US-based Sequential Algorithm Integrating an AI Model for Advanced Liver Fibrosis Screening.

Background Noninvasive tests can be used to screen patients with chronic liver disease for advanced liver fibrosis; however, the use of single tests may not be adequate. Purpose To construct sequential clinical algorithms that include a US deep learning (DL) model and compare their ability to predict advanced liver fibrosis with that of other noninvasive tests. Materials and Methods This retrospective study included adult patients with a history of chronic liver disease or unexplained abnormal liver function test results who underwent B-mode US of the liver between January 2014 and September 2022 at three health care facilities. A US-based DL network (FIB-Net) was trained on US images to predict whether the shear-wave elastography (SWE) value was 8.7 kPa or higher, indicative of advanced fibrosis. In the internal and external test sets, a two-step algorithm (Two-step#1) using the Fibrosis-4 Index (FIB-4) followed by FIB-Net and a three-step algorithm (Three-step#1) using FIB-4 followed by FIB-Net and SWE were used to simulate screening scenarios where liver stiffness measurements were not or were available, respectively. Measures of diagnostic accuracy were calculated using liver biopsy as the reference standard and compared between FIB-4, SWE, FIB-Net, and European Association for the Study of the Liver guidelines (ie, FIB-4 followed by SWE), along with sequential algorithms. Results The training, validation, and test data sets included 3067 (median age, 42 years [IQR, 33-53 years]; 2083 male), 1599 (median age, 41 years [IQR, 33-51 years]; 1124 male), and 1228 (median age, 44 years [IQR, 33-55 years]; 741 male) patients, respectively. FIB-Net obtained a noninferior specificity with a margin of 5% (P < .001) compared with SWE (80% vs 82%). The Two-step#1 algorithm showed higher specificity and positive predictive value (PPV) than FIB-4 (specificity, 79% vs 57%; PPV, 44% vs 32%) while reducing unnecessary referrals by 42%. The Three-step#1 algorithm had higher specificity and PPV compared with European Association for the Study of the Liver guidelines (specificity, 94% vs 88%; PPV, 73% vs 64%) while reducing unnecessary referrals by 35%. Conclusion A sequential algorithm combining FIB-4 and a US DL model showed higher diagnostic accuracy and improved referral management for all-cause advanced liver fibrosis compared with FIB-4 or the DL model alone. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Ghosh in this issue.

Collaborative Enhancement of Consistency and Accuracy in US Diagnosis of Thyroid Nodules Using Large Language Models.

Background Large language models (LLMs) hold substantial promise for medical imaging interpretation. However, there is a lack of studies on their feasibility in handling reasoning questions associated with medical diagnosis. Purpose To investigate the viability of leveraging three publicly available LLMs to enhance consistency and diagnostic accuracy in medical imaging based on standardized reporting, with pathology as the reference standard. Materials and Methods US images of thyroid nodules with pathologic results were retrospectively collected from a tertiary referral hospital between July 2022 and December 2022 and used to evaluate malignancy diagnoses generated by three LLMs-OpenAI's ChatGPT 3.5, ChatGPT 4.0, and Google's Bard. Inter- and intra-LLM agreement of diagnosis were evaluated. Then, diagnostic performance, including accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC), was evaluated and compared for the LLMs and three interactive approaches: human reader combined with LLMs, image-to-text model combined with LLMs, and an end-to-end convolutional neural network model. Results A total of 1161 US images of thyroid nodules (498 benign, 663 malignant) from 725 patients (mean age, 42.2 years ± 14.1 [SD]; 516 women) were evaluated. ChatGPT 4.0 and Bard displayed substantial to almost perfect intra-LLM agreement (κ range, 0.65-0.86 [95% CI: 0.64, 0.86]), while ChatGPT 3.5 showed fair to substantial agreement (κ range, 0.36-0.68 [95% CI: 0.36, 0.68]). ChatGPT 4.0 had an accuracy of 78%-86% (95% CI: 76%, 88%) and sensitivity of 86%-95% (95% CI: 83%, 96%), compared with 74%-86% (95% CI: 71%, 88%) and 74%-91% (95% CI: 71%, 93%), respectively, for Bard. Moreover, with ChatGPT 4.0, the image-to-text-LLM strategy exhibited an AUC (0.83 [95% CI: 0.80, 0.85]) and accuracy (84% [95% CI: 82%, 86%]) comparable to those of the human-LLM interaction strategy with two senior readers and one junior reader and exceeding those of the human-LLM interaction strategy with one junior reader. Conclusion LLMs, particularly integrated with image-to-text approaches, show potential in enhancing diagnostic medical imaging. ChatGPT 4.0 was optimal for consistency and diagnostic accuracy when compared with Bard and ChatGPT 3.5. © RSNA, 2024 Supplemental material is available for this article.

