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Vibrational sum-frequency generation (VSFG), a second-order nonlinear optical signal, has traditionally been used to study molecules at interfaces as a spectroscopy technique with a spatial resolution of ~100 µm. However, the spectroscopy is not sensitive to the heterogeneity of a sample. To study mesoscopically heterogeneous samples, we, along with others, pushed the resolution limit of VSFG spectroscopy down to ~1 µm level and constructed the VSFG microscope. This imaging technique not only can resolve sample morphologies through imaging, but also record a broadband VSFG spectrum at every pixel of the images. Being a second-order nonlinear optical technique, its selection rule enables the visualization of non-centrosymmetric or chiral self-assembled structures commonly found in biology, materials science, and bioengineering, among others. In this article, the audience will be guided through an inverted transmission design that allows for imaging unfixed samples. This work also showcases that VSFG microscopy can resolve chemical-specific geometric information of individual self-assembled sheets by combining it with a neural network function solver. Lastly, the images obtained under brightfield, SHG, and VSFG configurations of various samples briefly discuss the unique information revealed by VSFG imaging.

BACKGROUND: Many predictors of morbidity caused by metabolic disease are associated with body shape. 3D optical (3DO) scanning captures body shape and has been shown to accurately and precisely predict body composition variables associated with mortality risk. 3DO is safer, less expensive, and more accessible than criterion body composition assessment methods such as dual-energy X-ray absorptiometry (DXA). However, 3DO scanning has not been standardized across manufacturers for pose, mesh resolution, and post processing methods. PURPOSE: We introduce a scanner-agnostic algorithm that automatically fits a topologically consistent human mesh to 3DO scanned point clouds and predicts clinically important body metrics using a standardized body shape model. Our models transform raw scans captured by any 3DO scanner into fixed topology meshes with anatomical consistency, standardizing the outputs of 3DO scans across manufacturers and allowing for the use of common prediction models across scanning devices. METHODS: A fixed-topology body mesh template was automatically registered to 848 training scans from three different 3DO systems. Participants were between 18 and 89 years old with body mass index ranging from 14 to 52 kg/m2 . Scans were registered by first performing a coarse nearest neighbor alignment between the template and the input scan with an anatomically constrained principal component analysis (PCA) domain deformation using a device and gender specific bootstrap basis trained on 70 seed scans each. The template mesh was then optimized to fit the target with a smooth per-vertex surface-to-surface deformation. A combined unified PCA model was created from the superset of all automatically fit training scans including all three devices. Body composition predictions to DXA measurements were learned from the training mesh PCA coefficients using linear regression. Using this final unified model, we tested the accuracy of our body composition models on a withheld sample of 562 scans by fitting a PCA parameterized template mesh to each raw scan and predicting the expected body composition metrics from the principal components using the learned regression model. RESULTS: We achieved coefficients of determination (R2 ) above 0.8 on all nine fat and lean predictions except female visceral fat (0.77). R2 was as high as 0.94 (total fat and lean, trunk fat), and all root-mean-squared errors were below 3.0 kg. All predicted body composition variables were not significantly different from reference DXA measurements except for visceral fat and female trunk fat. Repeatability precision as measured by the coefficient of variation (%CV) was around 2-3x worse than DXA precision, with visceral fat %CV below 2x DXA %CV and female total fat mass at 5x. CONCLUSIONS: Our method provides an accurate, automated, and scanner agnostic framework for standardizing 3DO scans and a low cost, radiation-free alternative to criterion radiology imaging for body composition analysis. We published a web-app version of this work at https://shapeup.shepherdresearchlab.org/3do-bodycomp-analyzer/ that accepts mesh file uploads and returns templated meshes with body composition predictions for demo purposes.

Since its approval in 2018 by the US Food and Drug Administration, peptide receptor radionuclide therapy (PRRT) has become a mainstay in the treatment of neuroendocrine tumors. Lutetium-177-DOTATATE, the only approved agent, is indicated for the treatment of gastroenteropancreatic-neuroendocrine tumors. Although patient selection appears straightforward with somatostatin receptor-positron emission tomography, there is considerable complexity when deciding which patients to treat and when to start PRRT. Herein, we review the many factors that affect patient selection, focusing on the optimal patients to treat. Although significant effort has been expended to determine which patients benefit the most from PRRT, a validated predictive biomarker remains elusive. Although PRRT has been used for more than 2 decades in Europe and standards of care exist for safe treatment, there remain numerous questions regarding when PRRT should be used relative to other treatments. It is important to remember that multidisciplinary discussions are essential. Currently, there are a number of ongoing studies looking to assess the efficacy of PRRT compared with other treatment options and to optimize treatment through combination therapy, different dosing strategies, or use of different radionuclides and radioligands.

PURPOSE: Kinetic parameters from dynamic 18F-fluorodeoxyglucose (FDG) imaging offer complementary insights to the study of disease compared to static clinical imaging. However, dynamic imaging protocols are cumbersome due to the long acquisition time. Long axial field-of-view (LAFOV) PET scanners (> 70 cm) have two advantages for dynamic imaging over clinical PET scanners with a standard axial field-of-view (SAFOV; 16-30 cm). The large axial coverage enables multi-organ dynamic imaging in a single bed position, and the high sensitivity may enable clinically routine abbreviated dynamic imaging protocols. METHODS: In this work, we studied two abbreviated protocols using data from a 65-min dynamic 18F-FDG scan: (A) dynamic imaging immediately post-injection (p.i.) for variable durations, and (B) dynamic imaging immediately p.i. for variable durations plus a 1-h p.i. (5-min-long) datapoint. Nine cancer patients were imaged on the Biograph Vision Quadra (Siemens Healthineers). Time-activity curves over the lesions (N = 39) were fitted using the Patlak graphical analysis and a 2-tissue-compartment (2C, k4 = 0) model for variable scan durations (5-60 min). Kinetic parameters from the complete dataset served as the reference. Lesions from all cancers were grouped into low, medium, and high flux groups, and bias and precision of Ki (Patlak) and Ki, K1, k2, and k3 (2C) were calculated for each group. RESULTS: Using only early dynamic data with the 2C (or Patlak) model, accurate quantification of Ki required at least 50 (or 55) min of dynamic data for low flux lesions, at least 30 (or 40) min for medium flux lesions, and at least 15 (or 20) min for high flux lesions to achieve both 10% bias and precision. The addition of the final (5-min) datapoint allowed for accurate quantification of Ki with a bias and precision of 10% using only 10-15 min of early dynamic data for either model. CONCLUSION: Dynamic imaging for 10-15 min immediately p.i. followed by a 5-min scan at 1-h p.i can accurately and precisely quantify 18F-FDG on a long axial FOV scanner, potentially allowing for more widespread use of dynamic 18F-FDG imaging.

