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Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 05/2013; 32(5):889-90. · 1.25 Impact Factor
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Jean-Charles Nault,
Aurélien de Reyniès,
Augusto Villanueva,
Julien Calderaro,
Sandra Rebouissou,
Gabrielle Couchy,
Thomas Decaens,
Dominique Franco,
Sandrine Imbeaud,
Francis Rousseau,
Daniel Azoulay,
Jean Saric,
Jean-Frédéric Blanc,
Charles Balabaud, Paulette Bioulac-Sage,
Alexis Laurent,
Pierre Laurent-Puig,
Josep M Llovet,
Jessica Zucman-Rossi
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ABSTRACT: BACKGROUND & AIMS: Due to the phenotypic and molecular diversity of hepatocellular carcinomas (HCC), it is a challenge to determine patients' prognosis. We aimed to identify new prognostic markers of patients with HCC treated by liver resection. METHODS: We collected 314 HCC samples from patients at Bordeaux (1998-2007) and Créteil (2003-2007) hospitals in France. We analyzed the gene expression patterns of the tumors and compared expression patterns with patient survival times. Using the coefficient and regression formula of the multivariate Cox model, we identified a '5-gene score' associated with survival times. This molecular score was then validated in 2 groups of patients from Europe, the United States (n=213), and China (n=221). RESULTS: The 5-gene score, based on combined expression level of HN1, RAN, RAMP3, KRT19, and TAF9, was associated with disease-specific survival times of 189 patients with resected HCC in Bordeaux (hazard ratio [HR], 3.5; 95% confidence interval [CI], 1.9-6.6; P<.0001). The association between the 5-gene score and disease-specific survival was validated in an independent cohort of 125 patients in Créteil (HR, 2.3; 95% CI, 1.1-4.9; P<.0001). The 5-gene score more accurately predicted patient outcomes than previously reported gene expression signatures. In multivariate analyses, the 5-gene score was associated with disease specific survival, independently of other clinical and pathology feature of HCC. Disease-specific survival was also predicted by combining data on microvascular invasion, the Barcelona Clinic Liver Cancer classification system, and the 5-gene score in a nomogram. The prognostic accuracy of the 5-gene score was further validated in European and US patients with hepatitis C, cirrhosis, and HCC (overall survival P=.002) and Asian patients with HCC with hepatitis B (overall survival, P=.02). Combining the 5-gene score with the expression pattern of 186 genes in corresponding cirrhotic tissues increased its prognostic accuracy. CONCLUSION: The molecular 5-gene score is associated with outcomes of patients with HCC treated by resection in different clinical settings worldwide. This new biomarker should be tested in clinical trials to stratify patients in therapeutic decision.
Gastroenterology 04/2013; · 11.68 Impact Factor
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Andrew R Hall,
Amar P Dhillon,
Anna C Green,
Linda Ferrell,
James M Crawford,
Venancio Alves,
Charles Balabaud,
Prithi Bhathal, Paulette Bioulac-Sage,
Maria Guido,
Prodromos Hytiroglou,
Yasuni Nakanuma,
Valerie Paradis,
Alberto Quaglia,
Dale Snover,
Neil Theise,
Swan Thung,
Wilson Tsui,
Dirk J van Leeuwen
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ABSTRACT: BACKGROUND & AIMS: Evaluate in liver biopsies: (i) interobserver agreement of estimates of fat proportionate area (eFPA) and steatosis grading, (ii) the relationship between steatosis grades and measured fat proportionate area (mFPA, digital image analysis), (iii) the accuracy of eFPA, (iv) to present images to aid standardization and accuracy of eFPA. METHODS: Twenty-one liver biopsies were selected from the Royal Free Hospital (RFH) histopathology archive to represent the full range of histopathological steatosis severity. As many non-overlapping fields of parenchyma as possible were photographed at ×20 objective magnification from the biopsies (n = 651). A total of 15 sample images were selected to represent the range of steatosis seen. Twelve hepatopathologists from 11 sites worldwide independently evaluated the sample images for steatosis grade [normal (none)/mild/moderate/severe], and eFPA (% area of liver parenchyma occupied by fat). RESULTS: The hepatopathologists had good linear correlation between eFPA and mFPA for sample images (r = 0.924, P < .001) and excellent concordance (kappa = 0.91, P < 0.001). Interobserver concordance of steatosis grade showed 'substantial agreement' (kappa = 0.64). There was significant difference between eFPA and mFPA in the sample images for mild, moderate and severe steatosis (P = 0.024, P < 0.001, P < 0.001 respectively): the observers consistently over-estimated the eFPA. CONCLUSION: Hepatopathologists showed 'excellent' interobserver agreement in eFPA and 'substantial' agreement in assigning steatosis grade (precision was high). However, compared with mFPA, eFPA was inaccurate. eFPA systematically exceeds mFPA; generally the overestimation increases with severity of steatosis. Considering that non-invasive technologies for estimating liver fat utilize histopathology as reference, such assessments would benefit from quantitative validation of visually estimated microscopic liver fat percentages.
