Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels.

Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative proteinopathy, in which a mutant protein (in this case, ATAXIN1) accumulates in neurons and exerts toxicity; in SCA1, this process causes progressive deterioration of motor coordination. Seeking to understand how post-translational modification of ATAXIN1 levels influences disease, we discovered that the RNA-binding protein PUMILIO1 (PUM1) not only directly regulates ATAXIN1 but also plays an unexpectedly important role in neuronal function. Loss of Pum1 caused progressive motor dysfunction and SCA1-like neurodegeneration with motor impairment, primarily by increasing Ataxin1 levels. Breeding Pum1(+/-) mice to SCA1 mice (Atxn1(154Q/+)) exacerbated disease progression, whereas breeding them to Atxn1(+/-) mice normalized Ataxin1 levels and largely rescued the Pum1(+/-) phenotype. Thus, both increased wild-type ATAXIN1 levels and PUM1 haploinsufficiency could contribute to human neurodegeneration. These results demonstrate the importance of studying post-transcriptional regulation of disease-driving proteins to reveal factors underlying neurodegenerative disease.

Loss of Katnal2 leads to ependymal ciliary hyperfunction and autism-related phenotypes in mice.

Autism spectrum disorders (ASD) frequently accompany macrocephaly, which often involves hydrocephalic enlargement of brain ventricles. Katnal2 is a microtubule-regulatory protein strongly linked to ASD, but it remains unclear whether Katnal2 knockout (KO) in mice leads to microtubule- and ASD-related molecular, synaptic, brain, and behavioral phenotypes. We found that Katnal2-KO mice display ASD-like social communication deficits and age-dependent progressive ventricular enlargements. The latter involves increased length and beating frequency of motile cilia on ependymal cells lining ventricles. Katnal2-KO hippocampal neurons surrounded by enlarged lateral ventricles show progressive synaptic deficits that correlate with ASD-like transcriptomic changes involving synaptic gene down-regulation. Importantly, early postnatal Katnal2 re-expression prevents ciliary, ventricular, and behavioral phenotypes in Katnal2-KO adults, suggesting a causal relationship and a potential treatment. Therefore, Katnal2 negatively regulates ependymal ciliary function and its deletion in mice leads to ependymal ciliary hyperfunction and hydrocephalus accompanying ASD-related behavioral, synaptic, and transcriptomic changes.

Neurodevelopmental disorder-associated CYFIP2 regulates membraneless organelles and eIF2α phosphorylation via protein interactors and actin cytoskeleton.

De novo variants in the Cytoplasmic FMR1-interacting protein 2 (CYFIP2) have been repeatedly associated with neurodevelopmental disorders and epilepsy, underscoring its critical role in brain development and function. While CYFIP2's role in regulating actin polymerization as part of the WAVE regulatory complex (WRC) is well-established, its additional molecular functions remain relatively unexplored. In this study, we performed unbiased quantitative proteomic analysis, revealing 278 differentially expressed proteins (DEPs) in the forebrain of Cyfip2 knock-out embryonic mice compared to wild-type mice. Unexpectedly, these DEPs, in conjunction with previously identified CYFIP2 brain interactors, included not only other WRC components but also numerous proteins associated with membraneless organelles (MLOs) involved in mRNA processing and translation within cells, including the nucleolus, stress granules, and processing bodies. Additionally, single-cell transcriptomic analysis of the Cyfip2 knock-out forebrain revealed gene expression changes linked to cellular stress responses and MLOs. We also observed morphological changes in MLOs in Cyfip2 knock-out brains and CYFIP2 knock-down cells under basal and stress conditions. Lastly, we demonstrated that CYFIP2 knock-down in cells, potentially through WRC-dependent actin regulation, suppressed the phosphorylation levels of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α), thereby enhancing protein synthesis. These results suggest a physical and functional connection between CYFIP2 and various MLO proteins and also extend CYFIP2's role within the WRC from actin regulation to influencing eIF2α phosphorylation and protein synthesis. With these dual functions, CYFIP2 may fine-tune the balance between MLO formation/dynamics and protein synthesis, a crucial aspect of proper mRNA processing and translation.

Emerging potentials of Fe-based nanomaterials for chiral sensing and imaging.

Fe-based nanostructures have possessed promising properties that make it suitable for chiral sensing and imaging applications owing to their ultra-small size, non-toxicity, biocompatibility, excellent photostability, tunable fluorescence, and water solubility. This review summarizes the recent research progress in the field of Fe-based nanostructures and places special emphases on their applications in chiral sensing and imaging. The synthetic strategies to prepare the targeted Fe-based structures were also introduced. The chiral sensing and imaging applications of the nanostructures are discussed in details.

