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Background & Aims: Controlled attenuation parameter (CAP) can measure hepatic steatosis. However, factors affecting its accuracy have not been described yet. This study investigated predictors of discordance between liver biopsy (LB) and CAP., Methods: A total of 161 consecutive patients with chronic liver disease who underwent LB and CAP were enrolled prospectively. Histological steatosis was graded as S0 (<5%), S1 (5-33%), S2 (34-66%), and S3 (>66% of hepatocytes). Cutoff CAP values were calculated from our cohort (250, 301, and 325 dB/m for ≥ S1, ≥ S2, and S3). Discordance was defined as a discrepancy of at least two steatosis stages between LB and CAP., Results: The median age (102 males and 59 females) was 49 years. Repartition of histological steatosis was as follows; S0 26.1% (n = 42), S1 49.7% (n = 80), S2 20.5% (n = 33), and S3 3.7% (n = 6). In multivariate linear regression analysis, CAP value was independently associated with steatosis grade along with body mass index (BMI) and interquartile range/median of CAP value (IQR/MCAP) (all P<0.05). Discordance was identified in 13 (8.1%) patients. In multivariate analysis, histological S3 (odd ratio [OR], 9.573; 95% confidence interval [CI], 1.207-75.931; P = 0.033) and CAP value (OR, 1.020; 95% CI, 1.006-1.034; P = 0.006) were significantly associated with discordance, when adjusting for BMI, IQR/MCAP, and necroinflammation, reflected by histological activity or ALT level., Conclusions: Patients with high grade steatosis or high CAP values have a higher risk of discordance between LB and CAP. Further studies are needed to improve the accuracy of CAP interpretation, especially in patients with higher CAP values.

Purpose: To evaluate differences in liver enhancement among patients with low and high morbidity risks and to determine the relationship between severity of liver dysfunction and the relative ratio of liver to aortic enhancement (RE) on MRI using hepatocyte-specific contrast., Materials and Methods: A total of 126 patients underwent magnetic resonance imaging (MRI) and blood serum testing including serology, bilirubin, international normalized ratio, and creatinine tests. Radiologists analyzed a region of interest in the liver and aorta on precontrast and 10- and 20-minute delayed hepatobiliary phase MR images. Liver enhancement after 10 (LE10min ) and 20 minutes (LE20min ) were compared between the low- and high-risk groups by independent t-test. Regression analysis was used to assess the relationship between the Model for Endstage Liver Disease (MELD) score and RE., Results: All 126 patients were classified into either the low-risk group (MELD <8; n = 85) or high-risk group (MELD ≥8; n = 41). The mean LE10min and LE20min were significantly higher in the low-risk group (471.61; 95% confidence interval [CI]: 449.79-493.43 and 510.69; 95% CI: 486.51-534.87, respectively) than in the high-risk group (401.6776; 95% CI: 364.75-438.61 and 413.81; 95% CI: 370.91-456.70). There was a moderate inverse correlation between MELD score and the relative ratio of liver enhancement (RLE) (r = -0.5442; 95% CI: -0.6480 to -0.4207; P<0.01), but a high positive correlation between MELD score and RE (r = 0.7470; 95% CI: 0.6665-0.8102; P < 0.01)., Conclusion: Although liver enhancement was significantly greater in low-risk patients compared to high-risk patients, RE may be a better predictor of liver function than RLE., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Controlled attenuation parameter (CAP) is a non-invasive method of measuring hepatic steatosis using a process based on transient elastography. We investigated the diagnostic accuracy of CAP in detecting hepatic steatosis in patients with chronic liver disease (CLD)., Methods: A total of 135 patients with CLD who underwent liver biopsy and CAP were consecutively enrolled in this prospective study. The performance of CAP for detection of hepatic steatosis compared with liver biopsy was calculated using area under receiver operating characteristics curves (AUROC). Steatosis was categorized into S0 (<5%), S1 (5-33%), S2 (34-66%) and S3 (>66% of hepatocytes)., Results: Male gender predominated (n = 87, 64%) and the median age was 51 years. The aetiologies of CLD included non-alcoholic fatty liver disease (n = 56, 41.5%) and chronic viral hepatitis because of hepatitis B (n = 47, 34.8%) and C (n = 12, 8.9%). Steatosis repartition was: S0 31.1% (n = 42), S1 43.7% (n = 59), S2 18.5% (n = 25) and S3 6.7% (n = 9) respectively. In the multivariate analysis, steatosis grade and body mass index were independently associated with CAP (all P < 0.001), whereas fibrosis stage and activity grade were not. The AUROCs of CAP were 0.885 for ≥S1 (sensitivity 73.1%, specificity 95.2%), 0.894 for ≥S2 (sensitivity 82.4%, specificity 86.1%) and 0.800 for S3 (sensitivity 77.8%, specificity 84.1%). The optimal cut-off CAP values that maximized the Youden index were 250 dB/m (≥S1), 299 dB/m (≥S2), and 327 dB/m (=S3) respectively., Conclusions: Our data showed that CAP had high diagnostic accuracy for detecting hepatic steatosis in patients with CLD and suggested that CAP is also applicable for Asian patients., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A 63-year-old man with a history of hepatitis-B-related hepatocellular carcinoma (HCC) in the left lateral portion of the liver received repeated transcatheter arterial chemoembolization (TACE) and salvage radiotherapy. Two months after completing radiotherapy, he presented with dysphagia, epigastric pain, and a protruding abdominal mass. Computed tomography showed that the bulging mass was directly invading the adjacent stomach. Endoscopy revealed a fistula from the HCC invading the stomach. Although the size of the mass had decreased with the drainage through the fistula, and his symptoms had gradually improved, he died of cancer-related bleeding and hepatic failure. This represents a case in which an HCC invaded the stomach and caused a hepatogastric fistula after repeated TACE and salvage radiotherapy.