Liver international: official journal of the International Association for the Study of the Liver 03/2013; · 3.82 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) is one of the commonest causes of death from cancer. A plethora of metabolomic investigations of HCC have yielded molecules in biofluids that are both up- and downregulated but no real consensus has emerged regarding exploitable biomarkers for early detection of HCC. We report here a different approach, a combined transcriptomics and metabolomics study of energy metabolism in HCC. A panel of 31 pairs of HCC tumors and corresponding non-tumor liver tissues from the same patients was investigated by gas chromatography-mass spectrometry (GCMS) based metabolomics. HCC was characterized by approximately two-fold depletion of glucose, glycerol 3- and 2-phosphate, malate, alanine, myo-inositol, and linoleic acid. Data are consistent with a metabolic remodeling involving a four-fold increase in glycolysis over mitochondrial oxidative phosphorylation. A second panel of 59 HCC that had been typed by transcriptomics and classified in G1 to G6 subgroups was also subjected to GCMS tissue metabolomics. No differences in glucose, lactate, alanine, glycerol 3-phosphate, malate, myo-inositol or stearic acid tissue concentrations were found, suggesting that the Wnt/β-catenin pathway activated by CTNNB1 mutation in subgroups G5 and G6 did not exhibit specific metabolic remodeling. However, subgroup G1 had markedly reduced tissue concentrations of 1-stearoylglycerol, 1-palmitoylglycerol, and palmitic acid, suggesting that the high serum α-fetoprotein phenotype of G1, associated with the known overexpression of lipid catabolic enzymes, could be detected through metabolomics as increased lipid catabolism. Conclusion: Tissue metabolomics yielded precise biochemical information regarding HCC tumor metabolic remodeling from mitochondrial oxidation to aerobic glycolysis and the impact of molecular subtypes on this process. (Hepatology 2013.)
Hepatology 03/2013; · 11.66 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) is one of the commonest causes of death from cancer. A plethora of metabolomic investigations of HCC have yielded molecules in biofluids that are both up- and downregulated but no real consensus has emerged regarding exploitable biomarkers for early detection of HCC. We report here a different approach, a combined transcriptomics and metabolomics study of energy metabolism in HCC. A panel of 31 pairs of HCC tumors and corresponding non-tumor liver tissues from the same patients was investigated by gas chromatography-mass spectrometry (GCMS) based metabolomics. HCC was characterized by approximately two-fold depletion of glucose, glycerol 3- and 2-phosphate, malate, alanine, myo-inositol, and linoleic acid. Data are consistent with a metabolic remodeling involving a four-fold increase in glycolysis over mitochondrial oxidative phosphorylation. A second panel of 59 HCC that had been typed by transcriptomics and classified in G1 to G6 subgroups was also subjected to GCMS tissue metabolomics. No differences in glucose, lactate, alanine, glycerol 3-phosphate, malate, myo-inositol or stearic acid tissue concentrations were found, suggesting that the Wnt/β-catenin pathway activated by CTNNB1 mutation in subgroups G5 and G6 did not exhibit specific metabolic remodeling. However, subgroup G1 had markedly reduced tissue concentrations of 1-stearoylglycerol, 1-palmitoylglycerol, and palmitic acid, suggesting that the high serum α-fetoprotein phenotype of G1, associated with the known overexpression of lipid catabolic enzymes, could be detected through metabolomics as increased lipid catabolism. Conclusion: Tissue metabolomics yielded precise biochemical information regarding HCC tumor metabolic remodeling from mitochondrial oxidation to aerobic glycolysis and the impact of molecular subtypes on this process. (Hepatology 2013.)
