GSDMD-Dependent Neutrophil Extracellular Traps Mediate Portal Vein Thrombosis and Associated Fibrosis in Cirrhosis.

Portal vein thrombosis (PVT) is a challenging and controversial complication of cirrhosis. Experimental models that reproduce cirrhotic PVT and effective pharmacological therapies are limited. We aimed to investigate the nature course and mechanisms of PVT in cirrhosis. A novel PVT model was developed via two-step total portal vein ligation in healthy and thioacetamide (TAA)-cirrhotic rats. Circulating and liver-infiltrating neutrophils were isolated from individuals with cirrhosis to examine neutrophil extracellular traps (NETs) and explore their unique characteristics and implications in PVT-associated fibrosis in cirrhosis. We further validated macrophage-myofibroblast transition (MMT) via multiplex immunofluorescence and single-cell sequencing. In the experimental model, cirrhosis promoted PVT development and portal vein intimal thickening. Interestingly, cirrhosis promoted spontaneous resolution of PVT due to instability of thrombus structure, along with pulmonary and intrahepatic clots. NETs-MMT mediate cirrhotic PVT and PVT-associated fibrosis, including fibrotic thrombus remodeling and increased hepatic collagen deposition. Mechanistically, caspase-4-dependent activation of neutrophils and GSDMD mediated the formation of NETs. The extracellular DNA of NETs promoted TGF-ß1/Smad3-driven MMT. Inhibiting GSDMD with disulfiram suppressed cirrhotic PVT and prevented associated fibrosis. The cirrhotic PVT model reflected the following three main characteristics of cirrhotic PVT: spontaneous resolution, immunothrombosis, and intimal fibrosis. Targeting NETs with GSDMD inhibitors may serve as a new therapeutic concept to treat cirrhotic PVT.

Validation of Baveno VII criteria for clinically significant portal hypertension by two-dimensional shear wave elastography.

BACKGROUND: The Baveno VII consensus proposed criteria for the non-invasively diagnosis of clinically significant portal hypertension (CSPH) in patients with compensated advanced chronic liver disease (cACLD). The performance of Baveno VII criteria for assessing CSPH by two-dimensional shear wave elastography (2D-SWE) had not been well validated. We aimed to validate the performance of Baveno VII criteria for rule-in and rule-out CSPH by 2D-SWE. METHOD: This is an international multicenter study including cACLD patients from China and Croatia with paired liver stiffness measurement (LSM), spleen stiffness measurement (SSM) by 2D-SWE, and hepatic venous pressure gradient (HVPG) were included. CSPH was defined as HVPG ≥ 10 mmHg. RESULT: A total of 146 patients with cACLD were enrolled, and finally 118 patients were included in the analysis. Among them, CSPH was documented in 79 (66.9%) patients. Applying the Baveno VII criteria for rule-out CSPH by 2D-SWE, [LSM ≤ 15 kPa and platelet count ≥ 150 × 109/L] OR SSM < 21 kPa, could exclude CSPH with sensitivity > 90% (93.5 or 98.7%) but negative predictive value < 90% (74.1 or 85.7%). Using the Baveno VII criteria for rule-in CSPH by 2D-SWE, LSM ≥ 25 kPa OR SSM ≥ 50 kPa, could diagnose CSPH with 100% specificity and 100% positive predictive values. CONCLUSION: Baveno VII criteria by 2D-SWE showed a good diagnostic performance for ruling in but not for ruling out CSPH, which might become an emerging non-invasive elastography tool to select the patients who needed non-selective beta blocker therapy.

Photosynthetic Bacteria-Hitchhiking 2D iMXene-mRNA Vaccine to Enable Photo-Immunogene Cancer Therapy.

Therapeutic mRNA vaccines have become powerful therapeutic tools for severe diseases, including infectious diseases and malignant neoplasms. mRNA vaccines encoding tumor-associated antigens provide unprecedented hope for many immunotherapies that have hit the bottleneck. However, the application of mRNA vaccines is limited because of biological instability, innate immunogenicity, and ineffective delivery in vivo. This study aims to construct a novel mRNA vaccine delivery nanosystem to successfully co-deliver a tumor-associated antigen (TAA) encoded by the Wilms' tumor 1 (WT1) mRNA. In this system, named PSB@Nb1.33C/mRNA, photosynthetic bacteria (PSB) efficiently delivers the iMXene-WT1 mRNA to the core tumor region using photo-driven and hypoxia-driven properties. The excellent photothermal therapeutic (PTT) properties of PSB and 2D iMxene (Nb1.33C) trigger tumor immunogenic cell death, which boosts the release of the WT1 mRNA. The released WT1 mRNA is translated, presenting the TAA and amplifying immune effect in vivo. The designed therapeutic strategy demonstrates an excellent ability to inhibit distant tumors and counteract postsurgical lung metastasis. Thus, this study provides an innovative and effective paradigm for tumor immunotherapy, i.e., photo-immunogene cancer therapy, and establishes an efficient delivery platform for mRNA vaccines, thereby opening a new path for the wide application of mRNA vaccines.

