Involvement of eNAMPT/TLR4 inflammatory signaling in progression of non-alcoholic fatty liver disease, steatohepatitis, and fibrosis.

Although the progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to steatohepatitis (NASH) and cirrhosis remains poorly understood, a critical role for dysregulated innate immunity has emerged. We examined the utility of ALT-100, a monoclonal antibody (mAb), in reducing NAFLD severity and progression to NASH/hepatic fibrosis. ALT-100 neutralizes eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel damage-associated molecular pattern protein (DAMP) and Toll-like receptor 4 (TLR4) ligand. Histologic and biochemical markers were measured in liver tissues and plasma from human NAFLD subjects and NAFLD mice (streptozotocin/high-fat diet-STZ/HFD, 12 weeks). Human NAFLD subjects (n = 5) exhibited significantly increased NAMPT hepatic expression and significantly elevated plasma levels of eNAMPT, IL-6, Ang-2, and IL-1RA compared to healthy controls, with IL-6 and Ang-2 levels significantly increased in NASH non-survivors. Untreated STZ/HFD-exposed mice displayed significant increases in NAFLD activity scores, liver triglycerides, NAMPT hepatic expression, plasma cytokine levels (eNAMPT, IL-6, and TNFα), and histologic evidence of hepatocyte ballooning and hepatic fibrosis. Mice receiving the eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg/week, IP, weeks 9 to 12) exhibited marked attenuation of each index of NASH progression/severity. Thus, activation of the eNAMPT/TLR4 inflammatory pathway contributes to NAFLD severity and NASH/hepatic fibrosis. ALT-100 is potentially an effective therapeutic approach to address this unmet NAFLD need.

Abdominal T2-Weighted Imaging and T2 Mapping Using a Variable Flip Angle Radial Turbo Spin-Echo Technique.

BACKGROUND: T2 mapping is of great interest in abdominal imaging but current methods are limited by low resolution, slice coverage, motion sensitivity, or lengthy acquisitions. PURPOSE: Develop a radial turbo spin-echo technique with refocusing variable flip angles (RADTSE-VFA) for high spatiotemporal T2 mapping and efficient slice coverage within a breath-hold and compare to the constant flip angle counterpart (RADTSE-CFA). STUDY TYPE: Prospective technical efficacy. SUBJECTS: Testing performed on agarose phantoms and 12 patients. Focal liver lesion classification tested on malignant (N = 24) and benign (N = 11) lesions. FIELD STRENGTH/SEQUENCE: 1.5 T/RADTSE-VFA, RADTSE-CFA. ASSESSMENT: A constrained objective function was used to optimize the refocusing flip angles. Phantom and/or in vivo data were used to assess relative contrast, T2 estimation, specific absorption rate (SAR), and focal liver lesion classification. STATISTICAL TESTS: t-Tests or Mann-Whitney Rank Sum tests were used. RESULTS: Phantom data did not show significant differences in mean relative contrast (P = 0.10) and T2 accuracy (P = 0.99) between RADTSE-VFA and RADTSE-CFA. Adding noise caused T2 overestimation predominantly for RADTSE-CFA and low T2 values. In vivo results did not show significant differences in mean spleen-to-liver (P = 0.62) and kidney-to-liver (P = 0.49) relative contrast between RADTSE-VFA and RADTSE-CFA. Mean T2 values were not significantly different between the two techniques for spleen (T2VFA  = 109.2 ± 12.3 msec; T2CFA  = 110.7 ± 11.1 msec; P = 0.78) and kidney-medulla (T2VFA  = 113.0 ± 8.7 msec; T2CFA  = 114.0 ± 8.6 msec; P = 0.79). Liver T2 was significantly higher for RADTSE-CFA (T2VFA  = 52.6 ± 6.6 msec; T2CFA  = 60.4 ± 8.0 msec) consistent with T2 overestimation in the phantom study. Focal liver lesion classification had comparable T2 distributions for RADTSE-VFA and RADTSE-CFA for malignancies (P = 1.0) and benign lesions (P = 0.39). RADTSE-VFA had significantly lower SAR than RADTSE-CFA increasing slice coverage by 1.5. DATA CONCLUSION: RADTSE-VFA provided noise-robust T2 estimation compared to the constant flip angle counterpart while generating T2-weighted images with comparable contrast. The VFA scheme minimized SAR improving slice efficiency for breath-hold imaging. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

First-Line Diagnostic Evaluation with MRI of Children Suspected of Having Acute Appendicitis.