Hepatology 03/2013; · 11.66 Impact Factor
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ABSTRACT: Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are benign hepatocellular tumors that develop most frequently in women without cirrhosis. Genomic approaches have identified signaling pathways related to these benign hepatocyte proliferations. FNH, a polyclonal lesion, is characterized by local vascular abnormalities and heterogenous activation of WNT-β-catenin and transforming growth factor-β signaling. Four major subgroups of HCA have been identified, based on mutations in specific oncogenes and tumor suppressor genes. Each molecular subtype of HCA has been associated with specific pathways, providing new information about benign tumorigenesis. Key features include metabolic alterations (induced by defects in HNF1A), oncogene-induced inflammation (activation of the JAK-STAT signaling in inflammatory adenomas), and an association between activation of WNT-β-catenin signaling and progression of HCAs within hepatocellular carcinomas. Benign hepatocellular tumors can be classified using immunohistochemical analyses. Studies of genotypes and phenotypes of FNH and HCAs have led to the identification of risk factors and improved invasive and non-invasive diagnostic techniques, evaluation of prognosis, and treatment. We review the molecular pathways involved in benign hepatocyte proliferation and discuss how this basic knowledge has been progressively translated into personalized clinical care.
Gastroenterology 02/2013; · 11.68 Impact Factor
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Stefano Cairo,
Carolina Armengol,
Aurélien De Reyniès,
Yu Wei,
Emilie Thomas,
Claire-Angélique Renard,
Andrei Goga,
Asha Balakrishnan,
Michaela Semeraro,
Lionel Gresh, [......],
François Plenat,
Dominique Zachar,
Madeleine Joubert,
Janick Selves,
Dominique Pasquier, Paulette Bioulac-Sage,
Michael Grotzer,
Margaret Childs,
Monique Fabre,
Marie-Annick Buendia
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Stefano Cairo,
Carolina Armengol,
Aurélien De Reyniès,
Yu Wei,
Emilie Thomas,
Claire-Angélique Renard,
Andrei Goga,
Asha Balakrishnan,
Michaela Semeraro,
Lionel Gresh, [......],
François Plenat,
Dominique Zachar,
Madeleine Joubert,
Janick Selves,
Dominique Pasquier, Paulette Bioulac-Sage,
Michael Grotzer,
Margaret Childs,
Monique Fabre,
Marie-Annick Buendia
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ABSTRACT: Objectives- Acoustic radiation force impulse (ARFI) technology represents an innovative method for the quantification of tissue elasticity. The aims of this study were to evaluate elasticity by ARFI in both liver tumors and background liver tissue and to compare ARFI measurements with histologic data in liver tumors and background liver. Methods- Seventy-nine tumors were prospectively studied: 43 benign and 36 malignant. Acoustic radiation force impulse measurements for each tumor type were expressed as mean ± standard deviation for both liver tumors and background liver; ARFI data were also correlated with histologic data. Results- For liver tumors, the mean stiffness values were 1.90 ± 0.86 m/s for hepatocellular adenoma (n = 9), 2.14 ± 0.49 m/s for hemangioma (n = 15), 3.14 ± 0.63 m/s for focal nodular hyperplasia (n = 19), 2.4 ± 1.01 m/s for hepatocellular carcinoma (n = 24), and 3.0 ± 1.36 m/s for metastasis (n = 12). Important variations were observed within each tumor type or within a single tumor. These variations could have been due to necrosis, hemorrhage, or colloid. There was no statistically significant difference between the benign and malignant groups. Regarding background liver, it was possible to observe pathologic abnormalities in histologic analyses or liver function tests to explain the ARFI data. The degree of fibrosis was not the only determinant of liver stiffness in background liver; other factors such as portal embolization, sinusoidal obstruction syndrome caused by chemotherapy, and cholestasis, also could have interfered. Conclusions- Acoustic radiation force impulse elastography could not allow differentiation between benign and malignant tumors. This study provides a better understanding of the correlation between ARFI and histologic data for both tumors and background liver.
Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 01/2013; 32(1):121-30. · 1.25 Impact Factor
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ABSTRACT: Immunohistochemistry is a valid method to classify hepatocellular adenoma (HCA). The aim was to test the performance of routine histology combined to glutamine synthetase (GS) staining to identify the 2 major HCA subtypes: HNF1 α inactivated (H-HCA) and inflammatory HCA (IHCA). 114 surgical cases, previously classified by immunohistochemistry, were analysed. Group A comprised 45 H-HCAs, 44 IHCAs, and 9 β -catenin-activated IHCAs (b-IHCA), and group B, 16 b-HCA and unclassified HCA (UHCA). Steatosis was the hallmark of H-HCA. IHCA and b-IHCA were mainly characterized by inflammation, thick arteries, and sinusoidal dilatation; b-IHCA could not be differentiated from IHCA by routine histology. Group B was identified by default. A control set (91 cases) was analyzed using routine and GS stainings (without knowing immunohistochemical results). Among the 45 H-HCAs and 27 IHCAs, 40 and 24 were correctly classified, respectively. Among the 10 b-IHCAs, 4 were identified as such using additional GS. Eight of the 9 HCAs that were neither H-HCA nor IHCA were correctly classified. Conclusion. Routine histology allows to diagnose >85% of the 2 major HCA subtypes. GS is essential to identify b-HCA. This study demonstrates that a "palliative" diagnostic approach can be proposed, when the panel of specific antibodies is not available.
International journal of hepatology. 01/2013; 2013:417323.
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Ping Yi,
Arisa Higa,
Said Taouji,
Mariana G Bexiga,
Esther Marza,
Daniela Arma,
Claire Castain,
Brigitte Le Bail,
Jeremy Simpson,
Jean Rosenbaum,
Charles Balabaud, Paulette Bioulac-Sage,
Jean-Frederic Blanc,
Eric Chevet
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Ping Yi,
Arisa Higa,
Said Taouji,
Mariana G Bexiga,
Esther Marza,
Daniela Arma,
Claire Castain,
Brigitte Le Bail,
Jeremy Simpson,
Jean Rosenbaum,
Charles Balabaud, Paulette Bioulac-Sage,
Jean-Frederic Blanc,
Eric Chevet
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Paulette Bioulac-Sage,
Gaelle Cubel,
Saïd Taouji,
Jean-Yves Scoazec,
Emmanuelle Leteurtre,
Valérie Paradis,
Nathalie Sturm,
Jeanne Tran Van Nhieu,
Dominique Wendum,
Brigitte Bancel,
Jeanne Ramos,
François Paraf,
Marie Christine Saint Paul,
Sophie Michalak,
Monique Fabre,
Catherine Guettier,
Brigitte Le Bail,
Jessica Zucman-Rossi,
Charles Balabaud
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ABSTRACT: Phenotypic identification of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) subtypes using immunohistochemical markers has been developed from their molecular characteristics. Our objective was to evaluate the sensitivity of these markers in the definitive diagnosis of these lesions by core needle biopsies. A total of 239 needle biopsies paired with their surgical resection specimen (group A) or without an associated resection specimen (group B) were reviewed. Using a step-by-step algorithm after standard staining, appropriate immunostaining analyses were performed to determine the certainty of diagnosis of FNH, HNF1α-inactivated HCA, inflammatory HCA, β-catenin-activated HCA, or unclassified HCA. The diagnosis of FNH was certain or probable on routine stains in 53% of needle biopsies of group A, whereas after glutamine synthetase staining, the diagnosis was certain in 86.7% as compared with 100% on the corresponding surgical specimen (P=0.04). In needle biopsies of group A, the diagnosis of HCA was certain on routine stains in 58.6% as compared with 94.3% on surgical specimens. After specific immunostaining, diagnosis was established on biopsies with 74.3% certainty, including all HCA subtypes, with similar distribution in surgical specimens. For each "certain diagnosis" paired diagnostic test (biopsy and surgical specimen), a positive correlation was observed (P<0.001). No significant difference was observed between groups A and B for FNH (P=0.714) or for HCA subtypes (P=0.750). Compared with surgical specimens, immunohistochemical analysis performed on biopsies allowed the discrimination of FNH from HCA and the identification of HCA subtypes with good performance.
