Correction: Numb Promotes Cell Proliferation and Correlates with Poor Prognosis in Hepatocellular Carcinoma.

[This corrects the article DOI: 10.1371/journal.pone.0095849.].

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-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.

Kinesin family member 2C aggravates the progression of hepatocellular carcinoma and interacts with competing endogenous RNA.

Kinesin family member 2C (KIF2C), a substantial mitotic regulator, has been verified to exert a malignant function in several cancers. However, its function in hepatocellular carcinoma (HCC) remains unclear. In this study, the expression profile of KIF2C in HCC was characterized through the dataset from the TCGA and clinical tissue microarrays containing 220 pairs of resected HCC tissues and adjacent nontumor tissues in our hospital. The results indicated that KIF2C was substantially higher expression in tumor tissues than adjacent nontumor tissues. High expression of KIF2C significantly correlated with large tumor (>5.0 cm) (P = .001) and implied a dismal postoperative overall survival (OS) (hazard ratio [HR] = 1.729; P = .002) in our cohort of patients. Gain and loss of function assays displayed that KIF2C promoted HCC cell proliferation, accelerated cell cycle progression, and impeded apoptosis. By bioinformatic tools and mechanistic investigation, we found that KIF2C interacted with various cell-cycle-related proteins and was significantly involved in growth-promoting pathways. KIF2C upregulated PCNA and CDC20 expression. Subsequently, we investigated the regulation of KIF2C by competing endogenous RNA and elucidated that has-miR-6715a-3p was directly bond to the 3'-untranslated region of KIF2C through dual luciferase assays, thereby inhibiting KIF2C expression. Furthermore, the long noncoding RNA GS1-358P8.4 was found to be a candidate of KIF2C for has-miR-6715a-3p binding. HCC patients with high lncRNA-GS1-358P8.4 expression had shorter OS and relapse-free survival compared to those with low expression, which was accordance with the KIF2C. Taken together, KIC2C aggravated HCC progression, it could serve as a prognostic indicator and confer a novel target for clinical treatment.

Outcomes after hepatectomy of patients with positive HBcAb Non-B Non-C hepatocellular carcinoma compared to overt hepatitis B virus hepatocellular carcinoma.

PURPOSE: Hepatitis B core antibody (HBcAb) positivity is regarded as a sensitive marker for occult and prior hepatitis B virus (HBV) infection. However, the prognosis of patients with HBcAb-positive in non-B, non-C hepatocellular carcinoma (NBNC-HCC) remains unclear. The study aimed to compare the clinicopathological characteristics of patients with HBcAb-positive NBNC-HCC to those with overt HBV (hepatitis B surface antigen positive) HCC. METHODS: 306 HCC patients underwent hepatectomy were divided into two groups: an overt HBV-HCC group and HBcAb-positive NBNC-HCC group. Then patients were analyzed using propensity score matching (PSM) to reduce selection bias. Clinicopathological characteristics and survival outcomes were compared between the two groups. Univariate and multivariate analysis for risk factors were also evaluated. RESULTS: HBcAb-positive NBNC-HCC group showed comparable survival outcomes to the overt HBV-HCC group (3-year overall survival rates 66% vs 62%, 69% vs 53%; 3-year recurrence-free survival rates 49% vs 40%, 47% vs 37%; P > 0.05) before and after PSM. Patients with HBcAb-positive NBNC-HCC were older, had more complications, higher proportions of vascular invasion, and larger tumor sizes but lower proportions of cirrhosis, elevated alanine aminotransferase and prothrombin time. CONCLUSIONS: HBcAb-positive NBNC-HCC group had more advanced tumors, but their prognosis was relatively comparable to that of the other group. Therefore, we believe that screening is also necessary in HBcAb-positive patients for early detection of HCC, especially in the elderly.

Low levels of glycoprotein 96 indicate a worse prognosis in early-stage hepatocellular carcinoma patients after hepatectomy.