Background Advances in abdominal MRI have enabled rapid, free-breathing imaging without the need for intravenous or oral contrast material. The use of MRI as the primary imaging modality for suspected appendicitis has not been previously studied. Purpose To determine the diagnostic performance of MRI as the initial imaging modality in children suspected of having acute appendicitis. Materials and Methods The study included consecutive patients 18 years of age and younger presenting with acute abdominal pain at a tertiary care institution from January 2013 through June 2016 who subsequently underwent an unenhanced MRI examination as the primary diagnostic imaging modality. Electronic medical records and radiology reports were retrospectively evaluated for the feasibility and diagnostic performance of MRI, with surgical pathology and follow-up electronic records as reference standards. Statistical analyses were performed by using simple binomial proportions to quantify sensitivity, specificity, and accuracy, and exact 95% confidence intervals (CIs) were obtained. Results After exclusions, 402 patients (median age: 13 years; interquartile range [IQR], 9-15 years; 235 female patients; 167 male patients) were included. Sedation for MRI was required in 13 of 402 patients (3.2%; 95% CI: 1.7%, 5.5%). The appendix was visualized in 349 of 402 patients (86.8%; 95% CI: 83.1%, 90%); for the remaining patients, a diagnosis was provided on the basis of secondary signs of appendicitis. The sensitivity, specificity, and accuracy of MRI as the primary diagnostic imaging modality for the evaluation of acute appendicitis were 97.9% (95 of 97; 95% CI: 92.8%, 99.8%), 99% (302 of 305; 95% CI: 97.2%, 99.8%), and 98.8% (397 of 402; 97.1%, 99.6%), respectively. Among patients with negative findings for appendicitis at MRI, an alternate diagnosis was provided in 113 of 304 patients (37.2%; 95% CI: 31.7%, 42.9%). Conclusion When performed as the initial imaging modality in children suspected of having acute appendicitis, MRI examinations had high diagnostic performance for the diagnosis of acute appendicitis and in providing alternative diagnoses. © RSNA, 2019 See also the editorial by Dillman and Trout in this issue.

Radial streak artifact reduction using phased array beamforming.

PURPOSE: A new method for streak artifact reduction in radial MRI based on phased array filtering. THEORY: Radial imaging in applications that require large fields-of-view can be susceptible to streaking artifacts due to gradient nonlinearities. Coil removal methods prune the coils contributing the most to streaking artifacts at the expense of signal loss. Phased array beamforming is a form of spatial filtering used to suppress unwanted signals. The proposed method uses interference covariance generated from the streaking artifact samples which are manually extracted with phased array beamforming to suppress streaking in the images. METHODS: The performance of the proposed method was evaluated on abdomen radial fast spin echo images acquired on a 1.5T Siemens scanner and compared with previously proposed methods. RESULTS: Our results demonstrate that the proposed method can effectively suppress streaking artifacts without any noticeable loss in signal levels. Coil removal methods can suppress streaks as well but they may incur significant signal loss due to coil pruning. Quantitative metrics also demonstrate the superiority of the proposed method over earlier methods. CONCLUSION: The use of interference covariance with phased array beamforming can help reduce streaking artifacts.

An efficient 3D stack-of-stars turbo spin echo pulse sequence for simultaneous T2-weighted imaging and T2 mapping.

