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Liver transplantation for hepatocellular carcinoma beyond the Milan criteria.

ABSTRACT: OBJECTIVE:Liver transplantation is an optimal radical therapy for selected patients with hepatocellular carcinoma. The stringent organ allocation system driven by the Milan criteria has been challenged by alternative sets of expanded criteria. Careful analysis is needed to prove that the Milan criteria can be expanded safely and effectively. DESIGN:This study collectively reviewed 6012 patients of hepatocellular carcinoma from the China Liver Transplant Registry. Expanded criteria were evaluated to characterise an optimised expansion with acceptable outcomes beyond the Milan criteria. RESULTS:Compared with the Milan criteria, Valencia, University of California, San Francisco, University Clinic of Navarra and Hangzhou criteria provided an expansion of 12.4%, 16.3%, 19.6%, and 51.5%, respectively. The post-transplant survivals of patients fulfilling the expanded criteria were comparable to that of the Milan criteria. The analysis of net reclassification improvement and area under the receiver operating characteristic curves showed an excellent efficiency in recurrence prediction for the expanded criteria compared with the Milan criteria. In patients exceeding Milan but fulfilling the Hangzhou criteria (N=1352), ?-fetoprotein (AFP) >100?ng/mL and tumour burden>8?cm were the only two independent prognostic factors (p<0.001). Accordingly, the Hangzhou criteria were stratified as type A (tumour burden ?8?cm, or tumour burden >8?cm but AFP?100?ng/mL) and type B (tumour burden >8?cm but AFP between 100 and 400?ng/mL). Type A showed significantly higher 5-year tumour-free survival rates compared with type B (p<0.001). CONCLUSIONS:The Milan criteria can be expanded safely and effectively. The prognostic stratification system based on the Hangzhou criteria serves as a hierarchy of transplant candidates for hepatocellular carcinoma.

SUBMITTER: Xu X

PROVIDER: S-EPMC4893115 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Liver transplantation for hepatocellular carcinoma beyond the Milan criteria.

Xu Xiao X Lu Di D Ling Qi Q Wei Xuyong X Wu Jian J Zhou Lin L Yan Sheng S Wu Liming L Geng Lei L Ke Qinghong Q Gao Feng F Tu Zhenhua Z Wang Weilin W Zhang Min M Shen Yan Y Xie Haiyang H Jiang Wenshi W Wang Haibo H Zheng Shusen S

Gut 20150324 6

<h4>Objective</h4>Liver transplantation is an optimal radical therapy for selected patients with hepatocellular carcinoma. The stringent organ allocation system driven by the Milan criteria has been challenged by alternative sets of expanded criteria. Careful analysis is needed to prove that the Milan criteria can be expanded safely and effectively.<h4>Design</h4>This study collectively reviewed 6012 patients of hepatocellular carcinoma from the China Liver Transplant Registry. Expanded criteria ...[more]

PMID: 25804634

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Project description:Introduction: Several attempts have been made to expand the indications of liver transplantation for hepatocellular carcinoma (HCC) beyond Milan criteria. We aimed to define genomic features that enable the identification of patients with HCC beyond Milan criteria who have acceptable transplant outcomes. Methods: Among 770 consecutive HCC patients transplanted at Mount Sinai Hospital and Mayo Clinic between 1990 and 2013, 132 had tumors exceeding Milan criteria on pathology and were enrolled in the study. Explant tumors were analyzed to assess genomic signatures of poor prognosis and immunohistochemical markers associated with tumor recurrence and overall survival. Results: Most of the patients were males (80%) and HCV positive (71%) with a median age of 56. HCC beyond Milan criteria was defined pre-operative in 67%. On pathology, 44% of the patients satisfied the ‘up-to-7 rule’. At a median follow-up of 88 months, 64 patients had died and 45 recurred; the 5-year overall survival (OS) and recurrence rates were 57% and 35%, respectively. CK19 gene signature was independently associated with recurrence (HR=2.95, p<0.001), along with tumor size >5 cm (HR=3.37, p=0.023) and presence of satellite lesions (HR=2.98, p=0.001). S2 subclass signature, which is known to be associated with progenitor cell markers, was independently associated with poor OS (HR=3.18, p=0.001), along with tumor size >5 cm (HR=5.06, p<0.001) and outside up-to-seven rule (HR=2.50, p=0.002). Using the presence of markers of progenitor cells (either CK19 or S2 subclass signatures) patients may be classified into poor-prognosis (n=58; 5-year recurrence 53%, survival 45%) and good-prognosis subgroups (n=74; 5-year recurrence 19%, survival 67%) (HR=3.16, p<0.001 for recurrence, and HR=1.72, p=0.04 for OS). Conclusion: Gene signatures associated with progenitor cell markers (CK19 and S2 subclass signatures) define outcome of HCC patients beyond Milan criteria after transplantation. Patients without these signatures achieve survival rates similar as those patients within Milan criteria. Once prospectively validated, these markers may provide the rationale for a limited expansion of liver transplantation indications.

