A Genetically Defined Compartmentalized Striatal Direct Pathway for Negative Reinforcement.

The striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 (Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a "conventional" striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs. These neurons are predominantly excited by punishment rather than reward and represent the anticipation of punishment or the motivation for avoidance. Furthermore, inhibiting these neurons impairs punishment-based learning without affecting reward learning or movement. These results establish a major role of striosomal neurons in behaviors reinforced by punishment and moreover uncover functions of the direct pathway unaccounted for in classic models.

Molecular Architecture of the Mouse Nervous System.

The mammalian nervous system executes complex behaviors controlled by specialized, precisely positioned, and interacting cell types. Here, we used RNA sequencing of half a million single cells to create a detailed census of cell types in the mouse nervous system. We mapped cell types spatially and derived a hierarchical, data-driven taxonomy. Neurons were the most diverse and were grouped by developmental anatomical units and by the expression of neurotransmitters and neuropeptides. Neuronal diversity was driven by genes encoding cell identity, synaptic connectivity, neurotransmission, and membrane conductance. We discovered seven distinct, regionally restricted astrocyte types that obeyed developmental boundaries and correlated with the spatial distribution of key glutamate and glycine neurotransmitters. In contrast, oligodendrocytes showed a loss of regional identity followed by a secondary diversification. The resource presented here lays a solid foundation for understanding the molecular architecture of the mammalian nervous system and enables genetic manipulation of specific cell types.

Molecular architecture of the developing mouse brain.

The mammalian brain develops through a complex interplay of spatial cues generated by diffusible morphogens, cell-cell interactions and intrinsic genetic programs that result in probably more than a thousand distinct cell types. A complete understanding of this process requires a systematic characterization of cell states over the entire spatiotemporal range of brain development. The ability of single-cell RNA sequencing and spatial transcriptomics to reveal the molecular heterogeneity of complex tissues has therefore been particularly powerful in the nervous system. Previous studies have explored development in specific brain regions1-8, the whole adult brain9 and even entire embryos10. Here we report a comprehensive single-cell transcriptomic atlas of the embryonic mouse brain between gastrulation and birth. We identified almost eight hundred cellular states that describe a developmental program for the functional elements of the brain and its enclosing membranes, including the early neuroepithelium, region-specific secondary organizers, and both neurogenic and gliogenic progenitors. We also used in situ mRNA sequencing to map the spatial expression patterns of key developmental genes. Integrating the in situ data with our single-cell clusters revealed the precise spatial organization of neural progenitors during the patterning of the nervous system.

Development and validation of an image biomarker to identify metabolic dysfunction associated steatohepatitis: MR-MASH score.

BACKGROUND AND AIMS: Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) requires histology. In this study, a magnetic resonance imaging (MRI) score was developed and validated to identify MASH in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Secondarily, a screening strategy for MASH diagnosis was investigated. METHODS: This prospective multicentre study included 317 patients with biopsy-proven MASLD and contemporaneous MRI. The discovery cohort (Spain, Portugal) included 194 patients. NAFLD activity score (NAS) and fibrosis were assessed with the NASH-CRN histologic system. MASH was defined by the presence of steatosis, lobular inflammation, and ballooning, with NAS ≥4 with or without fibrosis. An MRI-based composite biomarker of Proton Density Fat Fraction and waist circumference (MR-MASH score) was developed. Findings were afterwards validated in an independent cohort (United States, Spain) with different MRI protocols. RESULTS: In the derivation cohort, 51% (n = 99) had MASH. The MR-MASH score identified MASH with an AUC = .88 (95% CI .83-.93) and strongly correlated with NAS (r = .69). The MRI score lower cut-off corresponded to 88% sensitivity with 86% NPV, while the upper cut-off corresponded to 92% specificity with 87% PPV. MR-MASH was validated with an AUC = .86 (95% CI .77-.92), 91% sensitivity (lower cut-off) and 87% specificity (upper cut-off). A two-step screening strategy with sequential MR-MASH examination performed in patients with indeterminate-high FIB-4 or transient elastography showed an 83-84% PPV to identify MASH. The AUC of MR-MASH was significantly higher than that of the FAST score (p < .001). CONCLUSIONS: The MR-MASH score has clinical utility in the identification and management of patients with MASH at risk of progression.

RNA velocity of single cells.