The PFC-LH-VTA pathway contributes to social deficits in IRSp53-mutant mice.

Dopamine (DA) neurons in the ventral tegmental area (VTA) promote social brain functions by releasing DA onto nucleus accumbens neurons, but it remains unclear how VTA neurons communicate with cortical neurons. Here, we report that the medial prefrontal cortex (mPFC)-lateral hypothalamus (LH)-VTA pathway contributes to social deficits in mice with IRSp53 deletion restricted to cortical excitatory neurons (Emx1-Cre;Irsp53fl/fl mice). LH-projecting mutant mPFC neurons display abnormally increased excitability involving decreased potassium channel gene expression, leading to excessive excitatory synaptic input to LH-GABA neurons. A circuit-specific IRSp53 deletion in LH-projecting mPFC neurons also increases neuronal excitability and induces social deficits. LH-GABA neurons with excessive mPFC excitatory synaptic input show a compensatory decrease in excitability, weakening the inhibitory LHGABA-VTAGABA pathway and subsequently over-activating VTA-GABA neurons and over-inhibiting VTA-DA neurons. Accordingly, optogenetic activation of the LHGABA-VTAGABA pathway improves social deficits in Emx1-Cre;Irsp53fl/fl mice. Therefore, the mPFC-LHGABA-VTAGABA-VTADA pathway contributes to the social deficits in Emx1-Cre;Irsp53fl/fl mice.

Adnp-mutant mice with cognitive inflexibility, CaMKIIα hyperactivity, and synaptic plasticity deficits.

ADNP syndrome, involving the ADNP transcription factor of the SWI/SNF chromatin-remodeling complex, is characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD). Although Adnp-haploinsufficient (Adnp-HT) mice display various phenotypic deficits, whether these mice display abnormal synaptic functions remain poorly understood. Here, we report synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIα hyperactivity in Adnp-HT mice. These mice show impaired and inflexible contextual learning and memory, additional to social deficits, long after the juvenile-stage decrease of ADNP protein levels to ~10% of the newborn level. The adult Adnp-HT hippocampus shows hyperphosphorylated CaMKIIα and its substrates, including SynGAP1, and excessive long-term potentiation that is normalized by CaMKIIα inhibition. Therefore, Adnp haploinsufficiency in mice leads to cognitive inflexibility involving CaMKIIα hyperphosphorylation and excessive LTP in adults long after its marked expressional decrease in juveniles.

An imaging-based model to predict the malignant potential of intraductal papillary mucinous neoplasm of the pancreas.

OBJECTIVES: To develop and validate imaging-based models for predicting the malignancy risk of intraductal papillary mucinous neoplasm (IPMN). MATERIALS AND METHODS: We retrospectively analyzed data from 241 IPMN patients who underwent preoperative CT and MRI for model development. Cyst size, presence and size of the enhancing mural nodule (EMN), main pancreatic duct (MPD) diameter, thickened/enhancing cyst wall, abrupt MPD caliber change with distal atrophy, and lymphadenopathy were assessed. Multiple logistic regression models predicting malignancy risk were created using either continuous (Model C) or dichotomized variables (Model D) using these imaging features. Validation included internal (n = 55) and external (n = 43) datasets. Model performance was assessed using the area under the receiver operating characteristic curve (AUC) and compared with that of the international guideline-based model (Model F). RESULTS: Model C identified age, EMN size, MPD diameter, and lymphadenopathy as independent predictors on CT, and age and presence and size of EMN on MRI. Model D identified age ≥ 68, cyst size ≥ 31 mm, EMN ≥ 6 mm, MPD ≥ 7 mm, and lymphadenopathy as independent predictors on CT, and age ≥ 68, EMN ≥ 4.5 mm, and lymphadenopathy on MRI. Model C (AUC, 0.763-0.899) performed slightly better than Model D (AUC, 0.753-0.912) without statistical significance. No significant difference was observed between Models C and F (AUC, 0.729-0.952). Combining Model C with obstructive jaundice improved performance (AUC, 0.802-0.941) without statistical significance. CONCLUSION: Our imaging-based models effectively predicted the malignancy risk of IPMNs, comparable to international consensus guidelines. CLINICAL RELEVANCE STATEMENT: Imaging features are important for predicting the malignant potential of IPMNs. Our imaging-based model may help determine surgical candidacy for patients with IPMNs. KEY POINTS: Non-invasively determining the malignant potential of intraductal papillary mucinous neoplasms (IPMNs) allows for appropriate treatment decision-making We identified multiple imaging features that are associated with malignant transformation and developed models for this prediction. Our model performs comparably with international consensus guidelines in predicting the malignant potential of IPMNs.