Project description:ObjectivesTo assess survival after liver resection and transplantation in patients with hepatocellular carcinoma (HCC) beyond Milan criteria.BackgroundThe role of liver resection and transplantation remains controversial for patients with HCC beyond Milan criteria. Resection of advanced tumors and transplantation using extended-criteria are pursued at select high-volume center.MethodsPatients from 5 liver cancer centers in the United States who had liver resection or transplantation for HCC beyond Milan criteria between 1990 and 2011 were included in the study. Multivariable and propensity-matching analyses estimated the effects of clinical factors and operative selection on survival.ResultsOf 608 patients beyond Milan without vascular invasion, 480 (79%) patients underwent resection and 128 (21%) underwent transplantation. Clinicopathologic profiles between resection and transplant patients differed significantly. Hepatitis C and cirrhosis were more prevalent in transplantation group (P < 0.001). Resection patients had larger tumors [median 9 cm, interquartile range (IQR): 6.5-12.9 cm vs. median 4.1, IQR: 3.4-5.3 cm, P < 0.001]; transplant patients were more likely to have multiple tumors (78% vs 28%, P < 0.001).Overall (OS) and disease-free survival (DFS) were both greater after tumor downstaging and transplantation than resection (all P < 0.001). OS did not differ between liver transplant recipients who were not pretreated or pretreated and failed to downstage compared with propensity-matched liver resection patients (P ≥ 0.176); DFS in this propensity matched cohort was greater after liver transplantation (P ≤ 0.017).ConclusionsLiver resection and transplantation provide curative options for patients with HCC beyond Milan criteria. Further treatment strategies aimed at the efficiency and durability of tumor downstaging and expansion of the role of transplantation among suitable candidates could improve outcomes in patients with large or multifocal HCC.

Project description:BackgroundAccess to the liver transplant waitlist for patients with hepatocellular carcinoma (HCC) depends on tumour presentation, biology, and response to treatments. The Milan Criteria (MC) represent the benchmark for expanded criteria that incorporate additional prognostic factors. The purpose of this study was to determine the added value of skeletal muscle index (SMI) in HCC patients beyond the MC.MethodPatients with HCC that were transplanted beyond the MC were included in this retrospective multicentre study. SMI was quantified using the Computed Tomography (CT) within 3 months prior to transplantation. Cox regression models were used to identify predictors of overall survival (OS). The discriminative performance of SMI extended Metroticket 2.0 and AFP models was also assessed.ResultsOut of 889 patients transplanted outside the MC, 528 had a CT scan within 3 months prior to liver transplantation (LT), of whom 176 (33%) were classified as sarcopenic. The median time between assessment of the SMI and LT was 1.8 months (IQR: 0.77-2.67). The median follow-up period was 5.1 95% CI [4.7-5.5] years, with a total of 177 recorded deaths from any cause. In a linear regression model with SMI as the dependent variable, only male gender (8.55 95% CI [6.51-10.59], P < 0.001) and body mass index (0.74 95% CI [0.59-0.89], P < 0.001) were significant. Univariable survival analysis of patients with sarcopenia versus patients without sarcopenia showed a significant difference in OS (HR 1.44 95% CI [1.07 - 1.94], P = 0.018). Also the SMI was significant (HR 0.98 95% CI [0.96-0.99], P = 0.014). The survival difference between the lowest SMI quartile versus the highest SMI quartile was significant (log-rank: P = 0.005) with 5 year OS of 57% and 71%, respectively. Data from 423 patients, describing 139 deaths, was used for multivariate analysis. Both sarcopenia (HR 1.45 95% CI [1.02 - 2.05], P = 0.036) and SMI were (HR 0.98 95% CI [0.95-0.99], P = 0.035) significant. On the survival scale this translates to a 5 year OS difference of 11% between sarcopenia and no sarcopenia. Whereas for SMI, this translates to a survival difference of 8% between first and third quartiles for both genders.ConclusionsOverall, we can conclude that higher muscle mass contributes to a better long-term survival. However, for individual patients, low muscle mass should not be considered an absolute contra-indication for LT as its discriminatory performance was limited.

Project description:Background and aims Liver transplantation (LT) can be offered to patients with Hepatocellular carcinoma (HCC) beyond Milan criteria. However, there are currently limited molecular markers on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to derive a combined proteomic/transcriptomic signature on HCC explant predictive of recurrence post-transplant using unbiased, high-throughput approaches. Methods Patients who received a LT for HCC beyond Milan criteria in the context of hepatitis B cirrhosis were identified. Tumor explants from patients with post-transplant HCC recurrence (N = 7) versus those without recurrence (N = 4) were analyzed by mass spectrometry and gene expression array. Univariate analysis was used to generate a combined proteomic/transcriptomic signature linked to recurrence. Significantly predictive genes and proteins were verified and internally validated by immunoblotting and immunohistochemistry. Results Seventy-nine proteins and 636 genes were significantly differentially expressed in HCC tumors with subsequent recurrence (p < 0.05). Univariate survival analysis identified Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) gene (HR = 0.084, 95%CI 0.01–0.68, p = 0.0152), ALDH1A1 protein (HR = 0.039, 95%CI 0.16–0.91, p = 0.03), Galectin 3 Binding Protein (LGALS3BP) gene (HR = 7.14, 95%CI 1.20–432.96, p = 0.03), LGALS3BP protein (HR = 2.6, 95%CI 1.1–6.1, p = 0.036), Galectin 3 (LGALS3) gene (HR = 2.89, 95%CI 1.01–8.3, p = 0.049) and LGALS3 protein (HR = 2.6, 95%CI 1.2–5.5, p = 0.015) as key dysregulated analytes in recurrent HCC. In concordance with our proteome findings, HCC recurrence was linked to decreased ALDH1A1 and increased LGALS3 protein expression by Western Blot. LGALS3BP protein expression was validated in 29 independent HCC samples. Conclusions Significantly increased LGALS3 and LGALS3BP gene and protein expression on explant were associated with post-transplant recurrence, whereas increased ALDH1A1 was associated with absence of recurrence in patients transplanted for HCC beyond Milan criteria. This combined proteomic/transcriptomic signature could help in predicting HCC recurrence risk and guide post-transplant surveillance. Supplementary Information The online version contains supplementary material available at 10.1186/s12014-021-09333-x.

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Liver transplantation for hepatocellular carcinoma beyond the Milan criteria.

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Liver transplantation for hepatocellular carcinoma beyond the Milan criteria.

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