Uterine Uptake of Estrogen and Progestogen-Based Radiotracers in Rhesus Macaques with Endometriosis.

PURPOSE: Endometriosis is an estrogen-dependent disorder of menstruating primates where tissues similar to the inner lining of the uterus exist "ectopically" outside of the uterus. The ectopic endometrium, like the endometrium within the uterus, expresses estrogen receptors (ER) and progesterone receptors (PR) and undergoes hormone-dependent cell proliferation and bleeding each menstrual cycle. The goal of this study was to conduct abdominopelvic positron emission tomography (PET) scans with computed tomography (CT) imaging of rhesus macaques (Macaca mulatta) using radiotracers that target ER and PR [16α-[18F]fluoroestradiol (FES) and 12-[18F]fluoro-furanyl-nor-progesterone (FFNP)] in individuals with and without endometriosis. We also aimed to determine if menstrual cycle phase and/or the presence of endometriosis affected the uptake of these radiotracers. PROCEDURES: Rhesus macaques with either clinically diagnosed endometriosis (n = 6) or no endometriosis (n = 4) underwent PET/CT scans with FES. A subset of the animals also underwent PET/CT scans with FFNP. Standard uptake values corrected for body weight (SUVs) were obtained for each radiotracer in target and background tissues (e.g., intestinal). We performed repeated measure analysis of variance tests to determine how uterine and background uptake differed with scan time, phase of the menstrual cycle, and disease state. RESULTS: Abdominopelvic PET/CT could not resolve small, individual endometriotic lesions. However, macaques with endometriosis displayed higher uterine uptake compared to those without the disorder. Radiotracer uptake differed by menstrual cycle phase with increased uterine uptake of both radiotracers in the proliferative phase of the menstrual cycle. Background intestinal uptake of FFNP increased over time after infusion, but only during the proliferative phase. CONCLUSIONS: PET/CT with FES and FFNP support the concept that ER and PR levels are altered in individuals with endometriosis. This highlights the impact of the disease on typical reproductive tract function and may provide a novel pathway for the identification of individuals with endometriosis.

Uterine uptake of estrogen and progestogen-based radiotracers in rhesus macaques with endometriosis.

Purpose: Few investigations have examined the uptake of radiotracers that target the prominent sex-steroid receptors in the uterus across the menstrual cycle and with disease state. We aimed to determine if uptake of the radiotracers that target estrogen and progesterone receptors (ER and PR) differ with the presence of endometriosis and/or across the menstrual cycle. We performed PET and computed tomography (CT) imaging procedures on rhesus macaques (Macaca mulatta) using 16α-[18F]fluoroestradiol (FES) and 21-[18F]fluoro-furanyl-nor-progesterone (FFNP) in individuals with and without endometriosis in the proliferative and secretory phases of the menstrual cycle. Procedures: Macaques with either clinically diagnosed endometriosis (n = 6) or no endometriosis (n = 4) underwent abdominopelvic PET/CT scans with FES. A subset of these animals also underwent PET/CT scans with FFNP. Standard uptake values corrected for body weight (SUVbw) were obtained for each radiotracer in target and background tissues (i.e., intestinal and muscle). We performed repeated measure analysis of variance tests to determine how uterine and background uptake differed with scan time, phase of the menstrual cycle, and disease state. Results: PET/CT could not resolve small, individual endometriotic lesions. However, uterine uptake of both radiotracers was elevated in the proliferative phase compared to the secretory phase of the menstrual cycle. Intestinal uptake exhibited greater variation during the proliferative phase compared to the secretory phase. Further, intestinal uptake of FFNP increases as the scan progresses, but only during the proliferative phase. Muscle uptake did not differ with menstrual phase or radiotracer type. Lastly, macaques with endometriosis displayed higher uterine uptake of FES compared to those without endometriosis. Conclusions: PET/CT with FES and FFNP support the concept that ER and PR levels are altered in individuals with endometriosis. This highlights the impact of the disease on typical reproductive tract function and may provide a novel pathway for the identification of individuals with endometriosis.

In Vivo Cerebral Imaging of Mutant Huntingtin Aggregates Using 11C-CHDI-180R PET in a Nonhuman Primate Model of Huntington Disease.