Implications of ultrasound-based deep learning model for preoperatively differentiating combined hepatocellular-cholangiocarcinoma from hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

OBJECTIVES: The current study developed an ultrasound-based deep learning model to make preoperative differentiation among hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (cHCC-ICC). METHODS: The B-mode ultrasound images of 465 patients with primary liver cancer were enrolled in model construction, comprising 264 HCCs, 105 ICCs, and 96 cHCC-ICCs, of which 50 cases were randomly selected to form an independent test cohort, and the rest of study population was assigned to a training and validation cohorts at the ratio of 4:1. Four deep learning models (Resnet18, MobileNet, DenseNet121, and Inception V3) were constructed, and the fivefold cross-validation was adopted to train and validate the performance of these models. The following indexes were calculated to determine the differential diagnosis performance of the models, including sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), F-1 score, and area under the receiver operating characteristic curve (AUC) based on images in the independent test cohort. RESULTS: Based on the fivefold cross-validation, the Resnet18 outperformed other models in terms of accuracy and robustness, with the overall training and validation accuracy as 99.73% (± 0.07%) and 99.35% (± 0.53%), respectively. Furthers validation based on the independent test cohort suggested that Resnet 18 yielded the best diagnostic performance in identifying HCC, ICC, and cHCC-ICC, with the sensitivity, specificity, accuracy, PPV, NPV, F1-score, and AUC of 84.59%, 92.65%, 86.00%, 85.82%, 92.99%, 92.37%, 85.07%, and 0.9237 (95% CI 0.8633, 0.9840). CONCLUSION: Ultrasound-based deep learning algorithm appeared a promising diagnostic method for identifying cHCC-ICC, HCC, and ICC, which might play a role in clinical decision making and evaluation of prognosis.

Contrast-enhanced ultrasound features of hepatic sarcomatoid carcinoma different from hepatocellular carcinoma.

BACKGROUND: Hepatic sarcomatoid carcinoma (HSC) is a rare malignancy of the liver. The ultrasound and clinical features of HSC have not been determined. OBJECTIVE: To investigate and compare the ultrasound and clinical features of HSC and hepatocellular carcinoma (HCC), and to reveal the valuable features of HSC. METHODS: The ultrasound features and clinical data of pathologically proven HSC (n = 37) were compared with HCC (n = 92) in a matching ratio of 1:4 using the propensity score (age, gender and tumor size). RESULTS: The HSC patients were more likely to accompany with clinical symptoms and vascular invasion than HCC patients (40.5% vs 17.4%, 24.3% vs 6.5%, P < 0.05). The size of HSCs was significantly larger than that of HCCs (P < 0.05). The proportion of patients with elevated alpha-fetoprotein was significantly lower in HSC (35.1% vs 54.3%, P < 0.05). On gray-scale ultrasound images, the HSCs were more likely to demonstrate as indistinct margin and irregular shape lesions compared to HCCs (78.4% vs 48.8%; 70.3% vs 23.9%, P < 0.05). Under color Doppler flow imaging (CDFI), the blood flow signals were more frequently detected in HSC lesions (75.7% vs 56.5%, P < 0.05). Resistance index (RI) was higher in HSCs than in HCCs [0.78 (0.70,0.82) vs 0.70 (0.62,0.76), P < 0.05]. On contrast-enhanced ultrasound (CEUS), HSCs mainly showed entirety heterogeneous hyper-enhancement (48.6%), entirety homogeneous enhancement (18.9%), peripheral and internal septal enhancement (18.9%). The incidence of non-enhanced areas inside HSC lesions was higher than that inside HCC lesions (56.8% vs 31.5%, P < 0.05). During the portal venous and late phases, most of the lesions revealed hypo-enhancement in both groups, whereas earlier washout was observed in HSCs [43.0 s (30.5,58.0) vs 60.0 s (46.3,100.0), P < 0.05]. CONCLUSIONS: CEUS features are useful in preoperative and non-invasive differentiation of hepatic sarcomatoid carcinoma and hepatocellular carcinoma.