Identification of key genes in chronic intermittent hypoxia-induced lung cancer progression based on transcriptome sequencing.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased risk of lung cancer mortality. Nevertheless, little is known about the underlying molecular mechanisms. This research aimed to investigate differentially expressed genes (DEGs) and explore their function in Lewis lung carcinoma (LLC)-bearing mice exposed to chronic intermittent hypoxia (CIH) by transcriptome sequencing. METHODS: Lung cancer tissues in LLC-bearing mice exposed to CIH or normoxia were subjected for transcriptome sequencing to examine DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were employed to explore the function of DEGs. To evaluate the prognostic value of DEGs, the Kaplan-Meier survival analysis in combination with Cox proportional hazard model were applied based on The Cancer Genome Atlas. RESULTS: A total of 388 genes with 207 up-regulated and 181 down-regulated genes were differentially expressed between the CIH and normoxia control groups. Bioinformatics analysis revealed that the DEGs were related to various signaling pathways such as chemokine signaling pathway, IL-17 signaling pathway, TGF-ß signaling pathway, transcriptional misregulation in cancer, natural killer cell mediated cytotoxicity, PPAR signaling pathway. In addition, the DEGs including APOL1, ETFB, KLK8, PPP1R3G, PRL, SPTA1, PLA2G3, PCP4L1, NINJ2, MIR186, and KLRG1 were proven to be significantly correlated with poorer overall survival in lung adenocarcinoma. CONCLUSIONS: CIH caused a significant change of gene expression profiling in LLC-bearing mice. The DEGs were found to be involved in various physiological and pathological processes and correlated with poorer prognosis in lung cancer.

Predicting T Cell-Inflamed Gene Expression Profile in Hepatocellular Carcinoma Based on Dynamic Contrast-Enhanced Ultrasound Radiomics.

Purpose: The T cell-inflamed gene expression profile (GEP) quantifies 18 genes' expression indicative of a T-cell immune tumor microenvironment, playing a crucial role in the immunotherapy of hepatocellular carcinoma (HCC). Our study aims to develop a radiomics-based machine learning model using contrast-enhanced ultrasound (CEUS) for predicting T cell-inflamed GEP in HCC. Methods: The primary cohort of HCC patients with preoperative CEUS and RNA sequencing data of tumor tissues at the single center was used to construct the model. A total of 5936 radiomics features were extracted from the regions of interest in representative images of each phase, and the least absolute shrinkage and selection operator and logistic regression were used to construct four models including three phase-specific models and an integrated model. The area under the curve (AUC) was calculated to evaluate the performance of the model. The independent cohort of HCC patients with preoperative CEUS and Immunoscore based on immunohistochemistry and digital pathology was used to validate the correlation between model prediction value and T-cell infiltration. Results: There were 268 patients enrolled in the primary cohort and 46 patients enrolled in the independent cohort. Compared with the other three models, the AP model constructed by 36 arterial phase (AP) features showed good performance with a mean AUC of 0.905 in the 5-fold cross-validation and was easier to apply in the clinical setting. The decision curve and calibration curve confirmed the clinical utility of the model. In the independent cohort, patients with high Immunoscores showed significantly higher GEP prediction values than those with low Immunoscores (t=-2.359, p=0.029). Conclusion: The CEUS-based model is a reliable predictive tool for T cell-inflamed GEP in HCC, and might facilitate individualized immunotherapy decision-making.

Complementary Role of CEUS and CT/MR LI-RADS for Diagnosis of Recurrent HCC.

PURPOSE: We retrospectively compared the diagnostic performance of contrast-enhanced ultrasonography (CEUS) and contrast-enhanced computer tomography-magnetic resonance imaging (CT/MRI) for recurrent hepatocellular carcinoma (HCC) after curative treatment. MATERIALS AND METHODS: After curative treatment with 421 ultrasound (US) detected lesions, 303 HCC patients underwent both CEUS and CT/MRI. Each lesion was assigned a Liver Imaging Reporting and Data System (LI-RADS) category according to CEUS and CT/MRI LI-RADS. Receiver-operating characteristic (ROC) curves were computed to determine the optimal diagnosis algorithms for CEUS, CT and MRI. The diagnostic accuracy, sensitivity, specificity, and area under the curve (AUC) were compared between CEUS and CT/MRI. RESULTS: Among the 421 lesions, 218 were diagnosed as recurrent HCC, whereas 203 lesions were diagnosed as benign. In recurrent HCC, CEUS detected more arterial hyperenhancement (APHE) and washout than CT and more APHE than MRI. CEUS yielded better diagnostic performance than CT (AUC: 0.981 vs. 0.958) (p = 0.024) comparable diagnostic performance to MRI (AUC: 0.952 vs. 0.933) (p > 0.05) when using their optimal diagnostic criteria. CEUS missed 12 recurrent HCCs, CT missed one, and MRI missed none. The detection rate of recurrent HCC on CEUS (94.8%, 218/230) was lower than that on CT/MRI (99.6%, 259/260) (p = 0.001). Lesions located on the US blind spots and visualization score C would hinder the ability of CEUS to detect recurrent HCC. CONCLUSION: CEUS demonstrated excellent diagnostic performance but an inferior detection rate for recurrent HCC. CEUS and CT/MRI played a complementary role in the detection and characterization of recurrent HCC.

