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.

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.

PEGylated and Non-PEGylated TCP-1 Probes for Imaging of Colorectal Cancer.

PURPOSE: Previous studies indicate that 99mTc- and fluorescent-labeled c[Cys-Thr-Pro-Ser-Pro-Phe-Ser-His-Cys]OH (TCP-1) peptides were able to detect colorectal cancer (CRC) and tumor-associated vasculature. This study was designed to characterize the targeting properties of PEGylated and non-PEGylated TCP-1 peptides for CRC imaging. PROCEDURES: Cell uptake of cyanine 7 (Cy7)-labeled TCP-1 probes (Cy7-PEG4-TCP-1 and Cy7-TCP-1) was investigated in three CRC cell lines (human, HCT116 and HT29; mouse, CT26). Xenograft and orthotopic CRC tumor models with HCT116 and CT26 cells were used to characterize biodistribution and CRC tumor-targeting properties of TCP-1 fluorescence and radioligand with and without PEGylation, [99mTc]Tc-HYNIC-PEG4-TCP-1 vs. [99mTc]Tc-HYNIC-TCP-1. RESULTS: Fluorescence images showed that TCP-1 probes were distributed in the cytoplasm and nucleus of CRC cells. When CT26 cells were treated with unlabeled TCP-1 peptide prior to the cell incubation with Cy7-PEG4-TCP-1, cell fluorescent signals were significantly reduced relative to the cells without blockade. Relative to Cy7-TCP-1, superior brilliance and visibility of fluorescence was observed in the tumor with Cy7-PEG4-TCP-1 and maintained up to 18 h post-injection. [99mTc]Tc-HYNIC-PEG4-TCP-1 images in xenograft and orthotopic CRC models demonstrated that TCP-1 PEGylation preserved tumor-targeting capability of TCP-1, but its distribution (%ID/g) in the liver and intestine was higher than that of [99mTc]Tc-HYNIC-TCP-1 (1.51 ± 0.29 vs 0.53 ± 0.12, P < 0.01). Better tumor visualization by [99mTc]Tc-HYNIC-TCP-1 was observed in the orthotopic CRC model due to lower intestinal radioactivity. CONCLUSIONS: TCP-1-based probes undergo endocytosis and localize in the cytoplasm and nucleus of human and mouse CRC cells. Tumor detectability of fluorescent TCP-1 peptide with a PEG4 spacer is promising due to its enhanced tumor binding affinity and rapid clearance kinetics from nontumor tissues. Non-PEGylated [99mTc]Tc-HYNIC-TCP-1 exhibits lower nonspecific accumulation in the liver and gastrointestinal tract and might have better capability for detecting CRC lesions in clinical sites. TCP-1 may represent an innovative targeting molecule for detecting CRC noninvasively.

Use of radiolabeled hyaluronic acid for preclinical assessment of inflammatory injury and acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is accompanied by a dramatic increase in lung hyaluronic acid (HA), leading to a dose-dependent reduction of pulmonary oxygenation. This pattern is associated with severe infections, such as COVID-19, and other important lung injury etiologies. HA actively participates in molecular pathways involved in the cytokine storm of COVID-19-induced ARDS. The objective of this study was to evaluate an imaging approach of radiolabeled HA for assessment of dysregulated HA deposition in mouse models with skin inflammation and lipopolysaccharide (LPS)-induced ARDS using a novel portable intensified Quantum Imaging Detector (iQID) gamma camera system. METHODS: HA of 10 kDa molecular weight (HA10) was radiolabeled with 125I and 99mTc respectively to produce [125I]I-HA10 and [99mTc]Tc-HA10, followed by comparative studies on stability, in vivo biodistribution, and uptake at inflammatory skin sites in mice with 12-O-tetradecanoylphorbol-13-acetate (TPA)-inflamed ears. [99mTc]Tc-HA10 was used for iQID in vivo dynamic imaging of mice with ARDS induced by intratracheal instillation of LPS. RESULTS: [99mTc]Tc-HA10 and [125I]I-HA10 had similar biodistribution and localization at inflammatory sites. [99mTc]Tc-HA10 was shown to be feasible in measuring skin injury and monitoring skin wound healing. [99mTc]Tc-HA10 dynamic pulmonary images yielded good visualization of radioactive uptake in the lungs. There was significantly increased lung uptake and slower lung washout in mice with LPS-induced ARDS than in control mice. Postmortem biodistribution measurement of [99mTc]TcHA10 (%ID/g) was 11.0 ± 3.9 vs. 1.3 ± 0.3 in the ARDS mice (n = 6) and controls (n = 6) (P < 0.001), consistent with upregulated HA expression as determined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) staining. CONCLUSIONS: [99mTc]Tc-HA10 is promising as a biomarker for evaluating HA dysregulation that contributes to pulmonary injury in ARDS. Rapid iQID imaging of [99mTc]Tc-HA10 clearance from injured lungs may provide a functional template for timely assessment and quantitative monitoring of pulmonary pathophysiology and intervention in ARDS.

