Endothelial angiopoietin-2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantation
BackgroundThough the precise criteria for accessing LT are consistently being applied, HCC recurrence (HCC-R_LT) still affects more than 15% of the patients. We analyzed the clinical, histopathological, and biological features of patients with HCC to identify the predictive factors associated with c...
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.960808/full |
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| author | Simone Lasagni Simone Lasagni Filippo Leonardi Alessandra Pivetti Lorenza Di Marco Lorenza Di Marco Federico Ravaioli Matteo Serenari Stefano Gitto Rosina Maria Critelli Fabiola Milosa Adriana Romanzi Adriana Romanzi Serena Mancarella Francesco Dituri Mattia Riefolo Barbara Catellani Paolo Magistri Dante Romagnoli Ciro Celsa Ciro Celsa Marco Enea Nicola de Maria Filippo Schepis Antonio Colecchia Calogero Cammà Matteo Cescon Antonietta d’Errico Fabrizio di Benedetto Gianluigi Giannelli Maria Luz Martinez-Chantar Maria Luz Martinez-Chantar Erica Villa |
| author_facet | Simone Lasagni Simone Lasagni Filippo Leonardi Alessandra Pivetti Lorenza Di Marco Lorenza Di Marco Federico Ravaioli Matteo Serenari Stefano Gitto Rosina Maria Critelli Fabiola Milosa Adriana Romanzi Adriana Romanzi Serena Mancarella Francesco Dituri Mattia Riefolo Barbara Catellani Paolo Magistri Dante Romagnoli Ciro Celsa Ciro Celsa Marco Enea Nicola de Maria Filippo Schepis Antonio Colecchia Calogero Cammà Matteo Cescon Antonietta d’Errico Fabrizio di Benedetto Gianluigi Giannelli Maria Luz Martinez-Chantar Maria Luz Martinez-Chantar Erica Villa |
| author_sort | Simone Lasagni |
| collection | DOAJ |
| description | BackgroundThough the precise criteria for accessing LT are consistently being applied, HCC recurrence (HCC-R_LT) still affects more than 15% of the patients. We analyzed the clinical, histopathological, and biological features of patients with HCC to identify the predictive factors associated with cancer recurrence and survival after LT.MethodsWe retrospectively analyzed 441 patients with HCC who underwent LT in our center. Overall, 70 (15.8%) of them developed HCC-R_LT. We matched them by age at transplant and etiology with 70 non-recurrent patients. A comparable cohort from the Liver Transplant Centre of Bologna served as validation. The clinical and biochemical characteristics and pre-LT criteria (Milan, Metroticket, Metroticket_AFP, and AFP model) were evaluated. Histological analysis and immunohistochemistry for angiopoietin-2 in the tumor and non-tumor tissue of explanted livers were performed. Patients’ follow-up was until death, last clinical evaluation, or 31 December 2021. In patients with HCC-R_LT, the date of diagnosis of recurrence and anatomical site has been reported; if a biopsy of recurrence was available, histologic and immunohistochemical analyses were also performed.ResultsPatients were followed up for a mean period of 62.7 ± 54.7 months (median, 39 months). A higher risk of HCC-R_LT was evident for factors related indirectly (AFP) or directly (endothelial angiopoietin-2, microvascular invasion) to biological HCC aggressiveness. In multivariate analysis, only angiopoietin-2 expression was independently associated with recurrence. Extremely high levels of endothelial angiopoietin-2 expression were also found in hepatic recurrence and all different metastatic locations. In univariate analysis, MELD, Metroticket_AFP Score, Edmondson–Steiner grade, microvascular invasion, and endothelial angiopoietin-2 were significantly related to survival. In multivariate analysis, angiopoietin-2 expression, Metroticket_AFP score, and MELD (in both training and validation cohorts) independently predicted mortality. In time-dependent area under receiver operating characteristic curve analysis, the endothelial angiopoietin-2 expression had the highest specificity and sensitivity for recurrence (AUC 0.922, 95% CI 0.876–0.962, p < 0.0001).ConclusionsEndothelial angiopoietin-2 expression is a powerful independent predictor of post-LT tumor recurrence and mortality, highlighting the fundamental role of tumor biology in defining the patients’ prognosis after liver transplantation. The great advantage of endothelial angiopoietin-2 is that it is evaluable in HCC biopsy before LT and could drive a patient’s priority on the waiting list. |
| first_indexed | 2024-04-11T21:13:32Z |
| format | Article |
| id | doaj.art-04fffa84d0da483480db0b505887750f |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T21:13:32Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-04fffa84d0da483480db0b505887750f2022-12-22T04:02:53ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-09-011210.3389/fonc.2022.960808960808Endothelial angiopoietin-2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantationSimone Lasagni0Simone Lasagni1Filippo Leonardi2Alessandra Pivetti3Lorenza Di Marco4Lorenza Di Marco5Federico Ravaioli6Matteo Serenari7Stefano Gitto8Rosina Maria Critelli9Fabiola Milosa10Adriana Romanzi11Adriana Romanzi12Serena Mancarella13Francesco Dituri14Mattia Riefolo15Barbara Catellani16Paolo Magistri17Dante Romagnoli18Ciro Celsa19Ciro Celsa20Marco Enea21Nicola de Maria22Filippo Schepis23Antonio Colecchia24Calogero Cammà25Matteo Cescon26Antonietta d’Errico27Fabrizio di Benedetto28Gianluigi Giannelli29Maria Luz Martinez-Chantar30Maria Luz Martinez-Chantar31Erica Villa32Gastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyClinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, ItalyGastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, ItalyGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyClinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, ItalyGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyLiver Transplant Center, University of Bologna, Balogna, ItalyDepartment of Experimental and Clinical Medicine, University of