This review article summarizes recent technical developments in ultrashort echo time (UTE) magnetic resonance imaging of musculoskeletal (MSK) tissues with short-T2 relaxation times. A series of contrast mechanisms are discussed for high-contrast morphological imaging of short-T2 MSK tissues including the osteochondral junction, menisci, ligaments, tendons, and bone. Quantitative UTE mapping of T1, T2*, T1ρ, adiabatic T1ρ, magnetization transfer ratio, MT modeling of macromolecular proton fraction, quantitative susceptibility mapping, and water content is also introduced. Met and unmet needs in MSK imaging are discussed. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

OBJECTIVE: Systemic sclerosis (SSc)-associated gastrointestinal (GI) complications are attributed to a variety of factors, including diet, microbiota dysbiosis, or GI transit abnormalities. Our objective was to examine the contribution of abnormal GI transit to SSc Medsger GI severity scores and/or University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA GIT) 2.0 symptoms. METHODS: Patients with SSc and GI symptoms (n = 71) and healthy controls (n = 18) underwent whole gut transit (WGT) scintigraphy to assess transit from the esophagus to the colon. The presence of delayed transit and percent emptying in each GI region were measured. We compared the WGT measurements between categories of the Medsger GI severity score (0-4) and across UCLA GIT 2.0 domains and total score (0-3). RESULTS: A total of 88% of patients had >1 abnormal region of the gut on WGT scintigraphy. All patients requiring total parenteral nutrition had delayed small bowel transit, compared to only approximately 11% of patients in other Medsger GI severity groups (P ≤ 0.01). Severe colonic transit delays were more likely in patients with Medsger GI scores of 3 (pseudo-obstruction and/or malabsorption) compared to other Medsger GI groups (P = 0.02). Seventy-percent of these patients had ≤30% colonic emptying at 72 hours. Modest associations were noted between gastroesophageal reflux disease symptoms and delayed esophageal (r = -0.31, P = 0.05) and gastric emptying (r = -0.32, P = 0.05). CONCLUSION: These data are important in providing evidence that SSc bowel disease affects transit of GI content and that delay in transit accounts in part for both bowel symptoms and Medsger GI severity. Prospective studies examining the benefit of early therapeutic intervention targeting GI transit abnormalities in patients at high risk for severe GI complications are needed.

PURPOSE OF REVIEW: Chicago Classification has standardized clinical approach to primary esophageal motility disorders. With new clinical data and advancing treatments, Chicago Classification has undergone multiple revisions to reflect updated findings and enhance diagnostic accuracy. This review will describe the recently published Chicago Classification version 4.0 (CCv4.0), which aimed to enhance diagnostic characterization and limit overdiagnosis of inconclusive esophageal motility diagnoses. RECENT FINDINGS: Key revisions outlined in CCv4.0 include (1) a modified standardized HRM study protocol performed in supine and upright positions, (2) recommended ancillary testing and manometric provocation for inconclusive manometric diagnoses (3) the required presence of obstructive symptoms for conclusive diagnoses of esophagogastric junction outflow obstruction, distal esophageal spasm and hypercontractile esophagus, and (4) requirement of confirmatory testing for esophagogastric junction outflow obstruction. These key modifications aim to improve diagnostic accuracy and consistency of clinically relevant esophageal motility disorders, and subsequently clinical outcomes.

Assessing the position of the Bragg peak (BP) in hadron radiotherapy utilizing prompt-gamma imaging (PGI) presents many challenges in terms of detector physics. Gamma detectors with the capability of extracting the best energy, timing, and spatial information from each gamma interaction, as well as with high detection efficiency and count rate performance, are needed for this application. In this work we present the characterization of a pixel Čerenkov charge induction (CCI) thallium bromide (TlBr) detector in terms of energy and and electron drift time for its potential use in PGI. The CCI TlBr detector had dimensions of 4 × 4 × 5 mm3 and one of its electrodes was segmented in pixels with 1.7 mm pitch. A silicon photomultiplier (SiPM) was optically coupled to one of the faces of the TlBr slab to read out the Čerenkov light promptly emitted after the interaction of a gamma ray. The detector was operated stand-alone and the 1.275 prompt gammas from a 22Na radioactive source were used for the study. The electron drift time was obtained by combining the Čerenkov and charge induction signals and then used as a measure of the depth of interaction. The electron mobility in TlBr was estimated as ∼27 cm2 V-1 s-1. Energy resolutions between 3.4% and 4.0% at 1.275 MeV were obtained after depth-correction. These values improved to 3.0%-3.3% when events with drift times of 3-6 μs were selected. These results show the potential of pixel CCI TlBr detectors to resolve gamma interactions in the detector with mm-like accuracy in 3D and with excellent energy resolution. Previous studies with CCI TlBr devices have shown a timing resolution of

Eligibility for somatostatin receptor (SSTR) radionuclide therapy uses the qualitative Krenning score based on 111In-pentetreotide planar scintigraphy as was performed in the NETTER-1 trial. The purpose of this study was to determine the effect of using SSTR PET-based Krenning score in comparison to 111In-pentetreotide. Methods: This was a post hoc head-to-head comparison of 68Ga-DOTATATE-based and 111In-pentetreotide-based Krenning scores in 150 patients included in a prospective phase 2 study (NCT01967537). Patients were imaged using 68Ga-DOTATATE PET/CT, 111In-pentetreotide planar scintigraphy, and SPECT/CT within 1 wk. SSTR ligand uptake was graded using the Krenning score independently by 3 readers. Results: The detection rate of SSTR-expressing disease (Krenning scores 2-4) was 23%, 38%, and 72% with planar imaging, SPECT, and SSTR PET, respectively. The Krenning score was higher with SSTR PET (2.71 ± 1.74) than with planar imaging (0.75 ± 1.37; P < 0.001) or SPECT (1.23 ± 1.57; P < 0.001). In patients with a Krenning score of at least 3 on SSTR PET, the detection rate of planar imaging and SPECT was lower for lesions smaller than 2 cm than lesions 2 cm or larger: 15% and 24% versus 78% and 89%, respectively (P < 0.001). For lesions larger than 5 cm, Krenning scores between SSTR PET and 111In-pentetreotide were nearly equivalent. Lesion size did not have an impact on SSTR PET Krenning scores. Interreader agreement was higher for SSTR PET than for planar imaging or SPECT (0.79 vs. 0.67 and 0.50, respectively). Conclusion: SSTR PET results in higher Krenning scores than 111In-pentetreotide, particularly when lesions measured 2 cm or less. Small lesion size resulted in low Krenning scores using 111In-pentetreotide, but lesion size did not affect SSTR PET-based Krenning scores. The results of the NETTER-1 trial cannot be directly applied to patients with small lesions. Further study of peptide receptor radionuclide therapy in patients with small lesions negative on 111In-pentetreotide imaging and positive on SSTR PET is warranted.

The 18F-AV-1451 PET tracer binds to tau, an Alzheimer's disease biomarker. The standardized uptake value ratio (SUVR) 80-100 min window is widely used to quantify tau binding, although 18F-AV-1451 continues increasing relative to a reference region in regions with tau deposition. Left uncorrected, acquisition time inaccuracies can lead to errors from -4% to 6% in 20-min SUVR measurements in subjects with Alzheimer's disease. In 40 subjects with scans from 75-115 min following 18F-AV-1451 injection, we created 20-min reconstructions (4×5 min) of start-times ranging from 75-85 min, as proxies of offset scans and calculated the mean in regions of interest (ROIs). We developed a segmented least squares (SLS) method to obtain error-minimizing weighting coefficients for 18F-AV-1451 ROIs that best predict SUVR 80-100 from weighted means of SUVRs from offset start-times. We compared residual errors of our SLS method to those in: 1) uncorrected offset 20-min-SUVRs; 2) the mean of five-min frames within the 80-100 window; and 3) a least-squares interpolation method. We evaluated errors induced by start-time offset on SUVRs for each method. TheSLS, which corrected using least-squares coefficients of 5-min components, consistently reduced errors across all offset starttimes. Effect size analysis for simulated clinical longitudinal 18F-AV-1451 drug trials showed that uncorrected 20-min offset SUVRs would require up to 20% more participants to detect treatment effects compared with using SLS. Correction of SUVR scan-time errors by SLS minimizes errors compared with other correction methods and may be extended to other scanners and tracers.

