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PURPOSE: Clearance of brain waste in the cerebrospinal fluid (CSF) through the meningeal lymphatic vessels (mLV) has been evaluated mostly through the fluorescent imaging which has inherent limitations in the context of animal physiology and clinical translatability. The study aimed to establish molecular imaging for the evaluation of mLV clearance function. METHODS: Radionuclide imaging after intrathecal (IT) injection was acquired in C57BL/6 mice of 2–9 months. The distribution of [(99m)Tc]Tc-diethylenetriamine pentaacetate (DTPA) and [(64)Cu]Cu-human serum albumin (HSA) was comparatively evaluated. Evans Blue and [(64)Cu]Cu-HSA were used to evaluate the distribution of tracer under various speed and volume conditions. RESULTS: [(99m)Tc]Tc-DTPA is not a suitable tracer for evaluation of CSF clearance via mLV as no cervical lymph node uptake was observed while it was cleared from the body. A total volume of 3 to 9 μL at an infusion rate of 300 to 500 nL/min was not sufficient for the tracer to reach the cranial subarachnoid space and clear throughout the mLV. As a result, whole-body positron emission tomography imaging using [(64)Cu]Cu-HSA at 700 nL/min, to deliver 6 μL of injected volume, was set for characterization of the CSF to mLV clearance. Through this protocol, the mean terminal CSF clearance half-life was measured to be 123.6 min (range 117.0–135.0) in normal mice. CONCLUSIONS: We established molecular imaging to evaluate CSF drainage through mLV using [(64)Cu]Cu-HSA. This imaging method is expected to be extended in animal models of dysfunctional meningeal lymphatic clearance and translational research for disease-modifying therapeutic approaches. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13139-022-00746-6.

With advances in computational models, the cellular landscape can be tracked in various tissues using spatial transcriptomics. Since many single-cell RNA-seq (scRNA-seq) data have been obtained after cell sorting, such as when investigating immune cells, integrating these singlecell data with spatial data is limited due to a mismatch of cell types composing the two datasets. Here, we present a method, spSeudoMap, which utilizes sorted scRNA-seq data to train a model for predicting cell types of spatial spots by creating virtual cell mixtures that closely mimic the gene expression profile of spatial transcriptomic data. To overcome the mismatch issue, the cell type exclusively present in the spatial data, pseudotype, was defined. The proportion of pseudotype cells and virtual expression profiles in the cell mixture was determined by pseudobulk transcriptomes. The simulated cell mixture was considered a reference dataset, and the model that predicts the cell composition of the mixture was trained to predict the cell fraction of the spatial data using domain adaptation. First, spSeudoMap was evaluated in human and mouse brain tissues, and the main region-specific neuron types extracted from single-cell data could be precisely mapped to the expected anatomical locations. Moreover, the method was applied to human breast cancer data and described the spatial distribution of immune cell subtypes and their interactions in heterogeneous tissue. Taken together, spSeudoMap is a platform that predicts the spatial composition of cell subpopulations using sorted scRNA-seq data, and it may help to clarify the roles of a few but crucial cell types.

Background: We aimed to evaluate the reliability and feasibility of visual grading systems and various quantitative indexes of [99mTc]Tc-DPD imaging for cardiac amyloidosis (CA).Methods: Patients who underwent [99mTc]Tc-DPD imaging with suspicion of CA were enrolled. On the planar image, myocardial uptake was visually graded using Perugini’s and Dorbala’s methods (PS and DS). As [99mTc]Tc-DPD indexes, heart-to-whole body ratio (H/WB) and heart-to-contralateral lung ratio (H/CL) were measured on planar image. SUVmax, SUVmean, total myocardial uptake (TMU), and C-index were measured on SPECT/CT. Inter-observer agreement of the indexes and their association with visual grading and clinical factors were evaluated.Results: A total of 152 [99mTc]Tc-DPD images, of which 18 were positive, were analyzed. Inter-observer agreement was high for both DS (k = 0.95) and PS (k = 0.96). However, DS showed a higher correlation with quantitative indexes than PS. Inter-observer agreement was also high for SPECT/CT indexes, particularly SUVmax. SUVmax was significantly different between different DS groups (P = 0.014–0.036), and showed excellent correlations with H/WB and H/CL (r = 0.898 and 0.910). SUVmax also showed significant differences between normal, AL, and ATTR pathology (P = 0.022–0.037), and a significant correlation with extracellular volume on cardiac MRI (r = 0.772, P < 0.001).Conclusions: DS is a visual grading system for CA that is more significantly matched with quantitative indexes than PS. SUVmax is a reliable quantitative index on SPECT/CT, with a high inter-observer agreement, correlations with visual grade and cardiac MRI findings.

Background High levels of 18F-fluorodeoxyglucose (18F-FDG) tumor uptake are associated with worse prognosis in patients with non-small cell lung cancer (NSCLC). Meanwhile, high levels of immune cell infiltration in primary tumor have been linked to better prognosis in NSCLC. We conducted this study for precisely stratified prognosis of the lung adenocarcinoma patients using the integration of 18F-FDG positron emission tomography (PET) parameters and infiltrating immune cell scores as assessed by a genomic analysis. Results Using an RNA sequencing dataset, the patients were divided into three subtype groups. Additionally, 24 different immune cell scores and cytolytic scores (CYT) were obtained. In 18F-FDG PET scans, PET parameters of the primary tumors were obtained. An ANOVA test, a Chi-square test and a correlation analysis were also conducted. A Kaplan–Meier survival analysis with the log-rank test and multivariable Cox regression test was performed to evaluate prognostic values of the parameters. The terminal respiratory unit (TRU) group demonstrated lower 18F-FDG PET parameters, more females, and lower stages than the other groups. Meanwhile, the proximal inflammatory (PI) group showed a significantly higher CYT score compared to the other groups (P = .001). Also, CYT showed a positive correlation with tumor-to-liver maximum standardized uptake value ratio (TLR) in the PI group (P = .027). A high TLR (P = .01) score of 18F-FDG PET parameters and a high T follicular helper cell (TFH) score (P = .005) of immune cell scores were associated with prognosis with opposite tendencies. Furthermore, TLR and TFH were predictive of overall survival even after adjusting for clinicopathologic features and others (P = .024 and .047). Conclusions A high TLR score was found to be associated with worse prognosis, while high CD8 T cell and TFH scores predicted better prognosis in lung adenocarcinoma. Furthermore, TLR and TFH can be used to predict prognosis independently in patients with lung adenocarcinoma.

Background Neural stem cells (NSCs) have the ability to generate a variety of functional neural cell types and have a high potential for neuronal cell regeneration and recovery. Thus, they been recognized as the best source of cell therapy for neurodegenerative diseases, such as Parkinson’s disease (PD). Owing to the possibility of paracrine effect-based therapeutic mechanisms and easier clinical accessibility, extracellular vesicles (EVs), which possess very similar bio-functional components from their cellular origin, have emerged as potential alternatives in regenerative medicine. Material and methods EVs were isolated from human fibroblast (HFF) and human NSC (F3 cells). The supernatant of the cells was concentrated by a tangential flow filtration (TFF) system. Then, the final EVs were isolated using a total EV isolation kit. Results In this study, we demonstrate the potential protective effect of human NSC-derived EVs, showing the prevention of PD pathologies in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo mouse models. Human NSC and F3 cell (F3)-derived EVs reduced the intracellular reactive oxygen species (ROS) and associated apoptotic pathways. In addition, F3-derived EVs induced downregulation of pro-inflammatory factors and significantly decreased 6-OHDA-induced dopaminergic neuronal loss in vivo. F3 specific microRNAs (miRNAs) such as hsa-mir-182-5p, hsa-mir-183-5p, hsa-mir-9, and hsa-let-7, which are involved in cell differentiation, neurotrophic function, and immune modulation, were found in F3-derived EVs. Conclusions We report that human NSC-derived EVs show an effective neuroprotective property in an in vitro transwell system and in a PD model. The EVs clearly decreased ROS and pro-inflammatory cytokines. Taken together, these results indicate that NSC-derived EVs could potentially help prevent the neuropathology and progression of PD. Graphical Abstract

