Citations

Dynamic fluid and solute transportation across the arachnoid barrier in the meninges of healthy participants was measured by tracking intravenous gadolinium-based contrast agent entering cerebrospinal fluid from dural blood vessels using dynamic dual-spin-echo perfusion MRI.

AbstractIron Dextran is a widely used iron oxide compound to treat iron‐deficiency anemia patients in the clinic. Similar to other iron oxide compounds such as Ferumoxytol, it can also be used off‐label as an intravascular magnetic resonance imaging (MRI) contrast agent due to its strong iron‐induced T2 and T2* shortening effects. In this study, we seek to evaluate the feasibility of using Iron Dextran enhanced multi‐echo susceptibility weighted imaging (SWI) MRI at 7T to image arterial and venous blood vessels in the human brain. Phantom experiments were performed to measure the r2* relaxivity for Iron Dextran in blood, based on which the SWI sequence was optimized. Pre‐ and post‐infusion MR images were acquired in human subjects from which maps of arteries and veins were extracted. The post‐contrast SWI images showed enhanced susceptibility difference between blood and the surrounding tissue in both arteries and veins. Our results showed that the proposed Iron Dextran enhanced multi‐echo SWI approach allowed the visualization of blood vessels with diameters down to ~100 μm, including small blood vessels supplying and draining small brain structures such as the hippocampus. We conclude that Iron Dextran can be an alternative iron‐based MRI contrast agent for blood vessel imaging in the human brain.

11562 Background: High-grade soft tissue sarcomas (STS) pose a therapeutic challenge due to the high risk of recurrence, even following complete resection. Anlotinib is a multi-targeted tyrosine kinase inhibitor blocking angiogenesis pathways of VEGFR, FGFR, and PDGFR. Given a promising efficacy for treating patients with unresectable advanced STS in previous trials, we evaluated the role of anlotinib as adjuvant therapy for completely resected high-grade STS. Methods: In a single-center, double-blinded, randomized, controlled trial, eligible patients were those adults who had not received adjuvant chemotherapy regimens after complete resection of high-grade STS. Patients were randomly assigned in a 1:1 ratio to receive either oral 12 mg anlotinib or placebo once daily on days 1-14 every 3 weeks as a cycle, with up to six cycles until disease recurrence, unmanageable toxicity or death. The primary endpoints included 1-year, 2-year disease-free survival (DFS). Results: Between June 2019 and November 2023, 88 patients were randomly assigned to receive anlotinib (n=44) or placebo (n=44). With a median follow-up of 25.99 months at data accrual cutoff on Jan 15, 2024, the 1-year and 2-year DFS rates were 88% and 77% in the anlotinib group, compared to 64% and 58% in the placebo group. Compared to patients in the placebo group, patients in the anlotinib group had a reduced risk of disease recurrence (HR 0.47 [95% CI 0.22~1.00, P= 0.0445]). The median DFS was not reached. Based on tumor histology, the greatest improvement in DFS with anlotinib versus placebo was observed in patients with myxofibrosarcoma (1-year DFS rate: 82% versus 61%; 2-year DFS rate: 64% versus 43%, HR 0.54 [95% CI 0.17~1.65], P= 0.2698) and undifferentiated pleomorphic sarcoma (1-year DFS rate: 86% versus 67%; 2-year DFS rate: 78% versus 67%, HR 0.58 [95% CI 0.12~2.87], P= 0.4971). Thirty-eight patients experienced adverse events (AEs; 34 with grade 1~2, 4 with grade 3): 28 patients (64%) in the anlotinib group versus 10 patients (23%) in the placebo group ( P<0.001). Three patients discontinued anlotinib, including two for proteinuria/hematuresis (2/44, 5%) and one for secondary poor surgical wound healing (1/44, 2%). Conclusions: Current results suggest anlotinib could lower disease recurrence risk in patients with completely resected high-grade STS, with an acceptable toxicity profile. Clinical trial information: NCT03951571 . [Table: see text]

AbstractAccumulating evidence from recent studies has indicated the importance of studying the interaction between the microvascular and lymphatic systems in the brain. To date, most imaging methods can only measure blood or lymphatic vessels separately, such as dynamic susceptibility contrast (DSC) MRI for blood vessels and DSC MRI‐in‐the‐cerebrospinal fluid (CSF) (cDSC MRI) for lymphatic vessels. An approach that can measure both blood and lymphatic vessels in a single scan offers advantages such as a halved scan time and contrast dosage. This study attempts to develop one such approach by optimizing a dual‐echo turbo‐spin‐echo sequence, termed “dynamic dual‐spin‐echo perfusion (DDSEP) MRI”. Bloch simulations were performed to optimize the dual‐echo sequence for the measurement of gadolinium (Gd)‐induced blood and CSF signal changes using a short and a long echo time, respectively. The proposed method furnishes a T1‐dominant contrast in CSF and a T2‐dominant contrast in blood. MRI experiments were performed in healthy subjects to evaluate the dual‐echo approach by comparing it with existing separate methods. Based on simulations, the short and long echo time were chosen around the time when blood signals show maximum difference between post‐ and pre‐Gd scans, and the time when blood signals are completely suppressed, respectively. The proposed method showed consistent results in human brains as previous studies using separate methods. Signal changes from small blood vessels occurred faster than from lymphatic vessels after intravenous Gd injection. In conclusion, Gd‐induced signal changes in blood and CSF can be detected simultaneously in healthy subjects with the proposed sequence. The temporal difference in Gd‐induced signal changes from small blood and lymphatic vessels after intravenous Gd injection was confirmed using the proposed approach in the same human subjects. Results from this proof‐of‐concept study will be used to further optimize DDSEP MRI in subsequent studies.

