Diagnostic performance of transient elastography in differentiation between porto-sinusoidal vascular liver disease and compensated cirrhosis.

BACKGROUND AND AIMS: The efficacy of transient elastography (TE) in the differential diagnosis between porto-sinusoidal vascular disease (PSVD) and compensated cirrhosis has not been sufficiently studied. We aimed to investigate the diagnostic performance of TE and identify histological lesions associated with liver stiffness. METHODS: We conducted a retrospective cohort study including patients with PSVD and cirrhosis (Child-Turcotte-Pugh class A) and healthy subjects. Both the PSVD and cirrhotic patients had at least one sign of PH. The area under the receiver operating characteristic curve (AUROC) was used for differentiation. RESULTS: Ninety-two patients with PSVD (median age: 53 years, 33% male), 100 patients with compensated cirrhosis and 101 healthy subjects were included. The median TE-LSM in the PSVD patients (10.0 [7.0-13.0] kPa) was significantly lower than that in the cirrhotic patients (21.0 [15.0-28.0] kPa, p < .001) but was significantly higher than that in the healthy subjects (5.1 [4.6-6.0] kPa, p < .001). The AUROCs of TE-LSM for the discrimination of PSVD from the cirrhosis and healthy subjects were 0.886 (95% CI: 0.833-0.928) and 0.913 (95% CI: 0.864-0.949), respectively. The sensitivity and specificity to discriminate PSVD from compensated cirrhosis were 78.3% and 82.0%, respectively, at a cut-off of 13.6 kPa. Furthermore, portal fibrosis and aberrant cytokeratin 7 expression of centrilobular hepatocytes were significantly associated with higher TE-LSM (≥10.0 kPa). CONCLUSION: TE-LSM can be used to differentiate PSVD from compensated cirrhosis. Pathological features in association with increased liver stiffness are identified.

Enhanced CycleGAN Network with Adaptive Dark Channel Prior for Unpaired Single-Image Dehazing.

Unpaired single-image dehazing has become a challenging research hotspot due to its wide application in modern transportation, remote sensing, and intelligent surveillance, among other applications. Recently, CycleGAN-based approaches have been popularly adopted in single-image dehazing as the foundations of unpaired unsupervised training. However, there are still deficiencies with these approaches, such as obvious artificial recovery traces and the distortion of image processing results. This paper proposes a novel enhanced CycleGAN network with an adaptive dark channel prior for unpaired single-image dehazing. First, a Wave-Vit semantic segmentation model is utilized to achieve the adaption of the dark channel prior (DCP) to accurately recover the transmittance and atmospheric light. Then, the scattering coefficient derived from both physical calculations and random sampling means is utilized to optimize the rehazing process. Bridged by the atmospheric scattering model, the dehazing/rehazing cycle branches are successfully combined to form an enhanced CycleGAN framework. Finally, experiments are conducted on reference/no-reference datasets. The proposed model achieved an SSIM of 94.9% and a PSNR of 26.95 on the SOTS-outdoor dataset and obtained an SSIM of 84.71% and a PSNR of 22.72 on the O-HAZE dataset. The proposed model significantly outperforms typical existing algorithms in both objective quantitative evaluation and subjective visual effect.

Hepatic Venous Occlusion Type of Budd-Chiari Syndrome versus Pyrrolizidine Alkaloid-Induced Hepatic Sinusoidal Obstructive Syndrome: A Multi-Center Retrospective Study.

(1) Background: Hepatic venous occlusion type of Budd-Chiari syndrome (BCS-HV) and pyrrolizidine alkaloid-induced hepatic sinusoidal obstructive syndrome (PA-HSOS), share similar clinical features, and imaging findings, leading to misdiagnoses; (2) Methods: We retrospectively analyzed 139 patients with BCS-HV and 257 with PA-HSOS admitted to six university-affiliated hospitals. We contrasted the two groups by clinical manifestations, laboratory tests, and imaging features for the most valuable distinguishing indicators.; (3) Results: The mean patient age in BCS-HV is younger than that in PA-HSOS (p < 0.05). In BCS-HV, the prevalence of hepatic vein collateral circulation of hepatic veins, enlarged caudate lobe of the liver, and early liver enhancement nodules were 73.90%, 47.70%, and 8.46%, respectively; none of the PA-HSOS patients exhibited these features (p < 0.05). DUS showed that 86.29% (107/124) of patients with BCS-HV showed occlusion of the hepatic vein, while CT or MRI showed that only 4.55%(5/110) patients had this manifestation (p < 0.001). Collateral circulation of hepatic veins was visible in 70.97% (88/124) of BCS-HV patients on DUS, while only 4.55% (5/110) were visible on CT or MRI (p < 0.001); (4) Conclusions: In addition to an established history of PA-containing plant exposure, local hepatic vein stenosis and the presence of collateral circulation of hepatic veins are the most important differential imaging features of these two diseases. However, these important imaging features may be missed by enhanced CT or MRI, leading to an incorrect diagnosis.