Ciliated hepatic foregut cyst (CHFC) is very rare and apparently originated from embryologic foregut. It is generally benign, solitary cyst and microscopically consists of inner ciliated pseudostratified columnar epithelium, subepithelial connective tissue, a smooth muscle layer, and outer fibrous capsule. Although ciliated cysts commonly arise from the tracheal bronchial tree and the esophagus, they could also be found in the liver with rare incidence. There are several reports indicating this lesion can cause clinical problems, such as biliary obstruction and malignant transformation. Herein, we present a case of 56-year-old male patient who recently underwent laparoscopic excision of CHFC, focusing our discussion on review of literatures and rationale of laparoscopic surgery on CHFC.

Background: Telomerase reverse transcriptase (hTERT) is the rate-limiting determinant of telomerase, which is critical for carcinogenesis. Dysplastic nodules (DNs) appear to be preneoplastic lesions of hepatocellular carcinomas (HCCs). In this study, in order to characterize DNs, hTERT mRNA, hTERT gene dosage, and mRNA for c-myc, a transcriptional activator of hTERT were studied in human multi-step hepatocarcinogenesis., Methods: Fifty four hepatic nodules including 5 large regenerative nodules, 14 low-grade DNs, 7 high-grade DNs, 11 DNs with HCC foci and 17 HCCs, 23 livers with chronic hepatitis/cirrhosis, and 6 normal livers were examined. Transcript levels were measured by real-time quantitative RT-PCR and gene dosages by real-time PCR and Southern blotting., Results: The hTERT mRNA levels increased with the progression of hepatocarcinogenesis, and a significant induction in the transition between low- and high-grade DNs was seen. Most high-grade DNs strongly expressed hTERT mRNA at levels similar to those of HCCs. Twenty-one percent of low-grade DNs had high levels of hTERT mRNA, up to those of high-grade DNs and there was no difference in the pathological features between low-grade DNs with and without increased hTERT mRNA levels. No correlation was found between hTERT mRNA levels, hTERT gene dosage, and c-myc mRNA levels., Conclusions: These results suggest that the induction of hTERT mRNA is an important early event and that its measurement by real-time quantitative RT-PCR is a useful tool to detect premalignant/malignant tendencies in hepatic nodules. However, hTERT gene dosage and c-myc expression are not the main mechanisms regulating hTERT expression in hepatocarcinogenesis.