Huntington disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine (CAG) trinucleotide expansion in the huntingtin (HTT) gene that encodes the mutant huntingtin protein (mHTT). Visualization and quantification of cerebral mHTT will provide a proxy for target engagement and a means to evaluate therapeutic interventions aimed at lowering mHTT in the brain. Here, we validated the novel radioligand 11C-labeled 6-(5-((5-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazin-3(2H)-one (11C-CHDI-180R) using PET imaging to quantify cerebral mHTT aggregates in a macaque model of HD. Methods: Rhesus macaques received MRI-guided intrastriatal delivery of a mixture of AAV2 and AAV2.retro viral vectors expressing an HTT fragment bearing 85 CAG repeats (85Q, n = 5), a control HTT fragment bearing 10 CAG repeats (10Q, n = 4), or vector diluent only (phosphate-buffered saline, n = 5). Thirty months after surgery, 90-min dynamic PET/CT imaging was used to investigate 11C-CHDI-180R brain kinetics, along with serial blood sampling to measure input function and stability of the radioligand. The total volume of distribution was calculated using a 2-tissue-compartment model as well as Logan graphical analysis for regional quantification. Immunostaining for mHTT was performed to corroborate the in vivo findings. Results: 11C-CHDI-180R displayed good metabolic stability (51.4% ± 4.0% parent in plasma at 60 min after injection). Regional time-activity curves displayed rapid uptake and reversible binding, which were described by a 2-tissue-compartment model. Logan graphical analysis was associated with the 2-tissue-compartment model (r 2 = 0.96, P < 0.0001) and used to generate parametric volume of distribution maps. Compared with controls, animals administered the 85Q fragment exhibited significantly increased 11C-CHDI-180R binding in several cortical and subcortical brain regions (group effect, P < 0.0001). No difference in 11C-CHDI-180R binding was observed between buffer and 10Q animals. The presence of mHTT aggregates in the 85Q animals was confirmed histologically. Conclusion: We validated 11C-CHDI-180R as a radioligand to visualize and quantify mHTT aggregated species in a HD macaque model. These findings corroborate our previous work in rodent HD models and show that 11C-CHDI-180R is a promising tool to assess the mHTT aggregate load and the efficacy of therapeutic strategies.

Anion exchange and extraction chromatography tandem column isolation of zirconium-89 (89Zr) from cyclotron bombarded targets using an automated fluidic platform.

The long-lived positron emitter 89Zr is a highly promising nuclide employed in diagnostic Positron Emission Tomography (PET) imaging. Methods of radiochemical processing to obtain 89Zr for clinical use are traditionally performed with a single hydroxamate resin column. Herein, we present a tandem column purification method for the preparation of high-purity 89Zr from cyclotron bombarded natural Y metal foils. The primary column is a macroporous, strongly basic anion exchange resin on styrene divinylbenzene co-polymer. The secondary microcolumn, with an internal volume of 33 µL, is packed with an extraction chromatography resin (ExCR) loaded with di-(2-ethylhexyl)phosphoric acid (HDEHP). A condition of "inverted selectivity" is presented, wherein the 89Zr elution from the primary column is synonymous with the load condition on the secondary column. The ability to transfer 89Zr from one column to the next allows two sequential purification steps to be performed prior to the final elution of the 89Zr product. This approach assures delivery of high purity 89Zr. The tandem column purification process has been implemented into a prototype automated fluidic system. Optimization of the method is presented, followed by evaluation of the process using seven cyclotron bombarded Y metal foil targets. Once optimized, we found that 93.7 ± 2.3% of the 89Zr present in the foils was recovered in the secondary column elution fraction (0.8 M oxalic acid). Radiochromatograms of the product elution peaks enabled determination of full width at half-maximum (FWHM) and 89Zr collection yields as a function of volume. Because of the small size of the secondary microcolumn, a 89Zr product volume of ∼0.28 mL is reported, which provides a substantially increased nuclide concentration over traditional methods. Finally, we evaluated the transchelation of the resulting 89Zr oxalate product to deferoxamine mesylate (DFOM) salt. We observed effective specific activities (ESA) and bindable metals concentrations ([MB]) that exceed those reported by the traditional single hydroxamate column method.

