The estrogen receptor α (ERα) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ERα expression with the tracer 16α-18 F-fluoro-17β-estradiol ( 18 F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of 18 F-FES PET to determine tumor ERα expression noninvasively in epithelial ovarian cancer patients. Methods: 18 F-FES PET/CT was performed shortly before cytoreductive surgery. Tumor 18 F-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. 18 F-FES PET/CT findings were compared with histology and immunohistochemistry for ERα, ERβ, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells · staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis. Results: In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor 18 F-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative 18 F-FES uptake correlated with the semiquantitative immunoscore for ERα (ρ 5 0.65, P , 0.01) and weakly with progesterone receptor expression (ρ 5 0.46, P 5 0.03) and was not associated with ERβ expression (ρ 5 0.21, P 5 0.33). The optimum threshold to discriminate ERα-positive and ERα-negative lesions was a maximum standardized uptake value greater than 1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% confidence interval, 0.70-1.00). In 2 of 7 patients with cytology/histology available at primary diagnosis and at debulking surgery, immunohistochemical ERα expression had changed over time. 18 F-FES PET was in accordance with histology at debulking surgery but not at primary diagnosis, indicating that 18 F-FES PET could provide reliable information about current tumor ERα status. Conclusion: 18 F-FES PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases noninvasively. Evaluation of the predictive value of 18 F-FES PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted.

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In atherosclerotic plaques, the risk of rupture is increased at sites of macrophage accumulation. Activated macrophages express folate receptor-β (FR-β), which can be targeted by folate coupled to radioactive ligands to visualize vulnerability. The aim of this study was to explore the presence of activated macrophages in human atherosclerotic plaques by 99m Tc-folate imaging and to evaluate whether this technique can discriminate between an M1-like and M2-like macrophage phenotype. Methods: Carotid endarterectomy specimens of 20 patients were incubated with 99m Tc-folate, imaged using micro-SPECT, and divided into 3-mm slices. The mean accumulation was calculated per slice, and the distribution of M1-like and M2-like macrophages per slice was quantified by immunohistochemical staining for CD86 as well as inducible nitric oxide synthase (iNOS) for M1 and CD163 and FR-β for M2 macrophages. Monocytes from healthy donors were differentiated toward M1-like or M2-like phenotype by in vitro culturing. Messenger RNA levels of specific M1 and M2 markers were measured by reversetranscription polymerase chain reaction and expression of FR-β, CD86, and CD163 by flow cytometry. Results: There was a heterogeneous accumulation of 99m Tc-folate in plaques (median, 2.45 [0.77-6.40] MBq/g). Slices with the highest 99m Tc-folate accumulation of each plaque showed significantly more expression of FR-β and CD163, compared with slices with the lowest 99m Tc-folate accumulation, which showed significantly more expression of iNOS. In in vitro polarized macrophages, messenger RNA expression of FR-β, mannose receptor, IL-10, and matrix metalloproteinase-9 was significantly increased in M2-like macrophages, compared with M1-like macrophages. On a receptor level, CD86 was shown to be overexpressed on M1-like macrophages whereas FR-β and CD163 were overexpressed on M2-like macrophages measured by flow cytometry. Conclusion: Higher numbers of M2-like macrophages were present in areas of high 99m Tc-folate accumulation than areas with low accumulation. It is anticipated that 99m Tcfolate imaging using SPECT as a marker for M2-like macrophages in atherosclerosis might be a good indicator for plaque vulnerability.