- Email: [email protected]
Development and validation of a survival calculator for hepatocellular carcinoma patients undergoing liver transplantation: the Metroticket 2.0 model
ORAL PRESENTATIONS stage (extra-hepatic HCC disease, stage C: only SOR or BSC available). In all other ITA.LI.CA tumour stages (0, A, B1, B2, and B3) with preserved liver function (functional score ≤2) survival benefit estimations showed a fixed therapeutic hierarchy (i.e. LT [MS ≥ 120 months] > LR [MS 24–102 months] > ABL [MS 40–77 months] > IAT [MS 18–64 months] > SOR [MS 15–25 months] > BSC [MS 5–7 months]). All multivariable parametric models proved to give accurate survival estimations (C-index > 0.7). A large proportion of enrolled patients met the ITA.LI.CA criteria (65%), while only 55% and 43% of them met the HKLC and BCLC algorithms respectively. The concept of therapeutic hierarchy within ITA.LI.CA stages was validated also in the Taiwanese cohort. Conclusions: Based on weighted survival benefit estimations the concept of therapeutic hierarchy was established within each ITA.LI. CA stage in a large Italian population and validated in a large Taiwanese cohort. PS-019 Recurrent INHBE-GLI1 fusions in hepatocellular adenomas with sonic hedgehog pathway activation J.C. Nault1, G. Couchy2, C. Balabaud3, G. Morcrette4, S. Caruso4, J.-F. Blanc3, Y. Bacq5, J. Caldéraro6, V. Paradis7, J. Ramos8, V. Gnemmi9, N. Sturm10, E. Savier11, L. Chiche12, J. Selves13, C. Pilati4, A. Laurent14, A. DeMuret15, B. Lebail16, S. Rebouissou4, S. Imbeaud4, P. Bioulac-Sage16, E. Letouze4, J. Zucman-Rossi4. 1Inserm, INSERM UMR1162; 2Inserm, UMR1662, Paris; 3Service d’hépatologie, Bordeaux; 4 INSERM UMR1162, Paris; 5Service d’hépatologie, Tours; 6Service d’anatomopathologie, Créteil; 7Service d’anatomopathologie, Clichy; 8 Service d’anatomopathologie, Montpellier; 9Service d’anatomopathologie, Lille; 10Service d’anatomopatholohie, Grenoble; 11 Service de chirurgie digestive Pitié Salpétrier̀ e, Paris; 12Service de chirurgie digestive, Bordeaux; 13Service d’anatomopathologie, Toulouse; 14 Service de chirurgie digestive, Créteil; 15Service d’anatomopathologie, Tours; 16Service d’anatomopathologie, Bordeaux, France E-mail: [email protected] Background and Aims: Recently, we identified a new molecular subgroup of hepatocellular adenomas (HCA) characterized by activation of the sonic hedgehog pathway (sonic hedgehog HCA, shHCA) and associated with obesity and tumor bleeding. However, the genetic driver leading to the activation of sonic hedgehog signaling was unknown and, here, we aimed to unravel this mechanism using next-generation sequencing. Methods: 533 HCA from 411 patients were sequenced for CTNNB1, HNF1A, IL6ST, FRK, STAT3, JAK1, GNAS and TERT mutations, expression of 20 genes was quantified by qRT-PCR including 6 genes used to identify shHCA. We analyzed 11 shHCA by whole exome sequencing, 9 by RNA-sequencing and 3 also by whole genome sequencing. Results: 22 tumors (4% of HCA) were classified as shHCA including one case with malignant transformation, with the typical over-expression of HHIP, PTCH1, PTGDS and FRCLA genes. None of these tumors harbored mutations in genes belonging to other molecular subgroups. Whole exome and Whole genome analysis of shHCA showed a median of 2,021 mutations in the genome and 27 mutations in coding regions, corresponding to a low mutation rate of 0.7 mutations/Mb. We found no recurrent coding mutations in the series. In contrast, in all the cases analyzed, RNAseq showed GLI1 overexpression due to its fusion with the 5′ end of two different INHBE transcripts, a highly expressed gene located 2.1 kb upstream of GLI1. In all except one of the shHCA, the entire open reading frame of GLI1, the key transcription factor of sonic hedgehog pathway, was fused and over-expressed; the remaining one included exons 6 to 12 coding for the DNA-binding and the transactivation domains. All the 9 INHBE-GLI1 fusions were validated as somatic by Sanger sequencing of the cDNA. Specific GLI1 overexpression in shHCA was confirmed by quantitative RT-PCR. Whole genome and whole exome sequencing of the 9 shHCA harboring INHBE-GLI1 fusion revealed S14