PURPOSE: The precise quantification of dopamine transporter (DAT) density on N-(3-[(18)F]Fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane positron emission tomography ([(18)F]FP-CIT PET) imaging is crucial to measure the degree of striatal DAT loss in patients with parkinsonism. The quantitative analysis requires a spatial normalization process based on a template brain. Since the spatial normalization method based on a delayed-phase PET has limited performance, we suggest an early-phase PET-based method and compared its accuracy, referring to the MRI-based approach as a gold standard. METHODS: A total of 39 referred patients from the movement disorder clinic who underwent dual-phase [(18)F]FP-CIT PET and took MRI within 1 year were retrospectively analyzed. The three spatial normalization methods were applied for quantification of [(18)F]FP-CIT PET-MRI-based anatomical normalization, PET template-based method based on delayed PET, and that based on early PET. The striatal binding ratios (BRs) were compared, and voxelwise paired t tests were implemented between different methods. RESULTS: The early image-based normalization showed concordant patterns of putaminal [(18)F]FP-CIT binding with an MRI-based method. The BRs of the putamen from the MRI-based approach showed higher agreement with early image- than delayed image-based method as presented by Bland-Altman plots and intraclass correlation coefficients (early image-based, 0.980; delayed image-based, 0.895). The voxelwise test exhibited a smaller volume of significantly different counts in putamen between brains processed by early image and MRI compared to that between delayed image and MRI. CONCLUSION: The early-phase [(18)F]FP-CIT PET can be utilized for spatial normalization of delayed PET image when the MRI image is unavailable and presents better performance than the delayed template-based method in quantitation of putaminal binding ratio.

Amyloid PET which has been widely used for noninvasive assessment of cortical amyloid burden is visually interpreted in the clinical setting. As a fast and easy-to-use visual interpretation support system, we analyze whether the deep learning–based end-to-end estimation of amyloid burden improves inter-reader agreement as well as the confidence of the visual reading. A total of 121 clinical routines [18F]Florbetaben PET images were collected for the randomized blind-reader study. The amyloid PET images were visually interpreted by three experts independently blind to other information. The readers qualitatively interpreted images without quantification at the first reading session. After more than 2-week interval, the readers additionally interpreted images with the quantification results provided by the deep learning system. The qualitative assessment was based on a 3-point BAPL score (1: no amyloid load, 2: minor amyloid load, and 3: significant amyloid load). The confidence score for each session was evaluated by a 3-point score (0: ambiguous, 1: probably, and 2: definite to decide). Inter-reader agreements for the visual reading based on a 3-point scale (BAPL score) calculated by Fleiss kappa coefficients were 0.46 and 0.76 for the visual reading without and with the deep learning system, respectively. For the two reading sessions, the confidence score of visual reading was improved at the visual reading session with the output (1.27 ± 0.078 for visual reading-only session vs. 1.66 ± 0.63 for a visual reading session with the deep learning system). Our results highlight the impact of deep learning–based one-step amyloid burden estimation system on inter-reader agreement and confidence of reading when applied to clinical routine amyloid PET reading.

We investigated the relationship of physical activity with dietary habits and quality of life (QoL) in breast cancer survivors in accordance with the recommendations of the American Cancer Society. Data of 928 breast cancer survivors were obtained from the KROG 14-09 study to measure QoL in early phase after adjuvant radiotherapy. According to the extent of physical activity, survivors were divided into four groups: inactivity (0–149 min/week, N = 144), regular activity (150–450 min/week, N = 309), moderate activity (451–900 min/week, N = 229), and marked activity (901–1800 min/week, N = 164) excluding hyperactivity (> 1800 min/week, N = 82) as it is a difficult condition to recommend to survivors. Global physical activity questionnaire, 5-dimensional questionnaire by EuroQoL (EQ-5D-3L), QoL Questionnaire–breast cancer (QLQ-BR23) from EORTC, and dietary habits were surveyed. A linear-to-linear association test for EQ-5D-3L and Kruskal–Wallis analysis for QLQ-BR23 and dietary habit were conducted. Overall, 15.5% respondents (144/928) were classified as physically inactive. The trends of frequent intake of fruits (p = 0.001) and vegetable (p = 0.005) and reluctance toward fatty food (p

PURPOSE: EGFR-mutation (EGFR-mt) is a major oncogenic driver mutation in lung adenocarcinoma (ADC) and is more often observed in Asian population. In lung ADC, some radiomics parameters of FDG PET have been reported to be associated with EGFR-mt. Here, the associations between EGFR-mt and PET parameters, particularly asphericity (ASP), were evaluated in Asian population. METHODS: Lung ADC patients who underwent curative surgical resection as the first treatment were retrospectively enrolled. EGFR mutation was defined as exon 19 deletion and exon 21 point mutation and was evaluated using surgical specimens. On FDG PET, image parameters of maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and ASP were obtained. The parameters were compared between EGFR-mt and wild type (EGFR-wt) groups, and the relationships between these PET parameters and EGFR-mt were evaluated. RESULTS: A total of 64 patients (median age 66 years, M:F = 34:30) were included in the analysis, and 29 (45%) patients showed EGFR-mt. In EGFR-mt group, all the image parameters of SUVmax, MTV, TLG, and ASP were significantly lower than in EGFR-wt group (all adjusted P

Hyperbolic disc embedding and k-core percolation reveal the hierarchical structure of functional connectivity on resting-state fMRI (rsfMRI). Using 180 normal adults’ rsfMRI data from the human connectome project database, we visualized inter-voxel relations by embedding voxels on the hyperbolic space using the $${\mathbb{S}}^{1} /{\mathbb{H}}^{2}$$ S 1 / H 2 model. We also conducted k-core percolation on 30 participants to investigate core voxels for each individual. It recursively peels the layer off, and this procedure leaves voxels embedded in the center of the hyperbolic disc. We used independent components to classify core voxels, and it revealed stereotypes of individuals such as visual network dominant, default mode network dominant, and distributed patterns. Characteristic core structures of resting-state brain connectivity of normal subjects disclosed the distributed or asymmetric contribution of voxels to the kmax-core, which suggests the hierarchical dominance of certain IC subnetworks characteristic of subgroups of individuals at rest.

Background Quantum dots (QDs) have been used as fluorophores in various imaging fields owing to their strong fluorescent intensity, high quantum yield (QY), and narrow emission bandwidth. However, the application of QDs to bio-imaging is limited because the QY of QDs decreases substantially during the surface modification step for bio-application. Results In this study, we fabricated alloy-typed core/shell CdSeZnS/ZnS quantum dots (alloy QDs) that showed higher quantum yield and stability during the surface modification for hydrophilization compared with conventional CdSe/CdS/ZnS multilayer quantum dots (MQDs). The structure of the alloy QDs was confirmed using time-of-flight medium-energy ion scattering spectroscopy. The alloy QDs exhibited strong fluorescence and a high QY of 98.0%. After hydrophilic surface modification, the alloy QDs exhibited a QY of 84.7%, which is 1.5 times higher than that of MQDs. The QY was 77.8% after the alloy QDs were conjugated with folic acid (FA). Alloy QDs and MQDs, after conjugation with FA, were successfully used for targeting human KB cells. The alloy QDs exhibited a stronger fluorescence signal than MQD; these signals were retained in the popliteal lymph node area for 24 h. Conclusion The alloy QDs maintained a higher QY in hydrophilization for biological applications than MQDs. And also, alloy QDs showed the potential as nanoprobes for highly sensitive bioimaging analysis. Graphical Abstract