Heat shock proteins are a highly conserved group of cellular proteins and are up-expressed in hepatocellular carcinoma (HCC). As a member of the heat shock protein-90 family, glycoprotein 96 (gp96) modulates immunity and tumorigenicity, is increased during the development of HCC from normal liver tissue, and is considered a pro-oncogenic chaperone. However, the prognostic value of gp96 has not been well clarified. The purpose of this study was to investigate the relationship between gp96 and survival of postoperative HCC patients. The expressions of gp96 protein and messenger RNA were measured by immunohistochemistry and real-time quantitative polymerase chain reaction, respectively. The relations between gp96 expression level and clinicopathological factors were analyzed. Kaplan-Meier survival and Cox regression analyses were used to identify factors associated with prognosis. All normal liver tissue exhibited low gp96 expression, whereas high gp96 expression was present in 54% of HCC tissues. The expression of gp96 protein was inversely correlated with TNM stage (P = .037) and tumor recurrence (P = .004). Low gp96 expression was an independent risk factor for poor postoperative disease-free survival (hazard ratio, 0.385; 95% confidence interval, 0.226-0.655; P < .001), and overall survival (hazard ratio, 0.345; 95% confidence interval, 0.187-0.637; P = .001). Stratification analysis indicated that high gp96 had better predictive value for tumor recurrence in HCC patients with normal serum α-fetoprotein levels or with TNM stage I and tumor differentiation I-II HCC. In conclusion, gp96 is a potential and reliable prognostic biomarker for tumor recurrence and overall survival in HCC patients after curative resection.

Comparison between M-score and LR-M in the reporting system of contrast-enhanced ultrasound LI-RADS.

OBJECTIVE: To develop a contrast-enhanced ultrasound (CEUS) M-score and compare it with LR-M in CEUS Liver Imaging Reporting and Data System (LI-RADS). METHODS: We retrospectively enrolled 105 consecutive high-risk patients with hepatocellular carcinoma (HCC) and 105 with intrahepatic cholangiocarcinoma (ICC). The subjects were selected by propensity score matching between November 2003 and December 2017. A CEUS M-score for predicting ICC was constructed based on specific CEUS features by the least absolute shrinkage and selection operator regularised regression. M-score was used to develop a modified CEUS LI-RADS. The diagnostic performance of the modified CEUS LI-RADS using M-score for diagnosing HCC and ICC was compared with American College of Radiology (ACR) CEUS LI-RADS using LR-M. RESULTS: The most useful features for ICC were as follows: poorly circumscribed (69.52%), rim enhancement (63.81%), early washout (92.38%), intratumoural vein (56.19%), obscure boundary of intratumoural non-enhanced area (57.14%), and marked washout (59.05%, all p < 0.001). For predicting ICC, the M-score had a higher specificity (88.57% vs. 63.81%) with lower sensitivity (89.52% vs. 95.24%) compared with LR-M. For diagnosing HCC, the sensitivity of modified LI-RADS (80.95%) was much higher than that of ACR LI-RADS (57.14%), but the specificity was lower (90.48% vs. 96.19%). The area under the curve (AUC) of modified LI-RADS (0.857) was much higher than that of ACR LI-RADS (0.767, p = 0.0001). The modified positive predictive value (PPV) of ACR LI-RADS and modified LI-RADS were 99.42% and 98.99%, respectively. CONCLUSIONS: The modified LI-RADS with M-score had higher sensitivity for diagnosing HCC and higher specificity for diagnosing ICC than ACR LI-RADS. KEY POINTS: • For predicting ICC, the M-score had a higher specificity (88.57% vs. 63.81%) with lower sensitivity (89.52% vs. 95.24%) compared with LR-M. • A CEUS M-score for predicting ICC consisted of more detailed CEUS features (poorly circumscribed, rim enhancement, early washout, intratumoural vein, obscure boundary of intratumoural non-enhanced area, and marked washout) was constructed. • For diagnosing HCC, the sensitivity of modified LI-RADS (80.95%) was much higher than that of ACR LI-RADS (57.14%), but the specificity was lower (90.48% vs. 96.19%). The modified positive predictive value (PPV) of ACR LI-RADS and modified LI-RADS were 99.42% and 98.99%, respectively.