Single-event ion imaging enables the direct reconstruction of the relative stopping power (RSP) information required for ion-beam therapy. Helium ions were recently hypothesized to be the optimal species for such technique. The purpose of this work is to investigate the effect of secondary fragments on the image quality of helium CT (HeCT) and to assess the performance of a prototype proton CT (pCT) scanner when operated with helium beams in Monte Carlo simulations and experiment. Experiments were conducted installing the U.S. pCT consortium prototype scanner at the Heidelberg Ion-Beam Therapy Center (HIT). Simulations were performed with the scanner using the TOPAS toolkit. HeCT images were reconstructed for a cylindrical water phantom, the CTP404 (sensitometry), and the CTP528 (line-pair) [Formula: see text] ® modules. To identify and remove individual events caused by fragmentation, the multistage energy detector of the scanner was adapted to function as a [Formula: see text] telescope. The use of the developed filter eliminated the otherwise arising ring artifacts in the HeCT reconstructed images. For the HeCT reconstructed images of a water phantom, the maximum RSP error was improved by almost a factor 8 with respect to unfiltered images in the simulation and a factor 10 in the experiment. Similarly, for the CTP404 module, the mean RSP accuracy improved by a factor 6 in both the simulation and the experiment when the filter was applied (mean relative error 0.40% in simulation, 0.45% in experiment). In the evaluation of the spatial resolution through the CTP528 module, the main effect of the filter was noise reduction. For both simulated and experimental images the spatial resolution was  ∼4 lp cm-1. In conclusion, the novel filter developed for secondary fragments proved to be effective in improving the visual quality and RSP accuracy of the reconstructed images. With the filter, the pCT scanner is capable of accurate HeCT imaging.

Single-event ion imaging enables the direct reconstruction of the relative stopping power (RSP) information required for ion-beam therapy. Helium ions were recently hypothesized to be the optimal species for such technique. The purpose of this work is to investigate the effect of secondary fragments on the image quality of helium CT (HeCT) and to assess the performance of a prototype proton CT (pCT) scanner when operated with helium beams in Monte Carlo simulations and experiment. Experiments were conducted installing the U.S. pCT consortium prototype scanner at the Heidelberg Ion-Beam Therapy Center (HIT). Simulations were performed with the scanner using the TOPAS toolkit. HeCT images were reconstructed for a cylindrical water phantom, the CTP404 (sensitometry), and the CTP528 (line-pair) [Formula: see text] ® modules. To identify and remove individual events caused by fragmentation, the multistage energy detector of the scanner was adapted to function as a [Formula: see text] telescope. The use of the developed filter eliminated the otherwise arising ring artifacts in the HeCT reconstructed images. For the HeCT reconstructed images of a water phantom, the maximum RSP error was improved by almost a factor 8 with respect to unfiltered images in the simulation and a factor 10 in the experiment. Similarly, for the CTP404 module, the mean RSP accuracy improved by a factor 6 in both the simulation and the experiment when the filter was applied (mean relative error 0.40% in simulation, 0.45% in experiment). In the evaluation of the spatial resolution through the CTP528 module, the main effect of the filter was noise reduction. For both simulated and experimental images the spatial resolution was  ∼4 lp cm-1. In conclusion, the novel filter developed for secondary fragments proved to be effective in improving the visual quality and RSP accuracy of the reconstructed images. With the filter, the pCT scanner is capable of accurate HeCT imaging.

No prior studies have compared Tc-99m tilmanocept (TcTM) one-day and two-day injection protocols for sentinel lymph node (SLN) biopsy in breast cancer (BC). We retrospectively identified patients with clinically node-negative BC undergoing SLN biopsy at our institution. Patients received a single, intradermal peritumoral injection of TcTM on day of surgery or day prior to surgery in addition to an intraoperative injection of isosulfan blue dye. Univariable and multivariable Poisson regression count models were constructed to assess the effects of injection timing, radiologist, patient and surgeon characteristics on the number of removed SLNs. A total of 617 patients underwent SLN biopsy with TcTM and blue dye. Sixty-seven (10.9%) patients were injected with the two-day protocol. Patients in the one-day protocol had a mean of 3.0 (standard deviation (SD) 1.9) SLNs removed compared with 2.7 (SD 1.4) SLNs in the two-day protocol, P-value = .13. On multivariable analysis, patient age and operating surgeon significantly affected the number of removed SLNs; however, the injection timing and the nuclear radiologist did not influence the number of removed SLNs. The performance of Tc-99m tilmanocept did not differ significantly between one-day and two-day injection protocols. These results are similar to other radiotracers used for SLN biopsy in BC.

BACKGROUND:The objective of this study was to examine the use of preoperative cardiac stress testing (PCST) in the Southern California Vascular Outcomes Improvement Collaborative (So Cal VOICe). METHODS:A retrospective review was performed on data in all modules of the So Cal VOICe from September 2012 through May 2016. PCST was defined as stress echocardiogram or nuclear stress test. A new postoperative myocardial infarction (MI) was defined as troponin elevation and/or electrocardiogram/imaging changes with or without ischemic symptoms. Only elective cases in patients with asymptomatic cardiac status were included in the study. RESULTS:During the study period, 3,063 procedures meeting the inclusion criteria were performed in 7 registries: carotid endarterectomy (CEA), carotid artery stent, thoracic endovascular aneurysm repair, infrainguinal bypass (Infra), endovascular aneurysm repair (EVAR), suprainguinal bypass (Supra), and open abdominal aortic aneurysm repair (OAAA). PCST varied across registries from 17% in PVI to 62% in OAAA. PCST in CEA varied across 9 institutions from 10% to 79%. PCST in EVAR varied across 7 institutions from 14% to 83%. PCST in Infra varied across 4 institutions from 10% to 57%. Of the 12 patients across all registries who had a new MI, 6 had PCST, one of which was abnormal. CONCLUSIONS:The incidence of PCST varies widely across registries and institutions in the So Cal VOICe. Despite the wide variation, the incidence of new postoperative MI is exceptionally low. Further studies should evaluate the cost-effectiveness of the PCST practices and future quality improvement efforts should focus on standardization of indications for PCST.

New magnetic resonance (MR) molecular imaging techniques offer the potential for noninvasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a three-dimensional dynamic dual-agent hyperpolarized 13C magnetic resonance spectroscopic imaging approach with 13C-pyruvate and 13C-urea to investigate differences in perfusion and metabolism between low- and high-grade tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux (kPL ) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. kPL values were relatively higher for high-grade TRAMP tumors. The increase in kPL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1, and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased ktrans , attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased kPL This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials. Cancer Res; 77(12); 3207-16. ©2017 AACR.