The American journal of surgical pathology 10/2012; 36(11):1691-1699. · 4.06 Impact Factor
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Julien Calderaro,
Philippe Labrune,
Guillaume Morcrette,
Sandra Rebouissou,
Dominique Franco,
Sophie Prévot,
Alberto Quaglia,
Pierre Bedossa,
Louis Libbreccht,
Luigi Terracciano,
G Peter A Smit, Paulette Bioulac-Sage,
Jessica Zucman-Rossi
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ABSTRACT: BACKGROUND AND AIMS: Hepatocellular adenoma (HCA) are benign liver tumors mainly related to oral contraception and classified in 4 molecular subgroups: inflammatory (IHCA), HNF1A-inactivated (H-HCA), β-catenin activated (bHCA) or unclassified (UHCA). Glycogen storage disease type I (GSD) is a rare hereditary metabolic disease that predisposes to HCA development. The aim of our study was to characterize the molecular profile of GSD associated HCA. METHODS: We characterized a series of 25 HCAs developed in 15 patients with GSD by gene expression and DNA sequence of HNF1A, CTNNB1, IL6ST, GNAS and STAT3 genes. Moreover, we searched for glycolysis, gluconeogenesis and fatty acid synthesis alterations in GSD non-tumor livers and compared our results to those observed in a series of sporadic H-HCA and various non-GSD liver samples. Results: GSD adenomas were classified as IHCA (52%) mutated for IL6ST or GNAS, bHCA (28%) or UHCA (20%). In contrast, no HNF1A inactivation was observed, showing a different molecular subtype distribution in GSD associated HCA from that observed in sporadic HCA (p=0.0008). In non-tumor GSD liver samples, we identified glycolysis and fatty acid synthesis activation with gluconeogenesis repression. Interestingly, this gene expression profile was similar to that observed in sporadic H-HCA. CONCLUSIONS: Our study showed a particular molecular profile in GSD related HCA characterized by a lack of HNF1A inactivation. This exclusion could be explained by similar metabolic defects observed by HNF1A inactivation and glucose-6-phosphatase deficiency. Inversely, the high frequency of ß-catenin mutations could be related to the increased frequency of malignant transformation in hepatocellular carcinoma.
Journal of Hepatology 10/2012; · 9.26 Impact Factor
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Ping Yi,
Arisa Higa,
Said Taouji,
Mariana G Bexiga,
Esther Marza,
Daniela Arma,
Claire Castain,
Brigitte Le Bail,
Jeremy Simpson,
Jean Rosenbaum,
Charles Balabaud, Paulette Bioulac-Sage,
Jean-Frederic Blanc,
Eric Chevet
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ABSTRACT: The molecular mechanisms and cellular targets of Sorafenib, a multikinase inhibitor used for the treatment of hepatocellular carcinoma (HCC), remain to be fully characterized. Recent studies have shown that Sorafenib induces tumor cell death through the activation of endoplasmic reticulum (ER) stress signaling and/or autophagy in various cellular models. Using liver cancer-derived cell lines, we specifically demonstrate that the IRE1 and PERK arms of the Unfolded Protein Response (UPR) become activated upon Sorafenib treatment, whereas the ATF6 arm is inhibited. Our results also reveal that Sorafenib treatment causes disruption to the secretory pathway, as witnessed by the fragmentation of the Golgi apparatus and the induction of autophagy. Based on these observations we tested the relevance of the AAA+ ATPase p97/VCP as a potential functional target of Sorafenib. Our results show that p97/VCP tyrosine phosphorylation is prevented upon Sorafenib treatment, and that this can be correlated with enhanced membrane association. Moreover, we show that DBeQ, a recently discovered inhibitor of p97/VCP, enhances Sorafenib-mediated toxicity in cultured cells. Our data demonstrate a novel mechanism for Sorafenib-mediated cell death in HCC, which depends on the integrity of the secretory pathway; and we identify p97/VCP phosphorylation as a potential target for improved Sorafenib treatment efficacy in patients.