Abstract Background Dynamically altered microglia play an important role in the progression of Alzheimer’s disease (AD). Here, we found a close association of the metabolic reconfiguration of microglia with increased hippocampal glucose uptake on [18F]fluorodeoxyglucose (FDG) PET. Methods We used an AD animal model, 5xFAD, to analyze hippocampal glucose metabolism using both animal FDG PET and ex vivo FDG uptake test. Cells of the hippocampus were isolated to perform single-cell RNA-sequencing (scRNA-seq). The molecular features of cells associated with glucose metabolism were analyzed at a single-cell level. In order to apply our findings to human brain imaging study, brain FDG PET data obtained from the Alzheimer’s Disease Neuroimaging Initiative were analyzed. FDG uptake in the hippocampus was compared according to the diagnosis, AD, mild cognitive impairment, and controls. The correlation analysis between hippocampal FDG uptake and soluble TREM2 in cerebrospinal fluid was performed. Results In the animal study, 8- and 12-month-old 5xFAD mice showed higher FDG uptake in the hippocampus than wild-type mice. Cellular FDG uptake tests showed that FDG activity in hippocampal microglia was increased in the AD model, while FDG activity in non-microglial cells of the hippocampus was not different between the AD model and wild-type. scRNA-seq data showed that changes in glucose metabolism signatures including glucose transporters, glycolysis and oxidative phosphorylation, mainly occurred in microglia. A subset of microglia with higher glucose transporters with defective glycolysis and oxidative phosphorylation was increased according to disease progression. In the human imaging study, we found a positive association between soluble TREM2 and hippocampal FDG uptake. FDG uptake in the hippocampus at the baseline scan predicted mild cognitive impairment conversion to AD. Conclusions We identified the reconfiguration of microglial glucose metabolism in the hippocampus of AD, which could be evaluated by FDG PET as a feasible surrogate imaging biomarker for microglia-mediated inflammation.

The purpose of this study was to determine the prognostic value of metabolic volumetric parameters as a quantitative index on pre-treatment 18F-FDG PET/CT in addition to the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) in patients with diffuse large B-cell lymphoma (DLBCL). A total of 103 consecutive patients with DLBCL and baseline FDG PET/CT were retrospectively evaluated. Quantitative metabolic parameters, including total metabolic tumour volume (TMTV) using a standardized uptake value (SUV) of ≥2.5 as the threshold, were estimated. Receiver operating characteristic curve analysis was used to determine the optimal cut-off values for the metabolic parameters. The relationships between study variables and patient survival were tested using Cox regression analysis. Patient survival rates were derived from Kaplan-Meier curves and compared using the log-rank test. Median follow-up was 34 months. In patients with a low TMTV (

Nano-metallic nickel powders are highly-valued materials applied in energy, electronic devices and aerospace, which is known to be produced by the gaseous phase reduction method of NiCl2. In the case of a gaseous reduction method, size control is difficult due to the agglomeration of nickel powders. Therefore, a method of producing highly-valued nickel nano-powders from Ni(OH)2 has been proposed. Considering the reduction behavior of bulk nickel oxide has been reported to follow the topo-chemical model. However, reduction behavior of nano-particle is expected to be unknown state. It is necessary to clarify the mechanism of nickel oxide nano-particle reduction. Therefore, in this study, the temperature dependence and particle size dependence on the reduction behavior of from micro scale to nano scale particle was confirmed through TGA experiment. Also, the reduction mechanism of nickel oxide powder was also investigated based on kinetic considerations using the grain topo-chemical model. It was confirmed that the reduction reaction of nickel oxide powder undergoes through the 2nd Avrami model and reduction rate can be expressed by function of temperature and particle size of the powder. Due to the part of the diffusion, the particle size of the powder also affects the rate constant of the reduction reaction. $${\text{g}}_{{({\text{x}})}} = {\text{k}} \cdot {\text{f}}({\text{d}}) \cdot {\text{t}}$$

Purpose Although somatostatin receptor (SST) is a promising theranostic target and is widely expressed in tumors of various organs, the indication for therapies targeting SST is limited to typical gastroenteropancreatic neuroendocrine tumors (NETs). Thus, broadening the scope of the current clinical application of peptide receptor radiotherapy (PRRT) can be supported by a better understanding of the landscape of SST-expressing tumors. Methods SST expression levels were assessed in data from The Cancer Genome Atlas across 10,701 subjects representing 32 cancer types. As the major target of PRRT is SST subtype 2 (SST2), correlation analyses between the pan-cancer profiles, including clinical and genetic features, and SST2 level were conducted. The median SST2 expression level of pheochromocytoma and paraganglioma (PCPG) samples was used as the threshold to define “high-SST2 tumors.” The prognostic value of SST2 in each cancer subtype was evaluated by using Cox proportional regression analysis. Results We constructed a resource of SST expression patterns associated with clinicopathologic features and genomic alterations. It provides an interactive tool to analyze SST expression patterns in various cancer types. As a result, eight of the 31 cancer subtypes other than PCPG had more than 5% of tumors with high-SST2 expression. Low-grade glioma (LGG) showed the highest proportion of high-SST2 tumors, followed by breast invasive carcinoma (BRCA). LGG showed different SST2 levels according to tumor grade and histology. IDH1 mutation was significantly associated with high-SST2 status. In BRCA, the SST2 level was different according to the hormone receptor status. High-SST2 status was significantly associated with good prognosis in LGG patients. High-SST2 status showed a trend for association with poor prognosis in triple-negative breast cancer subjects. Conclusion A broad range of SST2 expression was observed across diverse cancer subtypes. The SST2 expression level showed a significant association with genomic and clinical aspects across cancers, especially in LGG and BRCA. These findings extend our knowledge base to diversify the indications for PRRT as well as SST imaging.

The purpose of this study is to investigate the role of dual time point (DTP) 18F-FDG PET/CT in the staging of oesophageal cancer, especially in lymph node metastasis. A total of 35 patients with oesophageal squamous cell carcinoma who underwent surgical treatment without neoadjuvant chemotherapy were enrolled as a test set and another 19 patients were enrolled as a validation set. The DTP PET/CT scans were obtained in dual time points at 60 and 120 min each, following the administration of 18F-FDG. Visual analysis was performed and semiquantitative analysis was performed using several PET parameters such as maximal standardized uptake values (SUVmax), peak SUV (SUVpeak) and retention indexes using SUVmax (RImax) and SUVpeak (RIpeak). Primary oesophageal lesions exhibited a significant difference for SUVmax at each time point scan (ANOVA, p

18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been investigated as a method to predict pancreatic cancer recurrence after pancreatic surgery. We evaluated the recently introduced heterogeneity indices of 18F-FDG PET/CT used for predicting pancreatic cancer recurrence after surgery and compared them with current clinicopathologic and 18F-FDG PET/CT parameters. A total of 93 pancreatic ductal adenocarcinoma patients (M:F = 60:33, mean age = 64.2 ± 9.1 years) who underwent preoperative 18F-FDG PET/CT following pancreatic surgery were retrospectively enrolled. The standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were measured on each 18F-FDG PET/CT, as metabolic parameters. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were examined as volumetric parameters. The coefficient of variance (heterogeneity index-1; SUVmean divided by the standard deviation) and linear regression slopes (heterogeneity index-2) of the MTV, according to SUV thresholds of 2.0, 2.5 and 3.0, were evaluated as heterogeneity indices. Predictive values of clinicopathologic and 18F-FDG PET/CT parameters and heterogeneity indices were compared in terms of pancreatic cancer recurrence. Seventy patients (75.3%) showed recurrence after pancreatic cancer surgery (mean recurrence = 9.4 ± 8.4 months). Comparing the recurrence and no recurrence patients, all of the 18F-FDG PET/CT parameters and heterogeneity indices demonstrated significant differences. In univariate Cox-regression analyses, MTV (P = 0.013), TLG (P = 0.007), and heterogeneity index-2 (P = 0.027) were significant. Among the clinicopathologic parameters, CA19–9 (P = 0.025) and venous invasion (P = 0.002) were selected as significant parameters. In multivariate Cox-regression analyses, MTV (P = 0.005), TLG (P = 0.004), and heterogeneity index-2 (P = 0.016) with venous invasion (P