Contrast-Enhanced Ultrasound With Perfluorobutane for Hepatocellular Carcinoma Diagnosis: Comparison of Imaging Phases and Diagnostic Criteria.

BACKGROUND. Contrast-enhanced ultrasound (CEUS) with perfluorobutane has used varying protocols and diagnostic criteria for hepatocellular carcinoma (HCC). OBJECTIVE. The purpose of this article was to assess diagnostic performance for HCC of CEUS with perfluorobutane in high-risk patients using various criteria. METHODS. This retrospective post hoc study evaluating individual patient data from three earlier prospective studies from one hospital included 204 patients (136 men, 68 women; mean age, 63 ± 11 [SD] years) at high risk of HCC with 213 liver observations. Patients underwent CEUS using perfluorobutane from March 2019 to June 2022. Three radiologists (the examination's operator and two subsequent reviewers) independently interpreted examinations, assessing arterial, portal venous (arterial phase completion through 2 minutes), transitional (2-5 minutes after injection), and Kupffer (≥ 10 minutes after injection) phase findings. Six criteria for HCC were tested: 1, any arterial phase hyperenhancement (APHE) with Kupffer phase hypoenhancement; 2, nonrim APHE with Kupffer phase hypoenhancement; 3, nonrim APHE with portal venous washout; 4, nonrim APHE with portal venous washout and/or Kupffer phase hypoenhancement; 5, nonrim APHE with portal venous and/or transitional washout; 6, nonrim APHE with any of portal venous washout, transitional washout, or Kupffer phase hypoenhancement. Depending on the criteria, observations were instead deemed to be a non-HCC malignancy if showing rim APHE, early washout (at < 1 minute), or marked washout (at 2 minutes). Reference was pathology for malignant observations and pathology or imaging follow-up for benign observations. Diagnostic performance was assessed, pooling readers' data. RESULTS. Criterion 1 (no recognized features of non-HCC malignancy) had highest sensitivity (86.9%) but lowest specificity (43.2%) for HCC. Compared with nonrim APHE and portal venous washout (criterion 3), the addition of Kupffer phase hypoenhancement (criterion 4), transitional washout (criterion 5), or either feature (criterion 6) significantly increased sensitivity (34.4% vs 62.6-64.2%) and accuracy (61.8% vs 75.1-76.5%), but significantly decreased specificity (98.5% vs 91.9-94.1%). Criteria 2, 4, 5, and 6 (all incorporating transitional washout and/or Kupffer phase hypoenhancement) showed no significant differences in sensitivity (62.6-64.2%), specificity (91.9-94.1%), or accuracy (75.1-76.5%). CONCLUSION. Recognition of features of non-HCC malignancy improved specificity for HCC. Incorporation of the findings of transitional washout and/or Kupffer phase hypoenhancement improved sensitivity and accuracy, albeit lowered specificity, versus arterial and portal venous findings alone, without further performance variation among criteria incorporating those two findings. CLINICAL IMPACT. Kupffer phase acquisition may be optional for observations classified as HCC or non-HCC malignancy by arterial, portal venous, and transitional phases.

High-resolution MR imaging with gadoxetate disodium for the comprehensive evaluation of potential living liver donors.

Several major transplantation centers have used composite multimodality evaluation for the preoperative evaluation of potential living liver donors. This approach can be time-consuming and, although rare, can cause complications. We aimed to demonstrate the clinical feasibility of our comprehensive preoperative MR protocol for the preoperative assessment of living liver donor candidates instead of composite multimodality evaluation. Thirty-five consecutive living liver donor candidates underwent multiphasic liver CT and comprehensive donor protocol MR examinations for preoperative evaluation in a single large-volume liver transplantation (LT) center. Three blinded abdominal radiologists reviewed the CT and MR images for vascular and biliary variations. The strength of agreement between CT and MR angiography was assessed using the kappa index. The detection rate of biliary anatomical variations was calculated. The sensitivity and specificity for detecting significant steatosis (>5%) were calculated. The estimated total volume and right lobe volumes measured by MR volumetry were compared with the corresponding CT volumetry measurements using the intraclass correlation coefficient (ICC). Among the 35 patients, 26 underwent LT. The measurement of agreement showed a moderate to substantial agreement between CT and MR angiography interpretations (kappa values, 0.47-0.79; p < 0.001). Combining T2-weighted and T1-weighted MR cholangiography techniques detected all biliary anatomical variations in 9 of the 26 patients. MR-proton density fat fraction showed a sensitivity of 100% (3/3) and a specificity of 91.3% (21/23) for detecting pathologically determined steatosis (>5%). MR volumetry reached an excellent agreement with CT volumetry (reviewers 1 and 2: ICC, 0.92; 95% CI, 0.84-0.96). Our one-stop comprehensive liver donor MR imaging protocol can provide complete information regarding hepatic vascular and biliary anatomies, hepatic parenchymal quality, and liver volume for living liver donor candidates and can replace composite multimodality evaluation.