PURPOSE: To design a pulse sequence for efficient 3D T2-weighted imaging and T2 mapping. METHODS: A stack-of-stars turbo spin echo pulse sequence with variable refocusing flip angles and a flexible pseudorandom view ordering is proposed for simultaneous T2-weighted imaging and T2 mapping. An analytical framework is introduced for the selection of refocusing flip angles to maximize relative tissue contrast while minimizing T2 estimation errors and maintaining low specific absorption rate. Images at different echo times are generated using a subspace constrained iterative reconstruction algorithm. T2 maps are obtained by modeling the signal evolution using the extended phase graph model. The technique is evaluated using phantoms and demonstrated in vivo for brain, knee, and carotid imaging. RESULTS: Numerical simulations demonstrate an improved point spread function with the proposed pseudorandom view ordering compared to golden angle view ordering. Phantom experiments show that T2 values estimated from the stack-of-stars turbo spin echo pulse sequence with variable refocusing flip angles have good concordance with spin echo reference values. In vivo results show the proposed pulse sequence can generate qualitatively comparable T2-weighted images as conventional Cartesian 3D SPACE in addition to simultaneously generating 3D T2 maps. CONCLUSION: The proposed stack-of-stars turbo spin echo pulse sequence with pseudorandom view ordering and variable refocusing flip angles allows high resolution isotropic T2 mapping in clinically acceptable scan times. The optimization framework for the selection of refocusing flip angles improves T2 estimation accuracy while generating T2-weighted contrast comparable to conventional Cartesian imaging.

Rapid high-resolution T1 mapping using a highly accelerated radial steady-state free-precession technique.

BACKGROUND: T1 mapping is often used in some clinical protocols. Existing techniques are limited in slice coverage, and/or spatial-temporal resolution, or require long acquisitions. Here we present a multi-slice inversion-recovery (IR) radial steady-state free precession (radSSFP) pulse sequence combined with a principal component (PC) based reconstruction that overcomes these limitations. PURPOSE: To develop a fast technique for multi-slice high-resolution T1 mapping. STUDY TYPE: Technical efficacy study done prospectively. PHANTOM/SUBJECTS: IR-radSSFP was tested in phantoms, five healthy volunteers, and four patients with abdominal lesions. FIELD STRENGTH/SEQUENCE: IR-radSSFP was implemented at 3T. ASSESSMENT: Computer simulations were performed to optimize the flip angle for T1 estimation; testing was done in phantoms using as reference an IR spin-echo pulse sequence. T1 mapping with IR-radSSFP was also assessed in vivo (brain and abdomen) and T1 values were compared with literature. T1 maps were also compared with a radial IR-FLASH technique. STATISTICAL TESTS: A two-tailed t-test was used to compare T1 values in phantoms. A repeatability study was carried out in vivo using Bland-Altman analysis. RESULTS: Simulations and phantom experiments showed that a flip angle of 20˚ was optimal for T1 mapping. When comparing single to multi-slice experiments in phantoms there were no significant differences between the means T1 values (P = 0.0475). In vivo results show that T1 maps with spatial resolution as high as 0.69 mm × 0.69 mm × 2.00 mm (brain) and 0.83 mm × 0.83 mm × 3.00 mm (abdomen) can be generated for 84 brain slices in 3 min and 10 abdominal slices in a breath-hold; T1 values were comparable to those reported in literature. The coefficients of variation from the repeatability study were 1.7% for brain and 2.5-2.7% in the abdomen. DATA CONCLUSION: A multi-slice IR-radSSFP technique combined with a PC-based reconstruction was demonstrated for higher resolution T1 mapping. This technique is fast, motion-insensitive and yields repeatable T1 values comparable to those in literature. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:239-252.

Notice of Withdrawal: No Incidence of Nephrogenic Systemic Fibrosis after Gadobenate Dimeglumine Administration in Patients Undergoing Dialysis or Those with Severe Chronic Kidney Disease.

The authors have requested to withdraw this manuscript from publication because the study was not conducted in full accordance with the relevant institutional IRB protocol. © RSNA, 2018.

Accelerated MR parameter mapping with a union of local subspaces constraint.