Triple-negative breast cancer has a poor prognosis. We evaluated several metabolic and volumetric parameters from preoperative 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in the prognosis of triple-negative breast cancer and compared them with current clinicopathologic parameters. A total of 228 patients with triple-negative breast cancer (mean age 47.0 ± 10.8 years, all women) who had undergone preoperative PET/CT were included. The PET/CT metabolic parameters evaluated included maximum, peak, and mean standardized uptake values (SUVmax, SUVpeak, and SUVmean, respectively). The volumetric parameters evaluated included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Metabolic and volumetric parameters were evaluated separately for tumor (T) and lymph nodes (N). The prognostic value of these parameters was compared with that of clinicopathologic parameters. All lymph node metabolic and volumetric parameters showed significant differences between patients with and without recurrence. However, tumor metabolic and volumetric parameters showed no significant differences. In a univariate survival analysis, all lymph node metabolic and volumetric parameters (SUVmax-N, SUVpeak-N, SUVmean-N, MTV-N, and TLG-N; all P

(18F-fluoropentyl)triphenylphosphonium salt (18F-FPTP) is a new promising myocardial PET imaging tracer. It shows high accumulation in cardiomyocytes and rapid clearance from liver. We performed compartmental analysis of 18F-FPTP PET images in rat and evaluated two linear analyses: linear least-squares (LLS) and a basis function method (BFM) for generating parametric images. The minimum dynamic scan duration for kinetic analysis was also investigated and computer simulation undertaken. 18F-FPTP dynamic PET (18 min) and CT images were acquired from rats with myocardial infarction (MI) (n = 12). Regions of interest (ROIs) were on the left ventricle, normal myocardium, and MI region. Two-compartment (K 1 and k 2; 2C2P) and three-compartment (K 1–k 3; 3C3P) models with irreversible uptake were compared for goodness-of-fit. Partial volume and spillover correction terms (V a and α = 1 − V a ) were also incorporated. LLS and BFM were applied to ROI- and voxel-based kinetic parameter estimations. Results were compared with the standard ROI-based nonlinear least-squares (NLS) results of the corresponding compartment model. A simulation explored statistical properties of the estimation methods. The 2C2P model was most suitable for describing 18F-FPTP kinetics. Average K 1, k 2, and V a values were, respectively, 6.8 (ml/min/g), 1.1 (min−1), and 0.44 in normal myocardium and 1.4 (ml/min/g), 1.1 (min−1), and 0.32, in MI tissue. Ten minutes of data was sufficient for the estimation. LLS and BFM estimations correlated well with NLS values for the ROI level (K 1: y = 1.06x + 0.13, r 2 = 0.96 and y = 1.13x + 0.08, r 2 = 0.97) and voxel level (K 1: y = 1.22x − 0.30, r 2 = 0.90 and y = 1.26x + 0.00, r 2 = 0.92). Regional distribution of kinetic parametric images (αK 1, K 1, k 2, V a) was physiologically relevant. LLS and BFM showed more robust characteristics than NLS in the simulation. Fast kinetics and highly specific uptake of 18F-FPTP by myocardium enabled quantitative analysis with the 2C2P model using only the initial 10 min of data. LLS and BFM were feasible for estimating voxel-wise parameters. These two methods will be useful for quantitative evaluation of 18F-FPTP distribution in myocardium and in further studies with different conditions, disease models, and species.

Human epidermal growth factor receptor 2 (HER2) is over-expressed in over 30% of ovarian cancer cases, playing an essential role in tumorigenesis and metastasis. Non-invasive imaging of HER2 is of great interest for physicians as a mean to better detect and monitor the progression of ovarian cancer. In this study, HER2 was assessed as a biomarker for ovarian cancer imaging usingHER2 expression and binding were examined in three ovarian cancer cell lines (SKOV3, OVCAR3, Caov3) using in vitro techniques, including western blot and saturation binding assays. PET imaging and biodistribution studies in subcutaneous models of ovarian cancer were performed for non-invasive in vivo evaluation of HER2 expression. Additionally, orthotopic models were employed to further validate the imaging capability ofHER2 expression was highest in SKOV3 cells, while OVCAR3 and Caov3 displayed lower HER2 expression.

Brain regions send and receive information through neuronal connections in an efficient way. In this paper, we modelled the information propagation in brain networks by a generalized Markov system associated with a new edge-transition matrix, based on the assumption that information flows through brain networks forever. From this model, we derived new global and local network measures, called a volume entropy and the capacity of nodes and edges on FDG PET and resting-state functional MRI. Volume entropy of a metric graph, a global measure of information, measures the exponential growth rate of the number of network paths. Capacity of nodes and edges, a local measure of information, represents the stationary distribution of information propagation in brain networks. On the resting-state functional MRI of healthy normal subjects, these measures revealed that volume entropy was significantly negatively correlated to the aging and capacities of specific brain nodes and edges underpinned which brain nodes or edges contributed these aging-related changes.

Renal metastasis of thyroid cancer is extremely rare. We report the case of a 62-year-old woman with Hürthle cell thyroid cancer (HCTC) with lungs, bones, and bilateral kidneys metastases. The renal metastatic lesions were clearly demonstrated by 131I whole body scan (WBS) with SPECT/CT. However, they exhibited false-negative results in 18F-FDG PET/CT, kidney ultrasonography, and contrast-enhanced CT scan. The findings imply that tumors have low glucose metabolism and are able to accumulate radioiodine, which is not commonly found in the relatively aggressive nature of HCTC. The patient received two sessions of 200 mCi 131I therapy within 6 months duration. There was complete treatment response as evaluated by the second post-therapeutic 131I SPECT/CT and serum thyroglobulin. To our knowledge, renal metastasis from HCTC with positive 131I but negative 18F-FDG uptake has not been reported in the literature. This case suggests that 131I SPECT/CT is useful for lesion localization and prediction of 131I therapy response.

The aim of this report was to investigate the clinical outcome of deep brain stimulation (DBS) for autism spectrum disorder (ASD) and the functional and structural changes in the brain after DBS. We present a 14-year-old boy with ASD and self-injurious behavior (SIB) refractory with medical and behavioral therapy. He was treated by bilateral nucleus accumbens (NAc) DBS. Remarkable clinical improvement was observed following NAc DBS. Brain fluorodeoxyglucose-positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) volumetric studies revealed that the metabolism in the prefrontal and the frontal cortex as well as the occipital cortex was markedly decreased in association with the decreased cortical volumes in those areas 2 years after NAc DBS. The therapeutic potential of NAc DBS is suggested for the clinical improvement of patients with ASD and SIB with structural and functional changes after DBS.

In this paper, a low phase noise 30-GHz frequency synthesizer with a linear transconductance voltage-controlled oscillator (VCO) and dual-injection-locked frequency divider (ILFD) is presented. In order to improve the phase noise of the frequency synthesizer, the LC VCO is designed with transconductance linearization of the active devices. A dual-ILFD is proposed in order to achieve a wide locking range with low power consumption. It is implemented in 65 nm CMOS and the die area is 1.2 mm × 0.8 mm. The power consumption is 55 mW from the supply voltage of 1 V. The measured phase noise of the VCO is respectively ?106 and ?97.88 dBc/Hz at a 1-MHz offset from carrier frequency of 30.24 and 60.48 GHz. The measured tuning range of the VCO is about 13 %. The locking frequency range of the ILFD is from 14.1 to 45.8 GHz at the injection power of ?6 dBm, with its load current being controlled automatically.

The linkage between oxidative stress and idiopathic chronic fatigue (ICF) has not been explored in detail. This study thoroughly compared the serum levels of biomarkers for oxidative stress and antioxidants from 103 subjects with ICF (20 men and 83 women) to those of 82 healthy volunteers (27 men and 55 women). Oxidative parameters, which included reactive oxygen species (ROS), malondialdehyde (MDA) and F2-isoprotan, and tumor necrosis factor-alpha (TNF-α) were significantly elevated, while antioxidant parameters, which included total antioxidant activity (TAC), catalase, superoxide dismutase, SOD and GSH activity, were decreased compared to those of healthy subjects (by approximately 1.2- to 2.3-fold, p

Fibromyalgia (FM), chronic widespread pain, exhibits spontaneous pain without external stimuli and is associated with altered brain activities during resting state. To understand the topological features of brain network in FM, we employed persistent homology which is a multiple scale network modeling framework not requiring thresholding. Spontaneous magnetoencephalography (MEG) activity was recorded in 19 healthy controls (HCs) and 18 FM patients. Barcode, single linkage dendrogram and single linkage matrix were generated based on the proposed modeling framework. In theta band, the slope of decrease in the number of connected components in barcodes showed steeper in HC, suggesting FM patients had decreased global connectivity. FM patients had reduced connectivity within default mode network, between middle/inferior temporal gyrus and visual cortex. The longer pain duration was correlated with reduced connectivity between inferior temporal gyrus and visual cortex. Our findings demonstrated that the aberrant resting state network could be associated with dysfunction of sensory processing in chronic pain. The spontaneous nature of FM pain may accrue to disruption of resting state network.

