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A retrospective analysis was performed of preclinical and clinical data acquired during the evaluation of the estrogen receptor (ER) PET tracer 4-fluoro-11β-methoxy-16α-[18F]-fluoroestradiol (4FMFES) and its comparison with 16α-[18F]-fluoroestradiol (FES) in mice, rats, and humans with a focus on the brain uptake. Breast cancer tumor-bearing female BALB/c mice from a previous study and female Sprague-Dawley rats (control and ovariectomized) were imaged by 4FMFES or FES-PET imaging. Immediately after, low-dose CT was performed in the same bed position. Semi-quantitative analysis was conducted to extract %ID/g data. Small cohorts of mice and rats were imaged with 4FMFES in an ultra-high-resolution small animal PET scanner prototype (LabPET II). Rat brains were dissected and imaged separately with both PET and autoradiography. In parallel, 31 breast cancer patients were enrolled in a clinical phase II study to compare 4FMFES with FES for oncological assessment. Since the head was included in the field of view, brain uptake of discernable foci was measured and reported as SUVMax. Regardless of the species studied, 4FMFES and FES uptake were relatively uniform in most regions of the brain, except for bilateral foci at the base of the skull, at the midsection of the brain. Anatomical localization of the PET signal using CT image fusion indicates that the signal origins from the pituitary in all studied species. 4FMFES yielded lower pituitary uptake than FES in patients, but an inverse trend was observed in rodents. 4FMFES pituitary contrast was higher than FES in all assessed groups. High-resolution small animal imaging of the brain of rats and mice revealed a supplemental signal anterior to the pituitary, which is likely to be the medial preoptic area. Dissection data further confirmed those findings and revealed additional signals corresponding to the arcuate and ventromedial nuclei, along with the medial and cortical amygdala. 4FMFES allowed visualization of ER expression in the pituitary in humans and two different rodent species with better contrast than FES. Improvement in clinical spatial resolution might allow visualization and analysis of other ER-rich brain areas in humans. Further work is now possible to link 4FMFES pituitary uptake to cognitive functions.

BackgroundNuclear medicine is on the constant search of precision radiopharmaceutical approaches to improve patient management. Although discordant expression of the estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2) in breast cancer is a known dilemma for appropriate patient management, traditional tumor sampling is often difficult or impractical. While 2-deoxy-2[18F]fluoro-D-glucose (18F-FDG)-positron emission tomography (PET) is an option to detect subclinical metastases, it does not provide phenotype information. Radiolabeled antibodies are able to specifically target expressed cell surface receptors. However, their long circulating half-lives (days) require labeling with long-lived isotopes, such as89Zr, in order to allow sufficient time for tracer clearance from the blood compartment and to accumulate adequately in target tumors and, thus, generate high-quality PET images. The aim of this study was to develop a dual-tracer PET imaging approach consisting of a fast-clearing small molecule and a slow-clearing antibody. This approach was evaluated in a model consisting of mice harboring separate breast cancer xenografts with either an ER+/HER2− or ER−/HER2+ phenotype, comparable to human metastatic disease with intertumor heterogeneity. Lastly, the aim of our study was to determine the feasibility of specifically identifying these two important phenotypes in an acceptable time window.MethodsFemale nude mice were subcutaneously implanted on opposite shoulders with the ER+/HER2− and ER−/HER2+ MCF-7 and JIMT-1 tumor cell lines, respectively. A second model was developed consisting of mice implanted orthotopically with either MCF-7 or JIMT-1 cells. Pharmacokinetic analysis, serial PET imaging, and biodistribution were first performed for [89Zr]Zr-DFO-trastuzumab (89Zr-T) up to 8 days post-injection (p.i.) in JIMT-1 bearing mice. Region-of-interest (ROI) and biodistribution-derived uptake (% injected-activity/gram of tissue [%IA/g]) values and tumor-to-background ratios were obtained. Results were compared in order to validate ROI and identify early time points that provided high contrast tumor images. For the dual-tracer approach, cohorts of tumor-bearing mice were then subjected to sequential tracer PET imaging. On day 1, mice were administered 4-fluoro-11β-methoxy-16α-[18F]-fluoroestradiol (4FMFES) which targets ER and imaged 45 min p.i. This was immediately followed by the injection of89Zr-T. Mice were then imaged on day 3 or day 7. ROI analysis was performed, and uptake was calculated in tumors and selected healthy organs for all radiotracers. Quality of tumor targeting for all tracers was evaluated by tumor contrast visualization, tumor and normal tissue uptake, and tumor-to-background ratios.Results89Zr-T provided sufficiently high tumor and low background uptake values that furnished high contrast tumor images by 48 h p.i. For the dual-tracer approach, 4FMFES provided tumor uptake values that were significantly increased in MCF-7 tumors. When89Zr-T-PET was combined with18F-4FMFES-PET, the entire dual-tracer sequential-imaging procedure provided specific high-quality contrast images of ER+/HER2− MCF-7 and ER−/HER2+ JIMT-1 tumors for 4FMFES and89Zr-T, respectively, as short as 72 h from start to finish.ConclusionsThis protocol can provide high contrast images of tumors expressing ER or HER2 within 3 days from injection of 4FMFES to final scan of89Zr-T and, hence, provides a basis for future dual-tracer combinations that include antibodies.

