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The macroscopic appearance of a tumor such as hepatocellular carcinoma (HCC) may be defined as its phenotype which is de facto dictated by its genotype. Therefore, macroscopic characteristics of HCC are unlikely random but rather reflect genomic traits of cancer, presumably acting as a valuable source of information that can be retrieved and exploited to infer prognosis. This review aims to provide a comprehensive overview of the available data on the prognostic value of macroscopic characterization in HCC. A total of 57 studies meeting eligible criteria were identified, including patients undergoing liver resection (LR; 47 studies, 83%) or liver transplant (LT; 9 studies, 16%). The following macroscopic variables were investigated: tumor size (n = 42 studies), number of nodules (n = 28), vascular invasion (n = 24), bile duct invasion (n = 6), growth pattern (n = 15), resection margin (n = 11), tumor location (n = 6), capsule (n = 2) and satellite (n = 1). Although the selected studies provided insightful data with notable prognostic performances, a lack of standardization and substantial gaps were noted in the report and the analysis of gross findings. This topic remains incompletely covered. While the available studies underscored the value of macroscopic variables in HCC prognostication, important lacks were also observed. Macroscopic characterization of HCC is likely an underexploited source of prognostic factors that must be actively explored by future multidisciplinary research. [ABSTRACT FROM AUTHOR]

Introduction: GNS561/Ezurpimtrostat is a first-in-class, orally bioavailable, small molecule that blocks cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent build-up of enlarged lysosomes by interacting with the palmitoyl-protein thioesterase 1 (PPT1). Methods: This phase I, open-label, dose-escalation trial (3 + 3 design) explored two GNS561 dosing schedules: one single oral intake 3 times a week (Q3W) and twice daily (BID) continuous oral administration in patients with advanced hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma or colorectal adenocarcinomas with liver metastasis. The primary objective was to determine GNS561 recommended phase II dose (RP2D) and schedule. Secondary objectives included evaluation of the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of GNS561. Results: Dose escalation ranged from 50 to 400 mg Q3W to 200–300 mg BID. Among 26 evaluable patients for safety, 20 were evaluable for efficacy and no dose-limiting toxicity was observed. Adverse events (AEs) included gastrointestinal grade 1–2 events, primarily nausea and vomiting occurred in 13 (50%) and 14 (54%) patients, respectively, and diarrhea in 11 (42%) patients. Seven grade 3 AEs were reported (diarrhea, decreased appetite, fatigue, alanine aminotransferase, and aspartate aminotransferase increased). Q3W administration was associated with limited exposure and the BID schedule was preferred. At 200 mg BID GNS561, plasma and liver concentrations were comparable to active doses in animal models. Liver trough concentrations were much higher than in plasma a median time of 28 days of administration with a mean liver to plasma ratio of 9,559 (Min 149–Max 25,759), which is in accordance with rat preclinical data observed after repeated administration. PPT1 expression in cancer tissues in the liver was reduced upon GNS561 exposure. There was no complete or partial response. Five patients experienced tumor stable diseases (25%), including one minor response (−23%). Conclusion: Based on a favorable safety profile, exposure, and preliminary signal of activity, oral GNS561 RP2D was set at 200 mg BID. Studies to evaluate the antitumor activity of GNS561 in hepatocarcinoma cells and intrahepatic cholangiocarcinoma are to follow NCT 03316222. [ABSTRACT FROM AUTHOR]