[18F]-fluoromisonidazole (FMISO) PET/MRI hypoxic fraction distinguishes neuroinflammatory pseudoprogression from recurrent glioblastoma in patients treated with pembrolizumab.

Response assessment after immunotherapy remains a major challenge in glioblastoma due to an expected increased incidence of pseudoprogression. Gadolinium-enhanced magnetic resonance imaging (MRI) is the standard for monitoring therapeutic response, however, is markedly limited in characterizing pseudoprogression. Given that hypoxia is an important defining feature of glioblastoma regrowth, we hypothesized that [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) could provide an additional physiological measure for the diagnosis of immunotherapeutic failure. Six patients with newly diagnosed glioblastoma who had previously received maximal safe resection followed by Stupp protocol CRT concurrent with pembrolizumab immunotherapy were recruited for FMISO PET and Gd-MRI at the time of presumed progression. The hypoxic fraction was defined as the ratio of hypoxic volume to T1-weighted gadolinium-enhancing volume. Four patients diagnosed with pseudoprogression demonstrated a mean hypoxic fraction of 9.8 ±â€…10%. Two with recurrent tumor demonstrated a mean hypoxic fraction of 131 ±â€…66%. Our results, supported by histopathology, suggest that the noninvasive assessment of hypoxic fraction by FMISO PET/MRI is clinically feasible and may serve as a biologically specific metric of therapeutic failure.

18F-fluorodeoxyglucose (FDG) PET or 18F-fluorothymidine (FLT) PET to assess early response to aromatase inhibitors (AI) in women with ER+ operable breast cancer in a window-of-opportunity study.

PURPOSE: This study evaluated the ability of 18F-Fluorodeoxyglucose (FDG) and 18F-Fluorothymidine (FLT) imaging with positron emission tomography (PET) to measure early response to endocrine therapy from baseline to just prior to surgical resection in estrogen receptor positive (ER+) breast tumors. METHODS: In two separate studies, women with early stage ER+ breast cancer underwent either paired FDG-PET (n = 22) or FLT-PET (n = 27) scans prior to endocrine therapy and again in the pre-operative setting. Tissue samples for Ki-67 were taken for all patients both prior to treatment and at the time of surgery. RESULTS: FDG maximum standardized uptake value (SUVmax) declined in 19 of 22 lesions (mean 17% (range -45 to 28%)). FLT SUVmax declined in 24 of 27 lesions (mean 26% (range -77 to 7%)). The Ki-67 index declined in both studies, from pre-therapy (mean 23% (range 1 to 73%)) to surgery [mean 8% (range < 1 to 41%)]. Pre- and post-therapy PET measures showed strong rank-order agreement with Ki-67 percentages for both tracers; however, the percent change in FDG or FLT SUVmax did not demonstrate a strong correlation with Ki-67 index change or Ki-67 at time of surgery. CONCLUSIONS: A window-of-opportunity approach using PET imaging to assess early response of breast cancer therapy is feasible. FDG and FLT-PET imaging following a short course of neoadjuvant endocrine therapy demonstrated measurable changes in SUVmax in early stage ER+ positive breast cancers. The percentage change in FDG and FLT-PET uptake did not correlate with changes in Ki-67; post-therapy SUVmax for both tracers was significantly associated with post-therapy Ki-67, an established predictor of endocrine therapy response.

18F-Fluoroestradiol PET Imaging in a Phase II Trial of Vorinostat to Restore Endocrine Sensitivity in ER+/HER2- Metastatic Breast Cancer.

