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Development and validation of an on-line web calculator for survival after trans-arterial chemo-embolization for hepatocellular carcinoma
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Abstracts / Digestive and Liver Disease 48S (2016) e18–e41
T-21
T-22
IN HEPATOCELLULAR CARCINOMA MIR-494 UP-REGULATES THE AKT/MTOR PATHWAY AND IS INVOLVED IN SORAFENIB RESISTANCE
DEVELOPMENT AND VALIDATION OF AN ON-LINE WEB CALCULATOR FOR SURVIVAL AFTER TRANS-ARTERIAL CHEMO-EMBOLIZATION FOR HEPATOCELLULAR CARCINOMA
D. Pollutri 1,1 , C. Patrizi 1,1 , S. Marinelli 1 , M. Ferracin 2 , M. Negrini 2 , M. Baron Toaldo 3 , L. Bolondi 1 , L. Gramantieri 1 , F. Fornari 1 1 Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S.Orsola-Malpighi e Università di Bologna, Bologna, Italy 2 Dipartimento di Medicina Sperimentale e Diagnostica e Centro Interdipartimentale per la Ricerca sul Cancro, Università di Ferrara, Italy 3 Dipartimento di Scienze Mediche Veterinarie, Università di Bologna, Bologna, Italy
Background and aims: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Despite the increase of surveillance programs for cirrhotic patients, most of HCCs are ineligible for curative treatments. The only approved anti-cancer drug for advanced HCC is Sorafenib, however this treatment has only little survival advantage in the presence of major side effects. MicroRNAs are aberrantly expressed in different cancer types. MiR-494 belongs to a miRNA cluster often deregulated in human malignancies. The aim of this study is to investigate the role of miR-494 in hepatocarcinogenesis and Sorafenib resistance. Methods: Real Time RT-PCR analysis was used to quantify miR494 expression in sera and tissue samples from HCC patients and two HCC animal models, as well as in HCC-derived cell lines. The modulation of the AKT/mTOR pathway by miR-494 was analysed by Western blot in transfected HCC cells. MiR-494 involvement in Sorafenib response was investigated in transfected HCC cell lines and in two HCC animal models following Sorafenib treatment. Results: An up-regulation of miR-494 expression was observed in a subgroup of HCC patients and in sera samples of cirrhotic patients with HCC. A correlation between circulating and tissue levels of miR-494 was found in HCC patients and HCC animals. MiR-494 up-regulates AKT/mTOR pathway in HCC cell lines by targeting PTEN mRNA. Transient and stable miR-494 over-expression induces Sorafenib resistance in HCC cells through the activation of mTOR signalling cascade and the inhibition of apoptotic cell death. High miR-494 levels associated with increased tumor size and reduced Sorafenib response in both HCC animal models. Conclusions: MiR-494 is aberrantly expressed in a subset of HCCs and increased circulating levels are detected in sera of cirrhotic patients with HCC. MiR-494 plays a key role in cell proliferation and Sorafenib resistance of HCC cells trough the up-regulation of the AKT/mTOR pathway. http://dx.doi.org/10.1016/j.dld.2015.12.071
A. Cucchetti 1 , A. Cappelli 2 , C. Sposito 3 , F. Brunero 3 , G. Cabibbo 4 , S. Attardo 4 , C. Mosconi 2 , A.D. Pinna 1 , R. Golfieri 2 , V. Mazzaferro 3 1 Department of Medical and Surgical Sciences – DIMEC; S.Orsola-Malpighi Hospital, Alma Mater Studiorum – University of Bologna, Bologna, Italy 2 Radiology Unit; Department of Diagnostic and Preventive Medicine; S.Orsola-Malpighi Hospital, Bologna, Italy 3 Gastrointestinal Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy 4 Section of Gastroenterology, DIBIMIS. University of Palermo, Palermo, Italy
Introduction: Pre-treatment prognostic models play important roles when deciding whether to submit a patient suffering from hepatocellular carcinoma (HCC) to trans-arterial chemoembolization (TACE). However, a personalized prognostic model easily accessible for routine clinical evaluation is currently not available. Aim: To develop, and validate, an individual prognostic calculator of survival after TACE that can be easily accessed through internet and smartphones. Material and methods: Data from two prospective databases, regarding 361 (training/internal validation) and 298 (external validation) patients who received TACE as first-line therapy (2000–2012), were used to develop, and validate, a continuous individual prognostic calculator. Patients with neoplastic portal vein invasion were excluded. The model was built through a bootstrap re-sampling technique for identifying prognostic predictors, and by carrying out a 10-fold internal cross validation. The calculator was then tested in the external validation group by means of Harrell’s c-statistic. Results: Bootstrap re-sampling procedure showed that in the training set of 361 patients, tumours number, serum total bilirubin and albumin, alpha-fetoprotein and maximum tumour size were independent predictors of mortality after TACE. In the external validation group of 298 patients, the model showed a Harrell’s c-statistic of 0.627 (95% CI: 0.580–0.673), significantly higher than that of the Hepatoma Arterial-embolization Prognostic (HAP) score (0.579; 95% CI: 0.533–0.626; P = 0.043) and than that of the modified HAP-II score (0.574; 95% CI: 0.531–0.617; P = 0.010), providing individual survival rates rather than risk classes. The web-based calculator is available for rapid consultation at the following URL: http://www.livercancer.eu/mhap3.html, optimized for smartphones. Conclusions: The availability of an online calculator can help physicians in the daily clinical practice when evaluating individual survival probabilities after TACE for each single patient with unresectable HCC. The proposed model can provide accurate information for both physicians and patients regarding prognosis without class stratification. http://dx.doi.org/10.1016/j.dld.2015.12.072
