Fluorine-18-Labeled Fluoroestradiol PET/CT: Current Status, Gaps in Knowledge, and Controversies-AJR Expert Panel Narrative Review.

PET/CT using 16α-[18F]-fluoro-17ß-estradiol (FES) noninvasively images tissues expressing estrogen receptors (ERs). FES has undergone extensive clinicopathologic validation for ER+ breast cancer and received FDA approval in 2020 for clinical use as an adjunct to biopsy in patients with recurrent or metastatic ER+ breast cancer. Clinical use of FES PET/CT is increasing, but is not widespread in the United States. This AJR Expert Panel Narrative Review explores the present status and future directions of FES PET/CT, including image interpretation, existing and emerging uses, knowledge gaps, and current controversies. Specific controversies discussed include whether both FES PET/CT and FDG PET/CT are warranted in certain scenarios, whether further workup is required after negative FES PET/CT results, whether FES PET/CT findings should inform endocrine therapy selection, and whether immunohistochemistry should remain the standalone reference standard for determining ER status for all breast cancers. Consensus opinions from the panel include agreement with the appropriate clinical uses of FES PET/CT published by a multidisciplinary expert workgroup in 2023; anticipated expanded clinical use of FES PET/CT for staging ER-positive invasive lobular carcinomas and low-grade invasive ductal carcinomas pending ongoing clinical trial results; and the need for further research regarding use of FES PET/CT for ER-expressing nonbreast malignancies.

18F-Fluoroestradiol: Current Applications and Future Directions.

In the United States, breast cancer is the second leading cause of cancer death in all women and the leading cause of cancer death in Black women. The breast cancer receptor profile, assessed with immunohistochemical staining of tissue samples, allows prediction of outcomes and direction of patient treatment. Approximately 80% of newly diagnosed breast cancers are hormone receptor (HR) positive, which is defined as estrogen receptor (ER) and/or progesterone receptor (PR) positive. Patients with ER-positive disease can be treated with therapies targeting the ER; however, the assessment of ER expression with immunohistochemical staining of biopsy specimens has several limitations including sampling error, false-negative results, challenging or inaccessible biopsy sites, and the inability to synchronously and serially assess all metastatic sites to identify spatial and/or temporal ER heterogeneity. In May 2020, after decades of research, the U.S. Food and Drug Administration approved the PET radiotracer fluorine 18 (18F) fluoroestradiol (FES) for clinical use in patients with ER-positive recurrent or metastatic breast cancer as an adjunct to biopsy. FES binds to the ER in the nucleus of ER-expressing cells, enabling whole-body in vivo assessment of ER expression. This article is focused on the approved uses of FES in the United States, including identification of a target lesion for confirmatory biopsy, in vivo assessment of biopsy-proven ER-positive disease, and evaluation of spatial and temporal ER heterogeneity. FES is an example of precision medicine that has been leveraged to optimize the care of patients with breast cancer. © RSNA, 2023 See the invited commentary by Fowler in this issue. Quiz questions for this article are available through the Online Learning Center.

Abbreviated scan protocols to capture 18F-FDG kinetics for long axial FOV PET scanners.