US LI-RADS in surveillance for recurrent hepatocellular carcinoma after curative treatment.

OBJECTIVES: To investigate the performance of US LI-RADS in surveillance for recurrent hepatocellular carcinoma (RHCC) after curative treatment. MATERIALS AND METHODS: This study enrolled 644 patients between January 2018 and August 2018 as a derivation cohort, and 397 patients from September 2018 to December 2018 as a validation cohort. The US surveillance after HCC curative treatment was performed. The US LI-RADS observation categories and visualization scores were analyzed. Four criteria using US LI-RADS or Alpha-fetoprotein (AFP) as the surveillance algorithm were evaluated. The sensitivity, specificity, and negative predictive value (NPV) were calculated. RESULTS: A total of 212 (32.9%) patients in derivation cohort and 158 (39.8%) patients in validation cohort were detected to have RHCCs. The criterion of US-2/3 or AFP ≥ 20 µg/L had higher sensitivity (derivation, 96.7% vs 92.9% vs 81.1% vs 90.6%; validation, 96.2% vs 90.5% vs 80.4% vs 89.9%) and NPV (derivation, 95.7% vs 93.3% vs 88.0% vs 91.8%; validation, 94.6% vs 89.4% vs 83.6% vs 89.0%), but lower specificity (derivation, 35.9% vs 48.2% vs 67.6% vs 51.9%; validation, 43.5% vs 52.7% vs 66.1% vs 54.0%) than criterion of US-2/3, US-3, and US-3 or AFP ≥ 20 µg/L. Analysis of the visualization score subgroups confirmed that the sensitivity (89.2-97.6% vs 81.0-83.3%) and NPV(88.4-98.0% vs 80.0-83.3%) of score A and score B groups were higher than score C group in criterion of US-2/3 in both two cohorts. CONCLUSIONS: In the surveillance for RHCC, US LI-RADS with AFP had a high sensitivity and NPV when US-2/3 or AFP ≥ 20 µg/L was considered a criterion. CLINICAL RELEVANCE STATEMENT: The criterion of US-2/3 or AFP ≥ 20 µg/L improves sensitivity and NPV for RHCC surveillance, which provides a valuable reference for patients in RHCC surveillance after curative treatment. KEY POINTS: • US LI-RADS with AFP had high sensitivity and NPV in surveillance for RHCC when considering US-2/3 or AFP ≥ 20 µg/L as a criterion. • After US with AFP surveillance, patients with US-2/3 or AFP ≥ 20 µg/L should perform enhanced imaging for confirmative diagnosis. Patients with US-1 or AFP < 20 µg/L continue to repeat US with AFP surveillance. • Patients with risk factors for poor visualization scores limited the sensitivity of US surveillance in RHCC.

Upregulation of the CD155-CD226 Axis Is Associated With Muscle Inflammation and Disease Severity in Idiopathic Inflammatory Myopathies.