Histone deacetylase inhibitors (HDACIs) may overcome endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer. We tested whether 18F-fluoroestradiol PET imaging would elucidate the pharmacodynamics of combination HDACIs and endocrine therapy. Methods: Patients with ER+/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer with prior clinical benefit from endocrine therapy but later progression on aromatase inhibitor (AI) therapy were given vorinostat (400 mg daily) sequentially or simultaneously with AI. 18F-fluoroestradiol PET and 18F-FDG PET scans were performed at baseline, week 2, and week 8. Results: Eight patients were treated sequentially, and then 15 simultaneously. Eight patients had stable disease at week 8, and 6 of these 8 patients had more than 6 mo of stable disease. Higher baseline 18F-fluoroestradiol uptake was associated with longer progression-free survival. 18F-fluoroestradiol uptake did not systematically increase with vorinostat exposure, indicating no change in regional ER estradiol binding, and 18F-FDG uptake did not show a significant decrease, as would have been expected with tumor regression. Conclusion: Simultaneous HDACIs and AI dosing in patients with cancer resistant to AI alone showed clinical benefit (6 or more months without progression) in 4 of 10 evaluable patients. Higher 18F-fluoroestradiol PET uptake identified patients likely to benefit from combination therapy, but vorinostat did not change ER expression at the level of detection of 18F-fluoroestradiol PET.

Correction to: a Phase 2 Study of 16α-[18F]-Fluoro-17ß-Estradiol Positron Emission Tomography (FES-PET) as a Marker of Hormone Sensitivity in Metastatic Breast Cancer (MBC).

Two data points from Table 1. (continued) were published in error. The corrected data in Table 1. (continued) are shown, in italic, below.

Molecular Imaging in Drug Discovery and Development.

Noninvasive imaging has played an increasing role in the process of cardiovascular drug development. This review focuses specifically on the use of molecular imaging, which has been increasingly applied to improve and accelerate certain preclinical steps in drug development, including the identification of appropriate therapeutic targets, evaluation of on-target and off-target effects of candidate therapies, assessment of dose response, and the evaluation of drug or biological biodistribution and pharmacodynamics. Unlike the case in cancer medicine, in cardiovascular medicine, molecular imaging has not been used as a primary surrogate clinical end point for drug approval. However, molecular imaging has been applied in early clinical trials, particularly in phase 0 studies, to demonstrate proof-of-concept or to explain variation in treatment effect. Many of these applications where molecular imaging has been used in drug development have involved the retasking of technologies that were originally intended as clinical diagnostics. With greater experience and recognition of the rich information provided by in vivo molecular imaging, it is anticipated that it will increasingly be used to address the enormous time and costs associated with bringing a new drug to clinical launch.

Estrogen Receptor Binding (18F-FES PET) and Glycolytic Activity (18F-FDG PET) Predict Progression-Free Survival on Endocrine Therapy in Patients with ER+ Breast Cancer.

PURPOSE: 18F-fluoroestradiol (FES) PET scans measure regional estrogen binding, and 18F-fluorodeoxyglucose (FDG) PET measures tumor glycolytic activity. We examined quantitative and qualitative imaging biomarkers of progression-free survival (PFS) in breast cancer patients receiving endocrine therapy. EXPERIMENTAL DESIGN: Ninety patients with breast cancer from an estrogen receptor-positive (ER+), HER2- primary tumor underwent FES PET and FDG PET scans prior to endocrine therapy (63% aromatase inhibitor, 22% aromatase inhibitor and fulvestrant, 15% other). Eighty-four had evaluable data for PFS prediction. RESULTS: Recursive partitioning with 5-fold internal cross-validation used both FES PET and FDG PET measures to classify patients into three distinct response groups. FDG PET identified 24 patients (29%) with low FDG uptake, suggesting indolent tumors. These patients had a median PFS of 26.1 months (95% confidence interval, 11.2-49.7). Of patients with more FDG-avid tumors, 50 (59%) had high average FES uptake, and 10 (12%) had low average FES uptake. These groups had median PFS of 7.9 (5.6-11.8) and 3.3 months (1.4-not evaluable), respectively. Patient and tumor features did not replace or improve the PET measures' prediction of PFS. Prespecified endocrine resistance classifiers identified in smaller cohorts did not individually predict PFS. CONCLUSIONS: A wide range of therapy regimens are available for treatment of ER+ metastatic breast cancer, but no guidelines are established for sequencing these therapies. FDG PET and FES PET may help guide the timing of endocrine therapy and selection of targeted and/or cytotoxic chemotherapy. A multicenter trial is ongoing for external validation. Clin Cancer Res; 23(2); 407-15. ©2016 AACR.

Temporal Heterogeneity of Estrogen Receptor Expression in Bone-Dominant Breast Cancer: 18F-Fluoroestradiol PET Imaging Shows Return of ER Expression.