Molecular Cancer Therapeutics 10/2012; · 5.23 Impact Factor
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Gastroenterology and Hepatology 09/2012; 8(9):633-634.
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ABSTRACT: We present five cases in whom two rare entities were simultaneously found within the liver, i.e. hepatocellular adenomas (HCAs) and granulomas. Coexistence of both entities confuses diagnosis. Our aim is to disclose the association between HCA and hepatic granulomas. Five patients presented with HCA for which they underwent resection. During laparotomy or at pathological examination, granulomas were found in tumorous and non-tumorous tissue. No specific cause for the granulomas was found. Immunohistochemistry showed overexpression of C-reactive protein and serum amyloid A in 4/5 patients, classifying these lesions as inflammatory HCA. HCA and especially the inflammatory subtype may cause formation of granulomas in (peri-)tumorous tissue as a local response to persistent inflammation and/or the presence of a tumor. Both HCA and hepatic granulomas have also been associated with oral contraceptive use. In conclusion, HCAs associated with hepatic granulomas derive from a local response to (inflammatory) HCA or neoplasm, chronic use of oral contraceptives, or a combination of these factors.
Case Reports in Gastroenterology 09/2012; 6(3):677-83.
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Marion Maurel,
Sandra Jalvy,
Yannick Ladeiro,
Chantal Combe,
Laetitia Vachet,
Francis Sagliocco, Paulette Bioulac-Sage,
Vincent Pitard,
Hélène Jacquemin-Sablon,
Jessica Zucman-Rossi,
Benoît Laloo,
Christophe F Grosset
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ABSTRACT: Hepatocellular Carcinoma (HCC) is the major primary liver cancer. Glypican-3 (GPC3), one of the most abnormally expressed genes in HCC, participates in liver carcinogenesis. Based on data showing that GPC3 expression is post-transcriptionally altered in HCC cells compared to primary hepatocytes, we investigated the implication of microRNAs (miRNAs) in GPC3 overexpression and HCC. To identify GPC3-regulating miRNAs, we developed a dual-fluorescence FunREG system which allowed us to screen a library of 876 individual miRNAs. Expression of candidate miRNAs and that of GPC3 mRNA was measured in 21 non-tumoral liver and 112 HCC samples. We then characterized the phenotypic consequences of modulating expression of one candidate miRNA in HuH7 cells and deciphered the molecular mechanism by which this miRNA controls the post-transcriptional regulation of GPC3. We identified 5 miRNAs targeting GPC3 3'UTR and regulating its expression about the 876 tested. Whereas miR-96 and its paralog miR-1271 repressed GPC3 expression, miR-129-1-3p, miR-1291 and miR-1303 had an inducible effect. We report that miR-1271 expression is downregulated in HCC tumour samples and inversely correlates with GPC3 mRNA expression in a particular subgroup of HCC. We also report that miR-1271 inhibits the growth of HCC cells in a GPC3-dependent manner and induces cell death. Conclusion: Using a functional screening, we found that miR-96, miR-129-1-3p, miR-1271, miR-1291 and miR-1303 differentially control GPC3 expression in HCC cells. In a subgroup of HCC, the up-regulation of GPC3 was associated with a concomitant down-regulation of its repressor miR-1271. Therefore we propose that GPC3 overexpression and its associated oncogenic effects are linked to the down-regulation of miR-1271 in HCC. (HEPATOLOGY 2012.).