PURPOSE: A new reconstruction method for multi-contrast imaging and parameter mapping based on a union of local subspaces constraint is presented. THEORY: Subspace constrained reconstructions use a predetermined subspace to explicitly constrain the relaxation signals. The choice of subspace size ( K ) impacts the approximation error vs noise-amplification tradeoff associated with these methods. A different approach is used in the model consistency constraint (MOCCO) framework to leverage the subspace model to enforce a softer penalty. Our proposed method, MOCCO-LS, augments the MOCCO model with a union of local subspaces (LS) approach. The union of local subspaces model is coupled with spatial support constraints and incorporated into the MOCCO framework to regularize the contrast signals in the scene. METHODS: The performance of the MOCCO-LS method was evaluated in vivo on T1 and T2 mapping of the human brain and with Monte-Carlo simulations and compared against MOCCO and the explicit subspace constrained models. RESULTS: The results demonstrate a clear improvement in the multi-contrast images and parameter maps. We sweep across the model order space ( K ) to compare the different reconstructions and demonstrate that the reconstructions have different preferential operating points. Experiments on T2 mapping show that the proposed method yields substantial improvements in performance even when operating at very high acceleration rates. CONCLUSIONS: The use of a union of local subspace constraints coupled with a sparsity promoting penalty leads to improved reconstruction quality of multi-contrast images and parameter maps.

MRI of patients with implanted cardiac devices.

Cardiac implanted electronic devices (CIEDs) have historically been regarded as a contraindication for performing magnetic resonance imaging (MRI), limiting the availability of this exam for large numbers of patients who may have otherwise benefited from the unique diagnostic capabilities of MRI. Interactions between CIEDs and the magnetic field associated with MRI systems have been documented, and include potential effects on CIED function, lead heating, and force/torque on the generator. Several device manufacturers have developed "MR-Conditional" CIEDs with specific hardware and software design changes to optimize the device for the MR environment. However, a substantial body of evidence has been accumulating that suggests that MRI may be safely performed in patients with either conditional or nonconditional CIEDs. Institutional policies and procedures, including preexam screening and assessment by skilled electrophysiology personnel and intraexam monitoring, allow MRI to be safely performed in CIED patients, as evidenced by at least two, large multicenter prospective studies and multiple smaller, single-institution studies. Cross-departmental collaboration and a robust safety infrastructure at sites that perform MRI should allow for the safe imaging of CIED patients who have a clinical indication for the study, regardless of the conditionality status of the device. LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:595-603.

A multi-band double-inversion radial fast spin-echo technique for T2 cardiovascular magnetic resonance mapping of the heart.

BACKGROUND: Double inversion recovery (DIR) fast spin-echo (FSE) cardiovascular magnetic resonance (CMR) sequences are used clinically for black-blood T2-weighted imaging. However, these sequences suffer from slice inefficiency due to the non-selective inversion pulses. We propose a multi-band (MB) encoded DIR radial FSE (MB-DIR-RADFSE) technique to simultaneously excite two slices. This sequence has improved signal-to-noise ratio per unit time compared to a single slice excitation. It is also motion robust and enables the reconstruction of high-resolution black-blood T2-weighted images and T2 maps for the excited slices. METHODS: Hadamard encoded MB pulses were used in MB-DIR-RADFSE to simultaneously excite two slices. A principal component based iterative reconstruction was used to jointly reconstruct black-blood T2-weighted images and T2 maps. Phantom and in vivo experiments were performed to evaluate T2 mapping performance and results were compared to a T2-prepared balanced steady state free precession (bSSFP) method. The inter-segment variability of the T2 maps were assessed using data acquired on healthy subjects. A reproducibility study was performed to evaluate reproducibility of the proposed technique. RESULTS: Phantom experiments show that the T2 values estimated from MB-DIR-RADFSE are comparable to the spin-echo based reference, while T2-prepared bSSFP over-estimated T2 values. The relative contrast of the black-blood images from the multi-band scheme was comparable to those from a single slice acquisition. The myocardial segment analysis on 8 healthy subjects indicated a significant difference (p-value < 0.01) in the T2 estimates from the apical slice when compared to the mid-ventricular slice. The mean T2 estimate from 12 subjects obtained using T2-prepared bSSFP was significantly higher (p-value = 0.012) compared to MB-DIR-RADFSE, consistent with the phantom results. The Bland-Altman analysis showed excellent reproducibility between the MB-DIR-RADFSE measurements, with a mean T2 difference of 0.12 ms and coefficient of reproducibility of 2.07 in 15 clinical subjects. The utility of this technique is demonstrated in two subjects where the T2 maps show elevated values in regions of pathology. CONCLUSIONS: The use of multi-band pulses for excitation improves the slice efficiency of the double inversion fast spin-echo pulse sequence. The use of a radial trajectory and a joint reconstruction framework allows reconstruction of TE images and T2 maps for the excited slices.

