Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals

Francesca Faillaci, Luca Marzi, Rosina Critelli, Fabiola Milosa, Filippo Schepis, Elena Turola, Silvia Andreani, Gabriele Vandelli, Veronica Bernabucci, Barbara Lei, Federica D'Ambrosio, Laura Bristot, Luisa Cavalletto, Liliana Chemello, Pamela Sighinolfi, Paola Manni, Antonino Maiorana, Cristian Caporali, Marcello Bianchini, Maria MarsicoLaura Turco, Nicola de Maria, Mariagrazia Del Buono, Paola Todesca, Luca di Lena, Dante Romagnoli, Paolo Magistri, Fabrizio di Benedetto, Savino Bruno, Gloria Taliani, Gianluigi Giannelli, Maria-Luz Martinez-Chantar, Erica Villa

Research output: Contribution to journalArticle

Abstract

Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA-treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin-2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo-Doppler work-up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = -0.412, P = 0.037 and r = -0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3-month follow-up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044-1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080-2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395-16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127-13.203; P = 0.032) were independent predictors of de novo HCC.CONCLUSION: Our study indicates that DAA-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo-angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000-000).
Original languageEnglish
Pages (from-to)1010-1024
Number of pages15
JournalHepatology
Volume68
Issue number3
DOIs
Publication statusPublished - Sep 2018

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Angiopoietin-2
Liver Neoplasms
Hepacivirus
Antiviral Agents
Hepatocellular Carcinoma
Liver
Fibrosis
Odds Ratio
Confidence Intervals
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor C
Portal Pressure
Recurrence
Viscera
Varicose Veins
Chronic Hepatitis C
Gastroenterology
Portal Vein
Liver Cirrhosis
C-Reactive Protein

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Faillaci, F., Marzi, L., Critelli, R., Milosa, F., Schepis, F., Turola, E., ... Villa, E. (2018). Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals. Hepatology, 68(3), 1010-1024. https://doi.org/10.1002/hep.29911

Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals. / Faillaci, Francesca; Marzi, Luca; Critelli, Rosina; Milosa, Fabiola; Schepis, Filippo; Turola, Elena; Andreani, Silvia; Vandelli, Gabriele; Bernabucci, Veronica; Lei, Barbara; D'Ambrosio, Federica; Bristot, Laura; Cavalletto, Luisa; Chemello, Liliana; Sighinolfi, Pamela; Manni, Paola; Maiorana, Antonino; Caporali, Cristian; Bianchini, Marcello; Marsico, Maria; Turco, Laura; de Maria, Nicola; Del Buono, Mariagrazia; Todesca, Paola; di Lena, Luca; Romagnoli, Dante; Magistri, Paolo; di Benedetto, Fabrizio; Bruno, Savino; Taliani, Gloria; Giannelli, Gianluigi; Martinez-Chantar, Maria-Luz; Villa, Erica.

In: Hepatology, Vol. 68, No. 3, 09.2018, p. 1010-1024.