Inflammatory pseudotumor (IPT) of the liver is rare benign tumor. When the diagnosis of IPT is established with biopsy, simple observation or conservative therapy is preferred because of the possibility of regression. But IPT is unresponsive to the conservative treatment, surgical resection should be considered. We experienced a 63-year-old male, who was suspected hepatocellular carcinoma in abdominal computed tomography (CT) and magnetic resonance image (MRI) scan, presented with 2-month history of intermittent fever and weight loss. Percutaneous ultrasound guided core biopsy confirmed IPT of the liver. Non-steroidal anti-inflammatory drugs and antibiotics were administered for 8 and 4 weeks, respectively, but fever continued. So, extended right hepatectomy was performed for IPT of the liver and then fever subsided. The patient remains well during a follow-up period of 12 months.

Mesenchymal hamartoma (MH) of the liver is an uncommon benign lesion related to ductal plate malformation. It is usually cystic and mainly composed of myxoid mesenchymal tissue with tortuous or cystic bile ducts. In order to characterize the clinicopathological features of MH, the Korean Gastrointestinal Pathology Study Group collected a total of 17 MH cases diagnosed in 7 hospitals from 1992 to 2002 and compared the clinicopathologic findings of cystic MH with those of solid variant. Among the 17 cases, 7 (41%) were solid. The solid form showed a higher serum level of alpha-fetoprotein (AFP), the smaller bile ducts, and more frequent proliferation of vessels. Serum AFP level was related to the amount of hepatocytes. Two of seven solid cases harbored a larger amount of evenly distributed hepatocytes and proliferation of small duct with focal hepatocyte-bile duct transition. These histologic findings are similar to those of mixed hamartoma. Therefore, the mixed hamartoma and the MH of both solid and cystic types could be the variants of one disease spectrum. And hepatocytes within MH might be rather a genuine tumor component than entrapped into the tumor. In conclusion, MH can show various clinicopathological features and recognition of these features will facilitate accurate diagnosis of MH.

Background/aim: Proliferative bile ductular reactions occur in a variety of liver diseases in humans. It is a matter of debate whether such reactions result from progenitor cell proliferation with biliary and hepatocytic differentiation, versus biliary metaplasia of damaged hepatocytes. We investigated bile ductular reactions in liver diseases, paying particular attention to the presence of cells with intermediate (hepatocytic/biliary) features (oval-like cells)., Methods: Five specimens each were selected of submassive hepatic necrosis and cirrhosis due to hepatitis B, hepatitis C, autoimmune hepatitis, alcohol injury, primary biliary cirrhosis and primary sclerosing cholangitis. Immunohistochemical stains were performed for biliary markers (cytokeratins [CKs] 7 and 19), as well as hepatocytic markers (HepParl and alpha-fetoprotein[AFP]) in sequential sections. The degree of staining of each cell type (biliary, hepatocytic, intermediate) was graded semiquantitatively., Results: Hepatocytes always stained diffusely for HepParl, occasionally for CK7, and rarely for CK19. Biliary cells were always diffusely positive for CK7 and CK19, and rarely for HepParl. Intermediate cells were identified in all cases and showed widespread staining for both HepParl and CK7, and less commonly for CK19. AFP was not expressed in any cell type. The morphologic and immunohistochemical features of bile ductular reactions were similar in the different diseases., Conclusions: Proliferating hepatic parenchymal cells with intermediate (hepatocytic/biliary) morphologic features and combined immunophenotype can be identified in a variety of acute and chronic liver diseases. The similarity of bile ductular reactions among chronic hepatitic, alcoholic and biliary diseases suggests that they result from proliferation of oval-like progenitor cells.

Background & Aims: Fatty change is commonly observed in hepatocellular carcinoma (HCC); however, the characteristics of steatotic and steatohepatitic HCCs are not well understood. Methods: This retrospective study included patients with HCCs who underwent resection between January 2014 and December 2019 to evaluate clinicopathological and magnetic resonance imaging features. Tumours were categorized as magnetic resonance imaging‐steatotic, pathology‐steatotic and steatohepatitic HCCs and were defined as HCCs with ≥50% steatosis on in‐and‐oppose phase images, ≥34% tumour cells with lipid droplets and ≥50% tumour areas with steatohepatitic features on light microscopy respectively. Results: Of 465 HCCs, 38 (8%), 23 (5%) and 15 (3%) were diagnosed as magnetic resonance imaging‐steatotic, pathology‐steatotic and steatohepatitic HCCs respectively. These HCC variants were less likely to be associated with hepatitis B virus infections than with type 2 diabetes mellitus, metabolic syndrome, non‐tumour liver steatosis and steatohepatitis. Moreover, microvascular invasion was less likely to be associated with them than either tumour size or differentiation. Type 2 diabetes and non‐tumour steatosis were independent risk factors for magnetic resonance imaging‐steatotic HCCs. Pathology‐steatotic HCCs and steatohepatitic HCCs were significantly associated with magnetic resonance imaging‐steatotic HCCs. A targetoid appearance in the transitional or hepatobiliary phase was also more prevalent in steatohepatitic‐HCCs than in non–steatohepatitic‐HCCs. When magnetic resonance imaging‐steatotic HCCs were combined with one or more ancillary features, the sensitivity and specificity were 60% and 97% respectively. Conclusion: Underlying fatty liver disease and metabolic syndrome are strongly associated with both steatotic and steatohepatitic HCCs. Clinicoradiological characteristics help identify steatohepatitic HCC with high specificity. [ABSTRACT FROM AUTHOR]

