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.

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-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.

The complex nature of research dissemination practices among public health faculty researchers.

OBJECTIVE: This study explores the variety of information formats used and audiences targeted by public health faculty in the process of disseminating research. METHODS: The authors conducted semi-structured interviews with twelve faculty members in the School of Public Health at the University of Illinois at Chicago, asking them about their research practices, habits, and preferences. RESULTS: Faculty scholars disseminate their research findings in a variety of formats intended for multiple audiences, including not only their peers in academia, but also public health practitioners, policymakers, government and other agencies, and community partners. CONCLUSION: Librarians who serve public health faculty should bear in mind the diversity of faculty's information needs when designing and improving library services and resources, particularly those related to research dissemination and knowledge translation. Promising areas for growth in health sciences libraries include supporting data visualization, measuring the impact of non-scholarly publications, and promoting institutional repositories for dissemination of research.

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.

Tandem column isolation of zirconium-89 from cyclotron bombarded yttrium targets using an automated fluidic platform: Anion exchange to hydroxamate resin columns.

The development of a tandem column purification method for the preparation of high-purity 89Zr(IV) oxalate is presented. The primary column was a macroporous strongly basic anion exchange resin on styrene divinylbenzene co-polymer. The secondary column, with an internal volume of 33 µL, was packed with hydroxamate resin. A condition of inverted selectivity was developed, whereby the 89Zr eluent solution for the primary column is equivalent to the 89Zr load solution for the secondary column. The ability to transfer 89Zr from one column to the next allows two sequential column clean-up methods to be performed prior to the final elution of the 89Zr(IV) oxalate. This approach assures delivery of high purity 89Zr product and assures a 89Zr product that is eluted in a substantially smaller volume than is possible when using the traditionally-employed single hydroxamate resin column method. The tandem column purification process has been implemented into a prototype automated fluidic system. The system is configured with on-line gamma detection so column effluents can be monitored in near-real time. The automated method was tested using seven cyclotron bombarded Y foil targets. It was found that 95.1 ±â€¯1.3% of the 89Zr present in the foils was recovered in the secondary column elution fraction. Furthermore, elution peak analysis of several 89Zr elution profile radiochromatograms made possible the determination of 89Zr recovery as a function of volume; a 89Zr product volume that contains 90% of the mean secondary column elution peak can be obtained in 0.29 ±â€¯0.06 mL (representing 86 ±â€¯5% of the 89Zr activity in the target). This product volume represents a significant improvement in radionuclide product concentration over the predominant method used in the field. In addition to the reduced 89Zr product elution volume, titrations of the 89Zr product with deferoxamine mesylate salt across two preparatory methods resulted in mean effective specific activity (ESA) values of 279 and 340 T Bq·mmole-1 and mean bindable metals concentrations ([MB]) of 13.5 and 16.7 nmole·g-1. These ESA and [MB] values infer that the 89Zr(IV) oxalate product resulting from this tandem column isolation method has the highest purity reported to date.

Hydroxamate column-based purification of zirconium-89 (89Zr) using an automated fluidic platform.

Zirconium-89 (89Zr) is a long-lived (t1/2 = 78.4h) positron-emitting isotope that is useful for positron emission tomography (PET) based diagnostic imaging using radiolabeled antibodies. Hydroxamate resin columns are predominantly used for the purification of 89Zr from cyclotron bombarded natY targets dissolved in strong HCl. 89Zr is conventionally eluted from the resin in 1M oxalic acid (H2C2O4), a complexant that is conducive to follow-on binding of 89Zr through a transchelation process to the deferoxamine siderophore. In the present study, we determined that a lower concentration of H2C2O4 eluent (0.8M) is adequate to efficiently remove 89Zr from a column containing 100mg hydroxamate resin. As a result, less buffering agents are needed to be added to the 89Zr product fraction prior to labeling. A simple automated fluidic system prototype has been developed to perform the steps required for 89Zr purification using a hydroxamate resin column (column conditioning in HCl, Y target dissolution, dissolved target solution load onto column, column washes using HCl and water, and 89Zr elution). The system performance was evaluated using several cyclotron bombarded Y targets; 89Zr product fractions demonstrated excellent chemical recoveries from these targets, with 1.0mL product volumes yielding 89±2% of the column elution peak activity and 84±2% of 89Zr recovered from the target (at EOB). These results compare favorably with previously published 89Zr product volumes and yields, despite the lower concentration of H2C2O4 eluent employed. Transchelation of resulting 89Zr product fractions was performed to assess product quality. The effective specific activity (ESA) ranged between 44(7) and 109(22) TBq·mmole-1, while the bindable metals concentration, a metric introduced for assessing and comparing product purity, ranged between 43(7) and 115(27) nmole·g-1.