Low dose of contrast agent and low radiation liver computed tomography with deep-learning-based contrast boosting model in participants at high-risk for hepatocellular carcinoma: prospective, randomized, double-blind study.

OBJECTIVE: To investigate the image quality and lesion conspicuity of a deep-learning-based contrast-boosting (DL-CB) algorithm on double-low-dose (DLD) CT of simultaneous reduction of radiation and contrast doses in participants at high-risk for hepatocellular carcinoma (HCC). METHODS: Participants were recruited and underwent four-phase dynamic CT (NCT04722120). They were randomly assigned to either standard-dose (SD) or DLD protocol. All CT images were initially reconstructed using iterative reconstruction, and the images of the DLD protocol were further processed using the DL-CB algorithm (DLD-DL). The primary endpoint was the contrast-to-noise ratio (CNR), the secondary endpoint was qualitative image quality (noise, hepatic lesion, and vessel conspicuity), and the tertiary endpoint was lesion detection rate. The t-test or repeated measures analysis of variance was used for analysis. RESULTS: Sixty-eight participants with 57 focal liver lesions were enrolled (20 with HCC and 37 with benign findings). The DLD protocol had a 19.8% lower radiation dose (DLP, 855.1 ± 254.8 mGy·cm vs. 713.3 ± 94.6 mGy·cm, p = .003) and 27% lower contrast dose (106.9 ± 15.0 mL vs. 77.9 ± 9.4 mL, p < .001) than the SD protocol. The comparative analysis demonstrated that CNR (p < .001) and portal vein conspicuity (p = .002) were significantly higher in the DLD-DL than in the SD protocol. There was no significant difference in lesion detection rate for all lesions (82.7% vs. 73.3%, p = .140) and HCCs (75.7% vs. 70.4%, p = .644) between the SD protocol and DLD-DL. CONCLUSIONS: DL-CB on double-low-dose CT provided improved CNR of the aorta and portal vein without significant impairment of the detection rate of HCC compared to the standard-dose acquisition, even in participants at high risk for HCC. KEY POINTS: • Deep-learning-based contrast-boosting algorithm on double-low-dose CT provided an improved contrast-to-noise ratio compared to standard-dose CT. • The detection rate of focal liver lesions was not significantly differed between standard-dose CT and a deep-learning-based contrast-boosting algorithm on double-low-dose CT. • Double-low-dose CT without a deep-learning algorithm presented lower CNR and worse image quality.

Protein interactome and cell-type expression analyses reveal that cytoplasmic FMR1-interacting protein 1 (CYFIP1), but not CYFIP2, associates with astrocytic focal adhesion.

The two members of the cytoplasmic FMR1-interacting protein family, CYFIP1 and CYFIP2, are evolutionarily conserved multifunctional proteins whose defects are associated with distinct types of brain disorders. Even with high sequence homology between CYFIP1 and CYFIP2, several lines of evidence indicate their different functions in the brain; however, the underlying mechanisms remain largely unknown. Here, we performed reciprocal immunoprecipitation experiments using CYFIP1-2 × Myc and CYFIP2-3 × Flag knock-in mice and found that CYFIP1 and CYFIP2 are not significantly co-immunoprecipitated with each other in the knock-in brains compared with negative control wild-type (WT) brains. Moreover, CYFIP1 and CYFIP2 showed different size distributions by size-exclusion chromatography of WT mouse brains. Specifically, mass spectrometry-based analysis of CYFIP1-2 × Myc knock-in brains identified 131 proteins in the CYFIP1 interactome. Comparison of the CYFIP1 interactome with the previously identified brain region- and age-matched CYFIP2 interactome, consisting of 140 proteins, revealed only eight common proteins. Investigations using single-cell RNA-sequencing databases suggested non-neuronal cell- and neuron-enriched expression of Cyfip1 and Cyfip2, respectively. At the protein level, CYFIP1 was detected in both neurons and astrocytes, while CYFIP2 was detected only in neurons, suggesting the predominant expression of CYFIP1 in astrocytes. Bioinformatic characterization of the CYFIP1 interactome, and co-expression analysis of Cyfip1 with astrocytic genes, commonly linked CYFIP1 with focal adhesion proteins. Immunocytochemical analysis and proximity ligation assay suggested partial co-localization of CYFIP1 and focal adhesion proteins in cultured astrocytes. Together, these results suggest a CYFIP1-specific association with astrocytic focal adhesion, which may contribute to the different brain functions and dysfunctions of CYFIP1 and CYFIP2. Cover Image for this issue: https://doi.org/10.1111/jnc.15410.