Multiresolution imaging using golden angle stack-of-stars and compressed sensing for dynamic MR urography.

PURPOSE: To develop a novel multiresolution MRI methodology for accurate estimation of glomerular filtration rate (GFR) in vivo. MATERIALS AND METHODS: A three-dimensional golden-angle radial stack-of-stars (SoS) trajectory was used for data acquisition on a 3 Tesla MRI scanner. Multiresolution reconstruction and analysis was performed using arterial input function reconstructed at 1-s. temporal resolution and renal dynamic data reconstructed using compressed sensing (CS) with 4-s temporal resolution. The method was first validated using simulations and the clinical utility of the technique was evaluated by comparing the GFR estimates from the proposed method to the estimated GFR (eGFR) obtained from serum creatinine for 10 subjects. RESULTS: The 4-s temporal resolution CS images minimized streaking artifacts and noise while the 1-s temporal resolution AIF minimized errors in GFR estimates. A paired t-test showed that there was no statistically significant difference between MRI based total GFR values and serum creatinine based eGFR estimates (P = 0.92). CONCLUSION: We have demonstrated the feasibility of multiresolution MRI using a golden angle radial stack-of-stars scheme to accurately estimate GFR as well as produce diagnostic quality dynamic images in vivo. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2017;46:303-311.

Accuracy of Unenhanced MR Imaging in the Detection of Acute Appendicitis: Single-Institution Clinical Performance Review.

PURPOSE: To determine the accuracy of unenhanced magnetic resonance (MR) imaging in the detection of acute appendicitis in patients younger than 50 years who present to the emergency department with right lower quadrant (RLQ) pain. MATERIALS AND METHODS: The institutional review board approved this retrospective study of 403 patients from August 1, 2012, to July 30, 2014, and waived the informed consent requirement. A cross-department strategy was instituted to use MR imaging as the primary diagnostic modality in patients aged 3-49 years who presented to the emergency department with RLQ pain. All MR examinations were performed with a 1.5- or 3.0-T system. Images were acquired without breath holding by using multiplanar half-Fourier single-shot T2-weighted imaging without and with spectral adiabatic inversion recovery fat suppression without oral or intravenous contrast material. MR imaging room time was measured for each patient. Prospective image interpretations from clinical records were reviewed to document acute appendicitis or other causes of abdominal pain. Final clinical outcomes were determined by using (a) surgical results (n = 77), (b) telephone follow-up combined with review of the patient's medical records (n = 291), or (c) consensus expert panel assessment if no follow-up data were available (n = 35). Logistic regression analysis was performed to evaluate the sensitivity and specificity of MR imaging in the detection of acute appendicitis, and corresponding 95% confidence intervals were determined. RESULTS: Of the 403 patients, 67 had MR imaging findings that were positive for acute appendicitis, and 336 had negative findings. MR imaging had a sensitivity of 97.0% (65 of 67) and a specificity of 99.4% (334 of 336). The mean total room time was 14 minutes (range, 8-62 minutes). An alternate diagnosis was offered in 173 (51.5%) of 336 patients. CONCLUSION: MR imaging is a highly sensitive and specific test in the evaluation of patients younger than 50 years with acute RLQ pain that uses a rapid imaging protocol performed without intravenous or oral contrast material.

Volumetric MRI of the lungs during forced expiration.