RNA abundance is a powerful indicator of the state of individual cells. Single-cell RNA sequencing can reveal RNA abundance with high quantitative accuracy, sensitivity and throughput1. However, this approach captures only a static snapshot at a point in time, posing a challenge for the analysis of time-resolved phenomena such as embryogenesis or tissue regeneration. Here we show that RNA velocity-the time derivative of the gene expression state-can be directly estimated by distinguishing between unspliced and spliced mRNAs in common single-cell RNA sequencing protocols. RNA velocity is a high-dimensional vector that predicts the future state of individual cells on a timescale of hours. We validate its accuracy in the neural crest lineage, demonstrate its use on multiple published datasets and technical platforms, reveal the branching lineage tree of the developing mouse hippocampus, and examine the kinetics of transcription in human embryonic brain. We expect RNA velocity to greatly aid the analysis of developmental lineages and cellular dynamics, particularly in humans.

Imaging Findings in Cirrhotic Liver: Pearls and Pitfalls for Diagnosis of Focal Benign and Malignant Lesions.

Cirrhosis is the end stage of chronic liver disease and causes architectural distortion and perfusional anomalies. It is a major risk factor for developing hepatocellular carcinoma (HCC). Common disease entities in noncirrhotic livers, such as hemangiomas, can be rare in cirrhotic livers, and benign entities such as confluent hepatic fibrosis and focal nodular hyperplasia-like lesions may mimic the appearance of malignancies,. HCC usually has typical imaging characteristics, such as the major features established by the Liver Imaging Reporting and Data System. However, HCC can also have a spectrum of atypical or uncommon appearances, such as cystic HCC, hypovascular HCC, or macroscopic fat-containing HCC. HCCs with certain genetic mutations such as CTNNB-1-mutated HCC can harbor unique imaging features not seen in other types of HCC. In addition, malignancies that are less common than HCC, such as cholangiocarcinoma and metastases, which can be difficult to differentiate, can still occur in cirrhotic livers. Atypical imaging features of benign and malignant lesions can be challenging to accurately diagnose. Therefore, familiarity with these features and an understanding of the prevalence of disease entities in cirrhotic livers are key in the daily practice of radiologists for evaluation of cirrhotic livers. The authors illustrate the typical and atypical features of benign and malignant lesions in cirrhosis and discuss the technical pitfalls and unique advantages associated with various imaging modalities in assessing cirrhotic livers, including noncontrast and contrast-enhanced US, CT, and MRI. Work of the U.S. Government published under an exclusive license with the RSNA. Quiz questions for this article are available in the supplemental material.

Characterization of hepatic steatosis using controlled attenuation parameter and MRI-derived proton density fat fraction in living donor liver transplantation.

BACKGROUND: The increasingly favorable outcomes of live donor liver transplant warrant development of screening techniques to expand current donor pool. Transient elastography (TE) with controlled attenuation parameter (CAP) is accessible and has promising diagnostic performance in non-obese individuals. Here, we demonstrate its utility in grading donor steatosis for risk assessment in living liver donors (LLD). STUDY DESIGN: In a prospective study of LLD and recipients, accuracy was determined using MRI-derived proton density fat fraction (PDFF) as reference. RESULTS: One hundred and one LLD underwent TE, 95 of whom had available PDFF. Median CAP and MRI-PDFF were 233 dB/m (206-270) and 2.9% (2.3-4.0), respectively. A CAP threshold of 270 dB/m captured all steatosis which was present in 13 (13%) LLD (AUROC .942, 100% sensitivity and 83% specificity). Performance further improved when excluding obese LLD and limiting analysis to M-probe (AUROC .971 and .974, respectively, with 87% specificity). There was no difference in CAP and MRI-PDFF between LLD and nondonors (P = .26 and .21, respectively). Early allograft dysfunction was observed in one recipient (CAP 316, PDFF 9.5%), zero underwent retransplant, and one died from sepsis. CONCLUSION: The specific role of CAP in living liver donation warrants further study, beginning with its use as screening tool across peripheral clinics.

Hepatocellular Carcinoma Staging: Differences Between Radiologic and Pathologic Systems and Relevance to Patient Selection and Outcomes in Liver Transplantation.