CT/MRI and CEUS LI-RADS Major Features Association with Hepatocellular Carcinoma: Individual Patient Data Meta-Analysis.

Background The Liver Imaging Reporting and Data System (LI-RADS) assigns a risk category for hepatocellular carcinoma (HCC) to imaging observations. Establishing the contributions of major features can inform the diagnostic algorithm. Purpose To perform a systematic review and individual patient data meta-analysis to establish the probability of HCC for each LI-RADS major feature using CT/MRI and contrast-enhanced US (CEUS) LI-RADS in patients at high risk for HCC. Materials and Methods Multiple databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus) were searched for studies from January 2014 to September 2019 that evaluated the accuracy of CT, MRI, and CEUS for HCC detection using LI-RADS (CT/MRI LI-RADS, versions 2014, 2017, and 2018; CEUS LI-RADS, versions 2016 and 2017). Data were centralized. Clustering was addressed at the study and patient levels using mixed models. Adjusted odds ratios (ORs) with 95% CIs were determined for each major feature using multivariable stepwise logistic regression. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) (PROSPERO protocol: CRD42020164486). Results A total of 32 studies were included, with 1170 CT observations, 3341 MRI observations, and 853 CEUS observations. At multivariable analysis of CT/MRI LI-RADS, all major features were associated with HCC, except threshold growth (OR, 1.6; 95% CI: 0.7, 3.6; P = .07). Nonperipheral washout (OR, 13.2; 95% CI: 9.0, 19.2; P = .01) and nonrim arterial phase hyperenhancement (APHE) (OR, 10.3; 95% CI: 6.7, 15.6; P = .01) had stronger associations with HCC than enhancing capsule (OR, 2.4; 95% CI: 1.7, 3.5; P = .03). On CEUS images, APHE (OR, 7.3; 95% CI: 4.6, 11.5; P = .01), late and mild washout (OR, 4.1; 95% CI: 2.6, 6.6; P = .01), and size of at least 20 mm (OR, 1.6; 95% CI: 1.04, 2.5; P = .04) were associated with HCC. Twenty-five studies (78%) had high risk of bias due to reporting ambiguity or study design flaws. Conclusion Most Liver Imaging Reporting and Data System major features had different independent associations with hepatocellular carcinoma; for CT/MRI, arterial phase hyperenhancement and washout had the strongest associations, whereas threshold growth had no association. © RSNA, 2021 Online supplemental material is available for this article.

Differentiation between small (< 4.5 cm) true subepithelial tumors and ectopic pancreas in the small bowel on computed tomography enterography.

OBJECTIVES: To identify imaging features that can differentiate ectopic pancreas from true subepithelial tumors (SETs) in the small bowel using CT enterography and to assess whether radiologists' performance for the differentiation can be improved with the knowledge of significant CT findings. METHODS: CT images of ectopic pancreas (n = 29) and pathologically proven SETs (n = 61) were retrospectively reviewed by two radiologists in consensus. CT items analyzed included lesion location, contour (round, ovoid, flat/conformed), growth pattern, margin, homogeneity, necrosis, feeding vessel, surface ulceration, and enhancement pattern. For quantitative analysis, Hounsfield unit, longer diameter (LD), and shorter diameter (SD) of the lesion were measured. Univariate and multivariate analyses were performed. Diagnostic performance for differentiating ectopic pancreas from SETs was independently evaluated by two other radiologists using a receiver operating characteristic analysis. RESULTS: Age < 63 years, female sex, flat/conformed appearance, homogeneous enhancement, the absence of feeding vessels and necrosis, and an LD/SD ratio > 1.5 were significant variables for differentiating ectopic pancreas from small bowel SETs (p < 0.05). In the multivariate analysis, flat/conformed appearance, the absence of feeding vessels, and female sex remained suggestive features for ectopic pancreas. Area under the curve values for differentiating between two disease entities increased by both independent reviewers with knowledge of these significant CT features. CONCLUSIONS: Ectopic pancreas in the small bowel can be effectively differentiated from small (< 4.5 cm) true SETs by a flat/conformed appearance and the absence of feeding vessels on CT enterography. In addition, radiologists' performance for differentiating ectopic pancreas from small bowel SETs was improved with the knowledge of these significant CT findings. KEY POINTS: • Ectopic pancreas in the small bowel can be differentiated from small (< 4.5 cm) subepithelial tumors on CT. • Differential CT findings of the ectopic pancreas are a flat or conformed appearance and the absence of a feeding vessel. • Radiologists' performance for differentiating ectopic pancreas from small bowel SETs can be improved with the knowledge of differential CT findings.