Malignant peritoneal mesothelioma (MPM) is a rare but fatal tumor. The clinical presentations and imaging findings are nonspecific and resemble various diseases, including peritoneal metastasis. Imaging findings of MPH on (18)F-(18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) are diverse and not well described. We report the two cases of biopsy-proven MPH using (18)F-FDG PET/CT. In our cases, interesting disease patterns-including MPH arising from visceral peritoneal lining of kidney that suffer from polycystic disease and from the parietal peritoneum beneath the appendectomy scar-were presented. One case showed classical metastases localized within the abdominal cavity; while the other case exhibited the rare pattern of extensive multi-organ metastases. By knowing the possible variations and diagnostic pitfalls of (18)F-FDG PET/CT findings in MPM, more accurate interpretation of such mysterious cancer is attainable.

This paper presents a 50/150/200 kbps, low power transceiver with one-point modulation and integrated single pole double throw (SPDT) switch for IEEE 802.15.4g application. To ensure that the proposed low power transceiver can operate at a multi data rate, multi data-rate (50/150/200 kbps) frequency shift keying (FSK) modulation is implemented using a phase-locked loop (PLL) with a programmable loop bandwidth. The bandwidth switching scheme is combined with the programmable loop bandwidth to support the high data rate in the PLL of the transmitter. In the receiver, the SPDT switch is integrated to share the antenna and matching network between the transmitter and receiver, thus minimizing the system cost. Also the active-RC band pass filter with the programmable bandwidth is designed to support the data rates of 50, 150, and 200 kbps. The capacitors in each data rate are shared efficiently to minimize the die area. The FSK transmitter is implemented using 0.18 μm 1-poly 6-metal complementary metal-oxide semiconductor technology. The die area of the transceiver is 4.0 mm2. The power consumption of the transmitter and receiver are 54 and 25 mW, respectively, when the output power level of the transmitter is +10.17 dBm at 1.8 V supply voltage. The phase noise of the PLL output at 1.8462 GHz is ?118.13 dBc/Hz with a 1 MHz offset.

Despite their abundance, the molecular functions of long non-coding RNAs in mammalian nervous systems remain poorly understood. Here we show that the long non-coding RNA, NEAT1, directly modulates neuronal excitability and is associated with pathological seizure states. Specifically, NEAT1 is dynamically regulated by neuronal activity in vitro and in vivo, binds epilepsy-associated potassium channel-interacting proteins including KCNAB2 and KCNIP1, and induces a neuronal hyper-potentiation phenotype in iPSC-derived human cortical neurons following antisense oligonucleotide knockdown. Next generation sequencing reveals a strong association of NEAT1 with increased ion channel gene expression upon activation of iPSC-derived neurons following NEAT1 knockdown. Furthermore, we show that while NEAT1 is acutely down-regulated in response to neuronal activity, repeated stimulation results in NEAT1 becoming chronically unresponsive in independent in vivo rat model systems relevant to temporal lobe epilepsy. We extended previous studies showing increased NEAT1 expression in resected cortical tissue from high spiking regions of patients suffering from intractable seizures. Our results indicate a role for NEAT1 in modulating human neuronal activity and suggest a novel mechanistic link between an activity-dependent long non-coding RNA and epilepsy.

Backgrounds Quality of life (QoL) has become a major concern as the survival time of breast cancer increases. We investigated the changes in QoL through comprehensive categorical analysis, for the first three years after breast cancer treatment including radiotherapy. Methods A total of 1156 patients were enrolled from 17 institutions. All survivors were grouped according to a surveillance period of 9–15 months (first year), 21–27 months (second year), and 33–39 months (third year) from the end of radiotherapy. The 5-dimensional questionnaire by the EuroQol group (EQ-5D) and the EORTC Quality of Life Questionnaire; breast cancer specific module (QLQ-BR23) were checked by self-administrated method. Results First, second and third year groups comprised 51.0, 28.9, and 21.0%. In EQ-5D-3 L (3-Likert scale) analysis, pain/discomfort and anxiety/depression categories showed lower QoL. In multivariate analyses of EQ-5D-VAS (visual-analogue scale), categories of pain/discomfort and self-care were improved with time; axillary dissection was a significant clinical factor deteriorates pain/discomfort, self-care and usual activities. In QLQ-BR23 analysis, the lowest scored category was sexual activity, followed by sexual enjoyment, future perspective, and hair loss, and the best scored category was breast symptoms. In multivariate analyses, arm symptoms, breast symptoms and body image were improved with time. Conclusions Categories of pain/discomfort and self-care in EQ-5D-VAS, arm/breast symptoms and body image in QLQ-BR23 were improved, while categories of anxiety/depression and future perspective BR23 were not, suggesting necessity of psychosocial support. This research provides comprehensive information on the categorical aspects of QoL and changes during early follow-up after breast cancer treatment.

Tracer kinetic modeling in dynamic positron emission tomography (PET) has been widely used to investigate the characteristic distribution patterns or dysfunctions of neuroreceptors in brain diseases. Its practical goal has progressed from regional data quantification to parametric mapping that produces images of kinetic-model parameters by fully exploiting the spatiotemporal information in dynamic PET data. Graphical analysis (GA) is a major parametric mapping technique that is independent on any compartmental model configuration, robust to noise, and computationally efficient. In this paper, we provide an overview of recent advances in the parametric mapping of neuroreceptor binding based on GA methods. The associated basic concepts in tracer kinetic modeling are presented, including commonly-used compartment models and major parameters of interest. Technical details of GA approaches for reversible and irreversible radioligands are described, considering both plasma input and reference tissue input models. Their statistical properties are discussed in view of parametric imaging.

Texture analysis on (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) scan is a relatively new imaging analysis tool to evaluate metabolic heterogeneity. We analyzed the difference in textural characteristics between non-small cell lung carcinoma (NSCLC) subtypes, namely adenocarcinoma (ADC) and squamous cell carcinoma (SqCC).Diagnostic (18)F-FDG PET/computed tomography (CT) scans of 30y patients (median age, 67; range, 42-88) with NSCLC (17 ADC and 13 SqCC) were retrospectively analyzed. Regions of interest were manually determined on selected transverse image containing the highest SUV value in tumors. Texture parameters were extracted by histogram-based algorithms, absolute gradient-based algorithms, run-length matrix-based algorithms, co-occurrence matrix-based algorithms, and autoregressive model-based algorithms. Twenty-four out of hundreds of texture features were selected by three algorithms: Fisher coefficient, minimization of both classification error probability and average correlation, and mutual information. Automated clustering of tumors was based on the most discriminating feature calculated by linear discriminant analysis (LDA). Each tumor subtype was determined by histopathologic examination after biopsy and surgery.Fifteen texture features had significant different values between ADC and SqCC. LDA with 24 automate-selected texture features accurately clustered between ADC and SqCC with 0.90 linear separability. There was no high correlation between SUVmax and texture parameters (|r| ≤ 0.62).Each subtype of NSCLC tumor has different metabolic heterogeneity. The results of this study support the potential of textural parameters on FDG PET as an imaging biomarker.