Liver transplant is indicated with curative intent for patients with early-stage hepatocellular carcinoma (HCC). The radiologic T category is used to determine candidacy and priority of patients on the waiting list. After transplant, the explant liver pathologic TNM stage is used as a predictor of postoperative outcomes and overall prognosis. Although the comparison of radiologic and pathologic T categories for concordance is often considered to be straightforward, the staging conventions significantly differ. Not accounting for these differences is in part the reason for the high rates of radiologic-pathologic discordance reported in the literature, with inconsistent terminology being an additional source of confusion when evaluating concordance. These factors may affect the understanding of important radiopathologic phenotypes of disease and the adequate investigation of their prognostic capabilities. The aims of this article are to provide an overview of the pathologic and radiologic TNM staging systems for HCC while describing staging procedures, emphasize the differences between these staging systems to highlight the limitations of radiologic-pathologic stage correlation, present a review of the literature on the prognostic value of individual features used for HCC staging; and signal significant aspects of preoperative risk stratification that could be improved to positively impact posttransplant outcomes.

Magnetic Resonance Elastography of the Liver: A Single-Institution Review of Cases Performed in a 5-Year Interval.

OBJECTIVE: This study aimed to assess the diagnostic accuracy of magnetic resonance elastography (MRE) in detecting hepatic fibrosis and determining clinically relevant stiffness cutoff values per stage of fibrosis. METHODS: This retrospective study assessed 1488 hepatic MRE evaluations performed at a single institution for 5 years. Mean liver stiffness measurements were collected from 282 patients who had an MRE study within 1 year of histopathologic analysis. Areas under receiver operating characteristic curves were calculated for each stage of fibrosis with nonparametric ordinal measures of accuracy, and Youden Index was determined. RESULTS: Mean liver stiffness measurement values were as follows: F0, 2.5± 0.55 kPa; F1, 3.1± 0.80 kPa; F2, 3.4±0.95 kPa; F3, 4.7±1.44 kPa; and F4, 7.9± 2.64 kPa. Nonparametric ordinal measures of accuracy per fibrosis stage were as follows: F0: 0.934, P < 0.001; F0-F1: 0.917, P < 0.001; F0-F2: 0.944, P < 0.001; and F0-F3: 0.941, P < 0.001. Youden Index values for fibrosis stages F2, F3, and F4 were 3.9, 4.0, and 4.5 kPa, respectively. CONCLUSIONS: Magnetic resonance elastography is an accurate diagnostic tool in assessing liver fibrosis.

A Central Amygdala-Globus Pallidus Circuit Conveys Unconditioned Stimulus-Related Information and Controls Fear Learning.

The central amygdala (CeA) is critically involved in a range of adaptive behaviors, including defensive behaviors. Neurons in the CeA send long-range projections to a number of extra-amygdala targets, but the functions of these projections remain elusive. Here, we report that a previously neglected CeA-to-globus pallidus external segment (GPe) circuit plays an essential role in classical fear conditioning. By anatomic tracing, in situ hybridization and channelrhodopsin (ChR2)-assisted circuit mapping in both male and female mice, we found that a subset of CeA neurons send projections to the GPe, and the majority of these GPe-projecting CeA neurons express the neuropeptide somatostatin. Notably, chronic inhibition of GPe-projecting CeA neurons with the tetanus toxin light chain (TeLC) completely blocks auditory fear conditioning. In vivo fiber photometry revealed that these neurons are selectively excited by the unconditioned stimulus (US) during fear conditioning. Furthermore, transient optogenetic inactivation or activation of these neurons selectively during US presentation impairs or promotes, respectively, fear learning. Our results suggest that a major function of GPe-projecting CeA neurons is to represent and convey US-related information through the CeA-GPe circuit, thereby regulating learning in fear conditioning.SIGNIFICANCE STATEMENT The central amygdala (CeA) has been implicated in the establishment of defensive behaviors toward threats, but the underlying circuit mechanisms remain unclear. Here, we found that a subpopulation of neurons in the CeA, which are mainly those that express the neuropeptide somatostatin, send projections to the globus pallidus external segment (GPe), and this CeA-GPe circuit conveys unconditioned stimulus (US)-related information during classical fear conditioning, thereby having an indispensable role in learning. Our results reveal a previously unknown circuit mechanism for fear learning.

Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct.