Perfluorobutane-enhanced ultrasonography with a Kupffer phase: improved diagnostic sensitivity for hepatocellular carcinoma.

OBJECTIVES: To evaluate the diagnostic accuracy of perfluorobutane contrast-enhanced ultrasonography (CEUS) for hepatocellular carcinoma (HCC) and to explore how accuracy can be improved compared to conventional diagnostic criteria in at-risk patients. METHODS: A total of 123 hepatic nodules (≥ 1 cm) from 123 at-risk patients who underwent perfluorobutane CEUS between 2013 and 2020 at three institutions were retrospectively analyzed. Ninety-three percent of subjects had pathological results, except benign lesions stable in follow-up images. We evaluated presence of arterial phase hyperenhancement (APHE), washout time and degree, and Kupffer phase (KP) defects. KP defects are defined as hypoenhancing lesions relative to the liver in KP. HCC was diagnosed in two ways: (1) Liver Imaging Reporting and Data System (LI-RADS) criteria defined as APHE and late (≥ 60 s)/mild washout, and (2) APHE and Kupffer (AK) criteria defined as APHE and KP defect. We explored grayscale features that cause misdiagnosis of HCC and reflected in the adjustment. Diagnostic performance was compared using McNemar's test. RESULTS: There were 77 HCCs, 15 non-HCC malignancies, and 31 benign lesions. An ill-defined margin without hypoechoic halo on grayscale applied as a finding that did not suggest HCC. Regarding diagnosis of HCC, sensitivity of AK criteria (83.1%; 95% confidence interval [CI]: 72.9-90.7%) was higher than that of LI-RADS criteria (75.3%; 95% CI: 64.2-84.4%; p = 0.041). Specificity was 91.3% (95% CI: 79.2-97.6%) in both groups. CONCLUSION: On perfluorobutane CEUS, diagnostic criteria for HCC using KP defect with adjustment by grayscale findings had higher diagnostic performance than conventional criteria without losing specificity. KEY POINTS: • Applying Kupffer phase defect instead of late/mild washout and adjusting with grayscale findings can improve the diagnostic performance of perfluorobutane-enhanced US for HCC. • Adjustment with ill-defined margins without a hypoechoic halo for features unlikely to be HCC decreases false positives for HCC diagnosis using the perfluorobutane-enhanced US. • After adjustment with grayscale findings, the sensitivity and accuracy of the APHE and Kupffer criteria were higher than those of the LI-RADS criteria; specificity was 91.3% for both.

Prediction of residual tumor and overall survival after first-line surgery in patients with pancreatic ductal adenocarcinoma using preoperative magnetic resonance imaging findings.

BACKGROUND: Complete resection is the only potentially curative treatment in patients with pancreatic ductal adenocarcinoma (PDA) and is associated with a longer overall survival (OS) than incomplete resection of tumor. Hence, prediction of the resection status after surgery would help predict the prognosis of patients with PDA. PURPOSE: To predict residual tumor (R) classification and OS in patients who underwent first-line surgery for PDA using preoperative magnetic resonance imaging (MRI). MATERIAL AND METHODS: In this study, 210 patients with PDA who underwent MRI and first-line surgery were randomly categorized into a test group (n=150) and a validation group (n=60). The R classification was divided into R0 (no residual tumor) and R1/R2 (microscopic/macroscopic residual tumor). Preoperative MRI findings associated with R classification and OS were assessed by using logistic regression and Cox proportional hazard models. In addition, the prediction models for the R classification and OS were validated using calibration plots and C statistics. RESULTS: On preoperative MRI, portal vein encasement (odds ratio 4.755) was an independent predictor for R1/R2 resection (P=0.040). Tumor size measured on MRI (hazard ratio [HR] per centimeter 1.539) was a predictor of OS, along with pathologic N1 and N2 stage (HR 1.944 and 3.243, respectively), R1/R2 resection (HR 3.273), and adjuvant chemoradiation therapy (HR 0.250) (P<0.050). Calibration plots demonstrated satisfactory predictive performance. CONCLUSION: Preoperative MRI was valuable for predicting R1/R2 resection using portal vein encasement. Tumor size measured on MRI was useful for the prediction of OS after first-line surgery for PDA.

Reduction of olecranon fractures with no or minimal dorsal cortex comminution based on the contour of the posterior ulnar cortex: does it restore the greater sigmoid notch?