Imaging biomarkers from functional imaging modalities were assessed as potential surrogate markers of disease status. Specifically, in this prospective study, we investigated the relationships between functional imaging parameters and histological prognostic factors and breast cancer subtypes. In total, 43 patients with large or locally advanced invasive ductal carcinoma (IDC) were analyzed (47.6 ± 7.5 years old). 68Ga-Labeled arginine-glycine-aspartic acid (RGD) and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) were performed. The maximum and average standardized uptake values (SUVmax and SUVavg) from RGD PET/CT and SUVmax and SUVavg from FDG PET/CT were the imaging parameters used. For histological prognostic factors, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression was identified using immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). Four breast cancer subtypes, based on ER/PR and HER2 expression (ER/PR+,Her2−, ER/PR+,Her2+, ER/PR−,Her2+, and ER/PR−,Her2−), were considered. Quantitative FDG PET parameters were significantly higher in the ER-negative group (15.88 ± 8.73 vs 10.48 ± 6.01, p = 0.02 for SUVmax; 9.40 ± 5.19 vs 5.92 ± 4.09, p = 0.02 for SUVavg) and the PR-negative group (8.37 ± 4.94 vs 4.79 ± 3.93, p = 0.03 for SUVavg). Quantitative RGD PET parameters were significantly higher in the HER2-positive group (2.42 ± 0.59 vs 2.90 ± 0.75, p = 0.04 for SUVmax; 1.60 ± 0.38 vs 1.95 ± 0.53, p = 0.04 for SUVavg) and showed a significant positive correlation with the HER2/CEP17 ratio (r = 0.38, p = 0.03 for SUVmax and r = 0.46, p

Purpose The expression of glucose transporter-1 (Glut-1) gene and those of major thyroid-specific genes were examined in papillary carcinoma tissues, and the expressions of these genes were compared with cancer differentiation grades. Materials and Methods Twenty-four human papillary carcinoma tissues were included in this study. The expressions of Glut-1- and thyroid-specific genes [sodium/iodide symporter (NIS), thyroid peroxidase, thyroglobulin, TSH receptor and pendrin] were analyzed by RT-PCR. Expression levels were expressed as ratios versus the expression of beta-actin. Pathologic differentiation of papillary carcinoma was classified into a relatively well-differentiated group (n = 13) and relatively less differentiated group (n = 11). Results Glut-1 gene expression was significantly higher in the less differentiated group (0.66 ± 0.04) than in the well-differentiated group (0.59 ± 0.07). The expression levels of the NIS, PD and TG genes were significantly higher in the well-differentiated group (NIS: 0.67 ± 0.20, PD: 0.65 ± 0.21, TG: 0.74 ± 0.16) than in the less differentiated group (NIS: 0.36 ± 0.05, PD: 0.49 ± 0.08, TG: 0.60 ± 0.11), respectively. A significant negative correlation was found between Glut-1 and NIS expression, and positive correlations were found between NIS and TG, and between NIS and PD. Conclusion The NIS, PD and TG genes were highly expressed in well-differentiated thyroid carcinomas, whereas the Glut-1 gene was highly expressed in less differentiated thyroid carcinomas. These findings provide a molecular rationale for the management of papillary carcinoma, especially in the selection of FDG PET or radioiodine whole-body scan and I-131-based therapy.

This paper presents a low power ring oscillator-based spread-spectrum clock generator with three-step frequency and voltage-controlled oscillator (VCO) gain calibration for S-ATA applications. To meet the low jitter requirements with a small VCO gain, a ring-type VCO with three step frequency calibration and gain calibration scheme is proposed. The proposed coarse tuning method selects the optimal tuning currents and capacitances of the ring VCO to optimize the phase noise. The gain of ring-type VCO can be reduced and kept constant with the proposed three-step frequency and VCO gain calibration. As a result, it can improve the phase noise characteristics of the ring-type VCO and make it more robust to the PVT variations. Also, charge pump up/down current mismatches are compensated with the current mismatch compensation block. This chip is fabricated with 65 nm CMOS technology, and the die area is 430 × 460 μm2. The power consumption is 12 mW at 1.2 V supply voltage. The measured RMS jitter and phase noise are 2.835 ps and ?96.83 dBc/Hz at 1 MHz offset, respectively.

Purpose The new modality of an integrated positron emission tomography/magnetic resonance imaging (PET/MRI) has recently been introduced but not validated. Our objective was to evaluate clinical performance of 18F-fluoro-2-deoxyglucose (18F-FDG) PET/MRI in patients with head and neck cancer. Methods This retrospective study was conducted between January 2013 and February 2013. Ten patients (eight men, two women; mean age, 61.4 ± 13.4 years) with histologically proven head and neck tumors were enrolled. Whole-body PET/MRI and regional positron emission tomography (PET) with dedicated MRI were sequentially obtained. Maximum standardized uptake value (SUVmax), SUVmean, metabolic tumor volume, total lesion glycolysis and contrast enhancement were analyzed. A total of ten whole-body positron emission tomography (PET), ten regional positron emission tomography (PET), ten dedicated MRI and ten regional PET/gadolinium-enhanced T1-weighted (Gd)-MRI images were analyzed for initial staging. Two nuclear medicine physicians analyzed positron emission tomography (PET) and PET/MRI with a consensus. One radiologist analyzed dedicated MRI. The primary lesions and number of metastatic lymph nodes analyzed from each image were compared. Results Eight patients were diagnosed with head and neck cancer (one tongue cancer, four tonsillar cancers, one nasopharyngeal cancer and two hypopharyngeal cancers) by histological diagnosis. Two benign tumors (pleomorphic adenoma and Warthin tumor) were diagnosed with surgical operation. Whole-body positron emission tomography (PET) and regional positron emission tomography (PET) attenuated by MRI showed good image quality for the lesion detection. Whole-body positron emission tomography (PET) and regional positron emission tomography (PET) detected ten primary sites and compensated for a missed lesion on dedicated MRI. A discordant number of suspicious lymph node metastases was noted according to the different images; 22, 16, 39 and 40 in the whole-body positron emission tomography (PET) only, dedicated MR, regional positron emission tomography (PET) only and regional PET/Gd-MRI, respectively. There was no distant metastasis based on analysis of whole-body positron emission tomography (PET) and whole-body PET/Dixon-volume interpolated breathhold examination (VIBE) MRI. Regional PET/Gd-MRI combined with whole-body PET/MRI modified staging in three patients. Lesions of primary tumor and suspicious metastasis were well detected on both value of SUVmax and visual analysis. The regional PET/Gd-MRI combined with whole-body PET/MRI showed convenient clinical staging performance compared with positron emission tomography (PET) and MRI alone. Conclusion In this preliminary study, PET attenuated by MRI showed good image quality to detect lesions. And whole-body PET/MRI as a single modality was feasible for staging in a clinical setting. Whole-body positron emission tomography (PET), regional positron emission tomography (PET), dedicated MRI and regional PET/Gd-MRI showed discordant results in lesion detection. These discordant results might be synergistic effect for accurate staging.

Population-based statistical probabilistic anatomical maps have been used to generate probabilistic volumes of interest for analyzing perfusion and metabolic brain imaging. We investigated the feasibility of automated analysis for dopamine transporter images using this technique and evaluated striatal binding potentials in Parkinson's disease and Wilson's disease.We analyzed 2β-Carbomethoxy-3β-(4-(123)I-iodophenyl)tropane ((123)I-beta-CIT) SPECT images acquired from 26 people with Parkinson's disease (M:F = 11:15, mean age = 49 ± 12 years), 9 people with Wilson's disease (M: F = 6:3, mean age = 26 ± 11 years) and 17 normal controls (M:F = 5:12, mean age = 39 ± 16 years). A SPECT template was created using striatal statistical probabilistic map images. All images were spatially normalized onto the template, and probability-weighted regional counts in striatal structures were estimated. The binding potential was calculated using the ratio of specific and nonspecific binding activities at equilibrium. Voxel-based comparisons between groups were also performed using statistical parametric mapping.Qualitative assessment showed that spatial normalizations of the SPECT images were successful for all images. The striatal binding potentials of participants with Parkinson's disease and Wilson's disease were significantly lower than those of normal controls. Statistical parametric mapping analysis found statistically significant differences only in striatal regions in both disease groups compared to controls.We successfully evaluated the regional (123)I-beta-CIT distribution using the SPECT template and probabilistic map data automatically. This procedure allows an objective and quantitative comparison of the binding potential, which in this case showed a significantly decreased binding potential in the striata of patients with Parkinson's disease or Wilson's disease.