BACKGROUND & AIMS: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes. METHODS: We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic CCAs from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n = 5, collected before surgery) and bile duct brushings (n = 2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls). RESULTS: All IOPNs evaluated were found to have recurring fusions of ATP1B1-PRKACB (n = 13), DNAJB1-PRKACA (n = 6), or ATP1B1-PRKACA (n = 4). These fusions also were found in corresponding invasive PDACs and intrahepatic CCAs, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions. CONCLUSIONS: We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas.

Termination of cell-type specification gene programs by the miR-183 cluster determines the population sizes of low-threshold mechanosensitive neurons.

Touch and mechanical sensations require the development of several different kinds of sensory neurons dedicated to respond to certain types of mechanical stimuli. The transcription factor Shox2 (short stature homeobox 2) is involved in the generation of TRKB+ low-threshold mechanoreceptors (LTMRs), but mechanisms terminating this program and allowing alternative fates are unknown. Here, we show that the conditional loss of the miR-183-96-182 cluster in mouse leads to a failure of extinction of Shox2 during development and an increase in the proportion of Aδ LTMRs (TRKB+/NECAB2+) neurons at the expense of Aß slowly adapting (SA)-LTMRs (TRKC+/Runx3-) neurons. Conversely, overexpression of miR-183 cluster that represses Shox2 expression, or loss of Shox2, both increase the Aß SA-LTMRs population at the expense of Aδ LTMRs. Our results suggest that the miR-183 cluster determines the timing of Shox2 expression by direct targeting during development, and through this determines the population sizes of Aδ LTMRs and Aß SA-LTMRs.

Diagnostic value of MRI-derived liver surface nodularity score for the non-invasive quantification of hepatic fibrosis in non-alcoholic fatty liver disease.

OBJECTIVES: To assess the accuracy of MRI-derived liver surface nodularity (LSN) score for staging of hepatic fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Forty-seven patients with clinicopathological diagnosis of NAFLD who underwent 1.5-T liver MRI within 12 months of liver biopsy were included. Axial non-contrast T1-weighted 3D GRE was used for image analysis. LSN of the left lobe was measured using a custom semiautomated software. Histopathologic analysis (F0-F4) served as the reference standard for staging of fibrosis. Mann-Whitney test and Spearman's correlation coefficient were used to compare LSN scores between different stages of fibrosis and to assess the correlation. Diagnostic performance of LSN score for detection of significant (F2-F4) and advanced (F3-F4) fibrosis was assessed by receiver operating characteristics (ROC) curve. p value of less than 0.05 was considered statistically significant different. RESULTS: Twenty-one subjects had advanced fibrosis. The LSN scores among different stages of fibrosis were significantly different (p < 0.001). The correlation between LSN score and stage of fibrosis was also strong (ρ = 0.71; p < 0.001). The areas under ROC curves for detection of significant and advanced fibrosis were 0.80 (95% CI 0.66-0.95) and 0.86 (95% CI 0.75-0.97), using a threshold of 2.23 and 2.44, respectively. This method showed 81% sensitivity and 88% specificity for detection of advanced fibrosis. CONCLUSION: MR-based LSN score is a promising non-invasive objective tool for detection of advanced fibrosis in patients with NAFLD. KEY POINTS: • Liver surface nodularity (LSN) score is a fast retrospective method for precise quantification of nodularity of liver surface. • MR-based LSN score is a promising non-invasive objective tool to accurately detect different stages of fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

Targetoid appearance on T2-weighted imaging and signs of tumor vascular involvement: diagnostic value for differentiating HCC from other primary liver carcinomas.