Background & Aims: Vascular invasion is a major prognostic factor in hepatocellular carcinoma (HCC). We previously identified histone H4 acetylated at lysine 16 (H4K16ac), a histone modification involved in transcription activation, as a biomarker of microvascular invasion (mVI) in HCC. This study aimed to investigate the role of hMOF, the histone acetyltransferase responsible for H4K16 acetylation, in the process of vascular invasion in HCC. Methods: hMOF expression was assessed by RT‐qPCR and immunohistochemistry in a retrospective series of HCC surgical samples, and correlated with the presence of mVI. The functional role of hMOF in HCC vascular invasion was investigated in vitro in HCC cell lines using siRNA, transcriptomic analysis and transwell invasion assay, and in vivo using a Zebrafish embryo xenograft model. Results: We found that hMOF was significantly upregulated at the protein level in HCC with mVI, compared with HCC without mVI (P <.01). Transcriptomic analysis showed that hMOF downregulation in HCC cell line lead to significant downregulation of key genes and pathways involved in vascular invasion. These results were confirmed by transwell invasion assay, where hMOF downregulation significantly reduced HCC cells invasion. Finally, hMOF downregulation significantly reduced tumour cell intravasation and metastasis in vivo. Conclusions: Altogether, these results underpin a critical role for hMOF in vascular invasion in HCC, via transcription activation of key genes involved in this process. These data confirm the major role of epigenetic alterations in HCC progression, and pave the way for future therapies targeting hMOF in HCC. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to compare survival outcomes in patients enlisted for liver transplantation following liver resection for hepatocellular carcinoma before or at recurrence.Methods: All patients enlisted for liver transplantation following liver resection for hepatocellular carcinoma from 1996 to 2013 were included and compared according to their status at the time of enlistment: before (de principe) or at (salvage) recurrence. Primary end-point was survival since resection.Results: One hundred and twenty-one patients were enlisted for liver transplantation following liver resection for hepatocellular carcinoma. Ten patients enlisted for cirrhosis decompensation were excluded from the analysis. Sixty-three patients were enlisted de principe, and 48 for a salvage transplantation. Eleven patients dropped-out. According to per-protocol analysis, the mean diameter of the largest tumor was the only different pathological characteristic of initial resection between groups (31.6 mm in the de principe group versus 48.3 in the salvage, p = 0.017). The 5-year overall survival rate was significantly increased in the de principe group compared to salvage (84.6 versus 74.8%, p = 0.017). In a multivariate analysis, the salvage strategy was the only independent prognostic factor for death (p = 0.040; OR = 2.5 [1.1-5.8]).Conclusion: De principe enlistment for liver transplantation following liver resection for hepatocellular carcinoma is associated with greater survival. [ABSTRACT FROM AUTHOR]

A variety of vascular liver disorders can induce hepatocellular tumors. They may be related to portal venous deprivation, venous outflow obstruction, or arterial diseases. Their common feature is an imbalance between hepatic arterial and portal venous blood flow leading to an increased hepatic arterial inflow. Consequently, hepatocellular tumors may arise, most commonly focal nodular hyperplasia-like lesions but hepatocellular adenomas and hepatocellular carcinoma may be seen as well. This article will review the most common vascular liver diseases associated with hepatocellular nodules (Budd-Chiari syndrome, congenital portosystemic shunt, hereditary hemorrhagic telangiectasia, and portal cavernoma). For each condition, imaging findings will be described as well as the differential diagnosis and the diagnostic clues. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Microvascular invasion (mVI) is a major prognostic factor in hepatocellular carcinoma (HCC) that cannot be detected before surgery. Predictive biomarkers of mVI are thus urgently needed. We have developed an original approach of virtual biopsy to assess the performance of an immunohistochemical panel comprising three biomarkers of mVI (H4K16ac, H4K20me2, PIVKA‐II) for the prediction of mVI in HCC core needle biopsies (CNB). Methods: A test set of HCC surgical specimens (n = 64) and an independent validation set of HCC CNB (n = 42) were retrospectively constituted. Immunostainings were first quantified in the test set on the whole tissue section, to determine optimal cut‐off values for each marker. From the digitised image of the whole section, three virtual biopsies were provided. Immunostainings and accuracy of the panel for the prediction of mVI were further assessed in virtual biopsies and in the validation set of CNB. Results: In virtual biopsies, PIVKA‐II/H4K16ac had the best performance for prediction of mVI, with sensitivity, specificity, predictive positive value (PPV), and predictive negative value (PNV) of 30%, 97%, 91%, 56%, respectively. In CNB, PIVKA‐II/H4K20me2 showed the best accuracy for prediction of mVI, with sensitivity, specificity, PPV, and NPV of 43%, 95%, 90%, and 62%, respectively. The two panels were independent predictive factors of mVI (PIVKA‐II/H4K16ac, P = .037; PIVKA‐II/H4K20me2, P = .026). Conclusion: This study shows that a panel of two markers is able to predict mVI in HCC CNB, and pave the way for the future development of prognostic biomarkers in HCC that could guide the therapeutic strategy. [ABSTRACT FROM AUTHOR]