A simple thick target for production of 89Zr using an 11MeV cyclotron.

The growing interest but limited availability of 89Zr for PET led us to test targets for the 89Y(p,n) reaction. The goal was an easily constructed target for an 11MeV Siemens cyclotron. Yttrium foils were tested at different thicknesses, angles and currents. A 90° foil tolerated 41µA without damage and produced ~800 MBq/h, >20mCi, an amount adequate for radiochemistry research and human doses in a widely available accelerator. This method should translate to higher energy cyclotrons.

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.

Assessment of the Effects of Age, Gender, and Exercise Training on the Cardiac Sympathetic Nervous System Using Positron Emission Tomography Imaging.

BACKGROUND: Using positron emission tomography (PET) imaging, we sought to determine whether normal age or exercise training cause changes in the cardiac sympathetic nervous system function in male or female healthy volunteers. METHODS: Healthy sedentary participants underwent PET studies before and after 6 months of supervised exercise training. Presynaptic uptake by the norepinephrine transporter-1 function was measured using PET imaging of [(11)C]-meta-hydroxyephedrine, a norepinephrine analog, and expressed as a permeability-surface area product (PSnt in mL/min/mL). Postsynaptic function was measured as ß-adrenergic receptor density (ß'max in pmol/mL tissue) by imaging the ß-receptor antagonist [(11)C]-CGP12177. Myocardial blood flow (MBF in mL/min/mL tissue) was measured by imaging [(15)O]-water. RESULTS: At baseline, there was no age difference in ß'max or MBF but PSnt declined with age (1.12±0.11 young vs 0.87±0.06 old, p = .036). Before training, women had significantly greater MBF (0.87±0.03 vs 0.69±0.03, p < .0001) and PSnt (1.14±0.08 vs 0.75±0.07, p < .001) than men. Training increased VO2 max by 13% (p < .0001), but there were no training effects on ß'max, PSnt, or MBF. Greater MBF in females and a trend to increased PSnt post-training persisted. CONCLUSION: With age, presynaptic uptake as measured by PSnt declines, but there were no differences in ß'max. Endurance training significantly increased VO2 max but did not cause any changes in the measures of cardiac sympathetic nervous system function. These findings suggest that significant changes do not occur or that current PET imaging methods may be inadequate to measure small serial differences in a highly reproducible manner.

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.

Modulation of P-glycoprotein at the Human Blood-Brain Barrier by Quinidine or Rifampin Treatment: A Positron Emission Tomography Imaging Study.

Permeability-glycoprotein (P-glycoprotein, P-gp), an efflux transporter at the human blood-brain barrier (BBB), is a significant obstacle to central nervous system (CNS) delivery of P-gp substrate drugs. Using positron emission tomography imaging, we investigated P-gp modulation at the human BBB by an approved P-gp inhibitor, quinidine, or the P-gp inducer, rifampin. Cerebral blood flow (CBF) and BBB P-gp activity were respectively measured by administration of (15)O-water followed by (11)C-verapamil. In a crossover design, healthy volunteers received quinidine and 11-29 days of rifampin treatment during different study periods. CBF and P-gp activity was measured in the absence (control; prior to quinidine treatment) and presence of P-gp modulation. At clinically relevant quinidine plasma concentrations, P-gp inhibition resulted in a 60% increase in (11)C-radioactivity distribution across the human BBB as measured by the brain extraction ratio (ER) of (11)C-radioactivity. Furthermore, the magnitude of BBB P-gp inhibition by quinidine was successfully predicted by a combination of in vitro and macaque data, but not by rat data. Although our findings demonstrated that quinidine did not completely inhibit P-gp at the human BBB, it has the potential to produce clinically significant CNS drug interactions with P-gp substrate drugs that exhibit a narrow therapeutic window and are significantly excluded from the brain by P-gp. Rifampin treatment induced systemic CYP3A metabolism of (11)C-verapamil; however, it reduced the ER by 6%. Therefore, we conclude that rifampin, at its usual clinical dose, cannot be used to induce P-gp at the human BBB to a clinically meaningful extent and is unlikely to cause inadvertent BBB-inductive drug interactions.