Restoration of FBP1 suppressed Snail-induced epithelial to mesenchymal transition in hepatocellular carcinoma.

Fructose-1,6-bisphosphatase (FBP1), one of the rate-limiting gluconeogenic enzymes, plays critical roles in several cancers and is treated as a tumour suppressor. However, its role in hepatocellular carcinoma (HCC) is unclear. Here, we demonstrated that FBP1 was significantly inhibited during Snail-induced epithelial to mesenchymal transition (EMT) and tissues in HCC. Restoration of FBP1 expression in HCC cancer cells suppressed EMT phenotype, tumour migration and tumour growth induced by Snail overexpression in SMMC-7721 cells. Gene set enrichment analyses revealed significantly enriched terms, including WNT, Notch, ESC, CSR and PDGF, in the group with high Snail and low FBP1 compared with those with low Snail and high FBP1. Low FBP1 expression was significantly correlated with higher AFP level, satellite nodules, portal vein tumour thrombus, and advanced tumour stage. Survival analyses showed that FBP1 was an independent prognostic factor for overall survival and recurrence-free survival. In conclusion, our study revealed a vital role for FBP1 in Snail-induced EMT and prognostic prediction in HCC.

Differentiation of intrahepatic cholangiocarcinoma from hepatocellular carcinoma in high-risk patients: A predictive model using contrast-enhanced ultrasound.

AIM: To develop a contrast-enhanced ultrasound (CEUS) predictive model for distinguishing intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC) in high-risk patients. METHODS: This retrospective study consisted of 88 consecutive high-risk patients with ICC and 88 high-risk patients with HCC selected by propensity score matching between May 2004 and July 2016. Patients were assigned to two groups, namely, a training set and validation set, at a 1:1 ratio. A CEUS score for diagnosing ICC was generated based on significant CEUS features. Then, a nomogram based on the CEUS score was developed, integrating the clinical data. The performance of the nomogram was then validated and compared with that of the LR-M of the CEUS Liver Imaging Reporting and Data System (LI-RADS). RESULTS: The most useful CEUS features for ICC were as follows: rim enhancement (64.5%), early washout (91.9%), intratumoral vein (58.1%), obscure boundary of intratumoral non-enhanced area (64.5%), and marked washout (61.3%, all P < 0.05). In the validation set, the area under the curve (AUC) of the CEUS score (AUC = 0.953) for differentiation between ICC and HCC was improved compared to the LI-RADS (AUC = 0.742) (P < 0.001). When clinical data were added, the CEUS score nomogram was superior to the LI-RADS nomogram (AUC: 0.973 vs 0.916, P = 0.036, Net Reclassification Improvement: 0.077, Integrated Discrimination Index: 0.152). Subgroup analysis demonstrated that the CEUS score model was notably improved compared to the LI-RADS in tumors smaller than 5.0 cm (P < 0.05) but not improved in tumors smaller than 3.0 cm (P > 0.05). CONCLUSION: The CEUS predictive model for differentiation between ICC and HCC in high-risk patients had improved discrimination and clinical usefulness compared to the CEUS LI-RADS.

Hornerin promotes tumor progression and is associated with poor prognosis in hepatocellular carcinoma.