PURPOSE: Lung function is typically characterized by spirometer measurements, which do not offer spatially specific information. Imaging during exhalation provides spatial information but is challenging due to large movement over a short time. The purpose of this work is to provide a solution to lung imaging during forced expiration using accelerated magnetic resonance imaging. The method uses radial golden angle stack-of-stars gradient echo acquisition and compressed sensing reconstruction. METHODS: A technique for dynamic three-dimensional imaging of the lungs from highly undersampled data is developed and tested on six subjects. This method takes advantage of image sparsity, both spatially and temporally, including the use of reference frames called bookends. Sparsity, with respect to total variation, and residual from the bookends, enables reconstruction from an extremely limited amount of data. RESULTS: Dynamic three-dimensional images can be captured at sub-150 ms temporal resolution, using only three (or less) acquired radial lines per slice per timepoint. The images have a spatial resolution of 4.6×4.6×10 mm. Lung volume calculations based on image segmentation are compared to those from simultaneously acquired spirometer measurements. CONCLUSION: Dynamic lung imaging during forced expiration is made possible by compressed sensing accelerated dynamic three-dimensional radial magnetic resonance imaging. Magn Reson Med 75:2295-2302, 2016. © 2015 Wiley Periodicals, Inc.

A Systematic Review and Meta-Analysis of Diagnostic Performance of MRI for Evaluation of Acute Appendicitis.

OBJECTIVE: A meta-analysis was performed to determine the accuracy of MRI in the diagnosis of acute appendicitis in the general population and in subsets of pregnant patients and children. MATERIALS AND METHODS: A systematic search of the PubMed and EMBASE databases for articles published through the end of October 2014 was performed to identify studies that used MRI to evaluate patients suspected of having acute appendicitis. Pooled data for sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: A total of 30 studies that comprised 2665 patients were reviewed. The sensitivity and specificity of MRI for the diagnosis of acute appendicitis are 96% (95% CI, 95-97%) and 96% (95% CI, 95-97%), respectively. In a subgroup of studies that focused solely on pregnant patients, the sensitivity and specificity of MRI were 94% (95% CI, 87-98%) and 97% (95% CI, 96-98%), respectively, whereas in studies that focused on children, sensitivity and specificity were found to be 96% (95% CI, 95-97%) and 96% (95% CI, 94-98%), respectively. CONCLUSION: MRI has a high accuracy for the diagnosis of acute appendicitis, for a wide range of patients, and may be acceptable for use as a first-line diagnostic test.

Magnetic Resonance Enterography Healing and Magnetic Resonance Enterography Remission Predicts Improved Outcome in Pediatric Crohn Disease.

BACKGROUND: Mucosal healing predicts clinical remission and improved outcomes in patients with Crohn disease (CD). Magnetic resonance enterography (MRE) is a noninvasive imaging modality that can assess small and large bowel wall inflammation. Evidence suggests that MRE may be an acceptable alternative to evaluate mucosal healing over endoscopy. Our objective is to determine whether MRE remission predicts clinical remission at follow-up in children with CD. METHODS: We performed an institutional review board-approved retrospecitve chart review using our prospectively maintained MRE CD database. Inclusion criteria were all children who underwent an MRE more than 6 months after diagnosis with CD who had follow-up of at least 1 year from imaging. RESULTS: A total of 101 children with CD underwent MRE, a median of 1.3 years from diagnosis with a median follow-up of 2.8 years after MRE. Active inflammation was detected in 65 MRE studies, whereas 36 MRE studies demonstrated MRE remission. A total of 88.9% of children demonstrating MRE remission were in clinical remission at follow-up, whereas only 44.6% of those demonstrating MRE active inflammation achieved clinical remission. Children demonstrating MRE-active inflammation were more likely to have a change in medication (44.6% vs 8.3%) and more likely to undergo surgery (18.5% vs 2.8%). CONCLUSIONS: MRE remission is associated with clinical remission at follow-up at least 1 year after MRE. MRE remission was associated with fewer medication changes and fewer surgeries suggesting that, similar to endoscopic remission, MRE remission demonstrates improved outcome. Additional research is needed to confirm that MRE can be used as a surrogate for mucosal healing.

Correcting partial volume effects in biexponential T2 estimation of small lesions.