a recurrent structural rearrangement within INHBE including 5 focal deletions and one inversion. Finally, INHBE-GLI1 fusions were identified in 15 shHCA with a typical pattern of gene expression and investigated by sequencing. Conclusions: Sonic hedgehog HCA is a new molecular subgroup of HCA driven by structural rearrangements of INHBE producing a highly expressed INHBE-GLI1 fusion leading to the constitutive activation of the sonic hedgehog pathway. These results underline for the first time in humans the role of sonic hedgehog signaling in benign liver tumorigenesis. PS-017 Development and validation of a survival calculator for hepatocellular carcinoma patients undergoing liver transplantation: the Metroticket 2.0 model Carlo Sposito1, Alessandro Cucchetti2, Jian Zhou3, Antonio D. Pinna2, Luciano De Carlis4, Marco Bongini1, Matteo Cescon2, Jia Fan3, Stefano Di Sandro4, He Yi-feng3, Andrea Lauterio4, Vincenzo Mazzaferro1. 1General Surgery and Liver Transplantation Unit, University of Milan at Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan; 2General Surgery and Transplant Unit - Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy; 3Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shangai, China; 4 General Surgery and Abdominal Transplantation, Niguarda Cà Granda Hospital, Milan, Italy E-mail: [email protected] Background and Aims: Patients’ survival after liver transplantation (LT) for hepatocellular carcinoma (HCC) is influenced by non-cncer and cancer-related events. In order to define which are the oncologic parameters that influence post-LT survival, cancer-related death studied with competitive risk analysis represents a reasonable and innovative endpoint. Aim of this study is develop, and validate, a calculator of post-LT cancer-related death based on pre-operative parameters. Methods: To predict individual post-transplant HCC-specific survival, a multivariable competing risk regression analysis was applied to a Western cohort of patients who underwent LT for HCC (training cohort). A continuous model predicting HCC-specific survival, based on the sum of number + size of the largest vital HCC combined with alpha-fetoprotein (AFP) was derived. In order to predict overall survival, baseline mortality was derived through predicted cumulative incidence functions (CIF) segregated for HCV. The model was then validated in an external cohort of Eastern patients who underwent LT for HCC.
Results: The training cohort consisted in a consecutive series of 1018 patients. In the competing-risk regression the sum of number + size of the largest vital HCC and Log10AFP were significant ( p < 0.001), and the average c-statistic of the model was 0.780 (95%C.I.: 0.763–0.798) for the prediction of HCC specific death. The CIF of non-HCC related death was 8.6% and 18.1% in HCV-negative and positive patients
Journal of Hepatology 2017 vol. 66 | S1–S32
ORAL PRESENTATIONS respectively. Continuous individual variation in 5-yrs risk of HCC-related death, and 5-yrs overall survival for HCV positive and HCV negative patients, is available at: http://hcc-olt-metroticket.org/ calculator (Figure 1). The model was then tested in an Eastern cohort of 341 patients, in which HBV-related chronic liver disease, high AFP levels and worse tumour stage were significantly more prevalent than in the training cohort. The model accuracy in the validation set was 0.721 (0.648–0.793), significantly higher than that of Milan, UCSF, Shangai-Fudan, Up-to-seven criteria ( p < 0.001) and AFP French model ( p = 0.044). Conclusions: Cancer-specific outcome after LT for HCC can be determined using pre-operative tumor parameters. The present AFP-adjusted-to-HCC-size criteria improve post-transplant outcome prediction in both Western and Eastern patients. PS-020 Evidence-based two-and-seven criteria according to tumor number and size best help to predict survival of patients with intermediate-stage hepatocellular carcinoma treated with transarterial chemoembolization D. Xia1, W. Bai1, M. Huang2, J. Sun3, E. Wang1, H. Li4, J. Li5, H. Zhao6, X. Pan7, S. Chen8, W. Gong9, X. Zhu10, G. Shao11, W. Mu12, Z. Chen13, J. Wu14, J. Liu15, J. Li16, J. Song17, C. Zhang18, H. Shi19, Z. Li20, S. Yang21, W.. Wang22, Y. Zheng23, J. Xu24, W. Wang1, J. Yuan1, X. Li1, J. Niu1, Z. Yin1, D. Fan1,25, J. Xia26, G. Han1. 1Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Forth Military Medical University, Xi’an; 2Department of Minimally Invasive International Therapy, The Third Affiliated Hospital of Kunming University, Tumor Hospital of Yunnan Province, Kunming; 3Department of Hepatobiliary and Pancreatic Interventional Center, The First Affiliated Hospital, School of Medicine of Zhejiang University, Hangzhou; 4 Department of Interventional Radiology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou; 5 Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing; 6Department of Interventional Radiology, Affiliated Hospital of Nantong University, Nantong; 7Clinical Liver Diseases Research Center, 180th Hospital of People’s Liberation Army, Quanzhou; 8Department of Interventional Radiology, Jiangsu Provincial Cancer Hospital, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing; 