Background & Aims: Late recurrence of hepatocellular carcinoma (HCC) is regarded as de novo HCC from chronic hepatitis. This study investigated clinicopathological and molecular factors to develop a nomogram for predicting late HCC recurrence (>2 years after curative resection). Methods: The training and validation cohorts included HCC patients with a major aetiology of hepatitis B who underwent curative resection. Clinicopathological features including lobular and porto‐periportal inflammatory activity, fibrosis and liver cell change were evaluated. Proteins encoded by genes related to late recurrence were identified using a reverse phase protein array of 95 non‐tumourous liver tissues. Immunoexpression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), plasminogen activator inhibitor‐1, phosphorylated extracellular signal‐regulated kinase 1/2 (pERK1/2) and spleen tyrosine kinase (SYK) was measured. Results: Late recurrence occurred in 74/402 (18%) and 47/243 (19%) in the training and validation cohorts respectively. Cirrhosis, moderate/severe lobular inflammatory activity, and expression of pSTAT3, pERK1/2, and SYK proteins correlated to the gene signature of hepatocyte injury and regeneration were independently associated with late recurrence, with odds ratios (95% confidence intervals) of 2.0 (1.2‐3.3), 21.1 (4.3‐102.7) and 6.0 (2.1‐17.7) respectively (P <.05 for all). A nomogram based on these variables (histological parameters and immunohistochemical marker combinations) showed high reliability in both the training and validation cohorts (Harrell's C index: 0.701 and 0.716; 95% confidence intervals: 0.64‐0.76 and 0.64‐0.79 respectively). Conclusions: The combination of pSTAT3, pERK1/2 and SYK immunoexpression with high lobular inflammatory activity and cirrhosis (fibrosis) predicts late HCC recurrence. [ABSTRACT FROM AUTHOR]

Background & Aims: Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous entity with diverse aetiologies, morphologies and clinical outcomes. Recently, histopathological distinction of cholangiolocellular differentiation (CD) of iCCA has been suggested. However, its genome-wide molecular features and clinical significance remain unclear. Methods: Based on CD status, we stratified iCCAs into iCCA with CD (n=20) and iCCA without CD (n=102), and performed an integrative analysis using transcriptomic and clinicopathological profiles. Results: iCCA with CD revealed less aggressive histopathological features compared to iCCA without CD, and iCCA with CD showed favourable clinical outcomes of overall survival and time to recurrence than iCCA without CD (P<.05 for all). Transcriptomic profiling revealed that iCCA with CD resembled an inflammation-related subtype, while iCCA without CD resembled a proliferation subtype. In addition, we identified a CD signature that can predict prognostic outcomes of iCCA (CD_UP, n=486 and CD_DOWN, n=308). iCCAs were subgrouped into G1 (positivity for CRP and CDH2, 7%), G3 (positivity for S100P and TFF1, 32%) and G2 (the others, 61%). Prognostic outcomes for overall survival (P=.001) and time to recurrence (P=.017) were the most favourable in G1-iCCAs, intermediate in G2-iCCAs and the worst in G3-iCCAs. Similar result was confirmed in the iCCA set from GSE26566 (n=68). Conclusions: CD signature was identified to predict the prognosis of iCCA. The combined evaluation of histology of CD and protein expression status of CRP, CDH2, TFF1 and S100P might help subtyping and predicting clinical outcomes of iCCA. [ABSTRACT FROM AUTHOR]