PURPOSE: T2 mapping provides a quantitative approach for focal liver lesion characterization. For small lesions, a biexponential model should be used to account for partial volume effects (PVE). However, conventional biexponential fitting suffers from large uncertainty of the fitted parameters when noise is present. The purpose of this work is to develop a more robust method to correct for PVE affecting small lesions. METHODS: We developed a region of interest-based joint biexponential fitting (JBF) algorithm to estimate the T2 of lesions affected by PVE. JBF takes advantage of the lesion fraction variation among voxels within a region of interest. JBF is compared to conventional approaches using Cramér-Rao lower bound analysis, numerical simulations, phantom, and in vivo data. RESULTS: JBF provides more accurate and precise T2 estimates in the presence of PVE. Furthermore, JBF is less sensitive to region of interest drawing. Phantom and in vivo results show that JBF can be combined with a reconstruction method for highly undersampled data, enabling the characterization of small abdominal lesions from data acquired in a single breath hold. CONCLUSION: The JBF algorithm provides more accurate and stable T2 estimates for small structures than conventional techniques when PVE is present. It should be particularly useful for the characterization of small abdominal lesions.

Synthesis and characterization of 64Cu-labeled Geldanamycin derivative for imaging HSP90 expression in breast cancer.

Heat shock protein 90 (HSP90) plays a crucial role in cancer cell growth and metastasis by stabilizing overexpressed signaling proteins. Inhibiting HSP90 has emerged as a promising anti-cancer strategy. In this study, we aimed to develop and characterize a HSP90-targeted molecular imaging probe, [64Cu]Cu-DOTA-BDA-GM, based on a specific HSP90 inhibitor, geldanamycin (GM), for PET imaging of cancers. GM is modified at the C-17 position with 1,4-butane-diamine (BDA) and linked to 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for 64Cu radiolabeling. We evaluated the probe's specific binding to HSP90-expressing cells using Chinese hamster ovary (CHO) cells and breast cancer cells including MDA-MB-231, MDA-MB-435S, MCF7, and KR-BR-3 cell lines. A competition study with non-radioactive GM-BDA yielded an IC50 value of 1.35 ± 0.14 nM, underscoring the probe's affinity for HSP90. In xenograft models of MDA-MB-231 breast cancer, [64Cu]Cu-DOTA-BDA-GM showcased targeted tumor localization, with significant radioactivity observed up to 18 h post-injection. Blocking studies using unlabeled GM-BDA and treatment with the anticancer drug Vorinostat (SAHA), which can affect the expression and activity of numerous proteins, such as HSPs, confirmed the specificity and sensitivity of the probe in cancer targeting. Additionally, PET/CT imaging in a lung metastasis mouse model revealed increased lung uptake of [64Cu]Cu-DOTA-BDA-GM in metastatic sites, significantly higher than in non-metastatic lungs, illustrating the probe's ability to detect metastatic breast cancer. In conclusion, [64Cu]Cu-DOTA-BDA-GM represents a sensitive and specific approach for identifying HSP90 expression in breast cancer and metastases, offering promising implications for clinical diagnosis and monitoring.

Characterization, Bioactivity, and Biodistribution of 35 kDa Hyaluronan Fragment.

It has been reported that hyaluronic acid (HA) with a 35 kDa molecular weight (HA35) acts biologically to protect tissue from injury, but its biological properties are not yet fully characterized. This study aimed to evaluate the cellular effects and biodistribution of HA35 compared to HA with a 1600 kDa molecular weight (HA1600). We assessed the effects of HA35 and HA1600 on cell migration, NO and ROS generation, and gene expression in cultured macrophages, microglia, and lymphocytes. HA35 was separately radiolabeled with 99mTc and 125I and administered to C57BL/6J mice for in vivo biodistribution imaging. In vitro studies indicated that HA35 and HA1600 similarly enhanced cell migration through HA receptor binding mechanisms, reduced the generation of NO and ROS, and upregulated gene expression profiles related to cell signaling pathways in immune cells. HA35 showed a more pronounced effect in regulating a broader range of genes in macrophages and microglia than HA1600. Upon intradermal or intravenous administration, radiolabeled HA35 rapidly accumulated in the liver, spleen, and lymph nodes. In conclusion, HA35 not only exhibits effects on cellular bioactivity comparable to those of HA1600 but also exerts biological effects on a broader range of immune cell gene expression. The findings herein offer valuable insights for further research into the therapeutic potential of HA35 in inflammation-mediated tissue injury.