Toroidal-spiral particles as a CAR-T cell delivery device for solid tumor immunotherapy.

Chimeric antigen receptor (CAR) T cell therapy has resulted in positive effects on patients with hematologic malignancy but shows limited efficacy in solid tumor treatments due to insufficient trafficking and tumor infiltration, intensive CAR-T-related toxicities, and antigen escape. In this work, we developed and investigated a biodegradable and biocompatible polymeric toroidal-spiral particle (TSP) as a in vivo cell incubator and delivery device that can be implanted near tumor through a minimally invasive procedure or injected near or into solid tumors by using a biopsy needle. The main matrix structure of the millimeter-sized TSP is made from crosslinking of gelatin methacrylamine (GelMA) and poly (ethylene glycol) diacrylate (PEGDA) with a tunable degradation rate from a few days to months, providing appropriate mechanical properties and sustained release of co-encapsulated drugs and/or stimulation compounds. The toroidal-spiral layer of the particles, presenting an internal void volume for high-capacity cell loading and flexibility of co-encapsulating small and large molecular compounds with individually manipulated release schedules, is filled with collagen and suspended T cells. The TSPs promote cell proliferation, activation, and migration in the tumor micro-environment in a prolonged and sustained manner. In this study, the efficacy of mesothelin (MSLN) CAR-T cells released from the TSPs was tested in preclinical mouse tumor models. Compared to systemic and intratumoral injection, peritumoral delivery of MSLN CAR-T cells using the TSPs resulted in a superior antitumor effect. The TSPs made of FDA approved materials as an in vivo reactor may provide an option for efficiently local delivery of CAR-T cells to solid tumors for higher efficacy and lower toxicity, with a minimally invasive administration procedure.

Pulmonary Cryoablation Outcomes in Octogenarians and Nonagenarians with Primary Lung Cancer.

PURPOSE: To characterize the effectiveness, safety, and length of stay (LOS) associated with pulmonary cryoablation for management of primary lung malignancies in patients aged ≥80 years. MATERIALS AND METHODS: A retrospective single-center database was compiled of all consecutive patients aged ≥80 years who underwent percutaneous computed tomography-guided cryoablation using modified triple-freeze protocol (1-3 ablation probes) for Stage IA-IIB primary lung malignancies between March 2017 and March 2020 (n = 19; 53% women; mean age, 85 years ± 3.5; range, 80-94 years). Follow-up imaging was assessed for local recurrence. Adverse events and LOS were recorded from chart review. Kaplan-Meier analysis was performed to assess both overall and local recurrence-free survival. RESULTS: Mean patient follow-up period was 21.6 months ± 10.8, and mean imaging follow-up period was 19.2 months ± 9.6. Overall survival at 3 years was 94% (95% CI, 81%-100%). Local recurrence-free survival was 100% throughout the imaging follow-up period. Intraprocedural pneumothorax occurred in 37% (7 of 19) of patients; pneumothorax risk was significantly associated with increased tumor distance from pleura (odds ratio, 1.2; P = .018). Sixty-three percent (12 of 19) of patients were discharged on the day of the procedure, with a mean LOS of 7.7 hours ± 1.6, whereas 37% of patients required overnight observation (2 of 19) or admission (5 of 19), with a mean LOS of 48.1 hours ± 19.4. Overall LOS for all patients was 22.6 hours ± 22.9. CONCLUSIONS: Percutaneous cryoablation of primary pulmonary malignancies can be performed in select octogenarians and nonagenarians with high 3-year overall and recurrence-free survival. Despite nonnegligible risk of pneumothorax, most patients are discharged on the day of the procedure.

Quantitative Diagnosis of Nonalcoholic Fatty Liver Disease with Ultrasound Attenuation Imaging in a Biopsy-Proven Cohort.