Silenced LINC01134 Enhances Oxaliplatin Sensitivity by Facilitating Ferroptosis Through GPX4 in Hepatocarcinoma.

Purpose: Recently, long noncoding RNA LINC01134 has been shown to reduce cell viability and apoptosis via the antioxidant stress pathway, thereby enhancing OXA resistance in hepatocellular carcinoma. However, the association of LINC01134 with ferroptosis and the underlying molecular mechanisms remain to be elucidated. Methods: Bioinformatics analysis was employed to screen lncRNAs positively correlated with GPX4 and poor clinical prognosis. And Western blot and RT-PCR analysis in HCC cells confirmed the effect of LINC01134 on GPX4 expression. In addition, LINC01134 siRNA was transfected in HCC cells to detect the changes in cell viability, ROS, lipid peroxidation, MDA levels and GSH/GSSG levels. CCK-8, colony formation and apoptosis assays were performed to determine the effect of LINC01134 on cell death. The effect of LINC01134 and OXA on Nrf2 transcriptional binding to GPX4 was analyzed using dual luciferase reporter assay and CHIP. The expression of GPX4 and Nrf2 in HCC tissues was detected by FISH and IHC. Results: LINC01134 is a novel lncRNA positively correlated with GPx4 and associated with poor clinical prognosis. Silenced LINC01134 conferred OXA sensitivity by enhancing total ROS, lipid ROS, MDA levels and decreasing GSH/GSSG ratio. Mechanistically, LINC01134 and OXA could promote Nrf2 recruitment to the GPX4 promoter region to exert transcriptional regulation of GPX4. Clinically, LINC01134 was positively correlated with GPX4 or Nrf2, demonstrating the clinical significance of LINC01134, Nrf2 and GPX4 in OXA resistance of HCC. Conclusions: We identified LINC01134/Nrf2/GPX4 as a novel and critical axis to regulate HCC growth and progression. Targeting GPX4, knocking down LINC01134 or Nrf2 could be a potential therapeutic strategy for HCC.

Multi-organ metastasis as destination for breast cancer cells guided by biomechanical architecture.

A majority of breast cancer patients die of widespread aggressive multidrug-resistant tumors. Aspartate ß-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase and oncofetal antigen involved in embryogenesis. To illustrate if ASPH could be targeted for metastatic breast cancer, embedded and on-top three-dimensional (3-D) cultures, 3-D invasion, mammosphere formation, immunofluorescence, immunohistochemistry, Western blot, co-IP and microarray were conducted. In vitro metastasis was developed to imitate how cancer cells invade basement membrane at the primary site, transendothelially migrate, consequently colonize and outgrow at distant sites. Orthotopic and experimental pulmonary metastatic (tail vein injection) murine models were established using stable breast cancer cell lines. Cox proportional hazards regression models and Kaplan-Meier plots were applied to assess clinical outcome of breast cancer patients. In adult non-cancerous breast tissue, ASPH is undetectable. Pathologically, ASPH expression re-emerged at ductal carcinoma in situ (DCIS), and enhanced with disease progression, from early-stage invasive ductal carcinoma (IDC) to late-stage carcinoma. ASPH at moderate to high levels contribute to aggressive molecular subtypes, early relapse or more frequent progression and metastases, whereas substantially shortened overall survival and disease-free survival of breast cancer patients. Through direct physical interactions with A disintegrin and metalloproteinase domain-containing protein (ADAM)-12/ADAM-15, ASPH could activate SRC cascade, thus upregulating downstream components attributed to multifaceted metastasis. ASPH-SRC axis initiated pro-invasive invadopodium formation causing breakdown/disorganization of extracellular matrix (ECM), simultaneously potentiated epithelial-mesenchymal transition (EMT), induced cancer stem cell markers (CD44 and EpCAM), enhanced mammosphere formation and intensified 3-dimentional invasion. Oncogenic SRC upregulated matrix metallopeptidases (MMPs) were assembled by invadopodia, acting as executive effectors for multi-step metastasis. ASPH-SRC signal guided multi-organ metastases (to lungs, liver, bone, spleen, lymph nodes, mesentery or colon) in immunocompromised mice. Malignant phenotypes induced by ASPH-SRC axis were reversed by the third-generation small molecule inhibitor (SMI) specifically against ß-hydroxylase activity of ASPH in pre-clinical models of metastatic breast cancer. Collectively, ASPH could activate ADAMs-SRC-MMPs cascades to promote breast cancer tumor progression and metastasis. ASPH could direct invadopodium construction as a biomechanical sensor and pro-metastatic outlet. ASPH-mediated cancer progression could be specifically/efficiently subverted by SMIs of ß-hydroxylase activity. Therefore, ASPH emerges as a therapeutic target for breast cancer.