OBJECTIVES: To evaluate targetoid appearance on T2-weighted imaging and signs of tumor vascular involvement as potential new LI-RADS features for differentiating hepatocellular carcinoma (HCC) from other non-HCC primary liver carcinomas (PLCs). METHODS: This IRB-approved, retrospective study was performed at two liver transplant centers. The final population included 375 patients with pathologically proven lesions imaged between 2007 and 2017 with contrast-enhanced CT or MRI. The cohort consisted of 165 intrahepatic cholangiocarcinomas and 74 combined hepatocellular-cholangiocarcinomas, with the addition of 136 HCCs for control. Two abdominal radiologists (R1; R2) independently reviewed the imaging studies (112 CT; 263 MRI) and recorded the presence of targetoid appearance on T2-weighted images and features of tumor vascular involvement including encasement, narrowing, tethering, occlusion, and obliteration. The sensitivity and specificity of each feature were calculated for the diagnosis of non-HCC PLCs. Cohen's kappa (k) test was used to assess inter-reader agreement. RESULTS: The sensitivity of targetoid appearance on T2-weighted images for the diagnosis of non-HCC PLCs was 27.5% and 32.6% (R1 and R2) and the specificity was 98.2% and 97.3% (R1 and R2). Among the features of tumor vascular involvement, those providing the highest sensitivity for non-HCC PLCs were vascular encasement (R1: 34.3%; R2: 37.2%) and obliteration (R1: 25.5%; R2: 29.7%). The highest specificity for non-HCC PLCs was provided by tethering (R1: 100%; R2: 97.1%) and occlusion (R1: 99.3%; R2: 99.3%). The inter-reader agreement was moderate to substantial (k = 0.48-0.77). CONCLUSIONS: Targetoid appearance on T2-weighted images and features of tumor vascular involvement demonstrated high specificity for non-HCC malignancy. KEY POINTS: • Targetoid appearance on T2-weighted imaging and signs of tumor vascular involvement have high specificity (92-100%) for the diagnosis of non-HCC PLCs, regardless of the presence of liver risk factors. • In the subset of patients with risk factors for HCC, the sensitivity of signs of tumor vascular involvement decreases for both readers (1.7-20.3%), while the specificity increases reaching values higher than 94.2%. • The inter-reader agreement is substantial for targetoid appearance on T2-weighted images (k = 0.74) and moderate to substantial for signs of tumor vascular involvement (k = 0.48-0.77).

Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) is a viable alternative to liver biopsy for steatosis quantification in living liver donor transplantation.

This study aimed to investigate whether magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) can be a viable noninvasive alternative to liver biopsy for the quantification of living liver donor steatosis. Hepatic steatosis for 143 donors was graded by MRI-PDFF. Study endpoints included liver volume regeneration in donors, recipient outcomes including length of hospital stay, deaths, primary non-function (PNF), early allograft dysfunction (EAD), and small for size syndrome (SFSS). Correlation between MRI-PDFF determined donor steatosis and endpoints were analyzed. Donors had lower steatosis grade than non-donors. Donor remnant liver regenerated to an average of 82% of pre-donation volume by 101 ± 24 days with no complications. There was no correlation between percent liver regeneration and steatosis severity. Among recipients, 4 underwent redo-transplantation and 6 died, with no association with degree of steatosis. 52 recipients (36%) fulfilled criteria for EAD (driven by INR), with no difference in hepatic steatosis between groups. MRI-PDFF reliably predicted donor outcomes. Living donors with no or mild steatosis based on MRI-PDFF (ie, <20%) and meeting other criteria for donation can expect favorable post-surgical outcomes, including liver regeneration. Recipients had a low rate of death or retransplantation with no association between mild hepatic steatosis and EAD.

Imaging Evaluation of Living Liver Donor Candidates: Techniques, Protocols, and Anatomy.

The need for liver transplants is increasing because the prevalence of liver diseases and the indications for transplants are growing. In response to the shortage of grafts from deceased donors, more transplants are being performed worldwide with grafts from living donors. Radiologic evaluation is an integral component in the assessment of donor candidates to ensure their eligibility and to choose the most appropriate surgical approach. MRI is the preferred modality for evaluation of the liver parenchyma and biliary tree. In most centers, a combination of MRI and CT is used to take advantage of the higher spatial resolution of CT for evaluation of arteries. However, MRI-only assessment is feasible. In addition to assessment of the liver parenchyma for abnormalities such as steatosis, a detailed evaluation of the hepatic vascular and biliary system for pertinent anatomic variants is crucial, because these variants can affect surgical techniques and outcomes in both recipients and donors. In this pictorial article, after a brief review of the most common surgical techniques and postsurgical liver anatomy, the biliary and vascular anatomy are discussed, with specific attention paid to the variants that are pertinent to this surgical procedure. The roles of liver segmentation and volumetric assessment and current imaging techniques and protocols are also discussed. Online supplemental material is available for this article. ©RSNA, 2021.

Contribution of neural crest and GLAST+ Wnt1+ bone marrow pericytes with liver fibrogenesis and/or regeneration.