Changes in estrogen receptor (ER) expression over the course of therapy may affect response to endocrine therapy. However, measuring temporal changes in ER expression requires serial biopsies, which are impractical and poorly tolerated by most patients. Functional ER imaging using (18)F-fluoroestradiol (FES)-PET provides a noninvasive measure of regional ER expression and is ideally suited to serial studies. Additionally, lack of measurable FES uptake in metastatic sites of disease predict tumor progression in patients with ER-positive primary tumors treated with endocrine therapy. This report presents a case of restored sensitivity to endocrine therapy in a patient with bone-dominant breast cancer who underwent serial observational FES-PET imaging over the course of several treatments at our center, demonstrating the temporal heterogeneity of regional ER expression. Although loss and restoration of endocrine sensitivity in patients who have undergone prior hormonal and cytotoxic treatments has been reported, this is, to our knowledge, the first time the accompanying changes in ER expression have been documented by molecular imaging.

Glioma FMISO PET/MR Imaging Concurrent with Antiangiogenic Therapy: Molecular Imaging as a Clinical Tool in the Burgeoning Era of Personalized Medicine.

The purpose of this article is to provide a focused overview of the current use of positron emission tomography (PET) molecular imaging in the burgeoning era of personalized medicine in the treatment of patients with glioma. Specifically, we demonstrate the utility of PET imaging as a tool for personalized diagnosis and therapy by highlighting a case series of four patients with recurrent high grade glioma who underwent 18F-fluoromisonidazole (FMISO) PET/MR (magnetic resonance) imaging through the course of antiangiogenic therapy. Three distinct features were observed from this small cohort of patients. First, the presence of pseudoprogression was retrospectively associated with the absence of hypoxia. Second, a subgroup of patients with recurrent high grade glioma undergoing bevacizumab therapy demonstrated disease progression characterized by an enlarging nonenhancing mass with newly developed reduced diffusion, lack of hypoxia, and preserved cerebral blood volume. Finally, a reduction in hypoxic volume was observed concurrent with therapy in all patients with recurrent tumor, and markedly so in two patients that developed a nonenhancing reduced diffusion mass. This case series demonstrates how medical imaging has the potential to influence personalized medicine in several key aspects, especially involving molecular PET imaging for personalized diagnosis, patient specific disease prognosis, and therapeutic monitoring.

PET imaging of Oatp-mediated hepatobiliary transport of [(11)C] rosuvastatin in the rat.

UNLABELLED: A novel positron emission tomography (PET) tracer, [(11)C]-rosuvastatin (RSV), was developed to dynamically and noninvasively measure hepatobiliary transport and tissue distribution of [(11)C]-RSV in rats. METHODS: Male Sprague-Dawley rats were administered either an Oatp inhibitor, rifampin (RIF, 40 mg/kg iv bolus plus 1.85 mg/min/kg iv infusion, n = 3), or the corresponding vehicle (saline, n = 3) for at least 90 min. Then, while these infusions were ongoing, the animals received [(11)C]-rosuvastatin (∼1 mCi/30 s, iv infusion). After [(11)C]-RSV administration, the lower abdominal region of the rats was imaged for 90 min. Time-activity curves for liver, intestine, and kidney were obtained and corrected for vascular content prior to noncompartmental and compartmental (five-compartment model) analysis. RESULTS: The majority of the [(11)C]-RSV dose was distributed into the liver. In the presence of RIF, the area under the [(11)C]-RSV radioactivity blood concentration-time profile (AUC0-90 min) was increased by ∼3-fold. Relative to the control animals, RIF reduced the distribution of [(11)C]-RSV radioactivity into the liver and kidney (tissue AUC0-15 min/blood AUC0-15 min) by 54% and 73% respectively. Compartmental modeling showed that RIF decreased CLBL, CLLI, CLBK, and CLK0 but had no effect on CLLB, where B, L, I, K, and 0 represent blood, liver, intestine, kidney, and irreversible loss. CONCLUSION: [(11)C]-RSV can be used to dynamically and noninvasively quantify hepatobiliary transport and hepatic concentration of the drug, in the absence and presence of drug interactions, in rats and could be used for the same purpose in humans.