PURPOSE: Kinetic parameters from dynamic 18F-fluorodeoxyglucose (FDG) imaging offer complementary insights to the study of disease compared to static clinical imaging. However, dynamic imaging protocols are cumbersome due to the long acquisition time. Long axial field-of-view (LAFOV) PET scanners (> 70 cm) have two advantages for dynamic imaging over clinical PET scanners with a standard axial field-of-view (SAFOV; 16-30 cm). The large axial coverage enables multi-organ dynamic imaging in a single bed position, and the high sensitivity may enable clinically routine abbreviated dynamic imaging protocols. METHODS: In this work, we studied two abbreviated protocols using data from a 65-min dynamic 18F-FDG scan: (A) dynamic imaging immediately post-injection (p.i.) for variable durations, and (B) dynamic imaging immediately p.i. for variable durations plus a 1-h p.i. (5-min-long) datapoint. Nine cancer patients were imaged on the Biograph Vision Quadra (Siemens Healthineers). Time-activity curves over the lesions (N = 39) were fitted using the Patlak graphical analysis and a 2-tissue-compartment (2C, k4 = 0) model for variable scan durations (5-60 min). Kinetic parameters from the complete dataset served as the reference. Lesions from all cancers were grouped into low, medium, and high flux groups, and bias and precision of Ki (Patlak) and Ki, K1, k2, and k3 (2C) were calculated for each group. RESULTS: Using only early dynamic data with the 2C (or Patlak) model, accurate quantification of Ki required at least 50 (or 55) min of dynamic data for low flux lesions, at least 30 (or 40) min for medium flux lesions, and at least 15 (or 20) min for high flux lesions to achieve both 10% bias and precision. The addition of the final (5-min) datapoint allowed for accurate quantification of Ki with a bias and precision of 10% using only 10-15 min of early dynamic data for either model. CONCLUSION: Dynamic imaging for 10-15 min immediately p.i. followed by a 5-min scan at 1-h p.i can accurately and precisely quantify 18F-FDG on a long axial FOV scanner, potentially allowing for more widespread use of dynamic 18F-FDG imaging.

Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy.

BACKGROUND AND AIMS: Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease-the principal causes of cancer mortality-have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are often not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE-induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence. APPROACH AND RESULTS: In this study, we characterized and leveraged the metabolic reprogramming demonstrated by latent HCC cells in response to TAE-induced ischemia to enable their detection in vivo using dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) of 13 carbon-labeled substrates. Under TAE-induced ischemia, latent HCC cells demonstrated reduced metabolism and developed a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP-MRSI of 1-13 C-pyruvate and its downstream metabolites, 1-13 C-lactate and 1-13 C-alanine, predicted histological viability. CONCLUSIONS: These studies provide a paradigm for imaging latent, treatment-refractory cancer cells, suggesting that DNP-MRSI provides a technology for this application.

Functional 4-D clustering for characterizing intratumor heterogeneity in dynamic imaging: evaluation in FDG PET as a prognostic biomarker for breast cancer.

PURPOSE: Probe-based dynamic (4-D) imaging modalities capture breast intratumor heterogeneity both spatially and kinetically. Characterizing heterogeneity through tumor sub-populations with distinct functional behavior may elucidate tumor biology to improve targeted therapy specificity and enable precision clinical decision making. METHODS: We propose an unsupervised clustering algorithm for 4-D imaging that integrates Markov-Random Field (MRF) image segmentation with time-series analysis to characterize kinetic intratumor heterogeneity. We applied this to dynamic FDG PET scans by identifying distinct time-activity curve (TAC) profiles with spatial proximity constraints. We first evaluated algorithm performance using simulated dynamic data. We then applied our algorithm to a dataset of 50 women with locally advanced breast cancer imaged by dynamic FDG PET prior to treatment and followed to monitor for disease recurrence. A functional tumor heterogeneity (FTH) signature was then extracted from functionally distinct sub-regions within each tumor. Cross-validated time-to-event analysis was performed to assess the prognostic value of FTH signatures compared to established histopathological and kinetic prognostic markers. RESULTS: Adding FTH signatures to a baseline model of known predictors of disease recurrence and established FDG PET uptake and kinetic markers improved the concordance statistic (C-statistic) from 0.59 to 0.74 (p = 0.005). Unsupervised hierarchical clustering of the FTH signatures identified two significant (p < 0.001) phenotypes of tumor heterogeneity corresponding to high and low FTH. Distributions of FDG flux, or Ki, were significantly different (p = 0.04) across the two phenotypes. CONCLUSIONS: Our findings suggest that imaging markers of FTH add independent value beyond standard PET imaging metrics in predicting recurrence-free survival in breast cancer and thus merit further study.

Prospective Study of Systemic Yttrium-90 Elution during Radioembolization of Hepatic Metastases.