BACKGROUND AND AIMS: Liver fibrosis results from cycles of liver damage and scar formation. We herein aimed at analysing neural crest cells and/or bone marrow stromal cells contribution to the liver. METHODS: Two liver fibrosis and one hepatectomy model were applied on double-transgenic loxP-Cre mouse lines. RESULTS: Increased numbers of glia with more complex processes were found in fibrotic livers. During embryonic development, only few cells were traced in the liver and bone marrow, in a minor fraction of mice of different neural crest reporter strains analysed: therefore, a neural crest origin of such cells is doubtful. In the fibrotic liver, a significantly higher incidence of endothelial cells and hepatocyte-like cells expressing the reporter gene Tomato were found in Wnt1-Cre-Tom and GLAST-CreERT2-Tom mice. Consistently, during early fibrogenesis stromal Wnt1-traced cells, with progenitor (CFU-F) properties, get likely mobilized to peripheral blood. Circulating adult Wnt1-traced cells are stromal cells and lack from the expression of other bone marrow and endothelial progenitor cells markers. Furthermore, in a 70% hepatectomy model GLAST+ Wnt1-traced pericytes were found to be mobilized from the bone marrow and the incidence of GLAST-traced hepatocyte-like cells was increased. Finally, GLAST-traced hepatocyte like-cells were found to maintain the expression of stromal markers. CONCLUSIONS: Our data suggest a gliosis process during liver fibrogenesis. While neural crest cells probably do not contribute with other liver cell types than glia, GLAST+ Wnt1-traced bone marrow pericytes are likely a source of endothelial and hepatocyte-like cells after liver injury and do not contribute to scarring.

Liver Imaging Reporting and Data System (LI-RADS) v2018: diagnostic value of ancillary features favoring malignancy in hypervascular observations ≥ 10 mm at intermediate (LR-3) and high probability (LR-4) for hepatocellular carcinoma.

OBJECTIVE: This study was conducted in order to assess the diagnostic accuracy of LI-RADS v2018 ancillary features (AFs) favoring malignancy applied to LR-3 and LR-4 observations on gadoxetate-enhanced MRI. METHODS: In this retrospective dual-institution study, we included consecutive patients at high risk for hepatocellular carcinoma (HCC) imaged with gadoxetate disodium-enhanced MRI between 2009 and 2014 fulfilling the following criteria: (i) at least one LR-3 or LR-4 observation ≥ 10 mm; (ii) nonrim arterial phase hyperenhancement; and (iii) confirmation of benignity or malignancy by pathology or imaging follow-up. We compared the distribution of AFs between HCCs and benign observations and the diagnostic performance for the diagnosis of HCC using univariate and multivariate analyses. Significance was set at p value < 0.05. RESULTS: Two hundred five observations were selected in 155 patients (108 M, 47 F) including 167 (81.5%) LR-3 and 38 (18.5%) LR-4. There were 126 (61.5%) HCCs and 79 (28.5%) benign lesions. A significantly larger number of AFs favoring malignancy were found in LR-3 and LR-4 lesions that progressed to HCC compared to benign lesions (p < 0.001 and p = 0.003, respectively). The most common AFs favoring malignancy in HCCs were hepatobiliary phase (HBP) hypointensity (p < 0.001), transitional phase hypointensity (p < 0.001), and mild-moderate T2 hyperintensity (p < 0.001). Sensitivity and specificity of AFs for the diagnosis of HCC ranged 0.8-76.2% and 86.1-100%, respectively. HBP hypointensity yielded the highest sensitivity but also the lowest specificity and was the only AF remaining independently associated with the diagnosis of HCC at multivariate logistic regression analysis (OR 14.83, 95% CI 5.81-42.76, p < 0.001). CONCLUSIONS: Among all AFs, HBP hypointensity yields the highest sensitivity for the diagnosis of HCC. KEY POINTS: • LR-3 and LR-4 observations diagnosed as HCC have a significantly higher number of ancillary features favoring malignancy compared to observations proven to be benign. • The presence of three or more ancillary features favoring malignancy has a high specificity (96.2%) for the diagnosis of HCC. • Among all ancillary features favoring malignancy, hepatobiliary phase hypointensity yields the highest sensitivity, but also the lowest specificity for the diagnosis of HCC.

Assessment of primary liver carcinomas other than hepatocellular carcinoma (HCC) with LI-RADS v2018: comparison of the LI-RADS target population to patients without LI-RADS-defined HCC risk factors.