A phase 2 study of 16α-[18F]-fluoro-17ß-estradiol positron emission tomography (FES-PET) as a marker of hormone sensitivity in metastatic breast cancer (MBC).

PURPOSE: 16α-[(18)F]-fluoro-17ß-estradiol positron emission tomography (FES-PET) quantifies estrogen receptor (ER) expression in tumors and may provide diagnostic benefit. PROCEDURES: Women with newly diagnosed metastatic breast cancer (MBC) from an ER-positive primary tumor were imaged before starting endocrine therapy. FES uptake was evaluated qualitatively and quantitatively, and associated with response and with ER expression. RESULTS: Nineteen patients underwent FES imaging. Fifteen had a biopsy of a metastasis and 15 were evaluable for response. Five patients had quantitatively low FES uptake, six had at least one site of qualitatively FES-negative disease. All patients with an ER-negative biopsy had both low uptake and at least one site of FES-negative disease. Of response-evaluable patients, 2/2 with low FES standard uptake value tumors had progressive disease within 6 months, as did 2/3 with qualitatively FES-negative tumors. CONCLUSIONS: Low/absent FES uptake correlates with lack of ER expression. FES-positron emission tomography can help identify patients with endocrine resistant disease and safely measures ER in MBC.

Factors influencing the uptake of 18F-fluoroestradiol in patients with estrogen receptor positive breast cancer.

INTRODUCTION: (18)F-Fluoroestradiol (FES) PET imaging provides a non-invasive method to measure estrogen receptor (ER) expression in tumors. Assessment of factors that could affect the quantitative level of FES uptake is important as part of the validation of FES PET for evaluating regional ER expression in breast cancer. METHODS: This study examines FES uptake in tumors from 312 FES PET scans (239 patients) with documented ER+ primary breast cancer. FES uptake was compared to clinical and laboratory data, treatment prior to or at time of scan, and properties of FES and its metabolism and transport. Linear mixed models were used to explore univariate, threshold-based and multivariate associations. RESULTS: Sex hormone-binding globulin (SHBG) was inversely associated with FES SUV. Average FES uptake did not differ by levels of plasma estradiol, age or rate of FES metabolism. FES tumor uptake was greater for patients with a higher body mass index (BMI), but this effect did not persist when SUV was corrected for lean body mass (LBM). In multivariate analysis, only plasma SHBG binding was an independent predictor of LBM-adjusted FES SUV. CONCLUSIONS: Calculation of FES SUV, possibly adjusted for LBM, should be sufficient to assess FES uptake for the purpose of inferring ER expression. Pre-menopausal estradiol levels do not appear to interfere with FES uptake. The availability and binding properties of SHBG influence FES uptake and should be measured. Specific activity did not have a clear influence on FES uptake, except perhaps at higher injected mass per kilogram. These results suggest that FES imaging protocols may be simplified without sacrificing the validity of the results.

Between-patient and within-patient (site-to-site) variability in estrogen receptor binding, measured in vivo by 18F-fluoroestradiol PET.