RATIONALE AND OBJECTIVES: To evaluate the performance of attenuation imaging (ATI) based on ultrasound for detection of hepatic steatosis in patients with nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: This prospective study was approved by our institutional review board (B2021-092R). Written informed consent was obtained from all patients. This study included 60 patients who had clinical suspicion of NAFLD and were referred for liver biopsy after ATI and controlled attenuation parameter (CAP) examinations between September 2020 and December 2021. The histologic hepatic steatosis was graded. The area under curve (AUC) analysis was performed. RESULTS: The success rate of the ATI examination was 100%. The intraobserver reproducibility of ATI was 0.981. The AUCs of ATI for detecting ≥S1, ≥S2, and S3 were 0.968 (cut-off value of 0.671 dB/cm/MHz), 0.911 (cut-off value of 0.726 dB/cm/MHz), and 0.766 (cut-off value of 0.757 dB/cm/MHz), respectively. The AUCs of CAP for detecting ≥S1, ≥S2, and S3 were 0.916 (cut-off value of 258.5 dB/m), 0.872 (cut-off value of 300.0 dB/m), and 0.807 (cut-off value of 315.0 dB/m), respectively. The diagnostic values showed no significant difference between ATI and CAP in detecting ≥S1, ≥S2, and S3 (P = .281, P = .254, and P = .330, respectively). The ATI had significant correlations with high-density lipoprotein cholesterol (P < .001), and with triglycerides (P = .015). CONCLUSION: ATI showed good feasibility and diagnostic performance in the detection of varying degrees of hepatic steatosis in NAFLD patients.

Clinical application of preoperative shear wave dispersion for prediction of post liver failure in patients with hepatocellular carcinoma after hepatectomy.

OBJECTIVE: The aim in this study was to determine the efficacy of shear wave dispersion (SWD) technique for the prediction of post hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma after hepatectomy and develop an SWD based risk prediction model. METHODS & MATERIALS: We prospectively enrolled 205 consecutive patients who were scheduled to undergo hepatectomy for hepatocellular carcinoma (HCC), pre-operative SWD examination, laboratory data and some other clinicopathological tests were collected. The risk factors of PHLF were identified according to univariate and multivariate analysis, a predictive model was established based on logistic regression analyses. RESULTS: SWD examination was successfully performed in 205 patients. PHLF occurred in 51 patients (24.9%), including 37/11/3 patients with Grade A/B/C, respectively. There was a high correlation between SWD value of liver and liver fibrosis stage (r = 0.873, p < 0.05). Patients with PHLF has a higher median SWD value of liver than patients without PHLF [17.4 vs 14.7 (m/s)/kHz, p < 0.05]. The SWD value of liver, total bilirubin (TB), international normalized ratio of prothrombin time (INR) and splenomegaly were significantly related to PHLF based on the multivariate analysis. A new prediction model (PM) for PHLF was established (PM = -12.918 + 0.183× SWD + 6.668× INR +0.100×TB+1.240×splenomegaly). The optimal cutoff value of SWD for predicting PHLF was 16.7 (m/s)/kHz. The area under the curve (AUC) of the PM for PHLF was 0.833, which was higher than that of SWD, INR, Forns, FIB4, APRI (p < 0.005, respectively). CONCLUSION: SWD is a promising and reliable method for PHLF prediction in patients with HCC who were undergoing hepatectomy. Compared with SWD, Forns, APRI and FIB-4, PM demonstrate better efficacy for preoperative PHLF prediction.

Comparison of contrast-enhanced ultrasound, IOTA simple rules and O-RADS for assessing the malignant risk of sonographically appearing solid ovarian masses.

PURPOSE: To explore the diagnostic accuracy of ovarian solid tumors by 2D ultrasound and contrast-enhanced ultrasound (CEUS). MATERIALS AND METHODS: We retrospectively evaluated the CEUS characteristics of prospectively enrolled 16 benign and 19 malignant ovarian solid tumors. We performed International Ovarian Tumor Analysis (IOTA) simple rules and Ovarian-Adnexal Reporting and Data System (O-RADS) for all lesions, and evaluated their characteristics on CEUS. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of IOTA simple rules, O-RADS and CEUS in the diagnosis of ovarian solid malignancies were calculated. RESULTS: The combination of time to wash-in earlier than or equal to the myometrium, time to PI earlier than or equal to the myometrium and the intensity at peak were higher than or equal to myometrium with sensibility of 0.947, specificity of 0.938, and PPV of 0.947, NPV of 0.938 which were higher than IOTA simple rules and O-RADS. According to the definition of ovarian solid tumor, the diagnostic accuracy of O-RADS 3 and CEUS were both 100%, CEUS improved the accuracy of O-RADS 4 from 47.4% to 87.5%, the accuracy of solid smooth CS 4 in O-RADS 5 and CEUS were both 100%, CEUS improved the accuracy of solid irregular in O-RADS 5 from 70% to 87.5%. CONCLUSION: For ovarian solid tumors that are difficult to distinguish between benign and malignant, the introduction of CEUS on the basis of 2D classification criteria can significantly improve the diagnostic accuracy.

A Comparative Study of Ultrasound Attenuation Imaging, Controlled Attenuation Parameters, and Magnetic Resonance Spectroscopy for the Detection of Hepatic Steatosis.