Vesicoureteral reflux (VUR) has been linked to recurrent urinary tract infections (UTIs), renal scarring, hypertension, renal insufficiency and end-stage kidney disease. Different imaging strategies have been proposed to approach children presenting with UTI to sort out patients with significant VUR while minimizing patient morbidity, radiation exposure and financial burden. None of these imaging strategies is universally accepted. The"top-down approach" (TDA) aims at restricting the number of voiding cystourethrograms (VCUGs) and its associated morbidity while identifying patients with clinically-significant reflux. In this approach, children presenting with febrile UTIs are acutely investigated with dimercapto-succinic acid (DMSA) renal scans to identify patients with renal parenchymal inflammation. Those with evidence of renal affection are offered VCUG and late DMSA scan to identify VUR and permanent renal scarring, respectively. Although TDA could identify clinically-significant VUR with high sensitivity, it is not without limitations. The approach segregates patients based on the presence of DMSA cortical lesions omitting the morbidity and the economic burden of UTI. Additionally, some of DMSA lesions are attributed to congenital dysplasia and unrelated to UTI. Ionizing radiation exposure, financial costs, limited availability of DMSA scans in the acute setting, variability in interpreting the results and low yield of actionable findings on DMSA scans are some other limitations. In this review, we tried to address the drawbacks of the TDA and reinforce the value of patient-centered approach for VUR.

IntroductionThe overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI-3, which began on August 1, 2016, is a 5-year renewal of the current ADNI-2 study.MethodsADNI-3 will follow current and additional subjects with normal cognition, mild cognitive impairment, and AD using innovative technologies such as tau imaging, magnetic resonance imaging sequences for connectivity analyses, and a highly automated immunoassay platform and mass spectroscopy approach for cerebrospinal fluid biomarker analysis. A Systems Biology/pathway approach will be used to identify genetic factors for subject selection/enrichment. Amyloid positron emission tomography scanning will be standardized using the Centiloid method. The Brain Health Registry will help recruit subjects and monitor subject cognition.ResultsMultimodal analyses will provide insight into AD pathophysiology and disease progression.DiscussionADNI-3 will aim to inform AD treatment trials and facilitate development of AD disease-modifying treatments.

IntroductionThe overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI-3, which began on August 1, 2016, is a 5-year renewal of the current ADNI-2 study.MethodsADNI-3 will follow current and additional subjects with normal cognition, mild cognitive impairment, and AD using innovative technologies such as tau imaging, magnetic resonance imaging sequences for connectivity analyses, and a highly automated immunoassay platform and mass spectroscopy approach for cerebrospinal fluid biomarker analysis. A Systems Biology/pathway approach will be used to identify genetic factors for subject selection/enrichment. Amyloid positron emission tomography scanning will be standardized using the Centiloid method. The Brain Health Registry will help recruit subjects and monitor subject cognition.ResultsMultimodal analyses will provide insight into AD pathophysiology and disease progression.DiscussionADNI-3 will aim to inform AD treatment trials and facilitate development of AD disease-modifying treatments.

Vesicoureteral reflux (VUR) has been linked to recurrent urinary tract infections (UTIs), renal scarring, hypertension, renal insufficiency and end-stage kidney disease. Different imaging strategies have been proposed to approach children presenting with UTI to sort out patients with significant VUR while minimizing patient morbidity, radiation exposure and financial burden. None of these imaging strategies is universally accepted. The"top-down approach" (TDA) aims at restricting the number of voiding cystourethrograms (VCUGs) and its associated morbidity while identifying patients with clinically-significant reflux. In this approach, children presenting with febrile UTIs are acutely investigated with dimercapto-succinic acid (DMSA) renal scans to identify patients with renal parenchymal inflammation. Those with evidence of renal affection are offered VCUG and late DMSA scan to identify VUR and permanent renal scarring, respectively. Although TDA could identify clinically-significant VUR with high sensitivity, it is not without limitations. The approach segregates patients based on the presence of DMSA cortical lesions omitting the morbidity and the economic burden of UTI. Additionally, some of DMSA lesions are attributed to congenital dysplasia and unrelated to UTI. Ionizing radiation exposure, financial costs, limited availability of DMSA scans in the acute setting, variability in interpreting the results and low yield of actionable findings on DMSA scans are some other limitations. In this review, we tried to address the drawbacks of the TDA and reinforce the value of patient-centered approach for VUR.

BackgroundPrimary hyperparathyroidism is the most common manifestation of multiple endocrine neoplasia type 1 (MEN1). Guidelines advocate subtotal parathyroidectomy (STP) or total parathyroidectomy with autotransplantation due to high prevalence of multiglandular disease; however, both are associated with a significant risk of permanent hypoparathyroidism. More accurate imaging and use of intraoperative PTH levels may allow a less extensive initial parathyroidectomy (unilateral clearance, removing both parathyroids with cervical thymectomy) in selected MEN1 patients with primary hyperparathyroidism.MethodsWe performed a retrospective cohort study at a high-volume tertiary medical center including patients with MEN1 and primary hyperparathyroidism, who underwent STP or unilateral clearance as their initial surgery from 1995 to 2015. Unilateral clearance was offered to patients who had concordant sestamibi and ultrasound showing a single enlarged parathyroid gland. For both the groups, we compared rates of persistent/recurrent disease and permanent hypoparathyroidism.ResultsEight patients had unilateral clearance and 16 had STP. Subtotal parathyroidectomy patients were younger (37 vs 52 years). One patient in each group had persistent disease. One (13 %) unilateral clearance and five (31 %) STP patients had recurrent hyperparathyroidism after a mean follow-up of 47 and 68 months (p = 0.62). No unilateral clearance patients and two of 16 SPT patients had permanent hypoparathyroidism (p = 0.54).ConclusionsSome MEN1 patients with primary hyperparathyroidism who have concordant localizing studies may be selected for unilateral clearance as an alternative to STP. For appropriately selected MEN1 patients, unilateral clearance can achieve similar results as STP and has no risk of permanent hypoparathyroidism, and may facilitate possible future reoperations.

BackgroundPrimary hyperparathyroidism is the most common manifestation of multiple endocrine neoplasia type 1 (MEN1). Guidelines advocate subtotal parathyroidectomy (STP) or total parathyroidectomy with autotransplantation due to high prevalence of multiglandular disease; however, both are associated with a significant risk of permanent hypoparathyroidism. More accurate imaging and use of intraoperative PTH levels may allow a less extensive initial parathyroidectomy (unilateral clearance, removing both parathyroids with cervical thymectomy) in selected MEN1 patients with primary hyperparathyroidism.MethodsWe performed a retrospective cohort study at a high-volume tertiary medical center including patients with MEN1 and primary hyperparathyroidism, who underwent STP or unilateral clearance as their initial surgery from 1995 to 2015. Unilateral clearance was offered to patients who had concordant sestamibi and ultrasound showing a single enlarged parathyroid gland. For both the groups, we compared rates of persistent/recurrent disease and permanent hypoparathyroidism.ResultsEight patients had unilateral clearance and 16 had STP. Subtotal parathyroidectomy patients were younger (37 vs 52 years). One patient in each group had persistent disease. One (13 %) unilateral clearance and five (31 %) STP patients had recurrent hyperparathyroidism after a mean follow-up of 47 and 68 months (p = 0.62). No unilateral clearance patients and two of 16 SPT patients had permanent hypoparathyroidism (p = 0.54).ConclusionsSome MEN1 patients with primary hyperparathyroidism who have concordant localizing studies may be selected for unilateral clearance as an alternative to STP. For appropriately selected MEN1 patients, unilateral clearance can achieve similar results as STP and has no risk of permanent hypoparathyroidism, and may facilitate possible future reoperations.