Aims The scirrhous variant of hepatocellular carcinoma (S- HCC) and fibrolamellar HCC ( FL- HCC) are less common subtypes of HCC that are characterized by abundant fibrous stroma. Here, we aimed to investigate differences in the tumour microenvironment and the tumour epithelial cell characteristics of S- HCC and FL- HCC. Methods and results Whole tissue sections of 17 S- HCCs and 9 FL- HCCs were subjected to immunohistochemical stains for keratin 7 (K7), K19, Ep CAM, CD56/ NCAM, CD163, CD68, pSTAT3, FAP, CCN2 and Ki-67. FL- HCC patients were younger than S- HCC patients ( P < 0.001), and chronic liver disease was seen in the background of 88.2% of S- HCC and in none of the FL- HCC. CD68 and CD163-positive tumour-infiltrating macrophages, and FAP-positive cancer-associated fibroblasts ( CAFs) were more abundant in the stroma of S- HCCs compared to FL- HCCs (all P < 0.05). Tumour epithelial K19 expression was more frequent in S- HCCs compared to FL- HCCs ( P = 0.023). Significant positive correlations were seen between pSTAT3 expression status in tumour epithelial cells and CAFs, the extent of stromal CAF and macrophage infiltration and K19 expression status. No significant differences were seen for K7, Ep CAM, CD56/ NCAM, CCN2 expression and Ki-67 labelling index between S- HCCs and FL- HCCs. Conclusion S- HCC and FL- HCC are subtypes of HCC with extensive fibrosis, and the nature of the fibrous stroma differs between them. While the stroma of FL- HCC is composed of dense lamellated collagenous bands with sparse cellular components, S- HCC demonstrates more abundant CAF and tumour-infiltrating macrophages and stemness-related marker expression, suggesting the presence of a complex tumour microenvironment that may influence the aggressive behaviour of S-HCCs. [ABSTRACT FROM AUTHOR]

Senescence secretome was recently reported to promote liver cancer in an obese mouse model. Steatohepatitic hepatocellular carcinoma (SH-HCC), a new variant of HCC, has been found in metabolic syndrome patients, and pericellular fibrosis, a characteristic feature of SH-HCC, suggests that alteration of the tumor stroma might play an important role in SH-HCC development. Clinicopathological characteristics and tumor stroma showing senescence and senescence-associated secretory phenotype (SASP) were investigated in 21 SH-HCCs and 34 conventional HCCs (C-HCCs). The expression of α-smooth muscle actin (α-SMA), p21Waf1/Cif1, γ-H2AX, and IL-6 was investigated by immunohistochemistry or immunofluorescence. SH-HCCs were associated with older age, higher body mass index, and a higher incidence of metabolic syndrome, compared to C-HCC (P <0.05, all). The numbers of α-SMA-positive cancer-associated fibroblasts (CAFs) (P = 0.049) and α-SMA-positive CAFs co-expressing p21Waf1/Cif1 (P = 0.038), γ-H2AX (P = 0.065), and IL-6 (P = 0.048) were greater for SH-HCCs than C-HCCs. Additionally, non-tumoral liver from SH-HCCs showed a higher incidence of non-alcoholic fatty liver disease and a higher number of α-SMA-positive stellate cells expressing γ-H2AX and p21Waf1/Cif1 than that from C-HCCs (P <0.05, all). In conclusion, SH-HCCs are considered to occur more frequently in metabolic syndrome patients. Therein, senescent and damaged CAFs, as well as non-tumoral stellate cells, expressing SASP including IL-6 may contribute to the development of SH-HCC. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs), a subset of tumor cells, contribute to an aggressive biological behavior, which is also affected by the tumor stroma. Despite the role of CSCs and the tumor stroma in hepatocellular carcinoma (HCC), features of stemness have not yet been studied in relation to tumor stromal alterations in multistep hepatocarcinogenesis. We investigated the expression status of stemness markers and tumor stromal changes in B viral carcinogenesis, which is the main etiology of HCC in Asia. Stemness features of tumoral hepatocytes (EpCAM, K19, Oct3/4, c-KIT, c-MET, and CD133), and tumor stromal cells expressing α-smooth muscle actin (α-SMA), CD68, CD163, and IL-6 were analyzed in 36 low grade dysplastic nodules (DNs), 48 high grade DNs, 30 early HCCs (eHCCs), and 51 progressed HCCs (pHCCs) by immunohistochemistry or real-time PCR. Stemness features (EpCAM and K19 in particular) were progressively acquired during hepatocarcinogenesis in combination with enrichment of stromal cells (CAFs, TAMs, IL-6+ cells). Stemness features were seen sporadically in DNs, more consistent in eHCCs, and peaked in pHCCs. Likewise, stromal cells were discernable in DNs, showed up as consistent cell densities in eHCCs and peaked in pHCCs. The stemness features and tumor stromal alterations also peaked in less differentiated or larger HCCs. In conclusion, progression of B viral multistep hepatocarcinogenesis is characterized by an enrichment of stemness features of neoplastic hepatocytes and a parallel alteration of the tumor stroma. The modulation of neoplastic hepatocytes and stromal cells was at low levels in precancerous lesions (DNs), consistently increased in incipient cancer (eHCCs) and peaked in pHCCs. Thus, in B viral hepatocarcinogenesis, interactions between CSCs and the tumor stroma, although starting early, seem to play a major role in tumor progression. [ABSTRACT FROM AUTHOR]