BACKGROUND: The function of hornerin (HRNR), a member of the S100 protein family, is poorly clarified in the development of human tumors. The role of HRNR in hepatocellular carcinoma (HCC) progression is investigated in the study. METHODS: The expression levels of HRNR were assessed in tumor samples from a cohort of 271 HCC patients. The effect of HRNR on proliferation, colony formation and invasion of tumor cells was examined. We further determined the role of HRNR in tumor growth in vivo by using xenograft HCC tumor models. The possible mechanism of the HRNR promotion of HCC progression was explored. RESULTS: We found that HRNR was overexpressed in HCC tissues. The high expression of HRNR in HCCs was significantly associated with vascular invasion, poor tumor differentiation, and advanced TNM stage. The disease-free survival (DFS) and overall survival (OS) of HCC patients with high HRNR expression were poorer than those in the low HRNR expression group. HRNR expression was an independent risk factor linked to both poor DFS (HR = 2.209, 95% CI = 1.627-2.998,P <  0.001) and OS (HR = 2.459,95% CI = 1.736-3.484, P <  0.001). In addition, the knockdown of HRNR by shRNAs significantly inhibited the proliferation, colony formation, migration and invasion of HCC tumor cells. HRNR silencing led to the decreased phosphorylation of AKT signaling. Notably, tumor growth was markedly inhibited by HRNR silencing in a xenograft model of HCC. CONCLUSIONS: HRNR promotes tumor progression and is correlated with a poor HCC prognosis. HRNR may contribute to HCC progression via the regulation of the AKT pathway.

Peritumoral tissue on preoperative imaging reveals microvascular invasion in hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Histologic microvascular invasion (MVI) substantially worsens the prognosis of patients with hepatocellular carcinoma, and can only be diagnosed postoperatively. Preoperative assessment of MVI by imaging has been focused on tumor-related features, while peritumoral imaging features have been indicated elsewhere to be more accurate. The aim of the present study is to evaluate the association between peritumoral imaging features and MVI. METHODS: Literature search was performed using the PubMed, Embase, and Cochrane Library databases. Summary results of the association between peritumoral imaging features and MVI were presented as the odds ratio (OR) and the 95% confidence interval. Meta-regression and subgroup analyses were performed when heterogeneity was detected. Diagnostic accuracy analysis was also conducted for identified features. RESULTS: Ten studies were included in the analysis. Moderate and low heterogeneities were found among the seven studies on peritumoral enhancement and four studies on peritumoral hypointensity on HBP, respectively. Summary results revealed a significant association between MVI and peritumoral enhancement (OR 4.04 [2.23, 7.32], p < 0.05), and peritumoral hypointensity on HBP (OR 10.62 [5.31, 21.26], p < 0.05). Diagnostic accuracy analysis revealed high specificity (0.90-0.94) but low sensitivity (0.29-0.40) for both features to assess MVI. CONCLUSION: The two peritumoral imaging features are significantly associated with MVI. The two features highly suggest MVI only when present with a high false negative rate. Promotion of their diagnostic efficiency can be a worthwhile task for future research.

Low expression of c-Myc protein predicts poor outcomes in patients with hepatocellular carcinoma after resection.

BACKGROUND: Embryonic Liver Fodrin (ELF) is an adaptor protein of transforming growth factor (TGF-ß) signaling cascade. Disruption of ELF results in mislocalization of Smad3 and Smad4, leading to compromised TGF-ß signaling. c-Myc is an important oncogenic transcription factor, and the disruption of TGF-ß signaling promotes c-Myc-induced hepatocellular carcinoma (HCC) carcinogenesis. However, the prognostic significance of c-Myc in HCC is less understood METHODS: The expression of c-Myc protein and mRNA were measured by immunohistochemistry (IHC) and qRT- PCR, respectively. IHC was performed to detect TGF-ß1 and ELF expression in HCC tissues. Their relationship with clinicopathological factors and overall survival (OS) and disease free survival (DFS) were examined. RESULTS: The expression of c-Myc protein and mRNA in HCC tissues were significantly higher in HCC area than those in normal liver tissues. However, the expression were low compared with those adjacent to HCC area. c-Myc protein was independently predictive of DFS and OS, and it was negatively correlated with tumor size (P = 0.031), tumor number (P = 0.038), and recurrence (P = 0.001). Low c-Myc expression was associated with short-term recurrence and poor prognosis. The predictive value of c-Myc combined with TGF-ß1 or/and ELF was higher than that of any other single marker. Low c-Myc, high TGF-ß1 or/and low ELF expression was associated with the worst DFS and OS. CONCLUSIONS: Low expression of c-Myc protein predicts poor outcomes in patients with HCC with hepatectomy. The combination of the expression of c-Myc, TGF-ß1, and ELF can be used to accurately predict outcomes of patients with HCC.