ObjectivesTo test the external validity of a previously developed risk table, designed to predict the probability of a positive bone scan among men with non-metastatic (M0) castration-resistant prostate cancer (CRPC), in a separate cohort.Patients and methodsWe retrospectively analysed 429 bone scans of 281 patients with CRPC, with no known previous metastases, treated at three Veterans Affairs Medical Centers. We assessed the predictors of a positive scan using generalized estimating equations. Area under the curve (AUC), calibration plots and decision-curve analysis were used to assess the performance of our previous model to predict a positive scan in the current data.ResultsA total of 113 scans (26%) were positive. On multivariable analysis, the only significant predictors of a positive scan were log-transformed prostate-specific antigen (PSA): hazard ratio (HR) 2.13; 95% confidence interval (CI) 1.71-2.66 (P < 0.001) and log-transformed PSA doubling time (PSADT): HR 0.53; 95% CI 0.41-0.68 (P < 0.001). Among men with a PSA level

ObjectivesTo test the external validity of a previously developed risk table, designed to predict the probability of a positive bone scan among men with non-metastatic (M0) castration-resistant prostate cancer (CRPC), in a separate cohort.Patients and methodsWe retrospectively analysed 429 bone scans of 281 patients with CRPC, with no known previous metastases, treated at three Veterans Affairs Medical Centers. We assessed the predictors of a positive scan using generalized estimating equations. Area under the curve (AUC), calibration plots and decision-curve analysis were used to assess the performance of our previous model to predict a positive scan in the current data.ResultsA total of 113 scans (26%) were positive. On multivariable analysis, the only significant predictors of a positive scan were log-transformed prostate-specific antigen (PSA): hazard ratio (HR) 2.13; 95% confidence interval (CI) 1.71-2.66 (P < 0.001) and log-transformed PSA doubling time (PSADT): HR 0.53; 95% CI 0.41-0.68 (P < 0.001). Among men with a PSA level

ImportanceEarly identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms.ObjectivesTo assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia.Design, setting, and participantsA randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity.InterventionsOral avagacestat or placebo daily.Main outcomes and measureSafety and tolerability of avagacestat.ResultsOf the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures.Conclusions and relevanceAvagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD.Trial registrationclinicaltrials.gov Identifier: NCT00890890.

ImportanceEarly identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms.ObjectivesTo assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia.Design, setting, and participantsA randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity.InterventionsOral avagacestat or placebo daily.Main outcomes and measureSafety and tolerability of avagacestat.ResultsOf the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures.Conclusions and relevanceAvagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD.Trial registrationclinicaltrials.gov Identifier: NCT00890890.

ObjectiveTo demonstrate altered N-methyl-d-aspartate (NMDA) receptor availability in patients with focal epilepsies using positron emission tomography (PET) and [(18)F]GE-179, a ligand that selectively binds to the open NMDA receptor ion channel, which is thought to be overactive in epilepsy.MethodsEleven patients (median age 33 years, 6 males) with known frequent interictal epileptiform discharges had an [(18)F]GE-179 PET scan, in a cross-sectional study. MRI showed a focal lesion but discordant EEG changes in two, was non-localising with multifocal EEG abnormalities in two, and was normal in the remaining seven patients who all had multifocal EEG changes. Individual patient [(18)F]GE-179 volume-of-distribution (VT) images were compared between individual patients and a group of 10 healthy controls (47 years, 7 males) using Statistical Parametric Mapping.ResultsIndividual analyses revealed a single cluster of focal VT increase in four patients; one with a single and one with multifocal MRI lesions, and two with normal MRIs. Post hoc analysis revealed that, relative to controls, patients not taking antidepressants had globally increased [(18)F]GE-179 VT (+28%; p

BackgroundProper localization is crucial in performing minimally invasive parathyroidectomy for primary hyperparathyroidism. Ultrasonography (US) and Tc-99m sestamibi (MIBI) scintigraphy are common methods used for localization. As the appearance and activity of the thyroid gland may impact parathyroid localization, the purpose of this study was to determine how exogenous use of the thyroid hormone, levothyroxine (LT), affects parathyroid localization.MethodsAdult patients with non-familial primary hyperparathyroidism who underwent initial parathyroidectomy from 2000-2014 were retrospectively identified. LT (+LT) and non-LT (-LT) patients were matched 1:3 based on age, gender, goiter status, and preoperative parathyroid hormone levels. Subgroup analysis was performed on patients previously treated with radioactive iodine and patients undergoing single adenoma resection.ResultsOf the 1737 patients that met inclusion criteria, 286 were on LT at the time of their parathyroid localization scan. Use of LT did not impact the percentage of correct MIBI localization scans when compared with -LT patients (P = 0.83). Interestingly, use of LT significantly hindered localization by US in comparison with the -LT group (48.4 versus 62.2%, P

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.

PurposeWe investigated imaging practice patterns in men with nonmetastatic (M0) castration resistant prostate cancer.Materials and methodsWe analyzed data on 247 patients with documented M0 CRPC from the SEARCH database. Patients were selected regardless of primary treatment modality and all had a negative bone scan after a castration resistant prostate cancer diagnosis. Cox models were used to test associations of time to a second imaging test with several demographic and clinical factors.ResultsDuring a median followup of 29.0 months (IQR 12.9-43.5) after a post-castration resistant prostate cancer bone scan was negative, 190 patients (77%) underwent a second imaging test. On univariable analysis patients with higher prostate specific antigen (HR 1.13, p = 0.016), shorter prostate specific antigen doubling time (HR 0.79, p < 0.001) and faster prostate specific antigen velocity (HR 1.01, p < 0.001) were more likely to undergo a second imaging test. Treatment center was also a significant predictor of a second imaging test (p = 0.010). No other factor was a significant predictor. Results were similar on multivariable analysis. It was estimated that approximately 20% of men with a prostate specific antigen doubling time of less than 3 months did not undergo an imaging test in the first year after a post-castration resistant prostate cancer negative bone scan. However, 50% of patients with prostate specific antigen doubling time 15 months or greater underwent a second imaging test in the first year.ConclusionsClinicians use some known predictors of positive imaging tests to determine which patients with M0 castration resistant prostate cancer undergo a second imaging test . However, there may be under imaging in those at high risk and over imaging in those at low risk. Further studies are needed to identify risk factors for metastasis and form clear imaging guidelines in patients with M0 castration resistant prostate cancer.