Haptic technologies are widely used in multimedia entertainment to psychophysiologically enhance user experience. Psychometric-based research regarding vibrokinetic stimulation during multimedia viewing supports this notion. However, scant neurophysiological evidence exists to verify this effect. Using a between groups design with source-localized electroencephalography, the present study analyzed the effect of high fidelity vibrokinetic (HFVK) stimulation during passive multimedia interaction (i.e. watching a haptically enhanced movie) on self-reported emotional state and intercortical theta coherence. Results indicate that HFVK increases emotional reactivity in association with increased interhemispheric coherence between the right inferiortemporal gyrus and the left insular cortex, thereby conferring neurophysiological support for the efficaciousness of HFVK to enhance emotional response during movie watching.

In this study, the preliminary results of a phase II clinical trial investigating the use of the Estrogen Receptor (ER) targeting PET tracer 4-fluoro-11β-methoxy-16α-[18F]fluoroestradiol (18F-4FMFES) and [18F]-fluorodeoxyglucose (18F-FDG)-PET in endometrial cancers will be accounted. In parallel, non-invasive interventions will be attempted to slow down progression of 18F-4FMFES metabolites in the intestines to reduce abdominal background. Methods: In an ongoing study, 25 patients that received prior pathological confirmation of an ER+ endometrial cancer or endometrial intraepithelial neoplasia agreed to participate to the ongoing clinical trial. Patients were scheduled for 18F-FDG and 18F-4FMFES PET/CT imaging in random order and within 2 weeks. Patients were administered either 4 mg loperamide per os before 18F-4FMFES tracer injection or repeated intravenous injection of 20 mg hyoscine N-butylbromide during 18F-4FMFES-PET/CT. Regions-of-interest (ROIs) covering the whole abdomen and excluding the liver, bladder and uterus were drawn for the 18F-4FMFES-PET images, and a threshold of SUV > 4 was applied. The volume of the resulting region was compared between the different interventions to estimate the extent of the intestinal background. Results: Repeated injection of hyoscine N-butylbromide substantially reduced the intestinal background volume, whereas loperamide had a significant but moderate effect. 18F-4FMFES tumor uptake ranged between SUVmax 3.0 and 14.4 (9.4 ± 3.2), whereas 18F-FDG uptake spreaded between SUVmax 0 and 22.0 (7.5 ± 5.1). Tumor-to-background ratio were significantly higher for 18F-4FMFES (16.4 ± 5.4) than for 18F-FDG (7.4 ± 4.6). Significant differences were observed between grade 1 and higher-grade tumors concerning 18F-4FMFES uptake and contrast. 18F-FDG uptake, and the 18F-FDG/18F-4FMFES uptake ratio. Conclusion: It is possible to improve 18F-4FMFES abdominal background using hyoscine N-butylbromide. Both 18F-FDG and 18F-4FMFES-PET are suitable for detection of ER+ endometrial cancers, although 18F-4FMFES yielded a better tumor contrast than 18F-FDG.