Background & Aims: Precise assessment of liver fibrosis is necessary in patients with chronic liver disease. We investigated the performance of red cell volume distribution width-to-platelet ratio for the assessment of liver fibrosis in patients with chronic hepatitis B. Methods: A total of 482 consecutive patients with chronic hepatitis B who underwent liver biopsy between October 2005 and May 2014 were recruited. Liver stiffness was measured using transient elastography. FIB-4 score, red cell volume distribution width-to-platelet ratio and the aspartate aminotransferase-to-platelet ratio index were also assessed. Results: A total of 271 (56.2%) patients were males. The median age was 44 years. F1, F2, F3 and F4 fibrosis stages were identified in 68 (14.1%), 137 (28.4%), 64 (13.3%) and 213 (44.2%) of the patients respectively. The mean red cell volume distribution width-to-platelet ratio increased with liver fibrosis severity: F1, 0.065; F2, 0.077; F3, 0.097 and F4, 0.121 (P < 0.01). The area under the receiver operating characteristic curve of the red cell volume distribution width-toplatelet ratio for predicting significant fibrosis (≥F2) was 0.747. This result was inferior to transient elastography (0.866, P = 0.004), but comparable to FIB-4 (0.782, P = 0.427) and aspartate aminotransferase-to-platelet ratio index (0.716, P = 0.507). The area under the receiver operating characteristic curve of red cell volume distribution width-to-platelet ratio for predicting cirrhosis (F4) was 0.811, which was inferior to liver stiffness (0.915, P < 0.001), but comparable to FIB-4 (0.804, P = 0.805) and superior to aspartate aminotransferase-to-platelet ratio index (0.680, P < 0.001). Conclusions: The accuracy of red cell volume distribution width-to-platelet ratio was acceptable for the assessment of liver fibrosis in patients with chronic hepatitis B. When transient elastography is not available, red cell volume distribution width-to-platelet ratio assessment is a simple method that can be used to reduce the need for liver biopsy. [ABSTRACT FROM AUTHOR]