Non-Invasive Diagnostic Criteria for Hepatocellular Carcinoma in Hepatitis B Virus-Endemic Areas: Is Cirrhosis Indispensable?

AIM: To confirm whether cirrhosis is indispensable for the non-invasive diagnostic criteria for hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-endemic areas. METHODS: Between January 2014 and December 2014, a total of 409 patients with pathologically proven focal liver lesions who underwent contrast-enhanced ultrasound (CEUS) were recruited from our institution. Clinical liver cirrhosis, HBV/HCV infection and HCC-typical vascular pattern of the targeted lesion on CEUS were evaluated. The following 3 criteria were applied to these patients to diagnose HCC: criterion 1, clinical liver cirrhosis and HCC-typical vascular pattern; criterion 2, HBV/HCV infection and HCC-typical vascular pattern; criterion 3, HBV/HCV infection or clinical liver cirrhosis and HCC-typical vascular pattern. Pathological reports were considered the gold standard. RESULTS: A total of 311 patients had confirmed HCC by pathology. The sensitivity, specificity, accuracy, positive predictive value, negative predictive value and area under the ROC curve for criterion 1 were 29.6, 90.8, 44.3, 91.1, 28.9, and 0.60% respectively. For criterion 2, they were 83.3, 74.5, 81.2, 91.2, 58.4, and 0.79%, respectively, and for criterion 3, they were 86.2, 72.5, 82.9, 90.9, 62.3, and 0.79% respectively. CONCLUSIONS: In HBV-endemic areas, when using the HBV/HCV infection instead of cirrhosis as the precondition of the non-invasive diagnostic criteria for HCC, we should be aware of the potential false positive. Cirrhosis still plays an important role in the non-invasive diagnostic criteria for HCC because of the high specificity.

Potential diagnostic performance of contrast-enhanced ultrasound and tumor markers in differentiating combined hepatocellular-cholangiocarcinoma from hepatocellular carcinoma and cholangiocarcinoma.

PURPOSE: To evaluate the diagnostic performance of the combination of tumor markers [alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9)] and imaging features in differentiating combined hepatocellular-cholangiocarcinoma (CHC) from hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). METHODS: Forty consecutive patients with pathologically proven CHC were retrospectively evaluated with contrast-enhanced ultrasound (CEUS). Additionally, 40 HCC and 40 CC patients who were randomly selected from the same period served as a control group. Images were classified as HCC-like or CC-like pattern according to CEUS guidelines recommended by World and European Federation for Ultrasound in Medicine and Biology (WFUMB-EFSUMB). The diagnostic criteria of CHC were defined as follows: (1) both AFP and CA19-9 are simultaneously elevated (AFP > 20 ng/ml and CA19-9 > 100 units/ml); or (2) elevated AFP with a CC-like pattern on CEUS and without elevated CA19-9 level; or (3) elevated CA19-9 with an HCC-like pattern on CEUS and without elevated AFP level. The diagnostic tests were performed with calculation of the sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC). RESULTS: For the 40 CHC patients, the rates of elevated AFP and CA19-9 serology were 55.0 and 30.0%, respectively. Twenty-three (57.5%) patients exhibited an HCC-like pattern, and 15 (37.5%) showed a CC-like pattern. After applying the above diagnostic criteria of CHC in the 120 patients, the sensitivity, specificity, PPV, NPV, accuracy, and AUC were 32.5, 93.8, 72.2, 73.5, 73.3, and 0.631%, respectively. When the actual prevalence rate (0.4-14.3%) was taken into account, the PPV and NPV were modified from 2.1 to 46.7% and 89.3 to 99.7%, respectively. CONCLUSION: The combination of enhancement patterns on CEUS and serum tumor markers (AFP and CA19-9) may be a potentially specific diagnostic method to differentiate CHC from HCC and CC.

miR-338-3p inhibits epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma cells.