OBJECTIVES: To investigate the methodology and clinical application of ultrasound attenuation imaging (ATI) and comparative analyze the diagnostic performance of ATI and controlled attenuation parameters (CAP) for detecting and grading hepatic steatosis. METHODS: A total of 159 patients with NAFLD were prospectively enrolled. CAP and ATI examinations were performed within a week before proton magnetic resonance spectroscopy (1 H-MRS). Ten liver attenuation coefficient (AC) measurements by ATI were obtained in each patient. The interclass correlation coefficients (ICCs) of the intraobserver consistencies and the ICCs between the median of the first two through the first nine measurements and all 10 measurements were calculated. The correlations between 1 H-MRS, CAP, biological data, and ATI were evaluated. The significant factors associated with ATI and the diagnostic performance of ATI and CAP for detecting hepatic steatosis was evaluated. RESULTS: The median value of AC for detecting hepatic steatosis was 0.831 dB/cm/MHz. For the intraobserver consistency of ATI, the ICC was 0.931. Compared with 10 measurements, a minimum of four ATI measurements was required. The correlation of AC with hepatic fat fraction (HFF) was significantly higher than that of CAP (0.603 vs 0.326, P = .0015). The HFF and triglyceride (TG) were the significant factors for the ATI. The area under the receiver operating characteristics (ROC) curves of ATI and CAP were 0.939 and 0.788 for detecting ≥10% hepatic steatosis; 0.751 and 0.572 for detecting >33% hepatic steatosis. The cutoff values of ATI and CAP were 0.697 dB/cm/MHz and 310 dB/m for detecting ≥10% hepatic steatosis; 0.793 dB/cm/MHz and 328 dB/m for detecting >33% hepatic steatosis. The sensitivity of ATI and CAP were 85.92% and 52.11% for detecting ≥10% hepatic steatosis; 87.50% and 82.14% for detecting >33% hepatic steatosis. The specificity of ATI and CAP were 94.12% and 100% for detecting ≥10% hepatic steatosis; 54.37% and 43.69% for detecting >33% hepatic steatosis. CONCLUSIONS: ATI technology showed excellent intraobserver consistency and the optimal minimum number of ATI measurements was 4. ATI is a promising noninvasive, quantitative and convenient tool for assessing hepatic steatosis.

Computed Tomography Evaluation of In Vivo Pulmonary Cryoablation Zone Sizes.

PURPOSE: To evaluate ablation zone sizes in patients undergoing pulmonary tumor cryoablation with 14-gauge cryoablation probes. MATERIALS AND METHODS: A single-center retrospective analysis of all consecutive patients who underwent cryoablation of pulmonary tumors with 1 or more 14-gauge probes (August 2017 to June 2020) was performed. Intraprocedural and 1-2-month postprocedural chest computed tomography (CT) scans were evaluated to characterize pulmonary lesions, ice balls, and ablation zones. Single-probe 14-gauge ablation zone volumes were compared with manufacturer reference isotherms and single- and 2-probe ablation zones from a prior investigation of 17-gauge probes. Overall survival and local recurrence-free survival were calculated to 3 years. RESULTS: Forty-seven pulmonary malignancies in 42 patients (women, 50%; mean age, 75.2 years ± 11.5) underwent cryoablation with 1 (n = 35), 2 (n = 10), or 3 (n = 2) cryoablation probes. One- to 2-month follow-up CT images were available for 30 of the 42 patients. The mean cryoablation zone volumes at 1-2 months when 1 (n = 21), 2 (n = 8), and 3 (n = 1) probes were used were 5.0 cm3 ± 2.3, 37.5 cm3 ± 20.5, and 28.4 cm3, respectively. The mean single-probe follow-up ablation zone volume was larger than that previously reported for 17-gauge probes (3.0 cm3 ± 0.3) (P < .001) but smaller than manufacturer-reported isotherms (11.6 cm3 for -40 °C isotherm) and the 2-probe ablation zone volume with 17-gauge devices (12.9 cm3 ± 2.4) (for all, P < 001). The 3-year overall survival and local recurrence-free survival were 69% (95% confidence interval [CI], 53%-89%) and 87% (95% CI, 74%-100%), respectively. CONCLUSIONS: Fourteen-gauge probes generate larger ablation volumes than those generated by 17-gauge probes. Manufacturer-reported isotherms are significantly larger than actual cryoablation zones. Cryoablation can attain low rates of local recurrence.