Accurate ultrasonography-based portal pressure assessment in patients with hepatocellular carcinoma.

BACKGROUND: Portal pressure is of great significance in the treatment of hepatocellular carcinoma (HCC), but direct measurement is complicated and costly; thus, non-invasive measurement methods are urgently needed. AIM: To investigate whether ultrasonography (US)-based portal pressure assessment could replace invasive transjugular measurement. METHODS: A cohort of 102 patients with HCC was selected (mean age: 54 ± 13 years, male/female: 65/37). Pre-operative US parameters were assessed by two independent investigators, and multivariate logistic analysis and linear regression analysis were conducted to develop a predictive formula for the portal pressure gradient (PPG). The estimated PPG predictors were compared with the transjugular PPG measurements. Validation was conducted on another cohort of 20 non-surgical patients. RESULTS: The mean PPG was 17.32 ± 1.97 mmHg. Univariate analysis identified the association of the following four parameters with PPG: Spleen volume, portal vein diameter, portal vein velocity (PVV), and portal blood flow (PBF). Multiple linear regression analysis was performed, and the predictive formula using the PVV and PBF was as follows: PPG score = 19.336 - 0.312 × PVV (cm/s) + 0.001 × PBF (mL/min). The PPG score was confirmed to have good accuracy with an area under the curve (AUC) of 0.75 (0.68-0.81) in training patients. The formula was also accurate in the validation patients with an AUC of 0.820 (0.53-0.83). CONCLUSION: The formula based on ultrasonographic Doppler flow parameters shows a significant correlation with invasive PPG and, if further confirmed by prospective validation, may replace the invasive transjugular assessment.

Transjugular intrahepatic portosystemic shunt and splenectomy are more effective than endoscopic therapy for recurrent variceal bleeding in patients with idiopathic noncirrhotic portal hypertension.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS), splenectomy plus esophagogastric devascularization (SED) and endoscopic therapy + non-selective ß-blockers (ET + NSBB) are widely applied in secondary prevention of recurrent gastroesophageal variceal bleeding in patients with liver cirrhosis. These different treatments, however, have not been compared in patients with idiopathic non-cirrhotic portal hypertension (INCPH). AIM: To compare the outcomes of TIPS, SED and ET + NSBB in the control of variceal rebleeding in patients with INCPH. METHODS: This retrospective study recruited patients from six centers across China. Demographic characteristics, baseline profiles and follow-up clinical outcomes were collected. Post-procedural clinical outcomes, including incidence of rebleeding, hepatic encephalopathy (HE), portal vein thrombosis (PVT) and mortality rates, were compared in the different groups. RESULTS: In total, 81 patients were recruited, with 28 receiving TIPS, 26 SED, and 27 ET + NSBB. No significant differences in demographic and baseline characteristics were found among these three groups before the procedures. After treatment, blood ammonia was significantly higher in the TIPS group; hemoglobin level and platelet count were significantly higher in the SED group (P < 0.01). Rebleeding rate was significantly higher in the ET + NSBB group (P < 0.01). Mortality was 3.6%, 3.8% and 14.8% in the TIPS, SED and ET + NSBB groups, respectively, with no significant differences (P = 0.082). Logistic regression analysis showed that mortality was significantly correlated with rebleeding, HE, portal thrombosis and superior mesenteric vein thrombosis (P < 0.05). CONCLUSION: In patients with INCPH, TIPS and SED were more effective in controlling rebleeding than ET + NSBB, but survival rates were not significantly different among the three groups. Mortality was significantly correlated with rebleeding, HE and PVT.

Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis.

To demonstrate multifaceted contribution of aspartate ß-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's ß-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.

ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis.

BACKGROUND: Aspartate ß-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer. METHODS: Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied. RESULTS: Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH's ß-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis. CONCLUSIONS: ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH's pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.

Hepatic amyloidosis leading to hepatic venular occlusive disease and Budd-Chiari syndrome: A case report.

BACKGROUND: Systemic amyloidosis in which multiple systems can be involved has become a common clinical disease. When the liver is affected, symptoms such as abdominal distension, fatigue, edema, liver, and jaundice could appear. To date, hepatic amyloidosis combined with hepatic venular occlusive disease and Budd-Chiari syndrome has not been reported. CASE SUMMARY: A 54-year-old female patient was admitted to the Beijing Shijitan Hospital with hepatic amyloidosis leading to hepatic venular occlusion and Budd-Chiari syndrome in 2018. The patient underwent surgery 1 mo previously for liver rupture and hemorrhage after Budd-Chiari syndrome was diagnosed. She was diagnosed with hepatic venular occlusion, liver amyloidosis, and Budd-Chiari syndrome (i.e. extensive hepatic vein occlusion). Transjugular intrahepatic portosystem shunt was performed. After the treatment, the clinical symptoms improved markedly with increase in urine volume. CONCLUSION: Hepatic amyloidosis with hepatic venous occlusion and Budd-Chiari syndrome is relatively rare clinically, and transjugular intrahepatic portosystem shunt is an effective treatment for this disease.

Safety and efficacy of transfemoral intrahepatic portosystemic shunt for portal hypertension: A single-center retrospective study.

BACKGROUND: Transfemoral intrahepatic portosystemic shunt (TFIPS) can be performed to treat portal hypertension. However, few studies have evaluated the safety and efficacy of this technique. AIM: To retrospectively evaluate the safety and clinical outcomes of TFIPS and compare them with those of typical transjugular intrahepatic portosystemic shunt (TIPS). METHODS: This retrospective study was approved by our hospital ethics committee. From November 2012 to November 2015, 19 patients who underwent successful TFIPS placement were included. In addition, 21 patients treated with TIPS during the same period were selected as controls. Data collected included the success rate and complications of TIPS and TFIPS. Continuous data were expressed as the mean ± SD and were compared using the Student's t test. All categorical data were expressed as count (percentage) and were compared using the χ 2 test or Fisher's exact test. The Kaplan-Meier method was used to calculate cumulative survival rate and survival curves. RESULTS: Baseline characteristics were comparable between the two groups. The success rate of TFIPS and TIPS was 95% (19/20) and 100% (21/21), respectively. Effective portal decompression and free antegrade shunt flow was completed in all patients. The portal pressure gradient prior to TIPS and TFIPS placement was 23.91 ± 4.64 mmHg and 22.61 ± 5.39 mmHg, respectively, and it was significantly decreased to 10.85 ± 3.33 mmHg and 10.84 ± 3.33 mmHg after stent placement, respectively. Time-to-event calculated rates of shunt patency at one and two years in the TFIPS and TIPS groups were not statistically different (94.7% vs 95.2% and 94.7% vs 90.5%, respectively). De nova hepatic encephalopathy was 27.5% (11/40) with five patients in the TFIPS group (26.3%) and six patients (28.6%) in the TIPS group experiencing it (P = 0.873). The cumulative survival rates were similar between the two groups: 94.7% and 94.7% at 1 and 2 years, respectively, in the TFIPS group vs 100% and 95.2% at 1 and 2 years, respectively, in the TIPS group (P = 0.942). CONCLUSION: TFIPS may be a valuable adjunct to traditional approaches in patients with portal hypertension.

Iodine-125 implantation with transjugular intrahepatic portosystemic shunt for main portal vein tumor thrombus.