Summary Hepatocellular adenomas (HCA) are rare benign liver tumors occurring in young women taking contraception. They are associated with rare complications such as bleeding or malignant transformation into hepatocellular carcinoma. A molecular classification has divided HCA in several subgroups linked with risk factors, clinical behaviour, histological features and imaging: HNF1A inactivated HCA, Inflammatory HCA, CTNNB1 mutated HCA in exon 3, CTNNB1 mutated in exon 7 and 8 HCA, sonic hedgehog HCA and unclassified HCA. CTNNB1 mutated HCA in exon 3 and sonic hedgehog HCA have been linked with a high risk of malignant transformation and bleeding respectively. Herein, we review how molecular classification has modified our understanding of the pathophysiology and risk factors of HCA development, analysing its impact on clinical care in the field of diagnosis and therapeutic stratification. [ABSTRACT FROM AUTHOR]

Background & Aims A broad range of hepatocellular nodules has been reported in hepatic vascular disorders. It is not clear whether hepatocellular adenoma (HCA) in this context share the same characteristics as conventional HCA. The aim of this study was to carry out a retrospective multicenter survey of hepatocellular nodules associated with hepatic vascular disorders. Methods Forty-five cases were reviewed, including 32 Budd-Chiari syndrome (BCS). Benign nodules were subtyped using the HCA immunohistochemical panel. Results Nodules with a HCA morphology were observed in 11 cases. Six originated in BCS: two were liver fatty acid binding protein (LFABP) negative (one with malignant transformation); two expressed glutamine synthetase (GS) and nuclear b-catenin, two expressed C reactive protein (CRP). Among three cases with portal vein agenesis, one nodule was LFABP negative, two expressed GS and nuclear b-catenin, both with malignant transformation. In a Fallot tetralogy case, there were multiple LFABP negative nodules with borderline features and in a hepatoportal sclerosis case, the nodule looked like an inflammatory HCA. Two additional cases had nodules expressing CRP, without typical characteristics of inflammatory HCA. Conclusion HCA of different immunohistochemical phenotype can develop in hepatic vascular disorders; they may have a different behavior compared to conventional HCA and be more at risk of malignant transformation. [ABSTRACT FROM AUTHOR]

Background & Aims Although potentially very useful in optimizing patient selection and follow-up, the individual response to transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) is generally unpredictable. The aim of this study was to identify tissue predictors of tumour resistance to TACE for use in clinical practice on pretreatment biopsies. Methods We investigated the association of residual tumour in post-TACE-resected HCC with pathological and immunophenotypical features, mainly related to hypoxia and angiogenesis. Comparison of tumour phenotype between post-TACE HCC and both paired pre-TACE biopsies and control TACE-untreated HCC was performed. Cases showing >50% residual tumour (RT) were defined as TACE-resistant. Results A consecutive series of 108 HCC from 41 patients was studied. Overall, 45/108 (44%) HCC were classified as TACE-resistant. Among these, 32 (71%) and 40 (89%) showed diffuse CD34 vascular staining and negative VEGF staining respectively (p<0.05). The association of these two parameters in a weighted score (TRIP) was able to predict TACE resistance with 81% accuracy, 89% sensitivity and 59% specificity. The effectiveness of TRIP was validated in an independent series of 28 HCC biopsies from patients subsequently treated with TACE and for whom radiological follow-up was available. Conclusions This study demonstrates the potential value of pretreatment tumour biopsy as predictors of TACE resistance in HCC. [ABSTRACT FROM AUTHOR]