Impact of Cerebrospinal Fluid Sample Handling on Cytokine Detection Results.

OBJECTIVE: To investigate the impact of different treatment methods on cerebrospinal fluid (CSF) cytokine detection. METHODS: CSF samples were collected from 25 patients. The levels of IL-6, IL-10, IFN-γ, and IL-2 were measured after CSF was stored at room temperature (25°C) or 4°C for 6, 12, and 24 hrs. The CSF was frozen at -80°C, thawed at room temperature for 1 hr every 8 hrs and then frozen. This process was repeated three times in a row, and then cytokine levels in CSF were detected again. RESULTS: The four cytokines were stable when the CSF was kept at room temperature for 6 hrs. After 12 hrs of storage, the levels of the four cytokines decreased, and the changes in IL-6 and IL-10 levels were statistically significant. After 24 hrs of storage, the levels of the four cytokines were further reduced, and the changes were statistically significant. Cytokines were stable when CSF was stored at 4°C, and only IL-10 exhibited statistically significant changes when stored for 24 hrs. IL-6, IL-10 IFN-γ, and IL-2 were stable in CSF samples after three freeze-thaw cycles. CONCLUSION: The stability of CSF cytokines is poor after storage at room temperature and good after storage at 4°C. Therefore, cytokine detection should be carried out after CSF collection as often as possible. If the detection cannot be done quickly enough, the specimens should be stored in cold storage for no more than 24 hrs.

Prediction of Microvascular Invasion in Combined Hepatocellular-Cholangiocarcinoma Based on Pre-operative Clinical Data and Contrast-Enhanced Ultrasound Characteristics.

The goal of the study described here was to define the predictive value of pre-operative clinical information and contrast-enhanced ultrasound (CEUS) imaging characteristics in combined hepatocellular-cholangiocarcinoma (CHC) patients with microvascular invasion (MVI). Seventy-six patients with pathologically confirmed CHC were enrolled in this study, comprising 18 patients with MVI-positive status and 58 with MVI-negative CHC nodules. The pre-operative clinical data and CEUS imaging features were retrospectively analyzed. Univariate and multivariate analyses were performed to identify the potential predictors of MVI in CHC. Recurrence-free survival (RFS) after hepatectomy was compared between patients with different MVI status using the log-rank test and Kaplan-Meier survival curves. Univariate analysis indicated that the following parameters of patients with CHC significantly differed between the MVI-positive and MVI-negative groups (p<0.05): tumor size, α-fetoprotein ≥400 ng/mL, enhancement patterns in arterial phase and marked washout during the portal venous phase on CEUS. On multivariate logistic regression analysis, only the CEUS characteristics of heterogeneous enhancement (odds ratio = 6.807; 95% confidence interval [CI]: 1.099, 42.147; p = 0.039) and marked washout (odds ratio = 4.380; 95% CI: 1.050,18.270; p = 0.043) were identified as independent predictors of MVI in CHC. The combination of the two risk factors in predicting MVI achieved a better diagnostic performance than each parameter alone, with an area under the receiver operating characteristic curve of 0.736 (0.622, 0.830). After hepatectomy, CHC patients with MVI exhibited earlier recurrence compared with those without MVI (hazard ratio = 1.859; 95% CI: 0.8699-3.9722, p = 0.046). The CEUS imaging features of heterogeneous enhancement in the arterial phase and marked washout during the portal venous phase were the potential predictors of MVI in CHC. Aside from that, CHC patients with MVI had an earlier recurrence rate than those without MVI after surgery.

Diagnostic Value of Tumor Markers in Peritoneal Lavage Fluid for Peritoneal Metastasis from Colorectal Cancer.

OBJECTIVE: To investigate the diagnostic value of tumor markers in peritoneal lavage fluid in the diagnosis of peritoneal metastasis from colorectal cancer. METHODS: One hundred eighty-six patients with colorectal cancer and 15 patients with benign disease who underwent surgical treatment were included. The abdominal cavity and pelvis of the patients were lavaged with 200 ml of normal saline immediately after abdominal cavity incision or pneumoperitoneum establishment. Five milliliters of lavage fluid was collected for peritoneal lavage fluid tumor marker detection (pCEA, pCA19-9, pCA125 and pCA724), and another 100 ml of lavage fluid was collected for cytological examination. RESULTS: There were 13 patients with abdominal and pelvic nodules found intraoperatively and confirmed by postoperative pathology as peritoneal metastasis, and 24 patients were cytologically peritoneal lavage-positive, with a positivity rate of 12.9%. Peritoneal metastasis from colorectal cancer was related to tumor T stage, N stage, and serum CEA and CA19-9 elevation. Peritoneal lavage fluid tumor markers had diagnostic value for patients with and without peritoneal metastasis from colorectal cancer, and the differences were statistically significant (P<0.05). Among them, pCA19-9 had the highest area under the curve (AUC), with 84.62% sensitivity and 85.19% specificity at the cutoff value. pCA19-9 had diagnostic value for peritoneal micrometastasis from colorectal cancer (P<0.05), with an AUC of 0.72. CONCLUSION: T stage, N stage, and serum CEA and CA19-9 elevation are associated with peritoneal metastasis from colorectal cancer. Peritoneal lavage fluid tumor markers have diagnostic value for peritoneal metastasis from colorectal cancer, among which pCA19-9 has the highest diagnostic value.