BACKGROUND: Main portal vein tumor thrombus (MPVTT), which has a high incidence, is the major complication of terminal liver cancer. The occurrence of MPVTT is always a negative prognostic factor for patients with hepatocellular carcinoma (HCC). Therefore, attention should be paid to the treatment of MPVTT and its complications. AIM: To evaluate the efficacy of transarterial chemoembolization/transarterial embolization (TACE/TAE)+125I seeds implantation with transjugular intrahepatic portosystemic shunt (TIPS) in treating MPVTT and its complications. METHODS: From January 2007 to March 2015, 85 consecutive patients with MPVTT were nonrandomly assigned to undergo treatment with TACE/TAE + TIPS and 125I implantation (TIPS-125I group) or TACE/TAE + TIPS only (TIPS only group) in Beijing Shijitan Hospital, and all clinical data were collected. During 24 mo follow-up, the incidence of overall survival, stent stenosis and symptom recurrence was analyzed to evaluate the efficacy of TIPS-125I. RESULTS: During 24 mo follow-up of all patients, we collected data at 6, 12 and 24 mo. The rates of survival were 80%, 45%, and 20%, respectively, in the TIPS-125I group, whereas those in the TIPS only group were 64.4%, 24.4%, and 4.4%, respectively (P < 0.05). The rates of symptom recurrence were 7.5%, 22.5%, and 35%, respectively, in the TIPS-125I group, whereas those in the TIPS only group were 31.1%, 62.2%, and 82.2% (P < 0.05). The rates of stent restenosis were 12.5%, 27.5%, and 42.5%, respectively, in the TIPS-125I group, and 42.2%, 68.9%, and 84.4%, respectively, in the TIPS only group (P < 0.05). TIPS-125I was found to be significantly favorable in treating MPVTT and its complications in patients with HCC. CONCLUSION: TACE/TAE+125I combined with TIPS is effective in treating MPVTT and its complications, improving quality of life of patients and reducing mortality.

Correlation analysis of collagen proportionate area in Budd-Chiari syndrome: A preliminary clinicopathological study.

BACKGROUND: Collagen proportionate area (CPA) is an important index for assessing the severity of liver fibrosis. Budd-Chiari syndrome can frequently progress to liver fibrosis and cirrhosis. CPA might play an important role in the pathological progress of Budd-Chiari syndrome. AIM: To explore the role of CPA in predicting the outcomes of patients with Budd-Chiari syndrome. METHODS: Nine patients with Budd-Chiari syndrome undergoing transjugular intrahepatic portosystemic shunt (TIPS) were included. The median CPA level and correlation of CPA and prognosis of TIPS were determined. RESULTS: Median CPA was 23.07% (range: 0%-40.20%). Pearson's χ2 test demonstrated a significant correlation of CPA with history of gastrointestinal bleeding (Pearson's coefficient: 0.832, P = 0.005), alanine aminotransferase (Pearson's coefficient: -0.694, P = 0.038), and prothrombin time (Pearson's coefficient: 0.68, P = 0.044). Although CPA was not significantly correlated with shunt dysfunction or hepatic encephalopathy after TIPS, the absolute CPA was relatively larger in patients who developed shunt dysfunction or hepatic encephalopathy after TIPS. CONCLUSION: This preliminary clinicopathological study found a marginal effect of CPA on the outcomes of Budd-Chiari syndrome patients treated with TIPS.

Aspartate ß-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway.

BACKGROUND: Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate ß-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis. METHODS: To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH's ß-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models. RESULTS: ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0-2 (n = 4), 3-5 (n = 8), 6-8 (n = 24), and 9-12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001). CONCLUSION: Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.

Iodine density Changes in Hepatic and Splenic Parenchyma in Liver Cirrhosis with Dual Energy CT (DECT): A Preliminary Study.

PURPOSE: To investigate the hemodynamic changes in liver cirrhosis by comparing iodine density in hepatic and splenic parenchyma with 8 cm detector dual energy CT (DECT). MATERIALS AND METHODS: Forty-six consecutive patients with liver cirrhosis and 22 healthy volunteers were recruited in this study, and they were all performed contrast enhanced examination with 8 cm detector DECT. All raw data were reconstructed with 1.25 mm slice thickness, Iodine density (in milligrams per milliliter) were measured on iodine-based material decomposition images. Quantitative indices of iodine density (ID), including normalized ID of liver parenchyma for arterial phase (NIDLAP), ID of liver parenchyma for venous phase (IDLVP), ID of splenic parenchyma for arterial phase (IDSAP), ID of splenic parenchyma for venous phase (IDSVP), ID of portal vein in venous phase (IDPVP) and Liver arterial iodine density fraction (AIF) were measured and compared between two groups. The correlation between Child-Pugh grade and other quantitative indices were calculated, with statistical significance as P<0.05. RESULTS: For all 46 liver cirrhosis patients, 10 were classified in grade A, 24 in Grade B and 12 in Grade C. Compared with control group, patients with liver cirrhosis showed (1) no statistical difference in general data (age, gender, height and weight) (all P>0.05), (2) higher iodine density of NIDLAP, IDSVP, IDPVP and AIF, and lower NIDSAP (all P<0.01), (3) NIDLAP, AIF, IDSVP and IDPVP in grade A were all lower than Grade B and C (all P<0.01). (4) AIF and NIDLAP showed positive correlation with Child-Pugh grade, with coefficient of R = 0.71 and R = 0.46, respectively. CONCLUSION: Based on iodine density measurement in DECT, it is possible to evaluate the hemodynamic changes in liver and spleen parenchyma in liver cirrhosis. Quantitative indices of AIF and NIDLAP demonstrate positive correlation with Child-Pugh grade, which accommodates potential possibility for DECT as a noninvasive tool in assessing the severity of liver cirrhosis.