Lymph node (LN) characterization is crucial in determining the stage and treatment decisions in patient with lung cancer. Although (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) has a higher diagnostic accuracy in LN characterization than anatomical imaging, differentiating between metastatic and inflammatory LNs is still challenging because both could show high (18)F-FDG uptake. The purpose of this study was to assess if the heterogeneity of the (18)F-FDG uptake could help in differentiating between inflammatory and metastatic LNs in lung cancer, and to compare with other parameters.A total of 44 patients with adenocarcinoma of the lung, who underwent preoperative (18)F-FDG PET/CT without having any previous treatments and were revealed to have (18)F-FDG-avid LNs, were enrolled. There were 52 pathology-proven metastatic lymph nodes in 26 subjects. The pathology-proven metastatic LNs were compared with 42 pathology-proven inflammatory/benign LNs in 18 subjects. The coefficient of variation (CV) was used to assess the heterogeneity of (18)F-FDG uptake by dividing the standard deviation of standardized uptake value (SUV) by mean SUV. The volume of interest was manually drawn based on the combined CT images of (18)F-FDG PET/CT (no threshold is used). Comparisons were made with the maximum standardized uptake values (SUVmax), visual assessment of (18)F-FDG uptake, longest diameter, and maximum Hounsfield units (HUmax).Metastatic lymph nodes tended to have higher CVs than the inflammatory LNs. The mean CV of metastatic LNs (0.30 ± 0.08; range: 0.08-0.55) was higher than that of inflammatory LNs (0.17 + 0.06; range, 0.07-0.32; P 0.0001). On receiver operating characteristic (ROC) curve analysis, the area under curve was 0.901, and using 0.20 as cut-off value, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 88.5 %, 76.2 %, 82.2 %, 84.3, and 83.0 % respectively. Accuracy of CV was slightly higher than SUVmax and diameter, but significantly higher than visual assessment and HUmax.In patients with adenocarcinoma of the lung having no prior treatments, metastatic LNs showed more heterogeneous (18)F-FDG uptake than inflammatory LNs. Measuring the CV of the SUV derived from a manual volume of interest (VOI) can be helpful in determining metastatic LN of adenocarcinoma of the lung. Including diagnostic criteria of CV into the diagnostic approach can increase the accuracy of mediastinal node status.

In this study, the feasibility and kinetic characteristics of the (68)Ga-NOTA-RGD, a recently developed RGD peptide agent, were investigated for atherosclerosis imaging in comparison with (18)FDG.ApoE(-/-) mice were fed a high-fat diet for more than 20 weeks. To evaluate the feasibility, tissue uptakes of (68)Ga-NOTA-RGD and (18)FDG in the major organs were measured and compared between ApoE(-/-) and control mice. Animal PET imaging was also performed and relative uptake values in the thoracic aorta were compared between ApoE(-/-) and control mice. In humans, the kinetic characteristics and feasibility of (68)Ga-NOTA-RGD PET were assessed in 4 patients with known coronary artery disease.In the tissue uptake study, the thoracic aorta showed higher uptake in ApoE(-/-) than in control mice with both (68)Ga-NOTA-RGD and (18)FDG (P 0.001). On PET scans, the relative uptake values of the thoracic aorta were significantly higher in ApoE(-/-) with both (68)Ga-NOTA-RGD (P = 0.024) and (18)FDG (P = 0.038). In human PET, the appropriateness of reversible binding model and Logan plotting was clearly demonstrated. The aorta-to-jugular ratios were measured up to 1.25 and showed a tendency to correlate with the serum high-sensitivity C-reactive protein level (r = 0.899, P = 0.102).(68)Ga-NOTA-RGD has potential as an in vivo atherosclerosis imaging agent. However, the lower imaging contrast and sensitivity of (68)Ga-NOTA-RGD PET compared with (18)FDG PET may be a limitation for clinical application.

This study aimed at identifying the predictive parameters on quantitative gated myocardial perfusion single-photon emission computed tomography (QG-SPECT) in diabetic patients with normal perfusion but impaired function.Among the 533 consecutive diabetic patients, 379 patients with normal perfusion on rest Tl-201/dipyridamole-stress Tc-99m sestamibi Gated SPECT were enrolled. Patients were grouped into those with normal post-stress left ventricular function (Group I) and those with impaired function (EF50 or impaired regional wall motion, Group II). We investigated cardiac events and cause of death by chart review and telephone interview. Survival analysis and Cox proportional hazard model analysis were performed.Between the Group I and II, cardiac events as well as chest pain symptoms, smoking, diabetic complications were significantly different (P 0.05). On survival analysis, event free survival rate in Group II was significantly lower than in Group I (P = 0.016). In univariate Cox proportional hazard analysis on overall cardiac event, Group (II over I), diabetic nephropathy, summed motion score (SMS), summed systolic thickening score (STS), numbers of abnormal segmental wall motion and systolic thickening predicted more cardiac events (P 0.05). Multivariate analysis showed that STS was the only independent predictor cardiac event.The functional parameter, especially summed systolic thickening score on QG-SPECT had prognostic values, despite normal perfusion, in predicting cardiac events in diabetic patients, and QG-SPECT provides clinically useful risk stratification in diabetic patients with normal perfusion.

Facilitation of the ability of neuronal lineages derived from transplanted stem cells to differentiate is essential to improve the low efficacy of neuronal differentiation in stem cell therapy in vivo. Neurogenin 1 (Ngn1), a basic helix-loop-helix factor, has been used as an activator of neuronal differentiation. In this study, we monitored the in vivo activation of neuronal differentiation by Ngn1 in neuronal precursor cells using neuron-specific promoter-based optical reporters. The NeuroD promoter coupled with the firefly luciferase reporter system (pNeuroD-Fluc) was used to monitor differentiation in F11 neuronal precursor cells. In vitro luciferase activity was measured and normalized by protein content. The in vivo-jetPEITM system was used for in vivo transgene delivery. The IVIS 100 imaging system was used to monitor in vivo luciferase activity. The Ngn1-induced neuronal differentiation of F11 cells generated neurite outgrowth within 2 days of Ngn1 induction. Immunofluorescence staining demonstrated that early and late neuronal marker expression (βIII-tubulin, NeuroD, MAP2, NF-M, and NeuN) was significantly increased at 3 days after treatment with Ngn1. When Ngn1 and the pNeuroD-Fluc vector were cotransfected into F11 cells, we observed an approximately 11-fold increase in the luciferase signal. An in vivo study showed that bioluminescence signals were gradually increased in Ngn1-treated F11 cells for up to 3 days. In this study, we examined the in vivo tracking of neuronal differentiation induced by Ngn1 using an optical reporter system. This reporter system could be used effectively to monitor the activation efficiency of neuronal differentiation in grafted stem cells treated with Ngn1 for stem cell therapy.

Borderline ovarian tumors (BOTs) are more common in young women of reproductive age, and exhibit a better prognosis than malignant ovarian tumors (MOTs). Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) were compared in their ability to differentiate BOTs from stage I MOTs.Among 173 patients who had preoperative FDG PET/CT due to ovarian neoplasms between November 2006 and March 2009, there were 13 patients with BOTs or stage I MOTs. For differential diagnosis of the two tumors, cancer antigen-125 (CA-125) level, the longest diameter of tumors, metabolic indices including maximum standardized uptake value (SUVmax), and volumetric indices including metabolic tumor volume (MTV) were compared, respectively.The BOT group (n = 7) was comprised of five mucinous and two serous tumors, and the MOT group (n = 6) was comprised of three endometrioid, two clear cell and one mucinous tumors. Among the comparisons between two groups, SUVmax of the BOT group was significantly lower than that of the MOT group (2.9 ± 1.5 vs. 6.6 ± 2.9, p = 0.0223); otherwise, no significant difference was found in age, CA-125, diameter, or MTV. By receiver-operating characteristic curve analysis, SUVmax of 3.7 was the best cutoff value to differentiate BOTs from stage I MOTs, with a sensitivity of 83.3 % and specificity of 85.7, and the area under curve of 0.893 (p = 0.0001, 95 % CI: 0.601∼0.993).We demonstrated that SUVmax could distinguish BOTs from stage I MOTs, with a high sensitivity and specificity. Metabolic indices determined by FDG PET/CT were more suitable than volumetric indices for differential diagnosis of the two tumors.