Comparison of Non-Tumoral Portal Vein Thrombosis Management in Cirrhotic Patients: TIPS Versus Anticoagulation Versus No Treatment.

BACKGROUND: There is a lack of consensus in optimal management of portal vein thrombosis (PVT) in patients with cirrhosis. The purpose of this study is to compare the safety and thrombosis burden change for cirrhotic patients with non-tumoral PVT managed by transjugular intrahepatic portosystemic shunt (TIPS) only, anticoagulation only, or no treatment. METHODS: This single-center retrospective study evaluated 52 patients with cirrhosis and non-tumoral PVT managed by TIPS only (14), anticoagulation only (11), or no treatment (27). The demographic, clinical, and imaging data for patients were collected. The portomesenteric thrombosis burden and liver function tests at early follow-up (6-9 months) and late follow-up (9-16 months) were compared to the baseline. Adverse events including bleeding and encephalopathy were recorded. RESULTS: The overall portomesenteric thrombosis burden improved in eight (72%) TIPS patients, three (27%) anticoagulated patients, and two (10%) untreated patients at early follow-up (p = 0.001) and in seven (78%) TIPS patients, two (29%) anticoagulated patients, and three (17%) untreated patients in late follow-up (p = 0.007). No bleeding complications attributable to anticoagulation were observed. CONCLUSION: TIPS decreased portomesenteric thrombus burden compared to anticoagulation or no treatment for cirrhotic patients with PVT. Both TIPS and anticoagulation were safe therapies.

Differentiation between hepatocellular carcinoma and intrahepatic cholangiocarcinoma using contrast-enhanced ultrasound: A systematic review and meta-analysis.

AIM: To explore the diagnostic ability of contrast-enhanced ultrasound (CEUS) in distinguishing intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC). MATERIALS AND METHODS: PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched for studies reporting the diagnostic accuracy of CEUS in differentiating ICC from HCC. The diagnostic ability of CEUS was assessed based on the pooled sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and area under the curve (AUC) with 95% confidence intervals (CIs). The methodologic quality was assessed by the QUADAS-2 tool. Subgroup analyses, meta-regression and investigation of publication bias were performed to identify the source of heterogeneity. RESULTS: A total of eight studies were included, consisting of 1,116 patients with HCC and 529 with ICC. The general diagnostic performance of CEUS in distinguishing ICC and HCC were as follows: pooled sensitivity, 0.92 (95% CI: 0.84-0.96); pooled specificity, 0.87 (95% CI: 0.79-0.92); pooled PLR, 7.1 (95% CI: 4.1-12.0); pooled NLR, 0.09 (95% CI: 0.05-0.19); pooled DOR, 76 (95% CI: 26-220) and AUC, 0.95 (95% CI: 0.93-0.97). Different liver background may be a potential factor that influenced the diagnostic accuracy of CEUS according to the subgroup analysis, with the pooled DOR of 89.67 in the mixed liver background group and 46.87 in the cirrhosis group, respectively. Six informative CEUS features that may help differentiate HCC from ICC were extracted. The three CEUS features favoring HCC were arterial phase hyperenhancement (APHE), mild washout and late washout (>60s); the three CEUS favoring ICC were arterial rim enhancement, marked washout and early washout (<60s). No potential publication bias was observed. CONCLUSION: CEUS showed great diagnostic ability in differentiating ICC from HCC, which may be promising for noninvasive evaluation of these diseases.

Imaging findings of fibrolamellar hepatocellular carcinomas on ultrasonography: A comparison with conventional hepatocellular carcinomas.