PURPOSE: To evaluate total blood radioactivity (BR) after SIR-Spheres yttrium-90 (90Y) radioembolization and differences in BR based on delivery method. MATERIALS AND METHODS: Twenty participants with hepatic metastases undergoing first radioembolization were prospectively enrolled from December 2017 to June 2018. Blood samples were drawn at baseline and 0, 10, 20, 60, and 120 minutes after 90Y administration. BR was measured with a γ-counter and scaled by estimated blood volume. Percentage of instilled radioactivity in the bloodstream was calculated as area under the fitted curve, and differences between delivery methods were examined with nonparametric statistical tests. RESULTS: In 10 participants, resin microspheres were instilled with 50% Isovue 300 diluted in saline solution in the D line, and 10 others were treated with dextrose 5% in water (D5W) in the D line. Median administered activities were 944 MBq (range, 746-1,993 MBq) and 1,213 MBq (range, 519-2,066 MBq), respectively. Fraction of 90Y in blood was significantly higher with dilute contrast agent than with D5W (median, 0.5% of injected activity vs 0.2%; P = .001). Among all participants, the maximum activity delivered was 2,066 MBq, and a maximum of 1% of administered radioactivity was measured as free 90Y in blood. Assuming these highest-case values and complete decay of all free 90Y in bone, a dose to red marrow of 132.3 mGy was calculated by Organ Level INternal Dose Assessment/EXponential Modeling. CONCLUSIONS: Blood sampling after radioembolization allowed for estimation of the time-activity curve and BR. Delivery with 50% contrast agent in saline solution resulted in a significant increase in BR vs D5W, even though the total BR for both groups was nominal.

Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation.

Type I interferons (IFNs) play an important role in direct antiviral defense as well as linking the innate and adaptive immune responses. On dendritic cells (DCs), IFNs facilitate their activation and contribute to CD8(+) and CD4(+) T cell priming. However, the precise molecular mechanism by which IFNs regulate maturation and immunogenicity of DCs in vivo has not been studied in depth. Here we show that, after in vivo stimulation with the TLR ligand poly IC, IFNs dominate transcriptional changes in DCs. In contrast to direct TLR3/mda5 signaling, IFNs are required for upregulation of all pathways associated with DC immunogenicity. In addition, metabolic pathways, particularly the switch from oxidative phosphorylation to glycolysis, are also regulated by IFNs and required for DC maturation. These data provide evidence for a metabolic reprogramming concomitant with DC maturation and offer a novel mechanism by which IFNs modulate DC maturation.

PET Imaging of Metabolism, Perfusion, and Hypoxia: FDG and Beyond.

ABSTRACT: Imaging glucose metabolism with [18F]fluorodeoxyglucose positron emission tomography has transformed the diagnostic and treatment algorithms of numerous malignancies in clinical practice. The cancer phenotype, though, extends beyond dysregulation of this single pathway. Reprogramming of other pathways of metabolism, as well as altered perfusion and hypoxia, also typifies malignancy. These features provide other opportunities for imaging that have been developed and advanced into humans. In this review, we discuss imaging metabolism, perfusion, and hypoxia in cancer, focusing on the underlying biology to provide context. We conclude by highlighting the ability to image multiple facets of biology to better characterize cancer and guide targeted treatment.

Mycobacterial spindle cell pseudotumor of the spinal cord: Case report and literature review.

We report the first description of spinal cord mycobacterial spindle cell pseudotumor. A patient with newly diagnosed advanced HIV presented with recent-onset bilateral leg weakness and was found to have a hypermetabolic spinal cord mass on structural and molecular imaging. Biopsy and cultures from blood and cerebrospinal fluid confirmed spindle cell pseudotumor due to Mycobacterium avium-intracellulare. Despite control of HIV and initial reduction in pseudotumor volume on antiretrovirals and antimycobacterials (azithromycin, ethambutol, rifampin/rifabutin), he ultimately experienced progressive leg weakness due to pseudotumor re-expansion. Here, we review literature and discuss multidisciplinary diagnosis, monitoring and management challenges, including immune reconstitution inflammatory syndrome.