The objective of this study is to determine the efficacy of adding a prokinetic agent to proton pump inhibitors (PPI) for the treatment of laryngopharyngeal reflux (LPR) disease. A prospective, randomized open trial comparing lansoprazole plus itopride to lansoprazole single therapy was performed for 12 weeks. Sixty-four patients with a reflux finding score (RFS) >7 and a reflux symptom index (RSI) >13 were enrolled and received either lansoprazole 30 mg once daily with itopride 50 mg three times daily or lansoprazole 30 mg once daily for 12 weeks. RSI and RFS were completed at baseline, after 6 weeks, and after 12 weeks. During the treatment period, RSI and RFS were significantly improved compared with the pretreatment scores in both study groups. Reductions of total RSI and globus symptom were significantly higher in the lansoprazole plus itopride group compared to the lansoprazole group. In the RFS, however, there were no significant differences between the two groups. In conclusion, itopride in addition to PPI did not show any superior RFS improvement compared to PPI single therapy, but was helpful in speeding up relief of reflux symptoms in LPR patients. Thus, itopride may be considered as the secondary additive agent in the PPI treatment of LPR patients.

Detection of cellular expression of long noncoding RNAs (lncRNAs) was elusive due to the ambiguity of exposure of their reactive sequences associated with their secondary/tertiary structures and dynamic binding of proteins around lncRNAs. Herein, we developed graphene-based detection techniques exploiting the quenching capability of graphene oxide (GO) flakes for fluorescent dye (FAM)-labeled single-stranded siRNAs and consequent un-quenching by their detachment from GO by matching lncRNAs. A brain cytoplasmic 1 (BC1) lncRNA expression was significantly decreased by a siRNA, siBC1–1. GO quenched the FAM-labeled siBC1–1 peptide nucleic acid (PNA) probe, and this quenching was recovered by BC1. While FAM-siBC1–1-PNA-GO complex transfected spontaneously mouse or human neural stem cells, fluorescence was recovered only in mouse cells having high BC1 expression. Fluorescent dye-labeled single-stranded RNA-GO probe could detect the reactive exposed nucleic acid sequence of a cytoplasmic lncRNA expressing in the cytoplasm, which strategy can be used as a detection method of lncRNA expression.

There is a need for non-invasive monitoring the differentiation of transplanted cell in stem cell therapy. In this study, we evaluated the usefulness of sodium iodide symporter (NIS) gene as molecular imaging reporter gene during cardiomyogenic differentiation of bone marrow derived mesenchymal stem cells (BMSCs). In a previous study, we showed that a transgenic mouse model expressing NIS driven by the α-myosin heavy chain (α-MHC) promoter was developed to image cardiomyocytes in vivo with a γ-camera and micro positron emission tomography (microPET). BMSCs were found to express stem cell specific surface markers including stem cell antigen-1 (Sca-1) and CD44. After treatment with all-trans retinoic acid (ATRA), BMSCs morphologically changed and acquired a cardiomyocyte-like shape. The cardiomyogenic differentiation of BMSCs resulted in upregulated expression of cardiac specific genes including α-MHC and ventricular myosin light chain 2 (MLC-2v) and decreased expression of the stem cell specific marker, Sca-1. The ATRA treated BMSCs exhibited higher 125I uptake than that of nontreated cells, and this result suggested that the cardiomyogenic differentiation upregulated NIS gene activity as reporter in vitro. We demonstrated that, under the control of the α-MHC promoter, NIS activity reflected cardiomyogenic differentiation of BMSCs in vitro, and an imaging system based on NIS, the reporter gene, may be a useful tool for monitoring in the lineage specific differentiation of stem cells.

Sertraline hydrochloride (Zoloft®, Pfizer) is an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI). The aims of this study were evaluating its in vivo distribution and kinetic models in human brain. Also, this study was to determine optimal scan duration of dynamic positron emission tomography (PET) for accurate [11C]sertraline kinetic parameters and the feasibility of semi-quantitative approach for assessing distribution volume ratio (DVR). [11C]sertraline dynamic PET and magnetic resonance imaging (MRI) scans were performed in 5 healthy males. Blood sampling were collected for the input function. Tissue time-activity curves (TAC) were obtained in 7 brain regions using MRI. Goodness-of-fit for TAC using simple tissue compartment model (2C2P) and 3-compartment models with irreversible (3C3P) and reversible (3C4P) were compared. Total distribution volume (DV) for each region of interest (ROI) and DVR were calculated. Also, ratio between the standard uptake value (SUV) of each ROI and that of cerebellum (SUVr) was computed and correlated with the DVR. Akaike information criteria analysis showed that the 2C2P was the most suitable model. Average values of K 1 (mL/min/g) and k 2 (1/min) were 0.54 and 0.012 in putamen. PET scan time longer than 50 min was required for the accurate estimation of DV. SUVr in 50–90 min was well correlated with DVR.

The heat shock protein 90 inhibitor, tanespimycin, is an anticancer agent known to increase iodine accumulation in normal and cancerous thyroid cells. Iodine accumulation is regulated by membrane proteins such as sodium iodide symporter (NIS) and pendrin (PDS), and thus we attempted to characterize the effects of tanespimycin on those genes.Cells were incubated with tanespimycin in order to evaluate (125)I accumulation and efflux ability. Radioiodine uptake and efflux were measured by a gamma counter and normalized by protein amount. RT-PCR were performed to measure the level of gene expression.After tanespimycin treatment, (125)I uptake was increased by ∼2.5-fold in FRTL-5, hNIS-ARO, and hNIS-MDA-MB-231 cells, but no changes were detected in the hNIS-HeLa cells. Tanespimycin significantly reduced the radioiodine efflux rate only in the FRTL-5 cells. In the FRTL-5 and hNIS-ARO cells, PDS mRNA levels were markedly reduced; the only other observed alteration in the levels of NIS mRNA after tanespimycin treatment was an observed increase in the hNIS-ARO cells.These results indicate that cellular responses against tanespimycin treatment differed between the normal rat thyroid cells and human cancer cells, and the reduction in the (125)I efflux rate by tanespimycin in the normal rat thyroid cells might be attributable to reduced PDS gene expression.

Although many biomarkers have emerged in non-small cell lung cancer (NSCLC), the predictive value of site-specific spread is not fully defined. We designed this study to determine if there is an association between serum biomarkers and brain metastasis in advanced NSCLC. We evaluated 227 eligible advanced NSCLC patients between May 2005 and March 2010. Patients who had been newly diagnosed with stage IV NSCLC but had not received treatment previously, and had available information on at least one of the following pretreatment serum biomarkers were enrolled: carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA 21-1), cancer antigen 125 (CA 125), cancer antigen 19-9, and squamous cancer cell antigen. Whole body imaging studies and magnetic resonance imaging of the brain were reviewed, and the total number of metastatic regions was scored. Brain metastasis was detected in 66 (29.1%) patients. Although serum CEA, CYFRA 21-1, and CA 125 levels were significantly different between low total metastatic score group (score 1–3) and high total metastatic score group (score 4–7), only CEA level was significantly different between patients with brain metastasis and those without brain metastasis (p < 0.0001). The area under the receiver operating curve of serum CEA for the prediction of brain metastasis was 0.724 (p = 0.0001). The present study demonstrated that the pretreatment serum CEA level was significantly correlated with brain metastasis in advanced NSCLC. These findings suggested the possible role of CEA in the pathogenesis of brain invasion. More vigilant surveillance would be warranted in the high-risk group of patients with high serum CEA level and multiple synchronous metastasis.