Purpose: The diagnosis and monitoring of liver fibrosis is an important clinical issue; however, this is usually achieved by invasive methods such as biopsy. We aimed to determine whether histogram analysis of hepatobiliary phase images of gadoxetic acid-enhanced magnetic resonance imaging (MRI) can provide non-invasive quantitative measurement of liver fibrosis. Methods: This retrospective study was approved by the institutional ethics committee, and a waiver of informed consent was obtained. Hepatobiliary phase images of preoperative gadoxetic acid-enhanced MRI studies of 105 patients (69 males, 36 females; age 56.1±12.2) with pathologically documented liver fibrosis grades were analyzed. Fibrosis staging was F0/F1/F2/F3/F4 (METAVIR system) for 11/20/13/15/46 patients, respectively. Four regions-of-interest (ROI, each about 2 cm2) were placed on predetermined locations of representative images. The measured signal intensity of pixels in each ROI was used to calculate corrected coefficient of variation (cCV), skewness, and kurtosis. An average value of each parameter was calculated for comparison. Statistical analysis was performed by ANOVA, receiver operating characteristic (ROC) curve analysis, and linear regression. Results: The cCV showed statistically significant differences among pathological fibrosis grades (P<0.001) whereas skewness and kurtosis did not. Univariable linear regression analysis suggested cCV to be a meaningful parameter in predicting the fibrosis grade (P<0.001, β = 0.40 and standard error  = 0.06). For discriminating F0-3 from F4, the area under ROC score was 0.857, standard deviation 0.036, 95% confidence interval 0.785–0.928. Conclusion: Histogram analysis of hepatobiliary phase images of gadoxetic acid-enhanced MRI can provide non-invasive quantitative measurements of hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Tumor behavior is affected by the tumor microenvironment, composed of cancer-associated fibroblasts (CAFs). Meanwhile, hepatocellular carcinomas (HCC) with fibrous stroma reportedly exhibit aggressive behavior suggestive of tumor-stroma interaction. However, evidence of the crosstalk remains unclear. In this study, CCN2, epithelial membrane antigen (EMA), fibroblast activation protein (FAP), and keratin 19 (K19) expression was studied in 314 HCCs (cohort 1), 42 scirrhous HCCs (cohort 2), and 36 chronic hepatitis/cirrhosis specimens by immunohistochemistry. Clinicopathological parameters were analyzed according to the expressions of these markers. In tumor epithelial cells from cohort 1, CCN2 and EMA were expressed in 15.3% and 17.2%, respectively, and their expressions were more frequent in HCCs with fibrous stroma (≥5% of tumor area) than those without (P<0.05 for all); CCN2 expression was well correlated with K19 and EMA expression. In tumor stromal cells, FAP expression was found in 6.7%. In cohort 2, CCN2, EMA, and FAP expression was noted in 40.5%, 40.5%, and 66.7%, respectively, which was more frequent than that in cohort 1 (P<0.05 for all). Additionally, EMA expression was associated with the expression of K19, CCN2, and FAP (P<0.05 for all); EMA expressing tumor epithelial cells showed a topographic closeness to FAP-expressing CAFs. Analysis of disease-free survival revealed CCN2 expression to be a worse prognostic factor in both cohort 1 (P = 0.005) and cohort 2 (P = 0.023), as well as EMA as a worse prognostic factor in cohort 2 (P = 0.048). In conclusion, expression of CCN2, EMA, and FAP may be involved in the activation of CAFs in HCC, giving rise to aggressive behavior. Significant correlation between EMA-expressing tumor cells and FAP-expressing CAFs and their topographic closeness suggests possible cross-talk between tumor epithelial cells and stromal cells in the tumor microenvironment of HCC. [ABSTRACT FROM AUTHOR]

Background: Preoperative liver stiffness (LS) measurement using transient elastography (TE) is useful for predicting late recurrence after curative resection of hepatocellular carcinoma (HCC). We developed and validated a novel LS value-based predictive model for late recurrence of HCC. Methods: Patients who were due to undergo curative resection of HCC between August 2006 and January 2010 were prospectively enrolled and TE was performed prior to operations by study protocol. The predictive model of late recurrence was constructed based on a multiple logistic regression model. Discrimination and calibration were used to validate the model. Results: Among a total of 139 patients who were finally analyzed, late recurrence occurred in 44 patients, with a median follow-up of 24.5 months (range, 12.4–68.1). We developed a predictive model for late recurrence of HCC using LS value, activity grade II-III, presence of multiple tumors, and indocyanine green retention rate at 15 min (ICG R15), which showed fairly good discrimination capability with an area under the receiver operating characteristic curve (AUROC) of 0.724 (95% confidence intervals [CIs], 0.632–0.816). In the validation, using a bootstrap method to assess discrimination, the AUROC remained largely unchanged between iterations, with an average AUROC of 0.722 (95% CIs, 0.718–0.724). When we plotted a calibration chart for predicted and observed risk of late recurrence, the predicted risk of late recurrence correlated well with observed risk, with a correlation coefficient of 0.873 (P<0.001). Conclusion: A simple LS value-based predictive model could estimate the risk of late recurrence in patients who underwent curative resection of HCC. [ABSTRACT FROM AUTHOR]