Benefits of Early Treatment for Patients with Hepatic Myelopathy Secondary to TIPS: A Retrospective Study in Northern China.

Transjugular intrahepatic portosystemic shunt (TIPS) is an effective therapy for reducing portal pressure. Hepatic myelopathy (HM), a rare complication of chronic liver diseases, remains obscure in terms of treatment and prognosis. We aimed to determine an optimal treat strategy for patients with HM after TIPS. Twenty-nine patients who developed HM after TIPS were stratified by time-lapse from onset to treatment: group A (n = 16), <6 months; group B (n = 13), ≥6 months. Therapeutic measures included shunt-limiting and medical treatments. Overall survival, lower-limb muscle strength, Fugl-Meyer score, Barthel index, and serum ammonia were recorded. Median survival time in group A or B was 30 months or 16.5 months, respectively (log rank p = 0.0172). All patients in group A obtained improvement in grading of muscle strength (p < 0.0001), Fugl-Meyer score (p = 0.0021), and Barthel index (p = 0.0003), particularly male patients and those subjected to shunt-limiting. Serum ammonia levels were decreased significantly in both group A (p = 0.0007) and group B (p = 0.0007). Collectively, once HM is confirmed after TIPS, active intervention is imperative and urgent, especially within the first 6 months from onset of symptom. TIPS shunt-limiting is particularly beneficial for rehabilitation in patients with early-onset HM.

Pathological Features of Mitochondrial Ultrastructure Predict Susceptibility to Post-TIPS Hepatic Encephalopathy.

Background: Post-TIPS hepatic encephalopathy (PSE) is a complex process involving numerous risk factors; the root cause is unclear, but an elevation of blood ammonia due to portosystemic shunt and metabolic disorders in hepatocytes has been proposed as an important risk factor. Aims: The aim of this study was to investigate the impact of pathological features of mitochondrial ultrastructure on PSE via transjugular liver biopsy at TIPS implantation. Methods: We evaluated the pathological damage of mitochondrial ultrastructure on recruited patients by the Flameng classification system. A score ≤2 (no or low damage) was defined as group A, and a score >2 (high damage level) was defined as group B; routine follow-up was required at 1 and 2 years; the incidence of PSE and multiple clinical data were recorded. Results: A total of 78 cases in group A and 42 in group B completed the study. The incidence of PSE after 1 and 2 years in group B (35.7% and 45.2%, respectively) was significantly higher than that in group A (16.7% and 24.4%, respectively); the 1- and 2-year OR (95% CI) were 2.778 (1.166-6.615) and 2.565 (1.155-5.696), respectively, for groups A and B. Importantly, group B had worse incidence of PSE than group A [P=0.014, hazard ratio (95%CI): 2.172 (1.190-4.678)]. Conclusion: Aggressive damage to mitochondrial ultrastructure in liver shunt predicts susceptibility to PSE. The registration number is NCT02540382.

Transjugular intrahepatic portosystemic shunt for hepatorenal syndrome: A systematic review and meta-analysis.