1
D. Pollutri, C. Patrizi equally contributed to this work.
Abstracts / Digestive and Liver Disease 48S (2016) e18–e41
T-21
T-22
IN HEPATOCELLULAR CARCINOMA MIR-494 UP-REGULATES THE AKT/MTOR PATHWAY AND IS INVOLVED IN SORAFENIB RESISTANCE
DEVELOPMENT AND VALIDATION OF AN ON-LINE WEB CALCULATOR FOR SURVIVAL AFTER TRANS-ARTERIAL CHEMO-EMBOLIZATION FOR HEPATOCELLULAR CARCINOMA
D. Pollutri 1,1 , C. Patrizi 1,1 , S. Marinelli 1 , M. Ferracin 2 , M. Negrini 2 , M. Baron Toaldo 3 , L. Bolondi 1 , L. Gramantieri 1 , F. Fornari 1 1 Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S.Orsola-Malpighi e Università di Bologna, Bologna, Italy 2 Dipartimento di Medicina Sperimentale e Diagnostica e Centro Interdipartimentale per la Ricerca sul Cancro, Università di Ferrara, Italy 3 Dipartimento di Scienze Mediche Veterinarie, Università di Bologna, Bologna, Italy
Background and aims: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Despite the increase of surveillance programs for cirrhotic patients, most of HCCs are ineligible for curative treatments. The only approved anti-cancer drug for advanced HCC is Sorafenib, however this treatment has only little survival advantage in the presence of major side effects. MicroRNAs are aberrantly expressed in different cancer types. MiR-494 belongs to a miRNA cluster often deregulated in human malignancies. The aim of this study is to investigate the role of miR-494 in hepatocarcinogenesis and Sorafenib resistance. Methods: Real Time RT-PCR analysis was used to quantify miR494 expression in sera and tissue samples from HCC patients and two HCC animal models, as well as in HCC-derived cell lines. The modulation of the AKT/mTOR pathway by miR-494 was analysed by Western blot in transfected HCC cells. MiR-494 involvement in Sorafenib response was investigated in transfected HCC cell lines and in two HCC animal models following Sorafenib treatment. Results: An up-regulation of miR-494 expression was observed in a subgroup of HCC patients and in sera samples of cirrhotic patients with HCC. A correlation between circulating and tissue levels of miR-494 was found in HCC patients and HCC animals. MiR-494 up-regulates AKT/mTOR pathway in HCC cell lines by targeting PTEN mRNA. Transient and stable miR-494 over-expression induces Sorafenib resistance in HCC cells through the activation of mTOR signalling cascade and the inhibition of apoptotic cell death. High miR-494 levels associated with increased tumor size and reduced Sorafenib response in both HCC animal models. Conclusions: MiR-494 is aberrantly expressed in a subset of HCCs and increased circulating levels are detected in sera of cirrhotic patients with HCC. MiR-494 plays a key role in cell proliferation and Sorafenib resistance of HCC cells trough the up-regulation of the AKT/mTOR pathway. http://dx.doi.org/10.1016/j.dld.2015.12.071
A. Cucchetti 1 , A. Cappelli 2 , C. Sposito 3 , F. Brunero 3 , G. Cabibbo 4 , S. Attardo 4 , C. Mosconi 2 , A.D. Pinna 1 , R. Golfieri 2 , V. Mazzaferro 3 1 Department of Medical and Surgical Sciences – DIMEC; S.Orsola-Malpighi Hospital, Alma Mater Studiorum – University of Bologna, Bologna, Italy 2 Radiology Unit; Department of Diagnostic and Preventive Medicine; S.Orsola-Malpighi Hospital, Bologna, Italy 3 Gastrointestinal Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy 4 Section of Gastroenterology, DIBIMIS. University of Palermo, Palermo, Italy
Introduction: Pre-treatment prognostic models play important roles when deciding whether to submit a patient suffering from hepatocellular carcinoma (HCC) to trans-arterial chemoembolization (TACE). However, a personalized prognostic model easily accessible for routine clinical evaluation is currently not available. Aim: To develop, and validate, an individual prognostic calculator of survival after TACE that can be easily accessed through internet and smartphones. Material and methods: Data from two prospective databases, regarding 361 (training/internal validation) and 298 (external validation) patients who received TACE as first-line therapy (2000–2012), were used to develop, and validate, a continuous individual prognostic calculator. Patients with neoplastic portal vein invasion were excluded. The model was built through a bootstrap re-sampling technique for identifying prognostic predictors, and by carrying out a 10-fold internal cross validation. The calculator was then tested in the external validation group by means of Harrell’s c-statistic. Results: Bootstrap re-sampling procedure showed that in the training set of 361 patients, tumours number, serum total bilirubin and albumin, alpha-fetoprotein and maximum tumour size were independent predictors of mortality after TACE. In the external validation group of 298 patients, the model showed a Harrell’s c-statistic of 0.627 (95% CI: 0.580–0.673), significantly higher than that of the Hepatoma Arterial-embolization Prognostic (HAP) score (0.579; 95% CI: 0.533–0.626; P = 0.043) and than that of the modified HAP-II score (0.574; 95% CI: 0.531–0.617; P = 0.010), providing individual survival rates rather than risk classes. The web-based calculator is available for rapid consultation at the following URL: http://www.livercancer.eu/mhap3.html, optimized for smartphones. Conclusions: The availability of an online calculator can help physicians in the daily clinical practice when evaluating individual survival probabilities after TACE for each single patient with unresectable HCC. The proposed model can provide accurate information for both physicians and patients regarding prognosis without class stratification. http://dx.doi.org/10.1016/j.dld.2015.12.072
1
D. Pollutri, C. Patrizi equally contributed to this work.