Research output: Contribution to journalArticle

Faillaci, F, Marzi, L, Critelli, R, Milosa, F, Schepis, F, Turola, E, Andreani, S, Vandelli, G, Bernabucci, V, Lei, B, D'Ambrosio, F, Bristot, L, Cavalletto, L, Chemello, L, Sighinolfi, P, Manni, P, Maiorana, A, Caporali, C, Bianchini, M, Marsico, M, Turco, L, de Maria, N, Del Buono, M, Todesca, P, di Lena, L, Romagnoli, D, Magistri, P, di Benedetto, F, Bruno, S, Taliani, G, Giannelli, G, Martinez-Chantar, M-L & Villa, E 2018, 'Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals', Hepatology, vol. 68, no. 3, pp. 1010-1024. https://doi.org/10.1002/hep.29911
Faillaci, Francesca ; Marzi, Luca ; Critelli, Rosina ; Milosa, Fabiola ; Schepis, Filippo ; Turola, Elena ; Andreani, Silvia ; Vandelli, Gabriele ; Bernabucci, Veronica ; Lei, Barbara ; D'Ambrosio, Federica ; Bristot, Laura ; Cavalletto, Luisa ; Chemello, Liliana ; Sighinolfi, Pamela ; Manni, Paola ; Maiorana, Antonino ; Caporali, Cristian ; Bianchini, Marcello ; Marsico, Maria ; Turco, Laura ; de Maria, Nicola ; Del Buono, Mariagrazia ; Todesca, Paola ; di Lena, Luca ; Romagnoli, Dante ; Magistri, Paolo ; di Benedetto, Fabrizio ; Bruno, Savino ; Taliani, Gloria ; Giannelli, Gianluigi ; Martinez-Chantar, Maria-Luz ; Villa, Erica. / Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals. In: Hepatology. 2018 ; Vol. 68, No. 3. pp. 1010-1024.
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abstract = "Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA-treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin-2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo-Doppler work-up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0{\%}) with previous HCC recurred whereas 21 of 155 (13.5{\%}) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = -0.412, P = 0.037 and r = -0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3-month follow-up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95{\%} confidence interval [CI], 1.044-1.137; P = 0.003) or occurrence (OR, 1.604; 95{\%} CI, 1.080-2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95{\%} CI, 1.395-16.316; P = 0.013) and large varices (OR, 3.857; 95{\%} CI, 1.127-13.203; P = 0.032) were independent predictors of de novo HCC.CONCLUSION: Our study indicates that DAA-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo-angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000-000).",
author = "Francesca Faillaci and Luca Marzi and Rosina Critelli and Fabiola Milosa and Filippo Schepis and Elena Turola and Silvia Andreani and Gabriele Vandelli and Veronica Bernabucci and Barbara Lei and Federica D'Ambrosio and Laura Bristot and Luisa Cavalletto and Liliana Chemello and Pamela Sighinolfi and Paola Manni and Antonino Maiorana and Cristian Caporali and Marcello Bianchini and Maria Marsico and Laura Turco and {de Maria}, Nicola and {Del Buono}, Mariagrazia and Paola Todesca and {di Lena}, Luca and Dante Romagnoli and Paolo Magistri and {di Benedetto}, Fabrizio and Savino Bruno and Gloria Taliani and Gianluigi Giannelli and Maria-Luz Martinez-Chantar and Erica Villa",
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T1 - Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals

AU - Faillaci, Francesca

AU - Marzi, Luca

AU - Critelli, Rosina

AU - Milosa, Fabiola

AU - Schepis, Filippo

AU - Turola, Elena

AU - Andreani, Silvia

AU - Vandelli, Gabriele

AU - Bernabucci, Veronica

AU - Lei, Barbara

AU - D'Ambrosio, Federica

AU - Bristot, Laura

AU - Cavalletto, Luisa

AU - Chemello, Liliana

AU - Sighinolfi, Pamela

AU - Manni, Paola

AU - Maiorana, Antonino

AU - Caporali, Cristian

AU - Bianchini, Marcello

AU - Marsico, Maria

AU - Turco, Laura

AU - de Maria, Nicola

AU - Del Buono, Mariagrazia

AU - Todesca, Paola

AU - di Lena, Luca

AU - Romagnoli, Dante

AU - Magistri, Paolo

AU - di Benedetto, Fabrizio

AU - Bruno, Savino

AU - Taliani, Gloria

AU - Giannelli, Gianluigi

AU - Martinez-Chantar, Maria-Luz

AU - Villa, Erica

N1 - © 2018 by the American Association for the Study of Liver Diseases.

PY - 2018/9

Y1 - 2018/9

N2 - Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA-treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin-2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo-Doppler work-up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = -0.412, P = 0.037 and r = -0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3-month follow-up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044-1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080-2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395-16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127-13.203; P = 0.032) were independent predictors of de novo HCC.CONCLUSION: Our study indicates that DAA-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo-angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000-000).

AB - Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA-treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin-2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo-Doppler work-up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = -0.412, P = 0.037 and r = -0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3-month follow-up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044-1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080-2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395-16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127-13.203; P = 0.032) were independent predictors of de novo HCC.CONCLUSION: Our study indicates that DAA-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo-angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000-000).

U2 - 10.1002/hep.29911

DO - 10.1002/hep.29911

M3 - Article

VL - 68

SP - 1010

EP - 1024

JO - Hepatology

JF - Hepatology

SN - 0270-9139

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