BACKGROUND AND OBJECTIVES: The CD155-CD226/T-cell Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) pathway plays a critical role in regulating T-cell responses and is being targeted clinically. However, research on the role of this pathway in autoimmune diseases is limited. This study aimed to investigate the expression and tissue-specific roles of CD155-CD226/TIGIT pathway molecules in the inflamed muscles of patients with idiopathic inflammatory myopathies (IIMs). METHODS: Immunohistochemistry, Western blot analysis, and polychromatic immunofluorescence staining were performed to examine the expression of CD155, CD226, and TIGIT in skeletal muscle biopsies from 30 patients with dermatomyositis (DM), 10 patients with amyopathic DM (ADM), 20 patients with immune-mediated necrotizing myopathy (IMNM), 5 patients with dysferlinopathy, and 4 healthy controls. Flow cytometry analysis was used to analyze the functions of T cells with different phenotypes. RESULTS: Strong expression of CD155 was observed in patients with DM and IMNM, while its expression was largely negative in those with ADM and dysferlinopathy and healthy controls. The costimulatory receptor CD226 was highly expressed on muscle-infiltrating cells, while the coinhibitory receptor TIGIT was expressed at low levels. These infiltrating CD226+ cells were mainly activated effector T cells that localized adjacent to CD155-expressing myofibers, but were faintly detectable within the muscle fascicles lacking CD155. A strong positive correlation between CD155 and CD226 expression scores was also observed. Polychromatic immunofluorescence staining revealed that CD155+ muscle cells coexpressed major histocompatibility complex classes I and II, and tumor necrosis factor alpha expression was detected in CD226+ T cells at their close sites with the myofibers. Furthermore, the expression levels of CD155 and CD226 showed a positive correlation with creatine kinase, lactate dehydrogenase, and the muscle histopathology damage scores and an inverse correlation with the Manual Muscle Testing-8 scores. In addition, CD155 and CD226 expressions were significantly decreased in representative patients who achieved remission posttreatment. DISCUSSION: These findings demonstrate that the CD155-CD226 axis is highly activated in inflamed muscle tissues of patients with IIM and is associated with muscle disease severity. Our data uncover the immunopathogenic role of the axis in the pathology of IIMs.

Surveillance for malignant progression of LI-RADS version 2017 category 3/4 nodules using contrast-enhanced ultrasound.

OBJECTIVES: To identify the risk factors for predicting the malignant progression of LR-3/4 observations on the baseline and contrast-enhanced ultrasound (CEUS). METHODS: In total, 245 liver nodules assigned to LR-3/4 in 192 patients from January 2010 to December 2016 were followed up by baseline US and CEUS. The differences in the rate and time of progression to hepatocellular carcinoma (HCC) among subcategories (defined as P1-P7) of LR-3/4 in CEUS Liver Imaging Reporting and Data System (LI-RADS) were analyzed. The risk factors to predict progression to HCC were analyzed by univariate and multivariate Cox proportional hazard model analysis. RESULTS: A total of 40.3% of LR-3 nodules and 78.9% of LR-4 nodules eventually progressed to HCC. The cumulative incidence of progression was significantly higher for LR-4 than LR-3 (p < 0.001). The rate of progression was 81.2% in nodules with arterial phase hyperenhancement (APHE), 64.7% in nodules with late and mild washout, and 100% in nodules with both characteristics. The overall progression rate and median progression time of subcategory P1 nodules (LR-3a) were lower (38.0% vs. 47.6-100.0%) and later (25.1 months vs. 2.0-16.3 months) than those of other subcategories. The cumulative incidence of progression of LR-3a (P1), LR-3b (P2/3/4), and LR-4 (P5/6/7) categories were 38.0%, 52.9%, and 78.9%. The risk factors of HCC progression were Visualization score B/C, CEUS characteristics (APHE, washout), LR-4 classification, echo changes, and definite growth. CONCLUSION: CEUS is a useful surveillance tool for nodules at risk of HCC. CEUS characteristics, LI-RADS classification, and changes in nodules provide useful information for the progress of LR-3/4 nodules. CLINICAL RELEVANCE STATEMENT: CEUS characteristics, LI-RADS classification, and nodule changes provide important predictions for LR-3/4 nodule progression to HCC, which may stratify the risk of malignant progression to provide a more optimized and refined, more cost-effective, and time-efficient management strategy for patients. KEY POINTS: • CEUS is a useful surveillance tool for nodules at risk of HCC, CEUS LI-RADS successfully stratified the risks that progress to HCC. • CEUS characteristics, LI-RADS classification, and changes in nodules can provide important information on the progression of LR-3/4 nodules, which may be helpful for a more optimized and refined management strategy.

The association between obstructive sleep apnea and lung nodule, carcinoembryonic antigen.

PURPOSE: The association between obstructive sleep apnea (OSA) and cancer risks gaining more and more attention. Data on the association between OSA and lung cancer risk are limited. This study is to investigate whether a link exists between low-dose computed tomography (LDCT) scanning of the chest findings, carcinoembryonic antigen (CEA) and OSA in patients suspected of OSA. METHODS: The cross-sectional study included patients aged 18 years or older who underwent continuous nocturnal polysomnography at our sleep center between February 2019 and November 2020. All subjects underwent chest LDCT and CEA. Patients with an apnea-hypopnea index (AHI) of ≥ 15/h were classified as clinically significant OSA group, whereas patients with an AHI < 15/h were classified as control group. RESULTS: A total of 277 patients were enrolled in the study. 176 patients were categorized into the OSA group, while 101 patients were categorized into the control group. There is no relationship between any OSA-related parameter and presence of lung nodule or presence of ≥ 6 mm lung nodule in the binary logistic regression analysis. OSA group demonstrated a significant higher value of CEA than control group. Stepwise multiple linear regression analysis showed that lowest O2 saturation (ß = - 0.256, p < 0.001), smoking status (ß = 0.156, p = 0.007) and age (ß = 0.153, p = 0.008) were independent predictors of elevated CEA. CONCLUSIONS: OSA was independently related to the elevated of serum CEA level, but not with presence of pulmonary nodule or ≥ 6 mm pulmonary nodule in LDCT. Further well-designed longitudinal studies with pathology available are needed to identify the association between OSA and risk of lung cancer.