68 Ga-DOTATATE PET to Characterize Lesions in the Neuroaxis.

AIM: The differentiation of paragangliomas, schwannomas, meningiomas, and other neuroaxis tumors in the head and neck remains difficult when conventional MRI is inconclusive. This study assesses the utility of 68 Ga-DOTATATE PET/CT as an adjunct to hone the diagnosis. PATIENTS AND METHODS: This retrospective study considered 70 neuroaxis lesions in 52 patients with 68 Ga-DOTATATE PET/CT examinations; 22 lesions (31%) had pathologic confirmation. Lesions were grouped based on pathological diagnosis and best radiologic diagnosis when pathology was not available. Wilcoxon rank sum tests were used to test for differences in SUV max among paragangliomas, schwannomas, and meningiomas. Receiver operator characteristic curves were constructed. RESULTS: Paragangliomas had a significantly greater 68 Ga-DOTATATE uptake (median SUV max , 62; interquartile range [IQR], 89) than nonparagangliomas. Schwannomas had near-zero 68 Ga-DOTATATE uptake (median SUV max , 2; IQR, 1). Intermediate 68 Ga-DOTATATE uptake was seen for meningiomas (median SUV max , 19; IQR, 6) and other neuroaxis lesions (median SUV max , 7; IQR, 9). Receiver operator characteristic analysis demonstrated an area under the curve of 0.87 for paragangliomas versus all other lesions and 0.97 for schwannomas versus all other lesions. CONCLUSIONS: Marked 68 Ga-DOTATATE uptake (>50 SUV max ) favors a diagnosis of paraganglioma, although paragangliomas exhibit a wide variability of uptake. Low to moderate level 68 Ga-DOTATATE uptake is nonspecific and may represent diverse pathophysiology including paraganglioma, meningioma, and other neuroaxis tumors but essentially excludes schwannomas, which exhibited virtually no uptake.

Prostate Cancer Recurrence: Examining the Role of Salvage Radiotherapy Field and Risk Factors for Regional Disease Recurrence Captured on 18F-DCFPyL PET/CT.

PURPOSE: The role of elective pelvic nodal irradiation in salvage radiotherapy (sRT) remains controversial. Utilizing 18F-DCFPyL PET/CT, this study aimed to investigate differences in disease distribution after whole pelvic (WPRT) or prostate bed (PBRT) radiotherapy and to identify risk factors for pelvic lymph node (LN) relapse. METHODS: This retrospective study included patients with PSA > 0.1 ng/mL post-radical prostatectomy (RP) or post-RP and sRT who underwent 18F-DCFPyL PET/CT. Disease distribution on 18F-DCFPyL PET/CT after sRT was compared using Chi-square tests. Risk factors were tested for association with pelvic LN relapse after RP and salvage PBRT using logistic regression. RESULTS: 979 18F-DCFPyL PET/CTs performed at our institution between 1/1/2022 - 3/24/2023 were analyzed. There were 246 patients meeting criteria, of which 84 received salvage RT after RP (post-salvage RT group) and 162 received only RP (post-RP group). Salvage PBRT patients (n = 58) had frequent pelvic nodal (53.6%) and nodal-only (42.6%) relapse. Salvage WPRT patients (n = 26) had comparatively lower rates of pelvic nodal (16.7%, p = 0.002) and nodal-only (19.2%, p = 0.04) relapse. The proportion of distant metastases did not differ between the two groups. Multiple patient characteristics, including ISUP grade and seminal vesicle invasion, were associated with pelvic LN disease in the post-RP group. CONCLUSION: At PSA persistence or progression, salvage WPRT resulted in lower rates of nodal involvement than salvage PBRT, but did not reduce distant metastases. Certain risk factors increase the likelihood of pelvic LN relapse after RP and can help inform salvage RT field selection.