eNAMPT Neutralization Preserves Lung Fluid Balance and Reduces Acute Renal Injury in Porcine Sepsis/VILI-Induced Inflammatory Lung Injury.

Background: Numerous potential ARDS therapeutics, based upon preclinical successful rodent studies that utilized LPS challenge without mechanical ventilation, have failed in Phase 2/3 clinical trials. Recently, ALT-100 mAb, a novel biologic that neutralizes the TLR4 ligand and DAMP, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), was shown to reduce septic shock/VILI-induced porcine lung injury when delivered 2 h after injury onset. We now examine the ALT-100 mAb efficacy on acute kidney injury (AKI) and lung fluid balance in a porcine ARDS/VILI model when delivered 6 h post injury. Methods/Results: Compared to control PBS-treated pigs, exposure of ALT-100 mAb-treated pigs (0.4 mg/kg, 2 h or 6 h after injury initiation) to LPS-induced pneumonia/septic shock and VILI (12 h), demonstrated significantly diminished lung injury severity (histology, BAL PMNs, plasma cytokines), biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue ratios, ultrasound-derived B lines, and chest radiograph opacities. Delayed ALT-100 mAb at 2 h was significantly more protective than 6 h delivery only for plasma eNAMPT while trending toward greater protection for remaining inflammatory indices. Delayed ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats when delivered up to 12 h after LPS. Conclusions: These studies indicate the delayed delivery of the eNAMPT-neutralizing ALT-100 mAb reduces inflammatory lung injury, preserves lung fluid balance, and reduces multi-organ dysfunction, and may potentially address the unmet need for novel therapeutics that reduce ARDS/VILI mortality.

Dynamic Tumor-Specific MHC-II Immuno-PET Predicts the Efficacy of Checkpoint Inhibitor Immunotherapy in Melanoma.

Despite the advance of immunotherapy, only a small subset of patients gains long-term survival benefit. This fact represents a compelling rationale to develop immuno-PET imaging that can predict tumor response to immunotherapy. An increasing number of studies have shown that tumor-specific major histocompatibility complex II (tsMHC-II) is associated with improved responses to targeted immunotherapy. The aim of this study was to investigate the potential of tsMHC-II protein expression and its dynamic change on treatment with interferon γ (IFNγ) as a new target for immuno-PET to predict response to immunotherapy. Methods: Major histocompatibility complex II (MHC-II) antibody was radiolabeled with DOTA-chelated 64Cu to derive an MHC-II immuno-PET tracer. Two melanoma models (B16SIY, B16F10) that are respondent and nonrespondent, respectively, to PD1/PD-L1 checkpoint inhibitor were used. Both tumor models were treated with anti-PD1 and IFNγ, enabling observation of dynamic changes in tsMHC-II. Small-animal PET imaging, biodistribution, and histologic studies were performed to validate the correlation of tsMHC-II with the tumor response to the immunotherapy. Results: Fluorescence-activated cell sorting analysis of the 2 tumors supported the consensual recognition of tsMHC-II correlated with the tumor response to the immunotherapy. The in vivo PET imaging revealed higher basal levels of tsMHC-II in the responder, B16SIY, than in the nonresponder, B16F10. When treated with anti-PD1 antibody in animals, B16SIY tumors displayed a sensitive increase in tsMHC-II compared with B16F10 tumors. In IFNγ stimulation groups, the greater magnitude of tsMHC-II was further amplified when the IFNγ signaling was activated in the B16SIY tumors, as IFNγ signaling positively upregulates tsMHC-II in the tumor immunity. Subsequent histopathologic analysis supported the correlative characteristics of tsMHC-II with tumor immunity and response to cancer immunotherapy. Conclusion: Collectively, the predictive value of tsMHC-II immuno-PET was validated for stratifying tumor immunotherapy responders versus nonresponders. Monitoring sensitivity of tsMHC-II to IFNγ stimulation may provide an effective strategy to predict the tumor response to immunotherapy.