After encouraging preclinical and human dosimetry results for the novel estrogen receptor (ER) PET radiotracer 4-fluoro-11β-methoxy-16α-18F-fluoroestradiol (18F-4FMFES), a phase II clinical trial was initiated to compare the PET imaging diagnostic potential of 18F-4FMFES with that of 16α-18F-fluoroestradiol (18F-FES) in ER-positive (ER+) breast cancer patients. Methods: Patients diagnosed with ER+ breast cancer (n = 31) were recruited for this study, including 6 who underwent mastectomy or axillary node dissection. For each patient, 18F-FES and 18F-4FMFES PET/CT scans were done sequentially (within a week) and in random order. One hour after injection of either radiotracer, a head-to-thigh static scan with a 2-min acquisition per bed position was obtained. Blood samples were taken at different times after injection to assess each tracer metabolism by reverse-phase thin-layer chromatography. The SUVmean of nonspecific tissues and the SUVmax of the tumor were evaluated for each detected lesion, and tumor-to-nonspecific organ ratios were calculated. Results: Blood metabolite analysis 60 min after injection of the tracer showed a 2.5-fold increase in metabolic stability of 18F-4FMFES over 18F-FES. Although for most foci 18F-4FMFES PET had an SUVmax similar to that of 18F-FES PET, tumor contrast improved substantially in all cases. Lower uptake was consistently observed in nonspecific tissues for 18F-4FMFES, notably a 4-fold decrease in blood-pool activity as compared with 18F-FES. Consequently, image quality was considerably improved using 18F-4FMFES, with lower overall background activity. As a result, 18F-4FMFES successfully identified 9 more lesions than 18F-FES. Conclusion: This phase II study with ER+ breast cancer patients showed that 18F-4FMFES PET achieves a lower nonspecific signal and better tumor contrast than 18F-FES PET, resulting in improved diagnostic confidence and lower false-negative diagnoses.

Permafrost occupies 20 million square kilometres of Earth's high-latitude and high-altitudelandscapes. These regions are sensitive to climate change and human activities; hence,permafrost research is of considerable scientific and societal importance. However, the resultsof this research are generally not known by the general public. Communicating scientificconcepts is an increasingly important task in the research world. Different ways to engagelearners and incorporate narratives in teaching materials exist, yet they are generallyunderused. Here we report on an international scientific outreach project called “FrozenGround Cartoons”, which aims at making permafrost science accessible and fun for students,teachers, and parents through the creation of comic strips. We present the context in whichthe project was initiated, and recent education and outreach activities. The future phases ofthe project primarily involve a series of augmented reality materials, such as maps, photos,videos, and 3D drawings. With this project we aim to foster understanding of permafrostresearch among broader audiences, inspire future permafrost researchers, and raise publicand science community awareness of polar science, education, outreach, and engagement.

Despite the high interest and concern due to an increasing incidence and death rate, patients who develop muscle invasive bladder cancer (MIBC) have few options available. However, the past decade has produced many candidate bladder tumor-specific markers but further development of these markers is still needed for creating effective targeted medications to solve this urgent need. Interleukin-5 receptor α-subunit (IL-5Rα) has recently been reported to be involved in MIBC progression. Thus, we aimed to validate IL-5Rα as a target for antibody-conjugates to better manage patients with MIBC. Patients were recruited and their tumors were processed for IL-5Rα immunohistochemical analysis. NOD/SCID mice were also heterotopically implanted with the human MIBC HT-1376 and HT-B9 cell lines and established xenografts immunohistochemically evaluated for IL-5Rα and compared against patient tumors. Using the mAb A14, an antibody-drug conjugate (ADC) and a radiolabeled immunoconjugate (RIC) were developed by conjugating to vinblastine and to the positron emitter copper-64 ( 64 Cu), respectively. As a proof-of-concept for ADC and RIC efficacy, in vitro cytotoxicity and in vivo positron emission tomography (PET) imaging in tumor-bearing mice were performed, respectively. In addition, as rapid internalization and accumulation are important components for effective antibody-conjugates, we evaluated these aspects in response to IL-5 and 64 Cu-A14 treatments. Our findings suggest that although IL-5Rα protein expression is preferentially increased in MIBC, it is rapid IL-5Rα-mediated internalization allowing vinblastine-A14 to have cytotoxic activity and 64 Cu-A14 to detect MIBC tumors in vivo. This is the first report to elucidate the potential of IL-5Rα as an attractive MIBC target for antibody-conjugate applications. Refereed/Peer-reviewed