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLHCC) is an unusual variant of hepatocellular carcinoma (HCC). Revealing the imaging features is important to the diagnosis of FLHCC. OBJECTIVE: The aim of this study was to investigate the imaging characteristics of FLHCCs. METHODS: This retrospective study included 29 patients with histopathologically proved FLHCC and 96 patients proved HCC. All patients underwent an ultrasound examination pre-operation. RESULTS: The average maximum diameters of the FLHCC and HCC lesions were 7.4±4.1 cm and 4.1±3.0 cm, respectively. On the ultrasound, 79.3% of the FLHCCs and 12.3% of the HCCs showed the internal hyperechoic area; 48.3% of the FLHCCs and 3.3% of the HCCs displayed a strip-like attenuation. Calcification was noted in 20.7% of the FLHCCs, while none in HCCs. On the contrast-enhanced ultrasound (CEUS), all FLHCC lesions and 87.7% of the HCCs displayed hyperenhancement in the arterial phase. An internal, unenhanced central scar appeared in all FLHCCs, while none in HCCs. CONCLUSIONS: The ultrasonographic features of FLHCC lesions indicate that they are relatively large masses showing the internal hyperechoic area or strip-like attenuation or calcification on the US and hypervascularity with an unenhanced central scar on the CEUS as compared with conventional HCC lesions.

Wnt/ß-catenin signaling contributes to prostate cancer heterogeneity through reciprocal suppression of H3K27 trimethylation.

Intratumoral heterogeneity remains as a major challenge in the treatment resistance of prostate cancer. Understanding the mechanism of prostate cancer heterogeneity is essential for developing effective therapies. In this study, we reported the heterogeneous activation of Wnt/ß-catenin signaling in prostate cancer. We developed a Wnt/ß-catenin signaling reporting system to directly characterize the differences between Wnt/ß-catenin signaling active (GFP+) and inactive (GFP-) cells. Compared to GFP- cells, GFP+ cells demonstrated cancer stem cell properties with higher colony formation efficiency, slower cell cycle, higher resistance to docetaxel and higher expression of cancer stem cell markers. In addition, we found that Wnt/ß-catenin signaling is negatively correlated with H3K27me3 levels. Further studies demonstrated that Wnt/ß-catenin signaling affected H3K27me3 levels by regulating the expression of KDM6A, one of the H3K27me3 demethylases. H3K27me3 suppressed Wnt/ß-catenin signaling by directly silencing LEF1 promoter. Together, our studies suggest that Wnt/ß-catenin signaling makes a major contribution to prostate cancer heterogeneity and targeting both Wnt/ß-catenin signaling active and inactive populations is essential for developing more effective therapies.

Transfer learning radiomics based on multimodal ultrasound imaging for staging liver fibrosis.

OBJECTIVES: To propose a transfer learning (TL) radiomics model that efficiently combines the information from gray scale and elastogram ultrasound images for accurate liver fibrosis grading. METHODS: Totally 466 patients undergoing partial hepatectomy were enrolled, including 401 with chronic hepatitis B and 65 without fibrosis pathologically. All patients received elastography and got liver stiffness measurement (LSM) 2-3 days before surgery. We proposed a deep convolutional neural network by TL to analyze images of gray scale modality (GM) and elastogram modality (EM). The TL process was used for liver fibrosis classification by Inception-V3 network which pretrained on ImageNet. The diagnostic performance of TL and non-TL was compared. The value of single modalities, including GM and EM alone, and multimodalities, including GM + LSM and GM + EM, was evaluated and compared with that of LSM and serological indexes. Receiver operating characteristic curve analysis was performed to calculate the optimal area under the curve (AUC) for classifying fibrosis of S4, ≥ S3, and ≥ S2. RESULTS: TL in GM and EM demonstrated higher diagnostic accuracy than non-TL, with significantly higher AUCs (all p < .01). Single-modal GM and EM both performed better than LSM and serum indexes (all p < .001). Multimodal GM + EM was the most accurate prediction model (AUCs are 0.950, 0.932, and 0.930 for classifying S4, ≥ S3, and ≥ S2, respectively) compared with GM + LSM, GM and EM alone, LSM, and biomarkers (all p < .05). CONCLUSIONS: Liver fibrosis can be staged by a transfer learning modal based on the combination of gray scale and elastogram ultrasound images, with excellent performance. KEY POINTS: • Transfer learning consists in applying to a specific deep learning algorithm that pretrained on another relevant problem, expected to reduce the risk of overfitting due to insufficient medical images. • Liver fibrosis can be staged by transfer learning radiomics with excellent performance. • The most accurate prediction model of transfer learning by Inception-V3 network is the combination of gray scale and elastogram ultrasound images.