INTRODUCTION: When treating olecranon fractures surgically, surgeons rely on the contour of the posterior cortex of the proximal ulna. However, it is unclear whether the greater sigmoid notch (GSN) is restored anatomically by this method. We analyzed whether reduction of fractures based on the posterior ulnar cortex contour is reliable for restoration of the GSN contour in displaced olecranon fractures with no or minimal dorsal cortex comminution. MATERIALS AND METHODS: We performed a retrospective review of 23 patients with Mayo type 2 olecranon fractures with no or minimal dorsal cortex comminution who were treated surgically. We analyzed pre- and postoperative elbow CT images and measured the interfragmentary distance (IFD), articular step-off, articular gap, contour defect and GSN angle to evaluate the restoration of the GSN contour. RESULTS: The mean preoperative IFD and contour defect were 16.5 mm (range 4.3-35.6 mm) and 4.3 mm (range 0.7-13.3 mm), respectively. Postoperatively, there was no residual IFD, and the mean contour defect decreased significantly to 1.4 mm (range 0-3.7 mm). The residual articular step-off and gap were 0.2 mm (range 0-3.8 mm) and 1.0 mm (range 0-5.9 mm), respectively. Acceptable GSN restoration was achieved in 14 of 23 patients (60.9%). Sixteen patients had > 2 mm of preoperative contour defect, and 7 (43.8%) achieved acceptable GSN restoration; the remaining 7 patients (100%) who had < 2 mm of the contour defect achieved acceptable GSN restoration. Patients whose preoperative contour defect was > 2 mm had a higher risk of unacceptable GSN restoration, with an odds ratio of 2.29 (p = 0.019). CONCLUSIONS: In displaced olecranon fractures without significant dorsal cortex comminution, reduction based on the posterior ulnar cortex could be reliable for fractures with under 2 mm of preoperative contour defect, but not for those with > 2 mm of contour defect. LEVEL OF EVIDENCE: IV.

Gadoxetate-enhanced MRI Features of Proliferative Hepatocellular Carcinoma Are Prognostic after Surgery.

Background Hepatocellular carcinomas (HCCs) are heterogeneous neoplasms, and the prognosis varies based on the subtype. Two broad molecular classes of HCC have been proposed: a proliferative and a nonproliferative class. Purpose To evaluate the gadoxetate-enhanced MRI findings of the proliferative class HCC and its prognostic significance after surgery. Materials and Methods This retrospective cohort study evaluated patients with surgically resected treatment-naive single HCC (≤5 cm) who underwent hepatic resection from January 2010 through February 2013 and preoperative gadoxetate-enhanced MRI. A Cox proportional hazards model was used to determine the predictive factors for overall survival (OS), intrahepatic distant recurrence, and extrahepatic metastasis (EM). The mean follow-up period was 75.5 months ± 30.2 (standard deviation). Multivariable logistic regression was performed to determine factors associated with proliferative class HCC. Results A total of 158 patients (mean age, 57 years ± 11; 128 men and 30 women) were evaluated. Forty-two of the 158 HCCs (26.6%) were proliferative class HCCs (17 macrotrabecular-massive HCCs, 14 keratin 19-positive HCCs, 10 scirrhous HCCs, and one sarcomatoid HCC). The proliferative class was associated with worse OS (hazard ratio [HR], 3.1; 95% CI: 1.5, 6.0; P = .01) and higher rates of intrahepatic distant recurrence (HR, 1.83; 95% CI: 1.1, 2.9; P = .01) and EM (HR, 9.97; 95% CI: 3.2, 31.4; P < .001). Rim arterial phase hyperenhancement (APHE) at gadoxetate-enhanced MRI (odds ratio [OR], 6.35; 95% CI: 1.9, 21.7; P = .01) and high serum α-fetoprotein (>100 ng/mL) (OR, 4.18; 95% CI: 1.64, 10.7; P = .01) were independent predictors for proliferative HCC. The presence of rim APHE was associated with poor OS (HR, 2.4; 95% CI: 1.2, 4.9; P = .02) and higher rates of EM (HR, 7.4; 95% CI: 2.5, 21.7; P < .01). Conclusion The proliferative class of hepatocellular carcinoma (HCC) is an independent factor for poor overall survival with increased rates of intrahepatic and extrahepatic metastasis. Rim arterial phase hyperenhancement at gadoxetate-enhanced MRI may help to identify proliferative class HCC and predict poor overall survival and an increased incidence of extrahepatic metastasis. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Krinsky and Shanbhogue in this issue.

Evaluation of LI-RADS Version 2018 Treatment Response Algorithm for Hepatocellular Carcinoma in Liver Transplant Candidates: Intraindividual Comparison between CT and Hepatobiliary Agent-enhanced MRI.