Purpose Trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) is a new drug intended to be used for the management of visceral pain in patients undergoing sedation-free, full colonoscopy. The objectives of this Phase I, single-center, randomized, double-blinded, placebo-controlled, integrated study were to evaluate the safety and pharmacokinetics of GIC-1001 after single ascending doses (SAD) and multiple ascending doses (MAD) and to evaluate the influence of food on the pharmacokinetics in healthy volunteers. Methods GIC-1001 or placebo was orally administered to 80 healthy male and female subjects (non- or ex-smokers) aged 18 to 50 years with a body mass index between 18.5 and 30 kg/m 2 . The SAD portion of the study consisted of 5 cohorts with dose levels of 125 to 1000 mg. The MAD portion included 4 cohorts in which subjects received TID doses of 125 to 500 mg over 7 days (19 consecutive doses). Subjects were randomized (6:2) to receive GIC-1001 or placebo. The third portion of the study included a single 375-mg dose of GIC-1001 in a randomized, 2-period, crossover design to assess the influence of food (n = 8 subjects). Safety was evaluated by using adverse events (AEs), vital signs, ECGs, physical examination, cardiac monitoring, and laboratory test results. The analytes were assayed by using validated HPLC-MS/MS methods. Pharmacokinetic parameters were evaluated by using a noncompartmental analysis, and regression models were used to assess dose linearity. To evaluate the effect of food, 90% CIs of the ratio of geometric least squares means from ln-transformed pharmacokinetic parameters were calculated. Findings The most frequently reported drug-related AEs were of nervous system and gastrointestinal origin. The most common AEs included headache, somnolence, and nausea. After single-dose administration, T max of trimebutine ranged from 1.0 to 1.5 hours. C max and AUC T were linear (nonlinearity P ≥ 0.05) and proportional ( P max and AUC of trimebutine; the ratio of geometric least squares means (90% CI) were 140% (84–234) and 174% (138–221), respectively. In the MAD study portion, the T max of trimebutine ranged from 0.5 to 2 hours and AUC τ increased from 38 to 170 ng · h/mL. AUC τ and C max were linear and proportional over the studied dose range. Implications GIC-1001 was well tolerated, and its safety profile was similar to that of placebo. Pharmacokinetics of GIC-1001 and its metabolites were mainly linear and proportional over the studied dose ranges. Steady state was generally considered to be reached after 3 days. Food consumption affected the pharmacokinetic profile of the analytes differently. (ClinicalTrials.gov identifier: NCT01738425.)