PurposeWe investigated imaging practice patterns in men with nonmetastatic (M0) castration resistant prostate cancer.Materials and methodsWe analyzed data on 247 patients with documented M0 CRPC from the SEARCH database. Patients were selected regardless of primary treatment modality and all had a negative bone scan after a castration resistant prostate cancer diagnosis. Cox models were used to test associations of time to a second imaging test with several demographic and clinical factors.ResultsDuring a median followup of 29.0 months (IQR 12.9-43.5) after a post-castration resistant prostate cancer bone scan was negative, 190 patients (77%) underwent a second imaging test. On univariable analysis patients with higher prostate specific antigen (HR 1.13, p = 0.016), shorter prostate specific antigen doubling time (HR 0.79, p < 0.001) and faster prostate specific antigen velocity (HR 1.01, p < 0.001) were more likely to undergo a second imaging test. Treatment center was also a significant predictor of a second imaging test (p = 0.010). No other factor was a significant predictor. Results were similar on multivariable analysis. It was estimated that approximately 20% of men with a prostate specific antigen doubling time of less than 3 months did not undergo an imaging test in the first year after a post-castration resistant prostate cancer negative bone scan. However, 50% of patients with prostate specific antigen doubling time 15 months or greater underwent a second imaging test in the first year.ConclusionsClinicians use some known predictors of positive imaging tests to determine which patients with M0 castration resistant prostate cancer undergo a second imaging test . However, there may be under imaging in those at high risk and over imaging in those at low risk. Further studies are needed to identify risk factors for metastasis and form clear imaging guidelines in patients with M0 castration resistant prostate cancer.

ObjectiveThe objective of this study was to test whether effects of β-amyloid (Aβ) pathology on episodic memory were mediated by metabolism and gray matter volume in the early stages of Alzheimer disease.MethodsThis was a prospective cohort study. We measured baseline Aβ (using florbetapir-PET), brain function (using fluorodeoxyglucose-PET), and brain structure (using MRI). A mediation analysis was performed to test whether statistical effects of Aβ positivity on cross-sectional and longitudinal episodic memory were mediated by hypometabolism or regional gray matter volume in cognitively healthy controls (CN, n = 280) and mild cognitive impairment (MCI, n = 463).ResultsLower memory scores were associated with Aβ positivity (CN, mildly; MCI, strongly), smaller gray matter volumes (CN, few regions, including hippocampus; MCI, widespread), and hypometabolism. Smaller volumes and hypometabolism mediated effects of Aβ in MCI but not in CN. The strongest individual regions mediated up to approximately 25%. A combination of brain structure and function mediated up to approximately 40%. In several regions, gray matter atrophy and hypometabolism predicted episodic memory without being associated (at p < 0.05) with Aβ positivity.ConclusionsChanges in brain structure and function appear to be, in part, downstream events from Aβ pathology, ultimately resulting in episodic memory deficits. However, Aβ pathology is also strongly related to memory deficits through mechanisms that are not quantified by these imaging measurements, and episodic memory decline is partly caused by Alzheimer disease-like brain changes independently of Aβ pathology.

OBJECTIVE:The objective of this study was to test whether effects of β-amyloid (Aβ) pathology on episodic memory were mediated by metabolism and gray matter volume in the early stages of Alzheimer disease. METHODS:This was a prospective cohort study. We measured baseline Aβ (using florbetapir-PET), brain function (using fluorodeoxyglucose-PET), and brain structure (using MRI). A mediation analysis was performed to test whether statistical effects of Aβ positivity on cross-sectional and longitudinal episodic memory were mediated by hypometabolism or regional gray matter volume in cognitively healthy controls (CN, n = 280) and mild cognitive impairment (MCI, n = 463). RESULTS:Lower memory scores were associated with Aβ positivity (CN, mildly; MCI, strongly), smaller gray matter volumes (CN, few regions, including hippocampus; MCI, widespread), and hypometabolism. Smaller volumes and hypometabolism mediated effects of Aβ in MCI but not in CN. The strongest individual regions mediated up to approximately 25%. A combination of brain structure and function mediated up to approximately 40%. In several regions, gray matter atrophy and hypometabolism predicted episodic memory without being associated (at p < 0.05) with Aβ positivity. CONCLUSIONS:Changes in brain structure and function appear to be, in part, downstream events from Aβ pathology, ultimately resulting in episodic memory deficits. However, Aβ pathology is also strongly related to memory deficits through mechanisms that are not quantified by these imaging measurements, and episodic memory decline is partly caused by Alzheimer disease-like brain changes independently of Aβ pathology.

Determining the relative contribution of amyloid plaques and neurofibrillary tangles to brain dysfunction in Alzheimer disease is critical for therapeutic approaches, but until recently could only be assessed at autopsy. We report a patient with posterior cortical atrophy (visual variant of Alzheimer disease) who was studied using the novel tau tracer [(18) F]AV-1451 in conjunction with [(11) C]Pittsburgh compound B (PIB; amyloid) and [(18) F]fluorodeoxyglucose (FDG) positron emission tomography. Whereas [(11) C]PIB bound throughout association neocortex, [(18) F]AV-1451 was selectively retained in posterior brain regions that were affected clinically and showed markedly reduced [(18) F]FDG uptake. This provides preliminary in vivo evidence that tau is more closely linked to hypometabolism and symptomatology than amyloid.

BackgroundThe efficacy of sentinel lymph node (SLN) surgery requires targeted removal of first-draining nodes; however, frequently more nodes are removed than necessary. [(99m)Tc]tilmanocept (TcTM) is a molecular-targeted radiopharmaceutical specifically designed for SLN mapping. We evaluated technical outcomes of SLN biopsy in breast cancer patients mapped with TcTM + vital blue dye (VBD) versus filtered [(99m)Tc]sulfur colloid (fTcSC) + VBD.MethodsThere were 84 versus 115 patients in the TcTM versus fTcSC cohorts, respectively. Main measures were the number of SLNs removed per patient and factors influencing number of nodes removed. We also evaluated whether the radiotracer injected affected the proportion of positive nodes removed in node-positive patients.ResultsFewer nodes were removed among patients mapped with TcTM compared to fTcSC (mean TcTM: 1.85 vs. fTcSC: 3.24, p < 0.001). Logistic regression analysis adjusted for tumor characteristics showed that injection of fTcSC (p < 0.001) independently predicted removal of greater than 3 nodes. A similar proportion of patients was identified as node-positive, whether mapped with TcTM or with fTcSC (TcTM: 24 % vs. fTcSC: 17 %, p = 0.3); however, TcTM detected a greater proportion of positive nodes among node-positive patients compared with fTcSC (0.73 vs. 0.43, p = 0.001).ConclusionsPatients undergoing SLN biopsy with TcTM required fewer SLNs to identify the same rate of node-positive patients compared with fTcSC in breast cancer patients with similar risk of axillary metastatic disease. These data suggest that a molecularly targeted mechanism of SLN identification may reduce the total number of nodes necessary for accurate axillary staging.