Down-regulation of the miRNA miR-338-3p correlates with the invasive ability of hepatocellular carcinoma (HCC) cells. However, it is currently unclear whether down-regulation of miR-338-3p induces epithelial-mesenchymal transition (EMT), which may be the underlying mechanism governing HCC invasion. Here, we demonstrate that restoration of miR-338-3p expression via transfection of a miR-338-3p mimic reversed EMT and inhibited the motility and invasiveness of HCC cells. Conversely, silencing of endogenous miR-338-3p expression with a miR-338-3p-specific inhibitor induced EMT and enhanced HCC cell motility. Additionally, Snail1 (an upstream regulatory protein of EMT) and Gli1 (a key transcription factor in the sonic hedgehog (SHH) signaling pathway) expression was up-regulated in cells treated with the miR-338-3p inhibitor and down-regulated by the miR-338-3p mimic. Further analyses demonstrated that miR-338-3p inhibitor-induced EMT in HCC cells was blocked by treatment with a small interfering RNA (siRNA) targeting Snail1, that the SHH signaling pathway was required for both miR-338-3p inhibitor-induced EMT and up-regulation of Snail1, and that miR-338-3p targeted a sequence within the 3'-untranslated region of N-cadherin mRNA. Notably, miR-338-3p expression was significantly down-regulated in HCC samples from patients with metastases and was associated with poor metastasis-free survival rates. Lastly, correlations between the expression levels of miR-338-3p and E-cadherin, Smoothened (SMO), Gli1, Snail1, N-cadherin, and vimentin were confirmed in HCC xenograft tumors and HCC patient specimens. Our findings suggest that miR-338-3p suppresses EMT and metastasis via both inhibition of the SHH/Gli1 pathway and direct binding of N-cadherin. miR-338-3p is a potential therapeutic target for metastatic HCC.

Diagnostic nomogram for gallbladder wall thickening mimicking malignancy: using contrast-enhanced ultrasonography or multi-detector computed tomography?

OBJECTIVES: To establish a diagnostic nomogram using contrast-enhanced ultrasonography (CEUS) in gallbladder wall thickening mimicking malignancy and compare with multi-detector computed tomography (MDCT). METHODS: Seventy-two patients with gallbladder wall thickening on B-mode ultrasonography (BUS) were examined by CEUS to develop independent predictors for diagnosing gallbladder carcinoma. Among the 72 cases, 48 patients underwent both CEUS and MDCT. The diagnostic performances of different sets of CEUS criteria and MDCT were compared. A prediction model of malignancy using CEUS was developed. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. RESULTS: Multivariate logistic regression indicated that inhomogeneous enhancement in the arterial phase was the strongest independent predictor of malignancy (odds ratio, OR 51.162), followed by interrupted inner layer (OR 19.788), washout time ≤40 s (OR 16.686), and wall thickness >1.6 cm (OR 3.019), which were all selected into the nomogram. Combined with the above significant features, the diagnostic performance of CEUS (AUC = 0.917) was higher than that of MDCT (AUC = 0.788, P = 0.070). The predictive model using CEUS showed good discrimination, with a concordance index of 0.974 (0.950 through internal validation), and good calibration. Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSIONS: CEUS could accurately differentiate between malignant and benign gallbladder wall thickening with equivalent efficacy compared to MDCT. The proposed nomogram could be conveniently used to facilitate the preoperative individualized prediction of malignancy in patients with gallbladder wall thickening.

Hepatocellular adenoma: comparison between real-time contrast-enhanced ultrasound and dynamic computed tomography.