A new synthetic TLR4 agonist, GLA, allows dendritic cells targeted with antigen to elicit Th1 T-cell immunity in vivo.

Protein-based vaccines offer safety and cost advantages but require adjuvants to induce immunity. Here we examined the adjuvant capacity of glucopyranosyl lipid A (GLA), a new synthetic non-toxic analogue of lipopolysaccharide. In mice, in comparison with non-formulated LPS and monophosphoryl lipid A, formulated GLA induced higher antibody titers and generated Type 1 T-cell responses to HIV gag-p24 protein in spleen and lymph nodes, which was dependent on TLR4 expression. Immunization was greatly improved by targeting HIV gag p24 to DCs with an antibody to DEC-205, a DC receptor for antigen uptake and processing. Subcutaneous immunization induced antigen-specific T-cell responses in the intestinal lamina propria. Immunity did not develop in mice transiently depleted of DCs. To understand how GLA works, we studied DCs directly from vaccinated mice. Within 4 h, GLA caused DCs to upregulate CD86 and CD40 and produce cytokines including IL-12p70 in vivo. Importantly, DCs removed from mice 4 h after vaccination became immunogenic, capable of inducing T-cell immunity upon injection into naïve mice. These data indicate that a synthetic and clinically feasible TLR4 agonist rapidly stimulates full maturation of DCs in vivo, allowing for adaptive immunity to develop many weeks to months later.

Excreted 99m Tc-Pertechnetate in a Renal Pelvis as a Potential False Positive in a Meckel's Scan.

ABSTRACT: A 14-year-old girl presented with right lower quadrant pain. A 99m Tc-pertechnetate scan with SPECT/CT was performed to exclude a Meckel's diverticulum. The images demonstrated focal tracer uptake in the right midabdomen, which appeared early and decreased over time. However, SPECT/CT revealed that this uptake corresponded to the right renal pelvis, which was located more inferior than expected. This case emphasizes the importance of recognizing anatomic variants that may cause focal tracer uptake, as well as leveraging an understanding of tracer kinetics to inform a diagnosis.

PSMA Uptake in a Subdural Hematoma.

ABSTRACT: An 81-year-old man with known metastatic prostate cancer with recent biochemical progression underwent a PSMA PET/CT ( 18 F-piflufolastat) for restaging. Review of the images demonstrated an acute or chronic left cerebral convexity subdural hematoma on CT with corresponding radiotracer activity throughout the collection on PET. Analysis of the patient's prior imaging showed that this subdural hematoma had significantly increased in size when compared with a head CT obtained 2 months prior. The patient was referred to a nearby emergency department and underwent repeat imaging and subdural drain placement. Unfortunately, the patient died secondary to rapid reaccumulation of subdural blood products after intervention.

18F-Fluciclovine PET Imaging of Glutaminase Inhibition in Breast Cancer Models.

Aggressive cancers such as triple-negative breast cancer (TNBC) avidly metabolize glutamine as a feature of their malignant phenotype. The conversion of glutamine to glutamate by the glutaminase enzyme represents the first and rate-limiting step of this pathway and a target for drug development. Indeed, a novel glutaminase inhibitor (GLSi) has been developed and tested in clinical trials but with limited success, suggesting the potential for a biomarker to select patients who could benefit from this novel therapy. Here, we studied a nonmetabolized amino acid analog, 18F-fluciclovine, as a PET imaging biomarker for detecting the pharmacodynamic response to GLSi. Methods: Uptake of 18F-fluciclovine into human breast cancer cells was studied in the presence and absence of inhibitors of glutamine transporters and GLSi. To allow 18F-fluciclovine PET to be performed on mice, citrate in the tracer formulation is replaced by phosphate-buffered saline. Mice bearing triple-negative breast cancer (TNBC) xenografts (HCC38, HCC1806, and MBA-MD-231) and estrogen receptor-positive breast cancer xenografts (MCF-7) were imaged with dynamic PET at baseline and after a 2-d treatment of GLSi (CB839) or vehicle. Kinetic analysis suggested reversible uptake of the tracer, and the distribution volume (VD) of 18F-fluciclovine was estimated by Logan plot analysis. Results: Our data showed that cellular uptake of 18F-fluciclovine is mediated by glutamine transporters. A significant increase in VD was observed after CB839 treatment in TNBC models exhibiting high glutaminase activity (HCC38 and HCC1806) but not in TNBC or MCF-7 exhibiting low glutaminase. Changes in VD were corroborated with changes in GLS activity measured in tumors treated with CB839 versus vehicle, as well as with changes in VD of 18F-(2S,R4)-fluoroglutamine, which we previously validated as a measure of cellular glutamine pool size. A moderate, albeit significant, decrease in 18F-FDG PET signal was observed in HCC1806 tumors after CB839 treatment. Conclusion: 18F-fluciclovine PET has potential to serve as a clinically translatable pharmacodynamic biomarker of GLSi.