BackgroundThe efficacy of sentinel lymph node (SLN) surgery requires targeted removal of first-draining nodes; however, frequently more nodes are removed than necessary. [(99m)Tc]tilmanocept (TcTM) is a molecular-targeted radiopharmaceutical specifically designed for SLN mapping. We evaluated technical outcomes of SLN biopsy in breast cancer patients mapped with TcTM + vital blue dye (VBD) versus filtered [(99m)Tc]sulfur colloid (fTcSC) + VBD.MethodsThere were 84 versus 115 patients in the TcTM versus fTcSC cohorts, respectively. Main measures were the number of SLNs removed per patient and factors influencing number of nodes removed. We also evaluated whether the radiotracer injected affected the proportion of positive nodes removed in node-positive patients.ResultsFewer nodes were removed among patients mapped with TcTM compared to fTcSC (mean TcTM: 1.85 vs. fTcSC: 3.24, p < 0.001). Logistic regression analysis adjusted for tumor characteristics showed that injection of fTcSC (p < 0.001) independently predicted removal of greater than 3 nodes. A similar proportion of patients was identified as node-positive, whether mapped with TcTM or with fTcSC (TcTM: 24 % vs. fTcSC: 17 %, p = 0.3); however, TcTM detected a greater proportion of positive nodes among node-positive patients compared with fTcSC (0.73 vs. 0.43, p = 0.001).ConclusionsPatients undergoing SLN biopsy with TcTM required fewer SLNs to identify the same rate of node-positive patients compared with fTcSC in breast cancer patients with similar risk of axillary metastatic disease. These data suggest that a molecularly targeted mechanism of SLN identification may reduce the total number of nodes necessary for accurate axillary staging.

Radiosynthesis of a fluorine-18 labeled organophosphate (OP) inhibitor of acetylcholinesterase (AChE) and subsequent positron emission tomography (PET) imaging using the tracer in the rat central nervous system are reported. The tracer structure, which contains a novel β-fluoroethoxy phosphoester moiety, was designed as an insecticide-chemical nerve agent hybrid to optimize handling and the desired target reactivity. Radiosynthesis of the β-fluoroethoxy tracer is described that utilizes a [(18)F]prosthetic group coupling approach. The imaging utility of the [(18)F]tracer is demonstrated in vivo within rats by the evaluation of its brain penetration and cerebral distribution qualities in the absence and presence of a challenge agent. The tracer effectively penetrates brain and localizes to cerebral regions known to correlate with the expression of the AChE target. Brain pharmacokinetic properties of the tracer are consistent with the formation of an OP-adducted acetylcholinesterase containing the fluoroethoxy tracer group. Based on the initial favorable in vivo qualities found in rat, additional [(18)F]tracer studies are ongoing to exploit the technology to dynamically probe organophosphate mechanisms of action in mammalian live tissues.

BackgroundCoronary artery calcium (CAC) is a well-established predictor of clinical outcomes for population screening. Limited evidence is available as to its predictive value in symptomatic patients without obstructive coronary artery disease (CAD). The aim of the current study was to assess the prognostic value of CAC scores among symptomatic patients with nonobstructive CAD.MethodsFrom the COronary Computed Tomographic Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry, 7,200 symptomatic patients with nonobstructive CAD (0% but

ObjectiveTo investigate the associations among β-amyloid (Aβ), cortical thickness, and episodic memory in a cohort of cognitively normal to mildly impaired individuals at increased risk of vascular disease.MethodsIn 67 subjects specifically recruited to span a continuum of cognitive function and vascular risk, we measured brain Aβ deposition using [(11)C] Pittsburgh compound B-PET imaging and cortical thickness using MRI. Episodic memory was tested using a standardized composite score of verbal memory, and vascular risk was quantified using the Framingham Coronary Risk Profile index.ResultsIncreased Aβ was associated with cortical thinning, notably in frontoparietal regions. This relationship was strongest in persons with high Aβ deposition. Increased Aβ was also associated with lower episodic memory performance. Cortical thickness was found to mediate the relationship between Aβ and memory performance. While age had a marginal effect on these associations, the relationship between Aβ and cortical thickness was eliminated after controlling for vascular risk except when examined in only Pittsburgh compound B-positive subjects, in whom Aβ remained associated with thinner cortex in precuneus and occipital lobe. In addition, only the precuneus was found to mediate the relationship between Aβ and memory after controlling for vascular risk.ConclusionThese results suggest strong links among Aβ, cortical thickness, and memory. They highlight that, in individuals without dementia, vascular risk also contributes to cortical thickness and influences the relationships among Aβ, cortical thickness, and memory.

Brown adipose tissue (BAT) is specialized to dissipate chemical energy in the form of heat as a defense against cold and excessive feeding. Interest in the field of BAT biology has exploded in the past few years because of the therapeutic potential of BAT to counteract obesity and obesity-related diseases, including insulin resistance. Much progress has been made, particularly in the areas of BAT physiology in adult humans, developmental lineages of brown adipose cell fate, and hormonal control of BAT thermogenesis. As we enter into a new era of brown fat biology, the next challenge will be to develop strategies for activating BAT thermogenesis in adult humans to increase whole-body energy expenditure. This article reviews the recent major advances in this field and discusses emerging questions.

ImportanceBecause deposition of cerebral β-amyloid (Aβ) seems to be a key initiating event in Alzheimer disease (AD), factors associated with increased deposition are of great interest. Whether elevated serum cholesterol levels act as such a factor is unknown.ObjectiveTo investigate the association between serum cholesterol levels and cerebral Aβ during life early in the AD process.Design, setting, and participantsA multisite, university medical center-based, cross-sectional analysis of potential associations between contemporaneously assayed total serum cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and cerebral Aβ, measured with carbon C11-labeled Pittsburgh Compound B (PIB) positron emission tomography. Seventy-four persons (mean age, 78 years) were recruited via direct outreach in stroke clinics and community senior facilities following a protocol designed to obtain a cohort enriched for cerebrovascular disease and elevated vascular risk. Three patients had mild dementia. All others were clinically normal (n = 33) or had mild cognitive impairment (n = 38).ResultsCerebral Aβ was quantified using a Global PIB Index, which averages PIB retention in cortical areas prone to amyloidosis. Statistical models that controlled for age and the apolipoprotein E ε4 allele revealed independent associations among the levels of LDL-C, HDL-C, and PIB index. Higher LDL-C and lower HDL-C levels were both associated with a higher PIB index. No association was found between the total cholesterol level and PIB index. No association was found between statin use and PIB index, and controlling for cholesterol treatment in the statistical models did not alter the basic findings.Conclusions and relevanceElevated cerebral Aβ level was associated with cholesterol fractions in a pattern analogous to that found in coronary artery disease. This finding, in living humans, is consistent with prior autopsy reports, epidemiologic findings, and animal and in vitro work, suggesting an important role for cholesterol in Aβ processing. Because cholesterol levels are modifiable, understanding their link to Aβ deposition could potentially and eventually have an effect on retarding the pathologic cascade of AD. These findings suggest that understanding the mechanisms through which serum lipids modulate Aβ could offer new approaches to slowing Aβ deposition and thus to reducing the incidence of AD.