218 Objectives: Several studies have shown that liver tumor burden (LTB), estimated by morphological modalities, such as CT and MR, is a significant factor for management and prognosis in patients with neuroendocrine tumors (NETs). PET/CT using 68Ga-DOTATOC or 18F-FDG, as a functional imaging tool, has been widely used in NETs, which might provide additional information for predicting prognosis. The aim of this study was to investigate the prognostic performance of DOTATOC-PET/CT and FDG-PET/CT in comparison to the morphological imaging modalities. Methods: We retrospectively analyzed 31 patients (male:female=17:14, 22-84 y.o.) with pancreatic NETs who had undergone DOTATOC-PET/CT and had been diagnosed to have liver metastasis by some imaging modalities. All patients had enhanced CT and/or MRI within a month of DOTATOC-PET/CT, and 26 patients FDG-PET/CT. We assessed LTB by a visual scale (0-10%, 10-25%, 25-50%, 50%-) on CT or MRI images. Then, we measured maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion uptake (TLU) on DOTATOC-PET/CT or total lesion glycolysis (TLG) on FDG-PET/CT for all metastatic liver tumors or all lesions in a whole body. In addition, the SUVmax ratio, MTV ratio, and TLU ratio, defined as a value in FDG-PET/CT divided by a value in DOTATOC-PET/CT, were calculated. The progression-free survival (PFS) and the overall survival (OS) were evaluated during their follow-up periods (8-83mo). The Kaplan-Meier analysis with the log-rank test was used to estimate and compare the correlation between each imaging parameter and PFS or OS. Results: On CT and/or MRI (n=31), LTB was significantly negatively correlated with PFS (p=0.003) and OS (p=0.007) [Fig. 1, 2]. On DOTATOC-PET/CT (n=31), 27 patients had DOTATOC-avid liver metastases and 30 patients had DOTATOC-avid lesions. The absence of DOTATOC-avid lesions was significantly negatively correlated with OS (p=0.041), although the number of the non-avid group was only one. Among the DOTATOC-PET/CT parameters, SUVmax, MTV, TLU for liver metastases and MTV for all lesions were significantly negatively correlated with PFS (p=0.003, p=0.005, p=0.006, p

The aim of this study was to compare the in vivo stability, uptake, and positron emission tomography (PET) imaging performance of a novel estrogen receptor PET tracer, 4-fluoro-11β-methoxy-16α-[(18)F]fluoroestradiol (4FMFES), with 16α-[(18)F]fluoroestradiol (FES).MC7-L1 and MC4-L2 (ER+) cell lines and their ERα-knockdown variants (ERαKD) were implanted subcutaneously in Balb/c mice. After 21 days, mice were imaged using either FES or 4FMFES. One hour post-injection, static images were acquired for 30 min and the tumor %ID/g uptake values were derived. Biodistribution data were also obtained 1 h following the injection of either FES or 4FMFES. Blood samples were taken at different times and analyzed on thin-layer chromatography to quantify the presence of radiometabolites for each radiotracer. To assess specific targeting to the estrogen receptors, mice bearing only ER+ tumors were treated with the competitive ER inhibitor fulvestrant 48 h prior to imaging with 4FMFES.Metabolic stability was found to be similar for both tracers in mice. Both FES and 4FMFES differentiated ER+ tumors from ERαKD tumors in biodistribution and PET imaging studies. 4FMFES achieved a significantly higher %ID/g uptake in ER+ tumors and MC4-L2 ERαKD tumors than FES in the PET imaging studies. Also, tumor-to-background ratio was higher in ER+ tumors using 4FMFES compared to FES. Dissection data showed a significantly higher %ID/g in all tested cell lines and ER-rich tissues using 4FMFES versus FES. Fulvestrant-treated mice had either low or undetectable tumor uptake.In a tumor-bearing mouse model, 4FMFES achieves better specific tumor uptake and better contrast than FES, making it a promising candidate for ER imaging.

Background The estrogen receptor α (ERα) is known to play an important role in the modulation of tumor response to hormone therapy. In this work, the effect of different hormone therapies on tumors having different ERα expression levels was followed up in vivo in a mouse model by PET imaging using 2-deoxy-2-[18F]fluoro-d-glucose (FDG) and [11C]-methionine ([11C]-MET). A new model of MC7-L1 ERα-knockdown (ERαKD) tumor cell lines was designed as a negative estrogen receptor control to follow up the effects of changes in ERα expression on the early metabolic tumor response to different hormone therapies. Methods MC7-L1 (ER+) and MC7-L1 ERα-knockdown cell lines were implanted subcutaneously in Balb/c mice and allowed to grow up to 4 mm in diameter. Animals were separated into 4 groups (n = 4 or 5) and treated with a pure antiestrogen (fulvestrant), an aromatase inhibitor (letrozole), a selective estrogen receptor modulator (tamoxifen), or not treated (control). Tumor metabolic activity was assessed by PET imaging with FDG and [11C]-MET at days 0 (before treatment), 7, and 14 after the treatment. Tumor uptake of each radiotracer in %ID/g was measured for each tumor at each time point and compared to tumor growth. Quantitative PCR (qPCR) was performed to verify the expression of breast cancer-related genes (ERα, ErbB2, progesterone receptor (PR), and BRCA1) in each tumor cell lines. Results While both ER+ and ERαKD tumors had similar uptake of both radiotracers without treatment, higher uptake values were generally seen in ERαKD tumors after 7 and 14 days of treatment, indicating that ERαKD tumors behave in a similar fashion as hormone-unresponsive tumors. Furthermore, the ERα-specific downregulation induced a slight PR expression decrease and overexpression of BRCA1 and ErbB2. Conclusion The results indicate that the proposed ER+/ERαKD tumor-bearing mouse model is suitable to test pure antiestrogen and aromatase inhibitor therapies in vivo in a preclinical setting and could help to elucidate the impact of ERα levels on tumor response to hormone therapy.