Abstract Androgen receptor (AR) is a major survival factor for prostate cancer. Inflammation is implicated in many cancer types, including prostate cancer. Activation of MAP3K7 (also termed TAK1) and downstream IκB kinase β (IKKβ) by proinflammatory cytokines such as TNFα stimulates NF-κB survival pathways. Paradoxically, MAP3K7 is often deleted in human prostate cancer. Here, we demonstrate that AR protein expression is lower in inflammatory tumor areas compared with non-inflammatory tissues in patients with prostate cancer. Map3k7 knockout increased AR protein levels and activity in the mouse prostate, and MAP3K7 and AR protein levels were inversely correlated in prostate cancer patient specimens. TNFα treatment increased AR protein ubiquitination and proteasomal degradation. Mechanistically, activation of IKKβ by TNFα induced phosphorylation and TRCP1/2 E3 ligase–mediated polyubiquitination and degradation of AR protein. TNFα suppressed prostate cancer proliferation, which could be rescued by blockade of AR degradation. These findings reveal a previously unrecognized tumor suppressive function of the inflammation-activated MAP3K7–IKKβ axis in degrading AR protein. Moreover, they suggest that aberrant elevation of AR protein could be a prognostic biomarker and therapeutic target for MAP3K7-deficient prostate cancer. Significance: This study identifies that MAP3K7–IKKβ signaling plays a tumor-suppressive role in prostate cancer by degrading AR, revealing potential prognostic and therapeutic strategies for MAP3K7-deficient tumors.

OBJECTIVES: Preoperative decision-making for differentiating malignant from benign lesions in the gallbladder remains challenging. We aimed to create a diagnostic nomogram to identify gallbladder cancer (GBC), especially for incidental GBC (IGBC), before surgical resection. METHODS: A total of 587 consecutive patients with pathologically confirmed gallbladder lesions from a hospital were randomly assigned to a training cohort (70%) and an internal validation cohort (30%), with 287 patients from other centers as an external validation cohort. Radiological features were developed by the least absolute shrinkage and selection operator logistic regression model. Significant radiological features and independent clinical factors, identified by multivariate analyses, were used to construct a nomogram. RESULTS: A diagnostic nomogram was established by age, CA19.9, and 6 radiological features. The values of area under the curve in the internal and external validation cohorts were up to 0.91 and 0.89, respectively. The calibration curves for probability of GBC showed optimal agreement between nomogram prediction and actual observation. Compared with previous methods, it demonstrated superior sensitivity (91.5%) and accuracy (85.1%) in the diagnosis of GBC. The accuracy using the nomogram was significantly higher in GBC groups compared with that by radiologists in the training cohort ( P < 0.001) and similarly in each cohort. Notably, most of the IGBC, which were misdiagnosed as benign lesions, were successfully identified using this nomogram. DISCUSSION: A novel nomogram provides a powerful tool for detecting the presence of cancer in gallbladder masses, with an increase in accuracy and sensitivity. It demonstrates an unprecedented potential for IGBC identification.

Abstract Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and antiandrogen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)–GPRC6A–CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human prostate cancer cell lines. Pten knockout mice were used to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results: We uncovered that activation of the AKT–RUNX2–OCN–GPRC6A–CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null prostate cancer cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level, and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions: Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null prostate cancer, including CRPC. Clin Cancer Res; 24(4); 834–46. ©2017 AACR.

Quantifying the pathological features of flexor tendon pulleys is essential for grading the trigger finger since it provides clinicians with objective evidence derived from microscopic images. Although manual grading is time consuming and dependent on the observer experience, there is a lack of image processing methods for automatically extracting pulley pathological features. In this paper, we design and develop a color-based image segmentation system to extract the color and shape features from pulley microscopic images. Two parameters which are the size ratio of abnormal tissue regions and the number ratio of abnormal nuclei are estimated as the pathological progression indices. The automatic quantification results show clear discrimination among different levels of diseased pulley specimens which are prone to misjudgments for human visual inspection. The proposed system provides a reliable and automatic way to obtain pathological parameters instead of manual evaluation which is with intra- and interoperator variability. Experiments with 290 microscopic images from 29 pulley specimens show good correspondence with pathologist expectations. Hence, the proposed system has great potential for assisting clinical experts in routine histopathological examinations.