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BACKGROUND: The purpose of the current study was to describe pure and mixed fibrolamellar hepatocellular carcinoma (FL-HCC). METHODS: Consecutive patients with pure and mixed FL-HCC were identified from a central pathological review using Edmondson's criteria. Clinical, pathological, and epigenetic characteristics of patients who underwent curative surgery were evaluated. Overall and disease-free survival as well as patterns of disease recurrence were examined. Methylation levels of L1 retrotransposon ( LINE-1) repetitive elements and Ras association domain family 1A gene ( RASSF1) promoter were also assessed using pyrosequencing. RESULTS: Forty of 53 patients with a median age of 22 years (range, 9 years-;65 years) met the criteria for analysis. Central pathological review found that 30 patients (75%) had pure and 10 patients (25%) had mixed FL-HCC. Pure FL-HCC typically occurred in patients aged < 30 years. These patients often presented with lymph node metastasis at the time of diagnosis and frequently experienced extrahepatic recurrences (n = 16). Conversely, mixed FL-HCC appeared to resemble to classic HCC, occurring in patients aged > 40 years and frequently involving the liver as the primary site of disease recurrence. With a median follow-up of 7.8 years, the median overall survival from the time of diagnosis in all patients was 6.4 years (range, 3.2 years-12 years). Multivariate analysis found that the risk of death was increased in patients with higher American Joint Committee on Cancer disease stages ( P = .003) and those with mixed FL-HCC ( P = .03). Methylation analysis of LINE-1 repetitive elements and RASSF1 promoter revealed different methylation levels between pure and mixed FL-HCC, suggesting a different epigenetic background. CONCLUSIONS: Pure and mixed FL-HCC display distinct clinical presentations and epigenetic backgrounds leading to different prognoses and as such may be regarded as separate clinical entities. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

We report two cases of locally advanced hepatocellular carcinoma (HCC) with portal vein tumour thrombosis (PVTT) who complete regression by sorafenib treatment allowed curative resection. Two male adult (59 and 57 years) cirrhotic patients with HCC associated with PVTT including one with lymph node involvement had elevated α-fetoprotein level (AFP) (867 and 17 000) and were treated with standard sorafenib treatment during 10 and 12 months respectively. Size decrease of the main tumour, disappearance of PVTT and normalization of AFP allowed curative surgical resection. No viable tumour cells were found in the specimen and the two patients are currently alive without recurrence 12 and 16 months after surgery. These first two cases of complete tumour necrosis after sorafenib treatment allow us to reconsider surgical treatment in patients with unresectable HCC responding to this medical treatment. [ABSTRACT FROM AUTHOR]

Summary: Glypican-3 (GPC3), a member of heparan sulfate proteoglycans, plays a role in cell growth, differentiation, and migration. The objectives of this study were to assess the diagnostic value of GPC3 immunostaining in hepatocellular carcinomas (HCCs) and to analyze its expression profile in preneoplastic lesions. Tissue microarrays were built by sampling 54 HCCs and adjacent liver tissues (21 developing from cirrhosis and 33 from normal liver) and 94 cirrhotic macronodules. Fourteen typical liver cell adenomas and 5 with malignant foci were also included. Sections were assessed for GPC3 expression by immunohistochemistry. GPC3 staining was observed in 19 (90%) of 21 HCC cases with cirrhosis and in 18 (64%) of 28 HCC cases with normal liver (P < .01). When staining was positive, it was both membranous and cytoplasmic. Positive staining was observed in 1 case of nonneoplastic adjacent liver. In cases of adenomas, only malignant foci were positive. Among the 94 macronodules, GPC3 immunostaining was noted in 48% (14/29) of high-grade dysplastic or early HCC and in 3% (2/65, P < .001) of benign or low-grade dysplastic macronodules. This study shows that GPC3 is an efficient diagnostic marker of HCC, potentially useful in the differential diagnosis of liver cell adenomas and well-differentiated HCC. Our results also suggest that GPC3 may be considered as an early marker of liver carcinogenesis because it is able to identify some cirrhotic macronodules with malignant potential. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies" by H. P. Chen and others in the 2013 issue.