Introduction The purpose of this study was to develop a noninvasive model in tumor-bearing mice to investigate the use of 16α-[ 18 F]fluoro-17β-estradiol (FES) positron emission tomography (PET) imaging as a tool to discriminate between tumors having different estrogen receptor (ER) α status. Methods MC7-L1 and MC4-L2 murine mammary adenocarcinoma cell lines (ER+) received a small hairpin RNA targeting the ERα gene by lentiviral infection. In vitro assessment of ERα levels of the new cell lines (MC7-L1 and MC4-L2 ERα-knockdown; ERαKD), compared to the parental cell lines, was performed by immunoblotting (−75% ERα protein) and binding assays (−50% estrogen binding). These cell lines were implanted subcutaneously in Balb/c mice and allowed to grow up to a volume of at least 20 mm 3 . FES and [ 18 F]fluorodeoxyglucose (FDG) PET images were acquired to measure FES and FDG uptake in the various tumors. Results FES uptake as assessed by PET imaging was 1.06±0.21 percent injected dose per gram of tissue (%ID/g) for MC7-L1 tumors and 0.47±0.08 %ID/g for MC7-L1 ERαKD tumors. MC4-L2 tumors had a FES uptake of 1.03±0.30 %ID/g, whereas its ERαKD equivalent was 0.51±0.19 %ID/g. Each ERαKD tumor had a significantly lower %ID/g value, by ∼50%, than its ER+ counterpart. Biodistribution studies confirmed these findings and gave %ID/g values that were not significantly different from PET imaging data. FDG PET showed no significant uptake difference between the ER+ and ERαKD tumors, indicating that the metabolic phenotype of the ERαKD cell lines was not altered. Conclusion FES PET imaging was able to reliably differentiate between tumors having differences in their ERα expression in vivo, in a mouse model. Quantitative data obtained by FES PET were in concordance with biodistribution studies and in vitro assays. It is concluded that FES PET imaging can likely be used to monitor subtle ER status changes during the course of hormone therapy.

A Boolean value of given a priori probability distribution is transmitted to a deciding agent by several processes. Each process fails independently with given probability, and faulty processes behave in a Byzantine way. A deciding agent has to make a decision concerning the transmitted value on the basis of messages obtained by processes. We construct a deterministic decision strategy which has the provably highest probability of correctness. It computes the decision in time linear in the number of processes.

A monolithic optoelectronic chip containing multiple emission wavelength laser diodes has been developed. The semiconductor quantum well lasers have Fabry-Perot cavities of 500 micrometers in length. Electrical insulation between individual integrated devices has been achieved by wet etching the top contact layer and by a lift-off of the surface metal contact between the different lasers. The electroluminescence peak emission spectra of the integrated laser diodes has been shifted over a 25 nm range and 74 nm for discrete devices. Blueshifting of the emission wavelength has been achieved by quantum well intermixing using an industrial low energy ion implanter to generate point defects and a rapid thermal annealer to promote interdiffusion of the barrier and quantum well atoms during the recrystallization anneal. Phosphorus ions were implanted with an energy of 360 keV to precisely defined regions of the heterostructure with SiO2 serving as a masking material. Thus reference and intermixed regions were integrated on a single component. Integrated and discrete laser diodes have been assessed in terms of threshold currents and emission wavelengths.© (1998) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.