Publish or perish but where? What is the value of impact factors?

The impact factor (IF) of a journal is often used beyond the intent for which it was developed. Other metrics have been developed to address biases associated with IF and are described. However, the question that needs to be addressed is whether impact factors are overused to evaluate the scientifc competency and productivity of individuals or institutions.

Activity of P-Glycoprotein, a ß-Amyloid Transporter at the Blood-Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease.

UNLABELLED: Studies in animals and postmortem human brain tissue support a role for P-glycoprotein in clearance of cerebral ß-amyloid across the blood-brain barrier (BBB). We tested the hypothesis that BBB P-glycoprotein activity is diminished in Alzheimer disease (AD) by accounting for an AD-related reduction in regional cerebral blood flow (rCBF). METHODS: We compared P-glycoprotein activity in mild-AD patients (n = 9) and cognitively normal, age-matched controls (n = 9) using PET with a labeled P-glycoprotein substrate, (11)C-verapamil, and (15)O-water to measure rCBF. BBB P-glycoprotein activity was expressed as the (11)C-verapamil radioactivity extraction ratio ((11)C-verapamil brain distributional clearance, K1/rCBF). RESULTS: Compared with controls, BBB P-glycoprotein activity was significantly lower in the parietotemporal, frontal, and posterior cingulate cortices and hippocampus of mild AD subjects. CONCLUSION: BBB P-glycoprotein activity in brain regions affected by AD is reduced and is independent of rCBF. This study improves on prior work by eliminating the confounding effect that reduced rCBF has on assessment of BBB P-glycoprotein activity and suggests that impaired P-glycoprotein activity may contribute to cerebral ß-amyloid accumulation in AD. P-glycoprotein induction or activation to increase cerebral ß-amyloid clearance could constitute a novel preventive or therapeutic strategy for AD.

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.

Modeling cyclosporine A inhibition of the distribution of a P-glycoprotein PET ligand, 11C-verapamil, into the maternal brain and fetal liver of the pregnant nonhuman primate: impact of tissue blood flow and site of inhibition.

UNLABELLED: Through PET imaging, our laboratory has studied the dynamic biodistribution of (11)C-verapamil, a P-gp substrate, in the nonhuman primate Macaca nemestrina. To gain detailed insight into the kinetics of verapamil transport across the blood-brain barrier (BBB) and the blood-placental barrier (BPB), we analyzed these dynamic biodistribution data by compartmental modeling. METHODS: Thirteen pregnant macaques (gestational age, 71-159 d; term, ∼172 d) underwent PET imaging with (11)C-verapamil before and during infusion (6, 12, or 24 mg/kg/h) of cyclosporine A (CsA, a P-glycoprotein [P-gp] inhibitor). Dynamic (11)C-verapamil brain or fetal liver (reporter of placental P-gp function) activity was assessed by a 1- or 2-tissue-compartment model. RESULTS: The 1-tissue-compartment model best explained the observed brain and fetal liver distribution of (11)C-radioactivity. When P-gp was completely inhibited, the brain and fetal liver distribution clearance (K1) approximated tissue blood flow (Q); that is, extraction ratio (K1/Q) was approximately 1, indicating that in the absence of P-gp function, the distribution of (11)C-verapamil radioactivity into these compartments is limited by blood flow. The potency of CsA to inhibit P-gp was tissue-independent (maternal BBB half-maximal inhibitory concentration [IC50], 5.67 ± 1.07 µM, vs. BPB IC50, 7.63 ± 3.16 µM). CONCLUSION: We propose that on deliberate or inadvertent P-gp inhibition, the upper boundary of increase in human brain (or fetal) distribution of lipophilic drugs such as verapamil will be limited by tissue blood flow. This finding provides a means to predict the magnitude of P-gp-based drug interactions at the BBB and BPB when only the baseline distribution of the drug (i.e., in the absence of P-gp inhibition) across these barriers is available through PET. Our data suggest that P-gp-based drug interactions at the human BBB and BPB can be clinically significant, particularly for those P-gp substrate drugs for which P-gp plays a significant role in excluding the drug from these privileged compartments.

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.