Background The Liver Imaging Reporting and Data System (LI-RADS), version 2018, treatment response algorithm (TRA) is used to assess hepatocellular carcinoma (HCC) after local-regional therapy (LRT). However, its diagnostic performance has not yet been fully compared between CT and hepatobiliary agent (HBA)-enhanced MRI in patients who have undergone liver transplant (LT). Purpose To compare the diagnostic performance of LI-RADS TRA when using CT versus using HBA-enhanced MRI in an intraindividual manner according to pathologic results. Materials and Methods Between January 2011 and September 2019, 165 patients with 237 clinically suspected HCCs underwent LRT followed by LT and were retrospectively included. All patients underwent both CT and HBA-enhanced MRI after LRT and before LT. Three radiologists independently assessed tumor viability with both modalities by using LI-RADS TRA and reached a consensus. Pathologic tumor viability categorized as either completely (100%) or incompletely (<100%) necrotic obtained from the explanted liver served as the reference standard. Sensitivity and specificity of the LI-RADS TRA in the consensus reading were then compared between CT and HBA-enhanced MRI by using the ratio estimator approach. Interobserver agreements were calculated by using Fleiss κ statistics. Results There were 165 patients (mean age, 62 years ± 9 [standard deviation]; 135 men) with a total of 237 lesions, of which 107 were viable tumors (45.1%) at pathologic evaluation. With the LI-RADS TRA, sensitivity and specificity of the viable category for detection of viable HCCs at pathologic evaluation were 42.1% (45 of 107 lesions) and 95.4% (124 of 130 lesions) with CT and 52.3% (56 of 107 lesions) and 93.9% (122 of 130 lesions) with HBA-enhanced MRI, with a significant difference in sensitivity but not specificity (P = .009 and P = .42, respectively). Interobserver agreements for the LI-RADS TRA were substantial for both CT and HBA-enhanced MRI (κ, 0.69 for both). Conclusion In patients who underwent local-regional therapy for hepatocellular carcinoma before liver transplant, hepatobiliary agent-enhanced MRI was more sensitive than CT in evaluating tumor viability with the Liver Imaging Reporting and Data System, version 2018, treatment response algorithm. ©RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Bashir and Mendiratta-Lala in this issue.

Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction.

OBJECTIVE: Genetic variants of the cytoplasmic FMR1-interacting protein 2 (CYFIP2) encoding an actin-regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2-associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/- ) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/- mice and specified a neuronal function mediating its efficacy. METHODS: We performed behavioral analyses of Cyfip2+/- mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/- prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. RESULTS: Adult Cyfip2+/- mice exhibited lithium-responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/- PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/- mice showed increased seizure susceptibility and auditory steady-state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/- L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/- PFC. Virus-mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium-responsive abnormal behavior. INTERPRETATION: These results suggest that L5-specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium-mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/- mice, which can be implicated in CYFIP2-associated brain disorders. ANN NEUROL 2020;88:526-543.

Joint segmentation and classification of hepatic lesions in ultrasound images using deep learning.

OBJECTIVES: To develop a convolutional neural network system to jointly segment and classify a hepatic lesion selected by user clicks in ultrasound images. METHODS: In total, 4309 anonymized ultrasound images of 3873 patients with hepatic cyst (n = 1214), hemangioma (n = 1220), metastasis (n = 1001), or hepatocellular carcinoma (HCC) (n = 874) were collected and annotated. The images were divided into 3909 training and 400 test images. Our network is composed of one shared encoder and two inference branches used for segmentation and classification and takes the concatenation of an input image and two Euclidean distance maps of foreground and background clicks provided by a user as input. The performance of hepatic lesion segmentation was evaluated based on the Jaccard index (JI), and the performance of classification was based on accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curve (AUROC). RESULTS: We achieved performance improvements by jointly conducting segmentation and classification. In the segmentation only system, the mean JI was 68.5%. In the classification only system, the accuracy of classifying four types of hepatic lesions was 79.8%. The mean JI and classification accuracy were 68.5% and 82.2%, respectively, for the proposed joint system. The optimal sensitivity and specificity and the AUROC of classifying benign and malignant hepatic lesions of the joint system were 95.0%, 86.0%, and 0.970, respectively. The respective sensitivity, specificity, and the AUROC for classifying four hepatic lesions of the joint system were 86.7%, 89.7%, and 0.947. CONCLUSIONS: The proposed joint system exhibited fair performance compared to segmentation only and classification only systems. KEY POINTS: • The joint segmentation and classification system using deep learning accurately segmented and classified hepatic lesions selected by user clicks in US examination. • The joint segmentation and classification system for hepatic lesions in US images exhibited higher performance than segmentation only and classification only systems. • The joint segmentation and classification system could assist radiologists with minimal experience in US imaging by characterizing hepatic lesions.