Above and Beyond Age: Prediction of Major Postoperative Adverse Events in Head and Neck Surgery.

OBJECTIVE: Major postoperative adverse events (MPAEs) following head and neck surgery are not infrequent and lead to significant morbidity. The objective of this study was to ascertain which factors are most predictive of MPAEs in patients undergoing head and neck surgery. METHODS: A cohort study was carried out based on data from patients registered in the National Surgical Quality Improvement Program (NSQIP) from 2006 to 2018. All patients undergoing non-ambulatory head and neck surgery based on Current Procedural Terminology codes were included. Perioperative factors were evaluated to predict MPAEs within 30-days of surgery. Age was classified as both a continuous and categorical variable. Retained factors were classified by attributable fraction and C-statistic. Multivariate regression and supervised machine learning models were used to quantify the contribution of age as a predictor of MPAEs. RESULTS: A total of 43 701 operations were analyzed with 5106 (11.7%) MPAEs. The results of supervised machine learning indicated that prolonged surgeries, anemia, free tissue transfer, weight loss, wound classification, hypoalbuminemia, wound infection, tracheotomy (concurrent with index head and neck surgery), American Society of Anesthesia (ASA) class, and sex as most predictive of MPAEs. On multivariate regression, ASA class (21.3%), hypertension on medication (15.8%), prolonged operative time (15.3%), sex (13.1%), preoperative anemia (12.8%), and free tissue transfer (9%) had the largest attributable fractions associated with MPAEs. Age was independently associated with MPAEs with an attributable fraction ranging from 0.6% to 4.3% with poor predictive ability (C-statistic 0.60). CONCLUSION: Surgical, comorbid, and frailty-related factors were most predictive of short-term MPAEs following head and neck surgery. Age alone contributed a small attributable fraction and poor prediction of MPAEs. LEVEL OF EVIDENCE: 3.

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.

Rapid high-resolution volumetric T1 mapping using a highly accelerated stack-of-stars Look Locker technique.

PURPOSE: To develop a fast volumetric T1 mapping technique. MATERIALS AND METHODS: A stack-of-stars (SOS) Look Locker technique based on the acquisition of undersampled radial data (>30× relative to Nyquist) and an efficient multi-slab excitation scheme is presented. A principal-component based reconstruction is used to reconstruct T1 maps. Computer simulations were performed to determine the best choice of partitions per slab and degree of undersampling. The technique was validated in phantoms against reference T1 values measured with a 2D Cartesian inversion-recovery spin-echo technique. The SOS Look Locker technique was tested in brain (n = 4) and prostate (n = 5). Brain T1 mapping was carried out with and without kz acceleration and results between the two approaches were compared. Prostate T1 mapping was compared to standard techniques. A reproducibility study was conducted in brain and prostate. Statistical analyses were performed using linear regression and Bland Altman analysis. RESULTS: Phantom T1 values showed excellent correlations between SOS Look Locker and the inversion-recovery spin-echo reference (r2 = 0.9965; p < 0.0001) and between SOS Look Locker with slab-selective and non-slab selective inversion pulses (r2 = 0.9999; p < 0.0001). In vivo results showed that full brain T1 mapping (1 mm3) with kz acceleration is achieved in 4 min 21 s. Full prostate T1 mapping (0.9 × 0.9 × 4 mm3) is achieved in 2 min 43 s. T1 values for brain and prostate were in agreement with literature values. A reproducibility study showed coefficients of variation in the range of 0.18-0.2% (brain) and 0.15-0.18% (prostate). CONCLUSION: A rapid volumetric T1 mapping technique was developed. The technique enables high-resolution T1 mapping with adequate anatomical coverage in a clinically acceptable time.

Improving subspace constrained radial fast spin echo MRI using block matching driven non-local low rank regularization.