9Department of Interventional Radiology, Tangdu Hospital, Forth Military Medical University, Xi’an; 10Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou; 11Department of Interventional Radiology, Zhejiang Provincial Tumor Hospital, Hangzhou; 12Department of Radiology, The Southwest Hospital, Third Military Medical University, Chongqing; 13 Department of Interventional Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou; 14Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang; 15 Department of Interventional Radiology and Vascular Surgery, Hunan Provincial People’s Hospital, Changsha; 16Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou; 17Department of Interventional Therapy, Shandong Provincial Tumor Hospital; 18Department of Gastroenterology and Hepatology, Shandong Province Hospital Affiliated to Shandong University, Jinan; 19Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing; 20 Interventional Medical Center, The Affiliated Hospital of Qingdao University, Qingdao; 21Department of Interventional Radiology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi; 22 Department of Interventional Medicine, The First Affiliated Hospital of Lanzhou University, Lanzhou; 23Department of Interventional Radiology, Yantai Yuhuangding Hospital, Yantai; 24Department of Medical Imaging, Nanjing General Hospital of Nanjing Military Command, Nanjing; 25 State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University; 26Department of Health Statistics, Forth Military Medical University, Xi’an, China E-mail: [email protected]
Background and Aims: Tumor burden have a great impact on prognosis of hepatocellular carcinoma(HCC) treated with transarterial chemoembolization (TACE), and it was frequently weighted by upto-seven criteria, which were originally developed from the setting of liver transplantation. Novel criteria of tumor load derived from TACE should be conducted to improve survival prediction. Methods: We retrospectively enrolled 1515 treatment-naïve HCC patients with intermediate-stage HCC and well-preserved liver function underwent TACE during January 2010 to December 2014 from 24 Chinese centers, which were randomly divided into training (12 centers, N = 820) and validation cohort (12 centers, N = 695). Cox regression analysis was used to determine prognostic factors, smoothing splines were used to determine the nature of the relationship between tumor burden and mortality, then we developed the criteria. We also analyzed discrimination of these criteria and compared with other criteria.
Results: Tumor size (Ts) and number(Tn) consistently were significant factors in multivariable analysis in training cohort and multivariable analysis of selected variables from whole cohort. Risk of death was correlated with increasing size and number, the effect of size is line, whereas, for tumor number, the effect tend to reach a plateau in both cohorts, with adjustment of confounding factors. Two-and-Seven criteria was developed and could classify the intermediate-stage patients into three sub-stage, ie, B-1: Tn ≦ 2, Ts ≦ 7 cm; B-2: Tn ≦ 2, Ts > 7 cm or Tn > 2, Ts ≦ 7 cm, but exceeding Milan criteria; B-3: Tn > 2, Ts > 7 cm, with statistical difference in overall survival (40 months, 18.5 months, 12.1 months for B-1, B-2 and B-3 sub-stage in training cohort; 41.2 months, 25.3 months, 10.1 months for validation cohort respectively, p < 0.001). These criteria provided better discriminative ability than up-to-seven and 4 and 7 criteria in both cohorts, and consistently in sub-group analysis of whole cohort. Conclusions: Two-and-Seven criteria offered a simple, validated, evidence-based objective method with higher discriminative ability in predicting overall survival of patients with intermediate-stage HCC underwent TACE and should be in considerations for the further clinical trails and treatment-decisions making. PS-106 Risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance – a territory-wide analysis of 5181 patients H.L.Y. Chan1, T.C.F. Yip1, V.W.S. Wong1, Y.K. Tse1, G.L.H. Wong1. 1Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China E-mail: [email protected] Background and Aims: Seroclearance of hepatitis B surface antigen (HBsAg) is often regarded as functional cure of chronic hepatitis B. Previous studies suggest hepatocellular carcinoma (HCC) can develop among patients who undergo spontaneous HBsAg seroclearance after 50 years old, but accurate risk assessment is limited by small cohort size and low event rate. This territory-wide study aimed to evaluate the risk of HCC after HBsAg seroclearance and the impact of age and gender on the development of HCC.
