Lower Alpha‐fetoprotein Threshold of 500 ng/mL for Liver Transplantation May Improve Post‐Transplant Outcomes in Patients with Hepatocellular Carcinoma

Abstract 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.

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Serological Risk Index Based on Alpha-Fetoprotein and C-Reactive Protein to Indicate Futile Liver Transplantation Among Patients with Advanced Hepatocellular Carcinoma

Digestive Diseases and Sciences ◽

10.1007/s10620-018-5296-9 ◽

2018 ◽

Vol 64 (1) ◽

pp. 269-280

Author(s):

Arno Kornberg ◽

Martina Schernhammer ◽

Jennifer Kornberg ◽

Helmut Friess ◽

Katharina Thrum

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Risk Index ◽

Alpha Fetoprotein ◽

Advanced Hepatocellular Carcinoma ◽

C Reactive Protein ◽

Reactive Protein

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Liver transplantation for hepatocellular carcinoma with portal vein tumor thrombosis

Journal of Liver Cancer ◽

10.17998/jlc.2021.03.17 ◽

2021 ◽

Vol 21 (2) ◽

pp. 105-112

Author(s):

Sang Jin Kim ◽

Jong Man Kim

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Radiation Therapy ◽

Portal Vein ◽

Alpha Fetoprotein ◽

Advanced Hepatocellular Carcinoma ◽

Portal Vein Tumor Thrombosis ◽

Donor Liver Transplantation ◽

Tumor Thrombosis ◽

Locoregional Therapies

Traditionally, liver transplantation for hepatocellular carcinoma with portal vein tumor thrombosis is not recommended. However, with recent developments in locoregional therapies for hepatocellular carcinoma, more aggressive treatments have been attempted for advanced hepatocellular carcinoma. Recently, various studies on locoregional therapies for downstaging followed by living donor liver transplantation reported inspiring overall survival and recurrence-free survival of patients. These downstaging procedures included three-dimensional conformal radiation therapy, trans-arterial chemoembolization, stereotactic body radiation therapy, trans-arterial radioembolization, hepatic arterial infusion chemotherapy and combinations of these therapies. Selection of the optimal downstaging protocol should depend on tumor location, biology and background liver status. The risk factors affecting outcome include pre-downstaging alpha-fetoprotein values, delta alpha-fetoprotein values, disappearance of portal vein tumor thrombosis on imaging and meeting the Milan criteria or not after downstaging. For hepatocellular carcinoma with portal vein tumor thrombosis, downstaging procedure with liver transplantation in mind would be helpful. If the reaction of the downstaged tumor is good, liver transplantation may be performed.

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Liver Transplantation for Extended Criteria Hepatocellular Carcinoma Using Stable Response to Locoregional Therapy and Alpha-Fetoprotein as Selection Criteria

Visceral Medicine ◽

10.1159/000506752 ◽

2020 ◽

Vol 36 (6) ◽

pp. 506-515

Author(s):

Markus Bo Schoenberg ◽

Hubertus Johann Wolfgang Anger ◽

Julian Nikolaus Bucher ◽

Gerald Denk ◽

Enrico Narciso De Toni ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Selection Criteria ◽

Validation Cohort ◽

Alpha Fetoprotein ◽

Long Term Results ◽

Locoregional Therapy ◽

Internal Validation ◽

Dynamic Selection ◽

Transplant Candidates

Introduction: Current practice to only prioritize hepatocellular carcinoma (HCC) that fulfill the Milan criteria (INMC) is changing, since it causes the exclusion of patients who could benefit from liver transplantation. To select patients outside MC (OUTMC) for transplantation, we implemented extended selection criteria without up-front morphometric restrictions containing surrogate parameters of tumor biology. Methods: OUTMC patients were considered without restrictions of morphometrics and received locoregional treatment after interdisciplinary consultation. Our dynamic selection criteria for OUTMC patients required (INMUC): (1) treatment response over (2) at least 6 months and (3) alpha-fetoprotein ≤400 ng/mL over the entire evaluation period. Patients with INMC tumors served as control and internal validation cohort. Results: 31 of 170 liver transplant candidates were OUTMC. Of these, 8 dropped out. The remaining 23 patients met the selection criteria and underwent transplantation. Recurrence-free survival was higher in patients transplanted INMC compared to those OUTMC INMUC (92.2% vs. 70.8%; p = 0.026) after 5 years of follow-up. Overall survival showed no significant difference (p = 0.552). With dynamic selection of transplant candidates, recurrence could also be predicted for the INMC patients as internal validation cohort (c-index: 0.896; CI 0.588–0.981, p = 0.005). Conclusion: Dynamic selection criteria for the stratification of patients with OUTMC HCCs is feasible and allows for excellent long-term results and acceptable tumor recurrence rates comparable to INMC patients.

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