BACKGROUND: Hepatorenal syndrome is a severe complication of advanced liver diseases with a dismal prognosis. AIMS: This systematic review and meta-analysis aims to explore the efficacy and safety of transjugular intrahepatic portosystemic shunt for the treatment of hepatorenal syndrome. METHOD: Publications were searched via PubMed and EMBASE databases. The pooled proportion and mean difference were calculated by using a random-effect model. RESULTS: Nine publications were included, in which 128 patients with hepatorenal syndrome were treated with transjugular intrahepatic portosystemic shunt. The pooled short-term and 1-year survival rates were 72% and 47% in type 1 hepatorenal syndrome and 86% and 64% in type 2 hepatorenal syndrome. No lethal procedure-related complications were observed. The pooled rate of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt was 49%. The pooled rate of renal function improvement after transjugular intrahepatic portosystemic shunt was 93% in type 1 hepatorenal syndrome and 83% in any type of hepatorenal syndrome. After transjugular intrahepatic portosystemic shunt, serum creatinine, blood urea nitrogen, serum sodium, sodium excretion, and urine volume were significantly improved; by comparison, serum bilirubin slightly increased, but the difference was not statistically significant. CONCLUSION: Limited evidence suggested a potential survival benefit of transjugular intrahepatic portosystemic shunt in patients with hepatorenal syndrome but with a high incidence of hepatic encephalopathy.

Stents combined with iodine-125 implantation to treat main portal vein tumor thrombus.

AIM: To evaluate the efficacy of main portal vein stents combined with iodine-125 (125I) to treat main portal vein tumor thrombus. METHODS: From January 1, 2010 to January 1, 2015, 111 patients were diagnosed with liver cancer combined with main portal vein tumor thrombus. They were non-randomly assigned to undergo treatment with transarterial chemoembolization (TACE)/transarterial embolization (TAE) + portal vein stents combined with 125I implantation (Group A) and TACE/TAE + portal vein stents only (Group B). After the operation, scheduled follow-up was performed at 6, 12 and 24 mo. The recorded information included clinical manifestations, survival rate, and stent restenosis rate. Kaplan-Meier curves, log-rank test and Cox regression were used for data analyses. RESULTS: From January 1, 2010 to January 1, 2015, 54 and 57 patients were allocated to Groups A and B, respectively. The survival rates at 6, 12 and 24 mo were 85.2%, 42.6% and 22.2% in Group A and 50.9%, 10.5% and 0% in Group B. The differences were significant [log rank P < 0.05, hazard ratio (HR): 0.37, 95%CI: 0.24-0.56]. The rates of stent restenosis were 18.5%, 55.6% and 83.3% in Group A and 43.9%, 82.5% and 96.5% in Group B. The differences were significant (log rank P < 0.05, HR: 0.42, 95%CI: 0.27-0.63). Cox regression identified that treatment was the only factor affecting survival rate in this study. CONCLUSION: Main portal vein stents combined with 125I can significantly improve survival rate and reduce the rate of stent restenosis.

Clinical efficacy of transjugular intrahepatic portosystemic shunt in the treatment of hepatopulmonary syndrome.

Transjugular intrahepatic portosystemic shunt (TIPS) reduces the portal venous pressure of patients with hepatopulmonary syndrome (HPS).To describe the patients who underwent TIPS for the treatment of HPS.A retrospective study was performed on 81 patients with HPS and gastrointestinal hemorrhage treated with TIPS. Thirty patients underwent TIPS through the main portal vein (group A), 24 through the left branch of the portal vein (group B), and 27 through the right branch of the portal vein (group C). The partial pressure of arterial oxygen (PaO2), alveolar-to-arterial oxygen partial pressure gradient (A-aPO2), oxygen saturation (SO2), and complications were recorded and compared. The survival rate for each group was calculated.The technical success rate was 100% in the 3 groups. Preoperative portal vein pressure showed no significant differences between the 3 groups, which was decreased post-TIPS operation. In group A, PaO2 and SO2 were higher in 15 days and 3 months postoperative than preoperative (P < .05), whereas A-aPO2 was lower (P < .05). No difference occurred between 12 months post- and preoperative group. In group C, PaO2 and SO2 did not alter significantly at each time point after operation (P > .05), whereas A-aPO2 decreased at 3 months (P = .041) than preoperative. In group B, all indicators at each follow-up time point after TIPS were improved significantly as compared with the preoperative group (P < .05), which showed an excellent effect on hypoxemia treatment. Although the 1-year survival rate of 3 groups of patients was 92.85%, 90.90%, and 91.67%, respectively, the rate of hepatic encephalopathy and hepatic myelopathy was 33.33% (10/30), 16.67% (4/24), and 33.33% (9/27) after TIPS.TIPS reduced the pressure of the portal vein effectively and alleviated hypoxemia in most HPS patients successfully. Thus, the left branch of the portal vein is optimal for TIPS owing to fewer complications and efficacy in improving PaO2 as compared with the main portal vein and right branch.