Subspace-constrained reconstruction methods restrict the relaxation signals (of size M) in the scene to a pre-determined subspace (of size K≪M) and allow multi-contrast imaging and parameter mapping from accelerated acquisitions. However, these constraints yield poor image quality at some imaging contrasts, which can impact the parameter mapping performance. Additional regularization such as the use of joint-sparse (JS) or locally-low-rank (LLR) constraints can help improve the recovery of these images but are not sufficient when operating at high acceleration rates. We propose a method, non-local rank 3D (NLR3D), that is built on block matching and transform domain low rank constraints to allow high quality recovery of subspace-coefficient images (SCI) and subsequent multi-contrast imaging and parameter mapping. The performance of NLR3D was evaluated using Monte-Carlo (MC) simulations and compared against the JS and LLR methods. In vivo T 2 mapping results are presented on brain and knee datasets. MC results demonstrate improved bias, variance, and MSE behavior in both the multi-contrast images and parameter maps when compared to the JS and LLR methods. In vivo brain and knee results at moderate and high acceleration rates demonstrate improved recovery of high SNR early TE images as well as parameter maps. No significant difference was found in the T2 values measured in ROIs between the NLR3D reconstructions and the reference images (Wilcoxon signed rank test). The proposed method, NLR3D, enables recovery of high-quality SCI and, consequently, the associated multi-contrast images and parameter maps.

Quantitative metric for assessment of pancreatic ductal adenocarcinoma treatment response in T1-weighted gadolinium-enhanced magnetic resonance imaging.

BACKGROUND: We theoretically derived a new quantitative metric reflecting the product of T1 signal intensity and contrast media concentration (T1C) using first principles for the signal provided by the gradient echo sequence. This metric can be used with conventional gadolinium contrast-enhanced magnetic resonance imaging (CE-MRI) exams. We used this metric to test our hypothesis that gadolinium enhancement changes with pancreatic ductal adenocarcinoma (PDA) treatment response, and that this metric may differentiate responders from non-responders. METHODS: Out of 264 initially identified patients, a final total of 35 patients with PDA were included in a retrospective study of responders (n=24) and non-responders (n=11), which used changes in cancer antigen 19-9 (CA 19-9) and tumor size as reference standards. T1C was computed for the pancreatic mass in the arterial, portal venous, and delayed phases in pre-treatment and post-treatment MRIs. Changes in measurements and correlations with treatment response were assessed by repeated measures analysis of variance and paired t-tests. RESULTS: In the treatment responder group, T1C significantly increased in the arterial, portal venous, and delayed phases (P=7.57e-5, P=3.25e-4, P=1.75e-4). In the non-responder group, T1C did not significantly change in any phase (P>0.58). Post-treatment T1C significantly differed between responders and non-responders (P=0.044) by repeated measures analysis of variance. CONCLUSIONS: T1C significantly increases in all phases of CE-MRI in responders to treatment, but does not change in non-responders. T1C correlates with treatment response, can be computed from clinical MRI exams, and may be useful as an additional metric to stratify patients undergoing treatment.

A multi-scale residual network for accelerated radial MR parameter mapping.

A deep learning MR parameter mapping framework which combines accelerated radial data acquisition with a multi-scale residual network (MS-ResNet) for image reconstruction is proposed. The proposed supervised learning strategy uses input image patches from multi-contrast images with radial undersampling artifacts and target image patches from artifact-free multi-contrast images. Subspace filtering is used during pre-processing to denoise input patches. For each anatomy and relaxation parameter, an individual network is trained. in vivo T1 mapping results are obtained on brain and abdomen datasets and in vivo T2 mapping results are obtained on brain and knee datasets. Quantitative results for the T2 mapping of the knee show that MS-ResNet trained using either fully sampled or undersampled data outperforms conventional model-based compressed sensing methods. This is significant because obtaining fully sampled training data is not possible in many applications. in vivo brain and abdomen results for T1 mapping and in vivo brain results for T2 mapping demonstrate that MS-ResNet yields contrast-weighted images and parameter maps that are comparable to those achieved by model-based iterative methods while offering two orders of magnitude reduction in reconstruction times. The proposed approach enables recovery of high-quality contrast-weighted images and parameter maps from highly accelerated radial data acquisitions. The rapid image reconstructions enabled by the proposed approach makes it a good candidate for routine clinical use.

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.

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.

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.