The Maillard reaction of sugars and amines resulting in the formation of glycosylamines and Amadori products is of biological significance, for drug delivery, role in central nervous system, and other potential applications. We have examined the interaction of (18) F-fluorodeoxyglucose ((18) F-FDG) with biological amines to study the formation of (18) F-fluorodeoxyglycosylamines ((18) F-FDGly). Respective amines N-allyl-2-aminomethylpyrrolidine (NAP) and 2-(4'-aminophenyl)-6-hydroxybenzothiazole (PIB precursor) were mixed with FDG to provide glycosylamines, FDGNAP and FDGBTA. Radiosynthesis using (18) F-FDG (2-5 mCi) was carried out to provide (18) F-FDGNAP and (18) F-FDGBTA. Binding of FDGBTA and (18) F-FDGBTA was evaluated in human brain sections of Alzheimer's disease (AD) patients and control subjects using autoradiography. Both FDGNAP and FDGBTA were isolated as stable products. Kinetics of (18) F-FDGNAP reaction indicated a significant product at 4 h (63% radiochemical yield). (18) F-FDGBTA was prepared in 57% yield. Preliminary studies of FDGBTA showed displacement of (3) H-PIB (reduced by 80%), and (18) F-FDGBTA indicated selective binding to Aβ-amyloid plaques present in postmortem AD human brain, with a gray matter ratio of 3 between the AD patients and control subjects. We have demonstrated that (18) F-FDG couples with amines under mild conditions to form (18) F-FDGly in a manner similar to click chemistry. Although these amine derivatives are stable in vitro, stability in vivo and selective binding is under investigation.

This study was designed to use real-time imaging to test the hypothesis that delayed cardiac protection induced by volatile anesthetics inhibits apoptosis. Rats were divided into two groups. One group was exposed to 120 min of 33 % O2 [control group (CON group)] and the other group was exposed to 2.5 % sevoflurane in 33 % O2 for 120 min [sevoflurane group (SEVO group)]. Both groups were allowed to return to their cages for 24 h. After 24 h recovery, all rats underwent 30 min myocardial ischemia by occluding coronary artery followed by 2 h of reperfusion. After reperfusion, technetium-99m-labeled annexin-V was administered intravenously to identify apoptosis. Left ventricular samples were obtained to measure infarct size and radionuclide imaging and caspase-3. Radionuclide imaging indicated that apoptosis was reduced in SEVO group (0.78 % ± 0.82) when compared with the CON group (1.15 % ± 0.61), and the infarct size was also decreased in the SEVO group (40 % ± 7). The transferase dUTP nick end labeling (TUNEL)-positive cardiomyocytes in the SEVO group (16 % ± 6) were significantly decreased in the peri-infarct zone when compared with the CON group (28 % ± 4). After reperfusion, caspase-3 expression was significantly blunted in the SEVO group than in CON group (50 % ± 11 vs. 68 % ± 10, p < 0.05). This study used technetium-99m-labeled annexin-V of real-time imaging to detect cardiomyocyte apoptosis and the results were confirmed by the TUNEL assay and caspase-3 expression. We concluded that delayed volatile anesthetic preconditioning (APC) protects against I/R in vivo. The method of technetium-99m-labeled annexin-V of real-time imaging can be used to detect cardiomyocyte apoptosis in delayed APC during ischemia/reperfusion.

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

Brown adipose tissue (BAT) is specialized to dissipate chemical energy in the form of heat as a defense against cold and excessive feeding. Interest in the field of BAT biology has exploded in the past few years because of the therapeutic potential of BAT to counteract obesity and obesity-related diseases, including insulin resistance. Much progress has been made, particularly in the areas of BAT physiology in adult humans, developmental lineages of brown adipose cell fate, and hormonal control of BAT thermogenesis. As we enter into a new era of brown fat biology, the next challenge will be to develop strategies for activating BAT thermogenesis in adult humans to increase whole-body energy expenditure. This article reviews the recent major advances in this field and discusses emerging questions.

This study was designed to use real-time imaging to test the hypothesis that delayed cardiac protection induced by volatile anesthetics inhibits apoptosis. Rats were divided into two groups. One group was exposed to 120 min of 33 % O2 [control group (CON group)] and the other group was exposed to 2.5 % sevoflurane in 33 % O2 for 120 min [sevoflurane group (SEVO group)]. Both groups were allowed to return to their cages for 24 h. After 24 h recovery, all rats underwent 30 min myocardial ischemia by occluding coronary artery followed by 2 h of reperfusion. After reperfusion, technetium-99m-labeled annexin-V was administered intravenously to identify apoptosis. Left ventricular samples were obtained to measure infarct size and radionuclide imaging and caspase-3. Radionuclide imaging indicated that apoptosis was reduced in SEVO group (0.78 % ± 0.82) when compared with the CON group (1.15 % ± 0.61), and the infarct size was also decreased in the SEVO group (40 % ± 7). The transferase dUTP nick end labeling (TUNEL)-positive cardiomyocytes in the SEVO group (16 % ± 6) were significantly decreased in the peri-infarct zone when compared with the CON group (28 % ± 4). After reperfusion, caspase-3 expression was significantly blunted in the SEVO group than in CON group (50 % ± 11 vs. 68 % ± 10, p < 0.05). This study used technetium-99m-labeled annexin-V of real-time imaging to detect cardiomyocyte apoptosis and the results were confirmed by the TUNEL assay and caspase-3 expression. We concluded that delayed volatile anesthetic preconditioning (APC) protects against I/R in vivo. The method of technetium-99m-labeled annexin-V of real-time imaging can be used to detect cardiomyocyte apoptosis in delayed APC during ischemia/reperfusion.

BackgroundTall cell variant (TCV) and diffuse sclerosing variant (DSV) of papillary thyroid cancer are aggressive subtypes, for which tumors ≤1 cm have not been exclusively studied.MethodsThe SEER database (1988-2009) was used to compare characteristics of TCV ≤1 cm (mTCV) and DSV ≤1 cm (mDSV) with classic papillary thyroid microcarcinoma (mPTC). Survival was analyzed with the Kaplan-Meier method and log-rank test, and risk factors for nodal metastases with chi-square analysis and binary logistic regression.ResultsThere were 97 mTCV, 90 mDSV, and 18,260 mPTC patients. mTCV incidence increased by 79.9% (p=0.153) over the study period, while mDSV incidence decreased by 10.3% (p=0.315). Compared to classic mPTC, mTCV tended to be larger on average (7.1 mm vs. 5.3 mm, p7 mm (odds ratio (OR) 4.4 [CI 1.5-13.6]) and nodal metastasis with multifocality (OR 5.4 [CI 1.3-23.4]) and extrathyroidal extension (OR 5.8 [CI 1.3-25.4]). No statistically significant predictors of extrathyroidal extension or nodal metastasis in mDSV were observed.ConclusionsAggressive variants of mPTC tend to exhibit more aggressive pathologic characteristics than classic mPTC, but survival appears to be similar. Treatment with total thyroidectomy and central lymphadenectomy may be warranted if the diagnosis can be made pre- or intraoperatively.

Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [(11)C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [(11)C]OMAR, which measures the volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [(11)C]OMAR VT values (F(2,53)=7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53)=5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively--OMAR VT, anandamide and cortisol--correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder.

Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [(11)C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [(11)C]OMAR, which measures the volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [(11)C]OMAR VT values (F(2,53)=7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53)=5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively--OMAR VT, anandamide and cortisol--correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder.

BackgroundSentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance.MethodsA total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept.ResultsA total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p

BackgroundSentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance.MethodsA total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept.ResultsA total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p