PURPOSE: To investigate and compare the contrast-enhanced ultrasound (CEUS) features of histologically proven HCA with those of contrast-enhanced computed tomography (CECT). METHODS: Eighteen patients with proven hepatic adenoma by pathology were retrospectively selected from the CEUS database. Fourteen of them had undergone liver CECT exams. The basic features on unenhanced imaging and the enhancement level and specific features on contrast-enhanced imaging were retrospectively analyzed, and the differences between CEUS and CECT were compared. RESULTS: All the HCAs showed hyper-enhancement in the arterial phase. During the portal and late phases, 12 HCAs (12/18, 66.7 %) on CEUS and 11 (11/14, 78.6 %) on CT showed washout. On CEUS, 10 (10/18, 55.5 %) showed centripetal filling in the arterial phase and persistent peripheral rim enhancement. Five of them (61.1 %, 11/18) showed delayed central washout in the portal or late phase. However, on CECT, 2 (14.3 %, 2/14) and 4 (28.6 %, 4/14) HCAs showed persistent enhancement of the peripheral rim and central non-enhancing hemorrhage areas, respectively. CONCLUSIONS: Compared with dynamic CT, CEUS was superior at characterizing specific dynamic features. Considering that it is radiation-free, readily availability and easy to use, CEUS is suggested as the first line imaging tool to diagnose HCA.

A novel and accurate predictor of survival for patients with hepatocellular carcinoma after surgical resection: the neutrophil to lymphocyte ratio (NLR) combined with the aspartate aminotransferase/platelet count ratio index (APRI).

BACKGROUND: The occurrence and development of hepatocellular carcinoma (HCC) depends largely on such non-tumor factors as inflammatory condition, immune state, viral infection and liver fibrosis. Various inflammation-based prognostic scores have been associated with survival in patients with HCC, such as the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR) and the prognostic nutritional index (PNI). The aspartate aminotransferase/platelet count ratio index (APRI) is thought to be a biomarker of liver fibrosis and cirrhosis. This study aims to evaluate the ability of these indices to predict survival in HCC patients after curative hepatectomy, and probe the increased prognostic accuracy of APRI combined with established inflammation-based prognostic scores. METHODS: Data were collected retrospectively from 321 patients who underwent curative resection for HCC. Preoperative NLR, PLR, PNI, APRI and clinico-pathological variables were analyzed. Univariate and multivariate analyses were performed to identify the predictive value of the above factors for disease-free survival (DFS) and overall survival (OS). RESULTS: Univariate analysis showed that NLR, PLR, PNI and APRI were significantly associated with DFS and OS in HCC patients with curative resection. Multivariate analysis showed that NLR and APRI were superior to PLR and PNI, and both were independently correlated with DFS and OS. Preoperative NLR >2 or APRI >1.68 predicted poor prognosis of patients with HCC after hepatectomy. Furthermore, the predictive range of NLR combined with APRI was more sensitive than that of either measure alone. CONCLUSIONS: Preoperative NLR and APRI are independent predictors of DFS and OS in patients with HCC after surgical resection. Higher levels of NLR or APRI predict poorer outcomes in HCC patients. Intriguingly, combining NLR and APRI increases the prognostic accuracy of testing.

Adjuvant antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after curative treatment: A systematic review and meta-analysis.

AIM: To investigate whether adjuvant antiviral treatment could improve prognosis and entecavir is the optimal nucleoside/nucleotide analog (NA) regimen after curative therapy of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: A comprehensive electronic search was performed. All controlled trials comparing antiviral treatment with placebo or no treatment for HBV-related HCC after curative treatment were included. The pooled hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Stata 12.0 software. An indirect treatment comparison method was used to compare the relative efficacy of different NA strategies. RESULTS: Twenty-one studies containing 8072 patients were included. NA was found to significantly improve recurrence-free survival (RFS) and overall survival (OS). Alternatively, for interferon, a non-significant benefit was found. By adjusted indirect comparisons among entecavir, lamivudine and adefovir, entecavir were found to display almost but not significant superiority to the other NA in improving RFS. No tendency favoring a specific NA regimen was found for OS. CONCLUSION: In HBV-HCC patient after curative treatment, NA improve the prognosis significantly but the role of interferon remains to be elucidated; entecavir was not found to be superior to other NA based on available data.