Imaging and pathology can be considered as two sides of the same diagnostic coin. Yet, pathology remains the gold-standard technique for the diagnosis of most diseases. Nevertheless, significant and constant progress in imaging has been made thanks to fruitful rad-path correlations. The aim of this article is to show how much imaging has benefited from pathology and to illustrate the different ways in which imaging has evolved according to different types of pathological references. Imaging of hepatocellular carcinoma shows how image-based knowledge and expertise can be exploited to yield a non-invasive diagnosis approaching that of a fixed, robust pathological reference. Hepatocellular adenomas provide an example of the constant radiological evolutions triggered by changing pathological definitions. Finally, hepatic steatosis illustrates the possibility for imaging to surpass its historical reference, and become a new gold-standard. For these three examples, we have taken a historical approach to demonstrate how rad-path interminglement creates knowledge. [ABSTRACT FROM AUTHOR]

Background & Aims: Based on the success of sorafenib, several anti-angiogenic therapies are currently evaluated in advanced hepatocellular carcinomas. Few biological data are currently available from patients that may help understanding mechanisms of acquired resistance to these drugs. Herein, we report translational data from a post-treatment surgical specimen in a patient who experienced acquired resistance to sunitinib. Methods: Clinical, radiological, and pathological data were collected before treatment, under treatment, and at the time of tumor progression. In addition, a biomolecular analysis was performed at the time of progression. Results: In this patient with non-alcoholic steatohepatitis, initial response to sunitinib was followed by tumor progression within 6months of treatment, requesting salvage surgical resection. Surprisingly, pathological examination on post-treatment specimens revealed the presence of two juxtaposed tissue components containing either sarcomatoid-like mesenchymal cells or well- to moderately-differentiated hepatocellular carcinoma cells. Cancer cells retain a high α-fetoprotein expression in both components. However, while cells from carcinoma expressed E-cadherin but no vimentin, cancer cells from the mesenchymal component highly expressed vimentin and lost E-cadherin protein expression as measured by immunostaining. HMGA2 and Ki67 mRNA were also expressed at higher levels in mesenchymal than in carcinoma cells. Conclusion: This case report suggests the occurrence of an epithelial-to-mesenchymal transition in discrete areas of hepatocellular carcinomas developing resistance to sunitinib. [Copyright &y& Elsevier]

Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis. Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti- TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model. Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model. Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti- TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti- TERT ASO treatment in HCC clinical trials. Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides. [Display omitted] • Age, sex, fibrosis and alcohol modulate liver telomere attrition. • Liver telomere length associates with variable HCC clinical and molecular subtypes. • HCC tumor telomere length is influenced by liver and tumor factors. • HCC cancer cells show actionable oncogenic addiction to TERT activation. [ABSTRACT FROM AUTHOR]

DNAJB1 - PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) that occurs in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered. A series of 151 liver tumors including 126 HCC, 15 FLC, and 10 mixed-FLC/HCC were analyzed by RNAseq and whole-genome- or whole-exome sequencing. Western blots were performed to validate genomic discoveries. Results were validated using the TCGA database. Most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of 17 tumors, which all had mutations or translocations inactivating BAP1 , the gene encoding BRCA1-associated protein-1. Like FLC, BAP1-HCC were significantly enriched in females, patients with a lack of chronic liver disease, and fibrotic tumors compared to non-BAP1 HCC. However, patients were older and had a poorer prognosis than those with FLC. BAP1 tumors were immune hot, showed progenitor features and did not show DNAJB1 - PRKACA fusion, while almost none of these tumors had mutations in CTNNB1 , TP53 and TERT promoter. In contrast, 80% of the BAP1 tumors showed a chromosome gain of PRKACA at 19p13, combined with a loss of PRKAR2A (coding for the inhibitory regulatory subunit of PKA) at 3p21, leading to a high PRKACA/PRKAR2A ratio at the mRNA and protein levels. We have characterized a subgroup of BAP1 -driven HCC with fibrolamellar-like features and a dysregulation of the PKA pathway, which could be at the root of the clinical and histological similarities between BAP1 tumors and DNAJB1 - PRKACA FLCs. Herein, we have defined a homogeneous subgroup of hepatocellular carcinomas in which the BAP1 gene is inactivated. This leads to the development of cancers with features similar to those of fibrolamellar carcinoma. These tumors more frequently develop in females without chronic liver disease or cirrhosis. The presence of PKA activation and T cell infiltrates suggest that these tumors could be treated with PKA inhibitors or immunomodulators. • BAP1 -inactivating alterations define a homogeneous subgroup of HCC characterized by fibrolamellar-like features. • These tumors frequently develop in females, with non-cirrhotic livers. • Patients with BAP1-inactivated HCC could benefit from drugs inactivating PKA and immunomodulators. [ABSTRACT FROM AUTHOR]