The role of ferroptosis and endoplasmic reticulum stress in intermittent hypoxia-induced myocardial injury.

PURPOSE: Obstructive sleep apnea (OSA) is related to increased risk of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by iron overload and plays critical roles in myocardial injury. This study aimed to investigate the role of ferroptosis in intermittent hypoxia (IH)-induced myocardial injury involving endoplasmic reticulum stress (ERS). METHODS: AC16 human cardiomyocytes were exposed to IH or normoxia conditions. Mice were randomly grouped as follows: normal control (NC), IH, ferrostatin-1 + IH (FIH), and N-acetylcysteine + IH (AIH). The mRNA levels of GPX4, xCT, FTH1, and FACL4 in AC16 cells were detected by qRT-PCR. The protein levels of GPX4, xCT, NOX4, ATF4, CHOP, Bcl-2, and Bax in myocardial tissue were detected by Western blot analysis. RESULTS: The mRNA expression levels of GPX4 and xCT in AC16 cells were significantly lower in IH group than that of NC group. In IH mice, myocardial tissues were injured accompanied by increased level of ferroptosis and ERS. Inhibition of ferroptosis and treatment of N-acetylcysteine reduced ERS and myocardial injury in mice exposed to IH. In addition, compared to ferrostatin-1, N-acetylcysteine exerted a greater effect in relieving IH-induced myocardial damage and ERS. CONCLUSIONS: Ferroptosis was involved in IH-related myocardial injury accompanied by the activation of ERS. Inhibition of ferroptosis and acetylcysteine treatment alleviated IH-related myocardial injury, which may be a potential target for therapeutic approaches to OSA-induced myocardial injury.

Differentiation between combined hepatocellular carcinoma and hepatocellular carcinoma: comparison of diagnostic performance between ultrasomics-based model and CEUS LI-RADS v2017.

BACKGROUND: The imaging findings of combined hepatocellular cholangiocarcinoma (CHC) may be similar to those of hepatocellular carcinoma (HCC). CEUS LI-RADS may not perform well in distinguishing CHC from HCC. Studies have shown that radiomics has an excellent imaging analysis ability. This study aimed to establish and confirm an ultrasomics model for differentiating CHC from HCC. METHODS: Between 2004 and 2016, we retrospectively identified 53 eligible CHC patients and randomly included 106 eligible HCC patients with a ratio of HCC:CHC = 2:1, all of whom were categorized according to Contrast-Enhanced (CE) ultrasonography (US) Liver Imaging Reporting and Data System (LI-RADS) version 2017. The model based on ultrasomics features of CE US was developed in 74 HCC and 37 CHC and confirmed in 32 HCC and 16 CHC. The diagnostic performance of the LI-RADS or ultrasomics model was assessed by the area under the curve (AUC), accuracy, sensitivity and specificity. RESULTS: In the entire and validation cohorts, 67.0% and 81.3% of HCC cases were correctly assigned to LR-5 or LR-TIV contiguous with LR-5, and 73.6% and 87.5% of CHC cases were assigned to LR-M correctly. Up to 33.0% of HCC and 26.4% of CHC were misclassified by CE US LI-RADS. A total of 90.6% of HCC as well as 87.5% of CHC correctly diagnosed by the ultrasomics model in the validation cohort. The AUC, accuracy, sensitivity of the ultrasomics model were higher though without significant difference than those of CE US LI-RADS in the validation cohort. CONCLUSION: The proposed ultrasomics model showed higher ability though the difference was not significantly different for differentiating CHC from HCC, which may be helpful in clinical diagnosis.

An assessment of liver lesions using a combination of CEUS LI-RADS and AFP.