An eNAMPT-neutralizing mAb reduces post-infarct myocardial fibrosis and left ventricular dysfunction.

Myocardial infarction (MI) triggers adverse ventricular remodeling (VR), cardiac fibrosis, and subsequent heart failure. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is postulated to play a significant role in VR processing via activation of the TLR4 inflammatory pathway. We hypothesized that an eNAMPT specific monoclonal antibody (mAb) could target and neutralize overexpressed eNAMPT post-MI and attenuate chronic cardiac inflammation and fibrosis. We investigated humanized ALT-100 and ALT-300 mAb with high eNAMPT-neutralizing capacity in an infarct rat model to test our hypothesis. ALT-300 was 99mTc-labeled to generate 99mTc-ALT-300 for imaging myocardial eNAMPT expression at 2 hours, 1 week, and 4 weeks post-IRI. The eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg) or saline was administered intraperitoneally at 1 hour and 24 hours post-reperfusion and twice a week for 4 weeks. Cardiac function changes were determined by echocardiography at 3 days and 4 weeks post-IRI. 99mTc-ALT-300 uptake was initially localized to the ischemic area at risk (IAR) of the left ventricle (LV) and subsequently extended to adjacent non-ischemic areas 2 hours to 4 weeks post-IRI. Radioactive uptake (%ID/g) of 99mTc-ALT-300 in the IAR increased from 1 week to 4 weeks (0.54 ± 0.16 vs. 0.78 ± 0.13, P < 0.01). Rats receiving ALT-100 mAb exhibited significantly improved myocardial histopathology and cardiac function at 4 weeks, with a significant reduction in the collagen volume fraction (%LV) compared to controls (21.5 ± 6.1% vs. 29.5 ± 9.9%, P < 0.05). Neutralization of the eNAMPT/TLR4 inflammatory cascade is a promising therapeutic strategy for MI by reducing chronic inflammation, fibrosis, and preserving cardiac function.

Paraduodenal pancreatitis: clinical performance of MR imaging in distinguishing from carcinoma.

PURPOSE: To evaluate the diagnostic performance of contrast material-enhanced magnetic resonance (MR) imaging for distinguishing paraduodenal pancreatitis (PDP) from pancreatic head duct adenocarcinoma (CA) in patients with diagnoses confirmed by histopathologic analysis. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and is HIPAA compliant. Between July 2007 and July 2010, 47 patients who underwent Whipple procedure and MR imaging less than 60 days before surgery were identified retrospectively. Two relatively inexperienced fellowship trainees with 9 months of body fellowship training were asked to record the presence or absence of three MR imaging features: focal thickening of the second portion of the duodenum; abnormal enhancement of the second portion of the duodenum; and cystic focus in the expected region of the accessory pancreatic duct. Strict criteria for diagnosis of PDP included presence of all three imaging features. Any case that did not fulfill the criteria was classified as CA. Sensitivity, specificity, positive predictive value, and negative predictive value for characterization of PDP was calculated for each reader with 95% confidence intervals. A κ test assessed level of agreement between readers. RESULTS: Each reader correctly categorized 15 of 17 (88.2%) PDP cases when all three imaging criteria were met. Alternatively, 26 of 30 (86.7%) pancreatic duct CA were correctly categorized as inconsistent with PDP. Four patients with histopathologic diagnosis of CA were incorrectly classified as PDP by each reader. Agreement between the two readers showed substantial κ agreement for the diagnosis of PDP and differentiation from pancreatic duct CA. CONCLUSION: Contrast-enhanced MR imaging may help accurately identify PDP and distinguish it from CA when strict diagnostic criteria are followed. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13112056/-/DC1.