Journal of Hepatology 2017 vol. 66 | S1–S32
S15
a recurrent structural rearrangement within INHBE including 5 focal deletions and one inversion. Finally, INHBE-GLI1 fusions were identified in 15 shHCA with a typical pattern of gene expression and investigated by sequencing. Conclusions: Sonic hedgehog HCA is a new molecular subgroup of HCA driven by structural rearrangements of INHBE producing a highly expressed INHBE-GLI1 fusion leading to the constitutive activation of the sonic hedgehog pathway. These results underline for the first time in humans the role of sonic hedgehog signaling in benign liver tumorigenesis. PS-017 Development and validation of a survival calculator for hepatocellular carcinoma patients undergoing liver transplantation: the Metroticket 2.0 model Carlo Sposito1, Alessandro Cucchetti2, Jian Zhou3, Antonio D. Pinna2, Luciano De Carlis4, Marco Bongini1, Matteo Cescon2, Jia Fan3, Stefano Di Sandro4, He Yi-feng3, Andrea Lauterio4, Vincenzo Mazzaferro1. 1General Surgery and Liver Transplantation Unit, University of Milan at Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan; 2General Surgery and Transplant Unit - Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy; 3Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shangai, China; 4 General Surgery and Abdominal Transplantation, Niguarda Cà Granda Hospital, Milan, Italy E-mail: [email protected] Background and Aims: Patients’ survival after liver transplantation (LT) for hepatocellular carcinoma (HCC) is influenced by non-cncer and cancer-related events. In order to define which are the oncologic parameters that influence post-LT survival, cancer-related death studied with competitive risk analysis represents a reasonable and innovative endpoint. Aim of this study is develop, and validate, a calculator of post-LT cancer-related death based on pre-operative parameters. Methods: To predict individual post-transplant HCC-specific survival, a multivariable competing risk regression analysis was applied to a Western cohort of patients who underwent LT for HCC (training cohort). A continuous model predicting HCC-specific survival, based on the sum of number + size of the largest vital HCC combined with alpha-fetoprotein (AFP) was derived. In order to predict overall survival, baseline mortality was derived through predicted cumulative incidence functions (CIF) segregated for HCV. The model was then validated in an external cohort of Eastern patients who underwent LT for HCC.
Results: The training cohort consisted in a consecutive series of 1018 patients. In the competing-risk regression the sum of number + size of the largest vital HCC and Log10AFP were significant ( p < 0.001), and the average c-statistic of the model was 0.780 (95%C.I.: 0.763–0.798) for the prediction of HCC specific death. The CIF of non-HCC related death was 8.6% and 18.1% in HCV-negative and positive patients
Journal of Hepatology 2017 vol. 66 | S1–S32
ORAL PRESENTATIONS respectively. Continuous individual variation in 5-yrs risk of HCC-related death, and 5-yrs overall survival for HCV positive and HCV negative patients, is available at: http://hcc-olt-metroticket.org/ calculator (Figure 1). The model was then tested in an Eastern cohort of 341 patients, in which HBV-related chronic liver disease, high AFP levels and worse tumour stage were significantly more prevalent than in the training cohort. The model accuracy in the validation set was 0.721 (0.648–0.793), significantly higher than that of Milan, UCSF, Shangai-Fudan, Up-to-seven criteria ( p < 0.001) and AFP French model ( p = 0.044). Conclusions: Cancer-specific outcome after LT for HCC can be determined using pre-operative tumor parameters. The present AFP-adjusted-to-HCC-size criteria improve post-transplant outcome prediction in both Western and Eastern patients. PS-020 Evidence-based two-and-seven criteria according to tumor number and size best help to predict survival of patients with intermediate-stage hepatocellular carcinoma treated with transarterial chemoembolization D. Xia1, W. Bai1, M. Huang2, J. Sun3, E. Wang1, H. Li4, J. Li5, H. Zhao6, X. Pan7, S. Chen8, W. Gong9, X. Zhu10, G. Shao11, W. Mu12, Z. Chen13, J. Wu14, J. Liu15, J. Li16, J. Song17, C. Zhang18, H. Shi19, Z. Li20, S. Yang21, W.. Wang22, Y. Zheng23, J. Xu24, W. Wang1, J. Yuan1, X. Li1, J. Niu1, Z. Yin1, D. Fan1,25, J. Xia26, G. Han1. 1Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Forth Military Medical University, Xi’an; 2Department of Minimally Invasive International Therapy, The Third Affiliated Hospital of Kunming University, Tumor Hospital of Yunnan Province, Kunming; 3Department of Hepatobiliary and Pancreatic Interventional Center, The First Affiliated Hospital, School of Medicine of Zhejiang University, Hangzhou; 4 Department of Interventional Radiology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou; 5 Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing; 6Department of Interventional Radiology, Affiliated Hospital of Nantong University, Nantong; 7Clinical Liver Diseases Research Center, 180th Hospital of People’s Liberation Army, Quanzhou; 8Department of Interventional Radiology, Jiangsu Provincial Cancer Hospital, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing; 9Department of Interventional Radiology, Tangdu Hospital, Forth Military Medical University, Xi’an; 10Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou; 11Department of Interventional Radiology, Zhejiang Provincial Tumor Hospital, Hangzhou; 12Department of Radiology, The Southwest Hospital, Third Military Medical University, Chongqing; 13 Department of Interventional Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou; 14Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang; 15 Department of Interventional Radiology and Vascular Surgery, Hunan Provincial People’s Hospital, Changsha; 16Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou; 17Department of Interventional Therapy, Shandong Provincial Tumor Hospital; 18Department of Gastroenterology and Hepatology, Shandong Province Hospital Affiliated to Shandong University, Jinan; 19Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing; 20 Interventional Medical Center, The Affiliated Hospital of Qingdao University, Qingdao; 21Department of Interventional Radiology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi; 22 Department of Interventional Medicine, The First Affiliated Hospital of Lanzhou University, Lanzhou; 23Department of Interventional Radiology, Yantai Yuhuangding Hospital, Yantai; 24Department of Medical Imaging, Nanjing General Hospital of Nanjing Military Command, Nanjing; 25 State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University; 26Department of Health Statistics, Forth Military Medical University, Xi’an, China E-mail: [email protected]
Background and Aims: Tumor burden have a great impact on prognosis of hepatocellular carcinoma(HCC) treated with transarterial chemoembolization (TACE), and it was frequently weighted by upto-seven criteria, which were originally developed from the setting of liver transplantation. Novel criteria of tumor load derived from TACE should be conducted to improve survival prediction. Methods: We retrospectively enrolled 1515 treatment-naïve HCC patients with intermediate-stage HCC and well-preserved liver function underwent TACE during January 2010 to December 2014 from 24 Chinese centers, which were randomly divided into training (12 centers, N = 820) and validation cohort (12 centers, N = 695). Cox regression analysis was used to determine prognostic factors, smoothing splines were used to determine the nature of the relationship between tumor burden and mortality, then we developed the criteria. We also analyzed discrimination of these criteria and compared with other criteria.
Results: Tumor size (Ts) and number(Tn) consistently were significant factors in multivariable analysis in training cohort and multivariable analysis of selected variables from whole cohort. Risk of death was correlated with increasing size and number, the effect of size is line, whereas, for tumor number, the effect tend to reach a plateau in both cohorts, with adjustment of confounding factors. Two-and-Seven criteria was developed and could classify the intermediate-stage patients into three sub-stage, ie, B-1: Tn ≦ 2, Ts ≦ 7 cm; B-2: Tn ≦ 2, Ts > 7 cm or Tn > 2, Ts ≦ 7 cm, but exceeding Milan criteria; B-3: Tn > 2, Ts > 7 cm, with statistical difference in overall survival (40 months, 18.5 months, 12.1 months for B-1, B-2 and B-3 sub-stage in training cohort; 41.2 months, 25.3 months, 10.1 months for validation cohort respectively, p < 0.001). These criteria provided better discriminative ability than up-to-seven and 4 and 7 criteria in both cohorts, and consistently in sub-group analysis of whole cohort. Conclusions: Two-and-Seven criteria offered a simple, validated, evidence-based objective method with higher discriminative ability in predicting overall survival of patients with intermediate-stage HCC underwent TACE and should be in considerations for the further clinical trails and treatment-decisions making. PS-106 Risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance – a territory-wide analysis of 5181 patients H.L.Y. Chan1, T.C.F. Yip1, V.W.S. Wong1, Y.K. Tse1, G.L.H. Wong1. 1Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China E-mail: [email protected] Background and Aims: Seroclearance of hepatitis B surface antigen (HBsAg) is often regarded as functional cure of chronic hepatitis B. Previous studies suggest hepatocellular carcinoma (HCC) can develop among patients who undergo spontaneous HBsAg seroclearance after 50 years old, but accurate risk assessment is limited by small cohort size and low event rate. This territory-wide study aimed to evaluate the risk of HCC after HBsAg seroclearance and the impact of age and gender on the development of HCC.
Journal of Hepatology 2017 vol. 66 | S1–S32
S15