Widespread micronodular hepatic metastases of neuroendocrine tumor detected by [68Ga]DOTATATE PET/CT.

Neuroendocrine tumors (NET) encompass a diverse, heterogeneous group of neoplasms that originate from the secretory cells of the neuroendocrine system. These neoplasms typically express the somatostatin receptor (SSTR), which can be targeted by molecular agents for imaging and therapy. This is particularly advantageous for imaging NETs that are indolent, slow-growing, and less well detected by [18F]FDG and for the detection of occult disease not easily identified by anatomic imaging. Herein, we present a case in which [68Ga]DOTATATE PET/CT was used to diagnose the etiology of biochemical recurrence in NET that was not apparent on MRI. The importance of understanding deviations from the normal biodistribution of the radiotracer is emphasized as key in interpreting nuclear medicine studies and establishing the diagnosis. Imaging the SSTR is of particular interest given the recent FDA approval of [68Cu]DOTATATE as a new and possibly more available molecular radiotracer.

Positron Emission Tomography (PET)/Computed Tomography (CT) Imaging in Radiation Therapy Treatment Planning: A Review of PET Imaging Tracers and Methods to Incorporate PET/CT.

Purpose: Positron emission tomography (PET)/computed tomography (CT) has become a critical tool in clinical oncology with an expanding role in guiding radiation treatment planning. As its application and availability grows, it is increasingly important for practicing radiation oncologists to have a comprehensive understanding of how molecular imaging can be incorporated into radiation planning and recognize its potential limitations and pitfalls. The purpose of this article is to review the major approved positron-emitting radiopharmaceuticals clinically being used today along with the methods used for their integration into radiation therapy including methods of image registration, target delineation, and emerging PET-guided protocols such as biologically-guided radiation therapy and PET-adaptive therapy. Methods and Materials: A review approach was utilized using collective information from a broad review of the existing scientific literature sourced from PubMed search with relevant keywords and input from a multidisciplinary team of experts in medical physics, radiation treatment planning, nuclear medicine, and radiation therapy. Results: A number of radiotracers imaging various targets and metabolic pathways of cancer are now commercially available. PET/CT data can be incorporated into radiation treatment planning through cognitive fusion, rigid registration, deformable registration, or PET/CT simulation techniques. PET imaging provides a number of benefits to radiation planning including improved identification and delineation of the radiation targets from normal tissue, potential automation of target delineation, reduction of intra- and inter-observer variability, and identification of tumor subvolumes at high risk for treatment failure which may benefit from dose intensification or adaptive protocols. However, PET/CT imaging has a number of technical and biologic limitations that must be understood when guiding radiation treatment. Conclusion: For PET guided radiation planning to be successful, collaboration between radiation oncologists, nuclear medicine physicians, and medical physics is essential, as well as the development and adherence to strict PET-radiation planning protocols. When performed properly, PET-based radiation planning can reduce treatment volumes, reduce treatment variability, improve patient and target selection, and potentially enhance the therapeutic ratio accessing precision medicine in radiation therapy.