PURPOSE: To improve noninvasive diagnosis of HCC using a combination of CE US LI-RADS and alpha-fetoprotein (AFP). METHODS: 757 solitary liver nodules from 757 patients at risk of HCC with CE US and serum AFP test were categorized as LR-1 to LR-5 through LR-M according to CE US LI-RADS version 2017. In LR-3, LR-4, and LR-M nodules, those with AFP > 200 ng/ml were reclassified as mLR-5. Nodules with LR-5 and mLR-5 were reclassified as definitely HCC to modify CE US LI-RADS. Diagnostic performance was assessed with specificity, sensitivity, and PPV. RESULTS: The sensitivity, specificity, and PPV of LR-5 as a predictor of HCC were 64.7%, 97.8%, and 98.9%, respectively. 32.1% patients with solitary liver nodule had AFP greater than 200 ng/ml, of which 98.8% were HCC (25.8%, 7.5%, 2.5% assigned to LR-M, LR-4, LR-3, respectively) and 1.2% were Combined Hepatocellular Cholangiocarcinoma. After modification, the sensitivity increased to 79.6% (P < 0.001), while specificity and PPV remained high (96.6% and 98.7%, P > 0.050). CONCLUSION: The combination of CE US LI-RADS and AFP for diagnosing HCC improved diagnostic sensitivity significantly, while maintaining high PPV and specificity in patients with the solitary liver nodule.

Long non-coding RNA MALAT1 affects intermittent hypoxia-induced endothelial injury by regulating miR-142-3p/HMGB1.

BACKGROUND: Obstructive sleep apnea (OSA) is a risk factor for atherosclerosis. Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is strongly linked to endothelial cell functions. However, the function of MALAT1 in intermittent hypoxia (IH) associated vascular endothelial injury has not been explored yet. The current study makes great attempts to investigate the function of MALAT1 in IH-induced endothelial injury and its latent control network. METHODS: To mimic the effect of OSA, we cultured the human umbilical vein endothelial cells (HUVECs) under intermittent hypoxia. Western blot was applied to measure the expression level of associated proteins including capase-3, Bax, Bcl-2 while qRT-PCR was used in measurement of MALAT1 and miR-142-3p. Cell Counting Kit-8 (CCK-8) was carried out in assessing cell viability. Dual-luciferase reporter assay was applied to verify the relationships among high mobility group box (HMGB)1 and MALAT1, miR-142-3p. RESULTS: IH treatment significantly reduced cell viability but enhanced cell apoptosis in HUVECs. Concomitantly, MALAT1 was significantly upregulated in IH-treated HUVECs. Further experiment showed that MALAT1 knockdown augmented IH-induced injury of HUVECs. In addition, it was confirmed by dual-luciferase reporter assay that MALAT1 interacted with miR-142-3p directly. Besides, inhibition of miR-142-3p alleviated damage induced by MALAT1 knockdown in IH-treated HUVECs. Finally, miR-142-3p interacted with HMGB1 directly and inhibition of HMGB1 protein expression mediated by MALAT1 knockdown was reversed by miR-142-3p inhibitor. CONCLUSIONS: IH resulted in increased expression of MALAT1 in HUVECs. MALAT1 knockdown augmented IH-induced injury of HUVECs. MALAT1 exerted its effects on IH-treated HUVECs via miR-142-3p/HMGB1.

Can monodisperse microbubble-based three-dimensional contrast-enhanced ultrasound reduce quantitative heterogeneity? An in vitro study.

BACKGROUND: Heterogeneity within the tumor may cause large heterogeneity in quantitative perfusion parameters. Three-dimensional contrast-enhanced ultrasound (3D-CEUS) can show the spatial relationship of vascular structure after post-acquisition reconstruction and monodisperse bubbles can resonate the ultrasound pulse, resulting in the increase in sensitivity of CEUS imaging. OBJECTIVES: To evaluate whether the combination of 3D-CEUS and monodisperse microbubbles could reduce the heterogeneity of quantitative CEUS. MATERIAL AND METHODS: Three in vitro perfusion models with perfusion volume ratio of 1:2:4 were set up. Both quantitative 2D-CEUS and 3D-CEUS were used to acquire peak intensity (PI) with 2 kinds of ultrasound agents. One was a new kind of monodisperse bubbles produced in this study, named Octafluoropropane-loaded cerasomal microbubbles (OC-MBs), the other was SonoVue®. The coefficient of variation (CV) was calculated to evaluate the cross-sectional variability. Pearson's correlation analysis was used to assess the correlation between weighted PIs (average of PIs of 3 different planes) and perfusion ratios. RESULTS: The average CVs of quantitative 3D-CEUS was slightly lower than that of 2D-CEUS (0.41 ±0.17 compared to 0.55 ±0.26, p = 0.3592). As for quantitative 3D-CEUS, the PI of the OC-MBs has shown better stability than that of SonoVue®, but without a significant difference (average CVs: 0.32 ±0.19 compared to 0.50 ±0.10, p = 0.0711). In the 2D-CEUS condition, the average CVs of OC-MBs group and SonoVue® group were 0.68 ±0.15 and 0.41 ±0.17 (p = 0.2747). As for 3D-CEUS condition, using OC-MBs group and SonoVue®, the r-values of the weighted PI and perfusion ratio were 0.8685 and 0.5643, respectively, while that of 2D-CEUS condition were 0.7760 and 0.3513, respectively. CONCLUSIONS: Our in vitro experiments showed that OC-MBs have the potential in acquiring more stable quantitative CEUS value, as compared to the SonoVue® in 3D-CEUS condition. The combination of 3D-CEUS and OC-MBs can reflect perfusion volume more precisely and may be a potential way to reduce quantitative heterogeneity.