Large cell change (LCC) is a noncommittal term used today to indicate liver cell dysplasia of the large cell type. Dysplasia was deleted from the original definition because not enough evidence has been collected over time to support premalignancy. LCC is a microscopically well-defined lesion, usually found in cirrhosis, whose origin, natural history, and fate are still debated. Different morphologic, phenotypic, molecular and clinical studies have been performed to address the issue of the dysplastic versus reactive nature of this lesion. The aim of this review is to critically evaluate the contributions to the topic and to underline that the heterogeneity of the lesion is an important issue to be taken into account for our biological understanding of it. While LCC has important morphologic analogies in experimental liver carcinogenesis, no comparable lesions are known in solid non-liver parenchymal human tissues that morphologically feature dysplasia, but in which it is uncertain whether the lesions are reactive or preneoplastic. The debate over the lesion may be useful in learning the actual limits of morphology and how additional information can be gained by looking inside the cells. [Copyright &y& Elsevier]

Background and aims Progressive hepatocarcinogenesis is a stepwise process that drives liver transformation. However, the molecular mechanisms of early liver transformation are far from clear. A role for micro RNAs (mi RNA) as diagnostic and prognostic factors in human tumours, including hepatocellular carcinoma ( HCC), is promising. We aimed to identify novel mi RNA as biomarkers for differential diagnosis and predictors of disease progression. Methods We used a low-density array platform to profile the expression of 664 mature mi RNA in a cohort of 60 hepatitis C virus-positive liver lesions representative of all stages of progressive hepatocarcinogenesis. We validated selected mi RNA in two independent patient series by qPCR and we characterized the genomic status of the mi RNA cluster C19 MC by fluorescent in situ hybridization and copy-number variation analyses. Results A 18-mi RNA signature distinguished cirrhosis, dysplastic nodules and HCC lesions. Four mi RNAs overexpressed in HCCs belonged to chromosome 19 mi RNA cluster ( C19 MC). Significant overexpression of C19 MC in early HCC compared to dysplastic nodules could be confirmed in a second series of hepatitis B virus-related liver lesions ( n = 30). In a third series of 61 HCCs, C19 MC cluster was overexpressed in HCCs compared to matched cirrhotic parenchyma and regardless of the type of viral infection. High C19 MC mi RNA levels were correlated with poor clinico-pathological features, increased risk of tumour recurrence and shorter overall survival time. HCCs overexpressing the C19 MC cluster showed genetic amplification of the corresponding locus. Conclusions C19 MC cluster is a novel molecular alteration characteristic of liver cancer and predictor of poor prognosis. C19 MC is an attractive candidate for novel HCC therapies. [ABSTRACT FROM AUTHOR]

Backgrounds & Aims: The clinical severity of cirrhosis varies widely. We investigated whether histological sub-classification of cirrhosis using the Laennec system can discriminate different outcomes among patients with cirrhosis. Methods: One hundred and seventy-five patients with chronic liver disease who underwent liver biopsy and showed stage 3 or 4 fibrosis between January 2001 and December 2008 were prospectively enrolled. Cirrhosis was sub-classified into three groups (4A, 4B, and 4C) according to the Laennec system. The end point was liver-related event (LRE) occurrence, including decompensation, hepatocellular carcinoma, and liver-related death. Results: The median age of the patients (110 men, 65 women) was 55years. Stages 3, 4A, 4B, and 4C were identified in 46 (26.3%), 16 (9.1%), 82 (46.9%), and 31 (17.7%) patients, respectively. During the follow-up period, LREs occurred in 32 (18.3%) patients: 4 (8.7%) with stage 3, 2 (12.5%) with stage 4A, 17 (20.7%) with stage 4B, and 9 (29.0%) with stage 4C. In a multivariate analysis, histological sub-classification of cirrhosis independently predicted LRE occurrence. While patients with stage 4A tended to be at higher risk of LRE occurrence than those with stage 3, patients with stages 4B and 4C had significantly higher risks of LRE occurrence, with hazard ratios of 6.158 (p =0.016) and 8.945 (p =0.004), respectively. Conclusions: Histological sub-classification of cirrhosis using the Laennec system can be used to assess the risk of LRE occurrence among patients with cirrhosis. Our study provides a solid basis for further studies of non-invasive methods for monitoring the risk of LRE occurrence and will help physicians to establish optimum treatment strategies. [ABSTRACT FROM AUTHOR]