Objective: To investigate the long-term oncological outcome of patients with resectable hepatocellular carcinoma (HCC) undergoing sequential transarterial chemoembolization (TACE) and portal vein embolization (PVE). Methods: Analysis of all Child A HCC patients who underwent TACE-PVE before major liver resection from 2006 to 2012 was performed according to whether or not they underwent surgical resection as planned. Results: 54 patients (50 men, 93% median 69-years (range 44-87)) were included. Thirty-nine (72%) patients underwent resection, including 19/25, 16/23, and 4/6 of patients with BCLC A, B, and C (p = 0.839). Twenty-two (56%) had tumor recurrence (median delay 10 months) including 9/19, 11/16, and 2/4 of the patients with BCLC A, B, and C (p = 0.430). Survival was significantly better in resected patients as compared to those who were not resected (median overall survival (OS): 44 vs. 18 months; p < 0.001). Recurrence was associated with a poorer prognosis as compared to patients without recurrence (median OS 43 months vs. not reached; p < 0.001). BCLC stage did not influence survival (p = 0.13). Conclusion: In patients with large unilobar HCC, TACE-PVE leads to resection in most patients, with a good oncological outcome regardless of the tumor burden. When this strategy fails, patients can be managed with TACE despite prior PVE. [ABSTRACT FROM AUTHOR]

Background & Aims Prothrombin induced by vitamin K absence-II (PIVKA-II) is a diagnostic and surveillance marker for HCC mainly used in Asia, and has also been shown to be a predictor of microvascular invasion (MVI), a major prognostic factor in HCC. However, experience with PIVKA-II in Europe remains limited. Methods In a French cohort, we conducted a case-control study to compare the performances of α-fetoprotein (AFP) and PIVKA-II serum levels for diagnosis of early stage HCC, and we determined the value of PIVKA-II serum and tissue expression in pre-operative detection of MVI. 43 cirrhotic control patients and 85 HCC cases were included, of which 54 (63.5%) had early stage HCC (n = 22 very early, n = 32 early). PIVKA-II tissue expression was assessed by immunohistochemistry in HCC surgical samples. Results For the diagnosis of early HCC, PIVKA-II had a sensitivity of 77% and a specificity of 82% at a cut-off of 42 mAU/ml, vs. 61% and 50% for AFP at a cut-off of 5.5 ng/ml (AUC 0.81 vs. 0.58, respectively). A PIVKA-II level >90 mAU/ml was an independent predictor of MVI (HR 3.5; 95% CI 1.08–11.8; p = 0.043). High PIVKA-II tissue expression was significantly associated with the presence of MVI ( p = 0.001). When combining PIVKA-II immunostaining with the PIVKA-II serum level, sensitivity and specificity for the diagnosis of MVI increased from 70% to 87% and 63% to 90%, respectively. Conclusions PIVKA-II was more efficient than AFP for the diagnosis of early HCC, and could be used as a predictive biomarker of MVI. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MS) is becoming the leading cause of chronic liver diseases worldwide. Hepatocellular carcinoma (HCC) development in MS is peculiar compared to other chronic liver diseases. Carbohydrate and lipid metabolic imbalance in MS increase reactive oxygen species damaging proteins. In the present work we study the difference in protein oxidative damage (carbonylation) in human HCC derived from virus C infection (VHC) and from MS (MS_HCC) as the only subjacent cause. We selected a patient cohort containing of 10 non-tumoral and 10 tumoral liver resections in each study group (virus C and MS HCC) based on clinical patient history and histological parameters. Protein samples were labeled to saturation using CF 647-hydrazide™ dye. This approach allows us to perform carbonyl detection alongside with a DIGE experiment. We detected a total of 1184 spots with 36 differentially expressed proteins and 47 spots differentially carbonylated between VHC and MS_HCC (fold change >1.5, p<0.05). VHC up-regulated proteins are involved in signaling pathways related to cancer development such as signaling by EGFR, Wnt, Cdc20 and cell cycle. Further, up-regulated proteins in MS HCC, are implicated in metabolism of carbohydrates and amino acids. Differential carbonylation analysis between VHC and MS_HCC showed protein damage in proteins such as glucose phosphate isomerase, isocitrate dehydrogenase, and 3-ketoacyl-CoA thiolase. Higher protein carbonylation in MS_HCC samples was observed in proteins involved in redox response and lipid metabolism. In conclusion, the observed difference in protein oxidative damage between MS and Virus C derived carcinoma could account for the different cancer development pathway. [ABSTRACT FROM AUTHOR]

