oncologic applications of PET/MR imaging in cancers of the head and neck. Although current published literature is relatively sparse, the potential benefits of a hybrid modality of PET/MR imaging are discussed along with several possible areas of research. With the increasing number of PET/MR imaging scanners in clinical use and ongoing research, the role of PET/MR imaging in the management of head and neck cancer is likely to become more evident in the near future.