UNLABELLED: Heterogeneity of estrogen receptor (ER) expression may be an important predictor of breast cancer therapeutic response. (18)F-fluoroestradiol PET produces in vivo quantitative measurements of regional estrogen binding in breast cancer tumors. We describe within-patient (site-to-site) and between-patient heterogeneity of lesions in patients scheduled to receive endocrine therapy. METHODS: In 91 patients with a prior ER-positive biopsy, 505 lesions were analyzed for both (18)F-fluoroestradiol and (18)F-FDG uptake and the (18)F-fluoroestradiol/(18)F-FDG uptake ratio. Standardized uptake values (SUVs) were recorded for up to 16 lesions per patient, of 1.5 cm or more and visible on (18)F-FDG PET or conventional staging. Linear mixed-effects regression models examined associations between PET parameters and patient or lesion characteristics and estimated variance components. A reader study of SUV measurements for 9 scans further examined sources of within-patient variability. RESULTS: Average (18)F-fluoroestradiol uptake and (18)F-fluoroestradiol/(18)F-FDG ratio varied greatly across these patients, despite a history of ER-positive disease: about 37% had low or absent (18)F-fluoroestradiol uptake even with marked (18)F-FDG uptake. (18)F-fluoroestradiol SUV and (18)F-fluoroestradiol/(18)F-FDG ratio measurements within patients with multiple lesions were clustered around the patient's average value in most cases. Summarizing these findings, the intraclass correlation coefficient (proportion of total variation that is between-patient) was 0.60 (95% confidence interval, 0.50-0.69) for (18)F-fluoroestradiol SUV and 0.65 (95% confidence interval, 0.56-0.73) for the (18)F-fluoroestradiol/(18)F-FDG ratio. Some within-patient variation in PET measures (22%-44%) was attributable to interobserver variability as measured by the reader study. A subset of patients had mixed uptake, with widely disparate (18)F-fluoroestradiol SUV or (18)F-fluoroestradiol/(18)F-FDG ratio for lesions in the same scan. CONCLUSION: (18)F-fluoroestradiol uptake and the (18)F-fluoroestradiol/(18)F-FDG ratio varied greatly between patients but were usually consistent across lesions in the same scan. The average (18)F-fluoroestradiol SUV and (18)F-fluoroestradiol/(18)F-FDG ratio for a limited sample of lesions appear to provide a reasonable summary of synchronous ER expression for most patients. However, imaging the entire disease burden remains important to identify the subset of patients with mixed uptake, who may be at a critical point in their disease evolution.

Fluoroestradiol positron emission tomography reveals differences in pharmacodynamics of aromatase inhibitors, tamoxifen, and fulvestrant in patients with metastatic breast cancer.

PURPOSE: To determine, by molecular imaging, how in vivo pharmacodynamics of estrogen-estrogen receptor (ER) binding differ between types of standard endocrine therapy. EXPERIMENTAL DESIGN: The ER has been a highly successful target for breast cancer treatment. ER-directed treatments include lowering ligand concentration by using aromatase inhibitors (AI) and blocking the receptor with agents like tamoxifen (TAM) or fulvestrant (FUL). We measured regional estrogen-ER binding by using positron emission tomography with (18)F-fluoroestradiol (FES PET) prior to and during treatment with AI, TAM, or FUL in a series of 30 metastatic breast cancer patients. FES PET measured in vivo estrogen binding at all tumor sites in heavily pretreated women with metastatic bone soft tissue-dominant breast cancer. In patients with uterus (n = 16) changes in uterine FES uptake were also measured. RESULTS: As expected, tumor FES uptake declined more markedly on ER blockers (TAM and FUL, average 54% decline) compared with a less than 15% average decline on estrogen-depleting AIs (P < 0.001). The rate of complete tumor blockade [FES standardized uptake value (SUV) ≤1.5] following TAM (5/5 patients) was greater than the blockade rate following FUL (4/11; 2-sided mid P = 0.019). Percent FES SUV change in the uterus showed a strong association with tumoral change (ρ = 0.63, P = 0.01). CONCLUSIONS: FES PET can assess the in vivo pharmacodynamics of ER-targeted agents and may give insight into the activity of established therapeutic agents. Imaging revealed significant differences between agents, including differences in the efficacy of blockade by different ER antagonists in current clinical use.

Multiagent PET for risk characterization in sarcoma.

UNLABELLED: A major goal of molecular imaging in cancer is to evaluate patient tumors for risk of treatment resistance and poor outcome using biologically specific PET agents. This approach was investigated using a multiagent imaging protocol for which patients were imaged in a single session to minimize changes in tumor parameters caused by multiple-day and -setting observation differences. METHODS: We present data from a pilot study in 10 soft-tissue sarcoma patients imaged with (11)C-thymidine for cellular proliferation, (18)F-fluoromisonidazole (FMISO) for tissue hypoxia, and (11)C-verapamil for P-glycoprotein activity, in comparison with (15)O-water for blood flow and (11)C-CO(2) for metabolite analysis and (18)F-FDG clinical scans. Several patients underwent repeated imaging after adriamycin-based chemotherapy. RESULTS: Quantitative imaging results showed that tumor uptake parameters vary between patients and with respect to each other in individual patients, suggesting that each patient's tumor biologic profile is unique. Specific tumor characteristics such as variable cellular proliferation, hypoxic volume, and upregulated P-glycoprotein activity were identified. CONCLUSION: This study shows that multiagent PET is feasible and yields unique and potentially complementary biologic information on individual tumors.