OBJECTIVES: To determine whether the LI-RADS imaging features of primary liver carcinomas (PLCs) other than hepatocellular carcinoma (non-HCC PLCs) differ between patients considered high risk (RF+) versus not high risk (RF-) for HCC and to compare rates of miscategorization as probable or definite HCC between the RF+ and RF- populations. METHODS: This retrospective study included all pathology-proven non-HCC PLCs imaged with liver-protocol CT or MRI from 2007 to 2017 at two liver transplant centers. Patients were defined per LI-RADS v2018 criteria as RF+ or RF-. Two independent, blinded readers (R1, R2) categorized 265 lesions using LI-RADS v2018. Logistic regression was utilized to assess for differences in imaging feature frequencies between RF+ and RF- patients. Fisher's exact test was used to assess for differences in miscategorization rates. RESULTS: Non-HCC PLCs were significantly more likely to exhibit nonrim arterial phase hyperenhancement (R1: OR = 2.94; R2: OR = 7.09) and nonperipheral "washout" (R1: OR = 3.65; R2: OR = 7.69) but significantly less likely to exhibit peripheral "washout" (R1: OR = 0.30; R2: OR = 0.10) and delayed central enhancement (R1: OR = 0.18; R2: OR = 0.25) in RF+ patients relative to RF- patients. Consequently, non-HCC PLCs were more often miscategorized as probable or definite HCC in RF+ versus RF- patients (R1: 23.3% vs. 3.6%, p < 0.001; R2: 11.0% vs. 2.6%, p = 0.009). CONCLUSIONS: Non-HCC PLCs are more likely to mimic HCCs on CT and MRI in the LI-RADS target population than in patients without LI-RADS-defined HCC risk factors. KEY POINTS: • The presence of LI-RADS-defined risk factors for HCC tends to alter the imaging appearances of non-HCC PLCs, resulting in higher frequencies of major features and lower frequencies of LR-M features. • Non-HCC PLCs are more likely to be miscategorized as probable or definite HCC in the LI-RADS target population than in patients without LI-RADS-defined HCC risk factors.

Comparison of 2D Shear Wave Elastography, Transient Elastography, and MR Elastography for the Diagnosis of Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

OBJECTIVE. The aim of the present study was to compare the diagnostic accuracy of liver stiffness measurements (LSMs) obtained using MR elastography (MRE), transient elastography (TE), and 2D shear wave elastography (SWE) in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). SUBJECTS AND METHODS. We prospectively enrolled 62 adult subjects (mean age [± SD], 50 ± 13 years; 58% women; body mass index [weight in kilograms divided by the square of height in meters], 35 ± 7). Two-dimensional SWE, MRE, and TE were performed at a mean of 105 ± 86 days after liver biopsy. The area under the ROC curve (AUROC) values and 95% CIs for the corresponding LSMs (expressed in kilopascals) were calculated, with significant fibrosis (Metavir liver fibrosis score, F2-F4) and advanced fibrosis (F3-F4) used as outcome measures. Pairwise comparisons of AUROC values were conducted using the DeLong test. Statistical significance was set at p < 0.05. RESULTS. For the 62 subjects, valid LSMs were obtained for 57 subjects with the use of 2D SWE, for 59 subjects with TE, for 59 subjects with MRE, and for 54 subjects with all three modalities combined. The AUROC values (95% CIs) of 2D SWE, TE, and MRE for the diagnosis of significant fibrosis were 0.80 (0.67-0.92), 0.77 (0.64-0.89), and 0.85 (0.74-0.95), respectively. The AUROC values (95% CIs) of 2D SWE, TE, and MRE for the diagnosis of advanced fibrosis were 0.89 (0.80-0.98), 0.86 (0.77-0.95), and 0.95 (0.89-1.00), respectively. Pairwise comparisons revealed similar diagnostic accuracy for significant fibrosis (2D SWE vs MRE, p = 0.431; 2D SWE vs TE, p = 0.317; and MRE vs TE, p = 0.052) and advanced fibrosis (2D SWE vs MRE, p = 0.348; 2D SWE vs TE, p = 0.293; and MRE vs TE, p = 0.059). CONCLUSION. For patients with biopsy-proven NAFLD, 2D SWE, MRE and TE exhibited comparable and very good to excellent diagnostic accuracy for advanced fibrosis and comparable but lower accuracy for significant fibrosis.