Imaging assessment of cardioprotection mediated by a dodecafluoropentane oxygen-carrier administered during myocardial infarction.

INTRODUCTION: The objective of this study was to investigate the cardioprotective effects of a dodecafluoropentane (DDFP)-based perfluorocarbon emulsion (DDFPe) as an artificial carrier for oxygen delivery to ischemic myocardium, using 99mTc-duramycin SPECT imaging. METHODS: Rat hearts with Ischemia-reperfusion (I/R) was prepared by coronary ligation for 45-min followed by reperfusion. The feasibility of 99mTc-duramycin in detecting myocardial I/R injury and its kinetic profile were first verified in the ischemic hearts with 2-h reperfusion (n = 6). DDFPe (0.6 mL/kg) was intravenously administered at 10 min after coronary ligation in fifteen rats and saline was given in thirteen rats as controls. 99mTc-duramycin SPECT images were acquired in the DDFPe-treated hearts and saline controls at 2-h (DDFPe-2 h, n = 7 and Saline-2 h, n = 6) or 24-h (DDFPe-24 h, n = 8 and Saline-24 h, n = 7) of reperfusion. RESULTS: SPECT images, showing "hot-spot" 99mTc-duramycin uptake in the ischemic myocardium, exhibited significantly lower radioactive retention and smaller hot-spot size in the DDFPe-2 h and DDFPe-24 h hearts compared to controls. The infarcts in the Saline-24 h hearts extended significantly relative to measurements in the Saline-2 h. The extension of infarct size did not reach a statistical difference between the DDFPe-2 h and DDFPe-24 h hearts. Ex vivo measurement of 99mTc-duramycin activity (%ID/g) was lower in the ischemic area of DDFPe-2 h and DDFPe-24 h than that of the Saline-2 h and Saline-24 h hearts (P < 0.05). The area of injured myocardium, delineated by the uptake of 99mTc-duramycin, extended more substantially outside the infarct zone in the controls. CONCLUSIONS: Significant reduction in myocardial I/R injury, as assessed by 99mTc-duramycin cell death imaging and histopathological analysis, was induced by DDFPe treatment after acute myocardial ischemia. 99mTc-duramycin imaging can reveal myocardial cell death in ischemic hearts and may provide a tool for the non-invasive assessment of cardioprotective interventions.

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.

Improved Detection of Pelvic Organ Prolapse: Comparative Utility of Defecography Phase Sequence to Nondefecography Valsalva Maneuvers in Dynamic Pelvic Floor Magnetic Resonance Imaging.

PURPOSE: To evaluate the utility of a defecography phase (DP) sequence in dynamic pelvic floor MRI (DPMRI), in comparison to DPMRI utilizing only non-defecography Valsalva maneuvers (VM). MATERIALS AND METHODS: Inclusion criteria identified 237 female patients with symptoms and/or physical exam findings of pelvic floor prolapse. All DPMRI exams were obtained following insertion of ultrasound gel into the rectum and vagina. Steady-state free-precession sequences in sagittal plane were acquired in the resting state, followed by dynamic cine acquisitions during VM and DP. In all phases, two experienced radiologists performed blinded review using the H-line, M-line, Organ prolapse (HMO) system. The presence of a rectocele, enterocele and inferior descent of the anorectal junction, bladder base, and vaginal vault were recorded in all patients using the pubococcygeal line as a fixed landmark. RESULTS: DPMRI with DP detected significantly more number of patients than VM (p<0.0001) with vaginal prolapse (231/237, 97.5% vs. 177/237, 74.7%), anorectal prolapse (227/237, 95.8% vs. 197/237, 83.1%), cystocele (197/237, 83.1% vs. 108/237, 45.6%), and rectocele (154/237, 65% vs. 93/237, 39.2%). The median cycstocele (3.2cm vs. 1cm), vaginal prolapse (3cm vs. 1.5cm), anorectal prolapse (5.4cm vs. 4.2cm), H-line (8cm vs. 7.2cm) and M-line (5.3cm vs. 3.9cm) were significantly higher with DP than VM (p<0.0001). CONCLUSIONS: Addition of DP to DPMRI demonstrates a greater degree of pelvic floor instability as compared to imaging performed during VM alone. Pelvic floor structures may show mild descent or appear normal during VM, with marked prolapse on subsequent DP images.