C11-acetate and F-18 FDG PET for men with prostate cancer bone metastases: relative findings and response to therapy.

PURPOSE OF THE REPORT: This study tested the feasibility of C11-acetate (acetate) positron emission tomography (PET) imaging to assess response to therapy in men with bone metastatic prostate cancer and compared results for disease detection and response evaluation with F-18 fluorodeoxyglucose (FDG) PET. MATERIALS AND METHODS: Men with ≥3 prostate cancer bone metastases identified by Tc-99m methylene diphosphonate (MDP) bone scintigraphy and/or computed tomography were enrolled in a prospective study of serial acetate and FDG PET imaging. Patients were imaged before and 6 to 12 weeks after initial androgen deprivation therapy for new metastatic prostate cancer or first-line chemotherapy with docetaxel for castration-resistant prostate cancer. Qualitative assessment and changes in the tumor:normal uptake ratio were used to assess response by both acetate and FDG PET. In addition, the detection of bone metastases pretherapy was compared for acetate and FDG PET. RESULTS: A total of 8 patients with documented bone metastases were imaged, of which 6 were imaged both pre- and post-therapy. Acetate PET detected bone metastases in all 8 patients, whereas FDG PET detected lesions in 6 of the 7 imaged patients. Acetate PET generally detected more metastases with a higher tumor:normal uptake ratio. Qualitative and quantitative assessments of post-treatment response correlated with composite clinical designations of response, stable disease, or progression in 6 of 6 and 5 of 6 by acetate and 4 of 5 and 3 of 5 by FDG PET, respectively. CONCLUSIONS: In this pilot study, results indicate that acetate PET holds promise for response assessment of prostate cancer bone metastases and is complementary to FDG PET in bone metastasis detection.

Imaging of cyclosporine inhibition of P-glycoprotein activity using 11C-verapamil in the brain: studies of healthy humans.

UNLABELLED: The multiple-drug resistance (MDR) transporter P-glycoprotein (P-gp) is highly expressed at the human blood-brain barrier (BBB). P-gp actively effluxes a wide variety of drugs from the central nervous system, including anticancer drugs. We have previously demonstrated P-gp activity at the human BBB using PET of (11)C-verapamil distribution into the brain in the absence and presence of the P-gp inhibitor cyclosporine-A (CsA). Here we extend the initial noncompartmental analysis of these data and apply compartmental modeling to these human verapamil imaging studies. METHODS: Healthy volunteers were injected with (15)O-water to assess blood flow, followed by (11)C-verapamil to assess BBB P-gp activity. Arterial blood samples and PET images were obtained at frequent intervals for 5 and 45 min, respectively, after injection. After a 60-min infusion of CsA (intravenously, 2.5 mg/kg/h) to inhibit P-gp, a second set of water and verapamil PET studies was conducted, followed by (11)C-CO imaging to measure regional blood volume. Blood flow was estimated using dynamic (15)O-water data and a flow-dispersion model. Dynamic (11)C-verapamil data were assessed by a 2-tissue-compartment (2C) model of delivery and retention and a 1-tissue-compartment model using the first 10 min of data (1C(10)). RESULTS: The 2C model was able to fit the full dataset both before and during P-pg inhibition. CsA modulation of P-gp increased blood-brain transfer (K(1)) of verapamil into the brain by 73% (range, 30%-118%; n = 12). This increase was significantly greater than changes in blood flow (13%; range, 12%-49%; n = 12, P < 0.001). Estimates of K(1) from the 1C(10) model correlated to estimates from the 2C model (r = 0.99, n = 12), indicating that a short study could effectively estimate P-gp activity. CONCLUSION: (11)C-verapamil and compartmental analysis can estimate P-gp activity at the BBB by imaging before and during P-gp inhibition by CsA, indicated by a change in verapamil transport (K(1)). Inhibition of P-gp unmasks verapamil trapping in brain tissue that requires a 2C model for long imaging times; however, transport can be effectively measured using a short scan time with a 1C(10) model, avoiding complications with labeled metabolites and tracer retention.