Hepatology 08/2012; · 11.66 Impact Factor
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ABSTRACT: Hepatocellular adenomas (HCAs) are divided into three subtypes according to genotype and phenotype. The two main subgroups are hepatocyte nuclear factor 1α (HNF1α)-inactivated HCA and inflammatory HCA. Specific imaging features of these subgroups of adenoma have been delineated with MRI. The aim of this study was to document the contrast-enhanced sonographic (CEUS) features specific for adenoma subtypes and to correlate them with MRI findings.
We retrospectively analyzed data on 38 patients with HCA confirmed at pathologic examination in all cases. All cases were classified with MRI.
HNF1α-inactivated HCA (n = 16) was found to have a homogeneous hyperechoic aspect at baseline gray-scale sonography, isovascularity or moderate hypervascularity with mixed filling in the arterial phase, and isoechogenicity in the portal and late portal venous phases. Homogeneous hyperechogenicity during B-mode sonography was the most specific pattern (sensitivity, 88%; specificity, 91%) and correlated with diffuse fat repartition observed on MR images obtained with chemical-shift sequences. In inflammatory HCA (n = 17) the association of arterial hypervascularity with centripetal filling, linear vascularities, peripheral rim of sustained enhancement, and central washout in the late venous phase was specific (sensitivity, 64%; specificity, 100%). Discrepancy between delayed washout during CEUS and sustained enhancement during MRI could be related to differences between gadolinium and microbubbles in diffusing in the interstitial spaces. In the five other HCA cases (four unclassified, one β-catenin activated) CEUS showed characteristics of benign hepatocellular tumors with no specific features.
HNF1α-inactivated HCA and inflammatory HCA had characteristic CEUS patterns. Delayed washout, an unusual finding in benign hepatic lesions, is of particular interest and was a characteristic of inflammatory HCA subtype.
American Journal of Roentgenology 08/2012; 199(2):341-8. · 2.78 Impact Factor
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Marion Maurel,
Sandra Jalvy,
Yannick Ladeiro,
Chantal Combe,
Laetitia Vachet,
Francis Sagliocco, Paulette Bioulac-Sage,
Vincent Pitard,
Hélène Jacquemin-Sablon,
Jessica Zucman-Rossi,
Benoît Laloo,
Christophe F. Grosset
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[hide abstract]
ABSTRACT: Hepatocellular Carcinoma (HCC) is the major primary liver cancer. Glypican-3 (GPC3), one of the most abnormally expressed genes in HCC, participates in liver carcinogenesis. Based on data showing that GPC3 expression is post-transcriptionally altered in HCC cells compared to primary hepatocytes, we investigated the implication of microRNAs (miRNAs) in GPC3 overexpression and HCC. To identify GPC3-regulating miRNAs, we developed a dual-fluorescence FunREG system which allowed us to screen a library of 876 individual miRNAs. Expression of candidate miRNAs and that of GPC3 mRNA was measured in 21 non-tumoral liver and 112 HCC samples. We then characterized the phenotypic consequences of modulating expression of one candidate miRNA in HuH7 cells and deciphered the molecular mechanism by which this miRNA controls the post-transcriptional regulation of GPC3. We identified 5 miRNAs targeting GPC3 3'UTR and regulating its expression about the 876 tested. Whereas miR-96 and its paralog miR-1271 repressed GPC3 expression, miR-129-1-3p, miR-1291 and miR-1303 had an inducible effect. We report that miR-1271 expression is downregulated in HCC tumour samples and inversely correlates with GPC3 mRNA expression in a particular subgroup of HCC. We also report that miR-1271 inhibits the growth of HCC cells in a GPC3-dependent manner and induces cell death. Conclusion: Using a functional screening, we found that miR-96, miR-129-1-3p, miR-1271, miR-1291 and miR-1303 differentially control GPC3 expression in HCC cells. In a subgroup of HCC, the up-regulation of GPC3 was associated with a concomitant down-regulation of its repressor miR-1271. Therefore we propose that GPC3 overexpression and its associated oncogenic effects are linked to the down-regulation of miR-1271 in HCC.
Hepatology 07/2012; · 11.66 Impact Factor