Using new criteria to improve the differentiation between HCC and non-HCC malignancies: clinical practice and discussion in CEUS LI-RADS 2017.

PURPOSE: Using contrast-enhanced ultrasound (CEUS) to evaluate the diagnostic performance of liver imaging reporting and data system (LI-RADS) version 2017 and to explore potential ways to improve the efficacy. METHODS: A total of 315 nodules were classified as LR-1 to LR-5, LR-M, and LR-TIV. New criteria were applied by adjusting the early washout onset (< 45 s) and the time of marked washout (within 3 min). Two subgroups of the LR-M nodules were recategorized as LR-5, respectively. The diagnostic performance was evaluated by calculating the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: By adjusting early washout onset to < 45 s, the LR-5 as a standard for diagnosing HCC had an improved sensitivity (74.1% vs. 56.1%, P < 0.001) without significant change in PPV (93.3% vs. 96.1%, P = 0.267), but the specificity was decreased (48.3% vs. 78.5%, P = 0.018). The LR-M as a standard for the diagnosis of non-HCC malignancies had an increase in specificity (89.2% vs. 66.2%, P < 0.001) but a decrease in sensitivity (31.5% vs. 68.4%, P = 0.023). After reclassification according to the time of marked washout, the sensitivity of the LR-5 increased (80% vs. 56.1%, P < 0.001) without a change in PPV (94.9% vs. 96.1%, P = 0.626) and specificity (80% vs. 78.5%, P = 0.879). For reclassified LR-M nodules, the specificity increased (87.5% versus 66.2%, P < 0.001) with a non-significant decrease in sensitivity (47.3% vs. 68.4%, P = 0.189). CONCLUSIONS: The CEUS LI-RADS showed good confidence in diagnosing HCC while tended to misdiagnose HCC as non-HCC malignancies. Adjusting the marked washout time within 3 min would reduce the possibility of this misdiagnosis.

Preoperative Survival Prediction in Intrahepatic Cholangiocarcinoma Using an Ultrasound-Based Radiographic-Radiomics Signature.

OBJECTIVES: To construct a preoperative model for survival prediction in intrahepatic cholangiocarcinoma (ICC) patients using ultrasound (US) based radiographic-radiomics signatures. METHODS: Between April 2010 and September 2015, 170 patients with ICC who underwent curative resection were retrospectively recruited. Overall survival (OS)-related radiographic signatures and radiomics signatures based on preoperative US were built and assessed through a time-dependent receiver operating characteristic curve analysis. A nomogram was developed based on the selected predictors from the radiographic-radiomics signatures and clinical and laboratory results of the training cohort (n = 127), validated in an independent testing cohort (n = 43) by the concordance index (C-index), and compared with the Tumor Node Metastasis (TNM) cancer staging system as well as the radiographic and radiomics nomograms. RESULTS: The median areas under the curve of the radiomics signature and radiographic signature were higher than that of the TNM staging system in the testing cohort, although the values were not significantly different (0.76-0.82 versus 0.62, P = .485 and .264). The preoperative nomogram with CA 19-9, sex, ascites, radiomics signature, and radiographic signature had C-indexes of 0.72 and 0.75 in the training and testing cohorts, respectively, and it had significantly higher predictive performance than the 8th TNM staging system in the testing cohort (C-index: 0.75 versus 0.67, P = .004) and a higher C-index than the radiomics nomograms (0.75 versus 0.68, P = .044). CONCLUSIONS: The preoperative nomogram integrated with the radiographic-radiomics signature demonstrated good predictive performance for OS in ICC and was superior to the 8th TNM staging system.

Contrast-Enhanced Ultrasound for Differentiation Between Poorly Differentiated Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.