Florence, Florence, ItalyGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyClinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, ItalyNational Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, ItalyNational Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, ItalyPathology Unit, Istituto di ricovero e cura a carattere scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyLiver Transplant Center, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyLiver Transplant Center, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalySection of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy0Department of Surgical, Oncological and Oral Sciences (Di.Chir.On.S.), University of Palermo, Palermo, Italy1Internal Medicine and Medical Specialties, Department of Health Promotion, Mother and Child Care (PROMISE) University of Palermo, Palermo, SpainGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalySection of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, ItalyLiver Transplant Center, University of Bologna, Balogna, ItalyPathology Unit, Istituto di ricovero e cura a carattere scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyLiver Transplant Center, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyNational Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, Italy2Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain3Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd “Instituto de Salud Carlos III”), Derio, SpainGastroenterology Unit, Department of Medical Specialties, University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena, Modena, ItalyBackgroundThough the precise criteria for accessing LT are consistently being applied, HCC recurrence (HCC-R_LT) still affects more than 15% of the patients. We analyzed the clinical, histopathological, and biological features of patients with HCC to identify the predictive factors associated with cancer recurrence and survival after LT.MethodsWe retrospectively analyzed 441 patients with HCC who underwent LT in our center. Overall, 70 (15.8%) of them developed HCC-R_LT. We matched them by age at transplant and etiology with 70 non-recurrent patients. A comparable cohort from the Liver Transplant Centre of Bologna served as validation. The clinical and biochemical characteristics and pre-LT criteria (Milan, Metroticket, Metroticket_AFP, and AFP model) were evaluated. Histological analysis and immunohistochemistry for angiopoietin-2 in the tumor and non-tumor tissue of explanted livers were performed. Patients’ follow-up was until death, last clinical evaluation, or 31 December 2021. In patients with HCC-R_LT, the date of diagnosis of recurrence and anatomical site has been reported; if a biopsy of recurrence was available, histologic and immunohistochemical analyses were also performed.ResultsPatients were followed up for a mean period of 62.7 ± 54.7 months (median, 39 months). A higher risk of HCC-R_LT was evident for factors related indirectly (AFP) or directly (endothelial angiopoietin-2, microvascular invasion) to biological HCC aggressiveness. In multivariate analysis, only angiopoietin-2 expression was independently associated with recurrence. Extremely high levels of endothelial angiopoietin-2 expression were also found in hepatic recurrence and all different metastatic locations. In univariate analysis, MELD, Metroticket_AFP Score, Edmondson–Steiner grade, microvascular invasion, and endothelial angiopoietin-2 were significantly related to survival. In multivariate analysis, angiopoietin-2 expression, Metroticket_AFP score, and MELD (in both training and validation cohorts) independently predicted mortality. In time-dependent area under receiver operating characteristic curve analysis, the endothelial angiopoietin-2 expression had the highest specificity and sensitivity for recurrence (AUC 0.922, 95% CI 0.876–0.962, p < 0.0001).ConclusionsEndothelial angiopoietin-2 expression is a powerful independent predictor of post-LT tumor recurrence and mortality, highlighting the fundamental role of tumor biology in defining the patients’ prognosis after liver transplantation. The great advantage of endothelial angiopoietin-2 is that it is evaluable in HCC biopsy before LT and could drive a patient’s priority on the waiting list.https://www.frontiersin.org/articles/10.3389/fonc.2022.960808/fullhepatocellular carcinomaliver transplantationrecurrenceangiopoietin-2survivalneoangiogenesis |
| spellingShingle | Simone Lasagni Simone Lasagni Filippo Leonardi Alessandra Pivetti Lorenza Di Marco Lorenza Di Marco Federico Ravaioli Matteo Serenari Stefano Gitto Rosina Maria Critelli Fabiola Milosa Adriana Romanzi Adriana Romanzi Serena Mancarella Francesco Dituri Mattia Riefolo Barbara Catellani Paolo Magistri Dante Romagnoli Ciro Celsa Ciro Celsa Marco Enea Nicola de Maria Filippo Schepis Antonio Colecchia Calogero Cammà Matteo Cescon Antonietta d’Errico Fabrizio di Benedetto Gianluigi Giannelli Maria Luz Martinez-Chantar Maria Luz Martinez-Chantar Erica Villa Endothelial angiopoietin-2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantation Frontiers in Oncology hepatocellular carcinoma liver transplantation recurrence angiopoietin-2 survival neoangiogenesis |
| title | Endothelial angiopoietin-2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantation |
| title_full | Endothelial angiopoietin-2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantation |
| title_fullStr | Endothelial angiopoietin-2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantation |
| title_full_unstemmed | Endothelial angiopoietin-2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantation |
| title_short | Endothelial angiopoietin-2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantation |
| title_sort | endothelial angiopoietin 2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantation |
| topic | hepatocellular carcinoma liver transplantation recurrence angiopoietin-2 survival neoangiogenesis |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.960808/full |
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