Background/Aims: Hepatic cholangiocarcinomas are tumors with poor prognosis and with increasing incidence worldwide. The aim of the study was to compare morphological features and protein profiles of hilar and peripheral cholangiocarcinomas. Methods: Clinicopathological data were collected from 111 cholangiocarcinomas (59 peripheral and 52 hilar). Protein expression, assessed on tissue samples using tissue microarray and protein array technologies, was compared between both types of tumors and with extrahepatic cholangiocarcinoma and hepatocholangiocarcinoma. Results: Hilar cholangiocarcinomas were smaller in size (mean: 2.7 vs. 8cm, p <0.001), were more often well differentiated adenocarcinomas (65% vs. 36% well differentiated, p <0.01) and carried out stronger perineural invasion (83% vs. 42%, p <0.001) than peripheral cholangiocarcinomas. Regarding protein expression, hilar cholangiocarcinomas more often expressed MUC5AC (62% vs. 22%, p <0.0001), Akt2 (54% vs. 27%, p <0.001), CK8 (98% vs. 81%, p <0.005) and annexin II (92% vs. 66%, p <0.001). Interestingly, VEGF A expression was more frequently encountered in peripheral cholangiocarcinoma (69% vs. 25%, p <0.0001) and correlated with increased vascular density. Using protein array antibody, we identified filamin A as significantly overexpressed (>2-fold) in peripheral cholangiocarcinomas. Conclusions: Our results show that hilar and peripheral cholangiocarcinomas display specific protein profiles, especially regarding VEGF expression. This suggests a potential benefit for anti-angiogenic therapies in peripheral hepatic CCs. [Copyright &y& Elsevier]

Purpose: To compare the features of hepatocellular adenoma subtypes (HCAs) in B-mode and contrast-enhanced ultrasound (CEUS).Method: Thirty-three patients (31 women [94 %] and two men [6%], median age [Q1-Q3] 43.5 years old [35-51]) with 44 pathologically proven and subtyped HCAs (including 29 inflammatory HCAs [I-HCA] and 15 HNF1-α inactivated HCAs [H-HCA]) who underwent CEUS were included. The features of HCA on B-mode and CEUS were independently reviewed by two radiologists and compared between HCA subtypes.Results: I-HCAs were mostly hypoechoic (23/29, 79 %) or isoechoic (4/29, 14 %) with B-mode. Twelve of them (41 %) were heterogeneous. All H-HCAs except one demonstrated homogeneous hyperechogenicity (93 %) (p = 0.001). Moderate or marked liver steatosis was only observed in I-HCAs (12/29, 41 %) (p = 0.001). Arterial hyperenhancement was observed on CEUS in 27/29 (93 %) I-HCAs and in 14/15 (93 %) H-HCAs (p=0.98). Washout was present in 6/29 (21 %) I-HCAs and 1/15 (7%) H-HCAs (p=0.27). A total of 23/29 (79 %) I-HCAs and 15/15 (100 %) HCAs were homogeneous on portal and delayed phase acquisitions (p=0.04). The specificity for identifying an H-HCA was 100 % when the lesion was homogeneous and hyperechoic on B-mode, and the sensibility to rule out an H-HCA was 100 % if neither of these two features was present in a liver with obvious steatosis.Conclusions: Most CEUS features, especially enhancement patterns, do not significantly differ between HCA subtypes. When HCA is suspected on CEUS, B-mode features should be considered, and a combination of lesion hyperechogenicity, homogeneity and the absence of obvious liver steatosis may be useful to distinguish H-HCAs from I-HCAs. [ABSTRACT FROM AUTHOR]