PURPOSE: To evaluate the diagnostic performance of LR-5 for diagnosing poorly differentiated hepatocellular carcinoma (p-HCC). To build a contrast-enhanced ultrasound (CEUS) signature for improving the differential diagnostic performance between p-HCC and intrahepatic cholangiocarcinoma (ICC). METHODS: The B-mode ultrasound (BUS) and CEUS features of 60 p-HCCs and 56 ICCs were retrospectively analyzed. The CEUS LI-RADS category was assigned according to CEUS LI-RADS v2017. A diagnostic CEUS signature was built based on the independent significant features. An ultrasound (US) signature combining both BUS and CEUS features was also built. The diagnostic performances of the CEUS signature, US signature, and LR-5 were evaluated by receiver operating characteristic (ROC) analysis. RESULTS: One (1.7%) p-HCC and 26 (46.4%) ICC patients presented cholangiectasis or cholangiolithiasis (P < .001). Fifty-four (90.0%) p-HCCs and 8 (14.3%) ICCs showed clear boundaries in the artery phase (P < .001). The washout times of p-HCCs and ICCs were 81.0 ± 42.5 s and 34.7 ± 8.6 s, respectively (P < .001). The AUC, sensitivity, and specificity of the CEUS signature, US signature, and LR-5 were 0.955, 91.67%, and 90.57% versus 0.976, 96.67%, and 92.45% versus 0.758, 51.67%, and 100%, respectively. The AUC and sensitivity of CEUS LI-RADS were much lower than those of the CEUS and US signatures (P < .001). CONCLUSION: LR-5 had high specificity but low sensitivity in diagnosing p-HCC. When the washout time and tumor boundary were included in the CEUS signature, the sensitivity and AUC were remarkably increased in the differentiation between p-HCC and ICC.

Contrast-Enhanced Ultrasound-Based Nomogram: A Potential Predictor of Individually Postoperative Early Recurrence for Patients With Combined Hepatocellular-Cholangiocarcinoma.

PURPOSES: To evaluate the postsurgical prognostic implication of contrast-enhanced ultrasound (CEUS) for combined hepatocellular-cholangiocarcinoma (CHC). To build a CEUS-based early recurrence prediction classifier for CHC, in comparison with tumor-node-metastasis (TNM) staging. METHODS: The CEUS features and clinicopathological findings of each case were analyzed, and the Liver Imaging Reporting and Data System categories were assigned. The recurrence-free survival associated factors were evaluated by Cox proportional hazard model. Incorporating the independent factors, nomograms were built to estimate the possibilities of 3-month, 6-month, and 1-year recurrence and whose prognostic value was determined by time-dependent receiver operating characteristics, calibration curves, and hazard layering efficiency validation, comparing with TNM staging system. RESULTS: In the multivariable analysis, the levels of carbohydrate antigen 19-9, prothrombin time and total bilirubin, and tumor shape, the Liver Imaging Reporting and Data System category were independent factors for recurrence-free survival. The LR-M category showed longer recurrence-free survival than did the LR-4/5 category. The 3-month, 6-month, and 1-year area under the curves of the CEUS-clinical nomogram, clinical nomogram, and TNM staging system were 0.518, 0.552, and 0.843 versus 0.354, 0.240, and 0.624 (P = .048, .049, and .471) vs. 0.562, 0.545, and 0.843 (P = .630, .564, and .007), respectively. The calibration curves of the CEUS-clinical model at different prediction time pionts were all close to the ideal line. The CEUS-clinical model effectively stratified patients into groups of high and low risk of recurrence in both training and validation set, while the TNM staging system only works on the training set. CONCLUSIONS: Our CEUS-clinical nomogram is a reliable early recurrence prediction tool for hepatocellular-cholangiocarcinoma and helps postoperative risk stratification.

Obstructive sleep apnea and the risk of mortality in patients with lung cancer: a meta-analysis.

PURPOSE: Prior reports have examined the relationship between obstructive sleep apnea (OSA) and the mortality rate of lung cancer. However, the findings remain controversial. The present meta-analysis was performed to assess the relationship between OSA and increased risk of mortality in patients with lung cancer. METHODS: PubMed, Web of Science, and Embase were systematically searched for the correlative studies. Data were analyzed and pooled to evaluate odds ratios (ORs) of lung cancer mortality related to OSA. RESULTS: From 249 identified studies, 3 met inclusion criteria and were analyzed, including 67 patients with lung cancer and comorbid OSA and 45 patients with lung cancer and no OSA. The meta-analysis indicated that OSA was not significantly correlated with mortality rate in lung cancer (OR = 2.005, 95% CI = 0.703 to 5.715, z = 1.30, p = 0.193). There was no significant publication bias according to Begg's tests (p = 0.296) and Egger's tests (p = 0.097). CONCLUSION: This meta-analysis suggests that OSA is not significantly correlated with the mortality rate in lung cancer.