Pre-Transplant Alpha-Fetoprotein > 25.5 and Its Dynamic on Waitlist Are Predictors of HCC Recurrence after Liver Transplantation for Patients Meeting Milan Criteria

Background and Aim: Hepatocellular carcinoma (HCC) recurrence rates after liver transplantation (LT) range between 8 and 20%. Alpha-fetoprotein (AFP) levels at transplant can predict HCC recurrence, however a defined cut-off value is needed to better stratify patients. The aim of this study was to evaluate the rate of HCC recurrence at our centre and to identify predictors, focusing on AFP. Methods: We retrospectively analysed 236 consecutive patients that were waitlisted for HCC who all met the Milan criteria from January 2001 to December 2017 at our liver transplant centre. A total of twenty-nine patients dropped out while they were waitlisted, and 207 patients were included in the final analysis. All survival analyses included the competing-risk model. Results: The mean age was 56.8 ± 6.8 years. A total of 14% were female (n = 29/207). The median MELD (model for end-stage liver disease) at LT was 12 (9–16). The median time on the waitlist was 92 (41–170) days. The HCC recurrence rate was 16.4% (n = 34/208). The mean time to recurrence was 3.3 ± 2.8 years. The median AFP levels at transplant were higher in patients with HCC recurrence (p < 0.001). At multivariate analysis, the AFP value at transplant that was greater than 25.5 ng/mL (AUC 0.69) was a strong predictor of HCC recurrence after LT [sHR 3.3 (1.6–6.81); p = 0.001]. The HCC cumulative incidence function (CIF) of recurrence at 10 years from LT was significantly higher in patients with AFP > 25.5 ng/mL [34.3% vs. 11.5% (p = 0.001)]. Moreover, an increase in AFP > 20.8%, was significantly associated with HCC recurrence (p = 0.034). Conclusions: In conclusion, in our retrospective study, the AFP level at transplant > 25.5 ng/mL and its increase greater than 20.8% on the waitlist were strong predictors of HCC recurrence after LT in a cohort of patients that were waitlisted within the Milan criteria. However further studies are needed to validate these data.

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Combined Heart-Liver and Domino Liver Transplantation in Familial Amyloidosis

The American Surgeon ◽

10.1177/00031348211023427 ◽

2021 ◽

pp. 000313482110234

Author(s):

Angela Sickels ◽

Keyur B. Shah ◽

Brianna Ruch ◽

Adrian Cotterell ◽

Inna Tchoukina ◽

...

Keyword(s):

Liver Transplantation ◽

Total Artificial Heart ◽

Donor Pool ◽

Cardiac Rejection ◽

Recipient Age ◽

Hospital Stays ◽

The Mean ◽

Domino Liver Transplantation ◽

End Stage

Background Combined heart-liver transplantation (CHLT) is the only curative option for patients with concomitant pathology affecting the heart and liver. In some cases, the native livers of familial amyloidosis (FA) patients may be suitable for domino transplantation into other recipients. Methods Retrospective analysis (2013 to 2019) of all CHLT at our center was performed. Continuous data were presented as mean with standard deviation and discrete variables as percentages. Results Familial amyloidosis was the indication for CHLT in 5 out of 6 patients. The mean recipient age was 55 ± 5.62 years. Two patients were bridged with total artificial heart. The mean model for end-stage liver disease score at transplant was 17.17 ± 3.7. Two explanted livers were used for transplantation in a domino fashion. The median intensive care and hospital stays were 5.5 and 19 days, respectively. Complications included renal failure (1), groin abscess (1), pulmonary embolism (1), and cardiac rejection (1). Patient and graft survival for both organs was 100% at a median follow-up of 59 (range 20-76) months. Discussion Combined heart-liver transplantation for FA achieves excellent outcomes. The possible use of livers explanted from patients with FA for domino liver transplantation can contribute to the liver donor pool.

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Combined proteomic/transcriptomic signature of recurrence post-liver transplantation for hepatocellular carcinoma beyond Milan

Clinical Proteomics ◽

10.1186/s12014-021-09333-x ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Mamatha Bhat ◽

Sergi Clotet-Freixas ◽

Cristina Baciu ◽

Elisa Pasini ◽

Ahmed Hammad ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Protein Expression ◽

Univariate Analysis ◽

Milan Criteria ◽

Post Transplant ◽

Gene And Protein Expression ◽

Galectin 3 ◽

Transcriptomic Signature ◽

Hcc Recurrence

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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Sirolimus Prolongs Survival after Living Donor Liver Transplantation for Hepatocellular Carcinoma Beyond Milan Criteria: A Prospective, Randomised, Open-Label, Multicentre Phase 2 Trial

Journal of Clinical Medicine ◽

10.3390/jcm9103264 ◽

2020 ◽

Vol 9 (10) ◽

pp. 3264

Author(s):

Kwang-Woong Lee ◽

Seong Hoon Kim ◽

Kyung Chul Yoon ◽

Jeong-Moo Lee ◽

Jae-Hyung Cho ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Living Donor ◽

Milan Criteria ◽

Secondary Outcome ◽

Open Label ◽

Multicentre Phase ◽

Donor Liver Transplantation ◽

Phase 2 Trial ◽

Hcc Recurrence

Sirolimus (SRL) has been reported to benefit patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). This study aimed to compare SRL with tacrolimus (TAC) in living-donor LT (LDLT) recipients beyond the Milan criteria. This study was initially designed to enrol 45 recipients who underwent LDLT for HCC beyond the Milan criteria. At 1 month after LT, the patients were randomly assigned to either SRL or TAC-based treatment, with both groups receiving mycophenolate mofetil. The primary outcome was three-year recurrence-free survival (RFS) and the secondary outcome was overall survival (OS). A total of 42 patients completed the study. HCC recurrence occurred in 8 of 22 (36.4%) patients in the SRL group and in 5 of 22 (25%) patients in the TAC group. No differences in RFS and OS were found between the two groups in simple comparison. The type of immunosuppressant remained a nonsignificant factor for recurrence in multivariate analysis; however, SRL significantly prolonged OS (TAC hazard ratio: 15 [1.3–172.85], p = 0.03) after adjusting for alpha-fetoprotein and positron emission tomography standardised uptake value ratio (tumour/background liver). In conclusion, SRL does not decrease HCC recurrence but prolongs OS after LDLT for HCC beyond the Milan criteria.

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Use of Adjuvant Sorafenib in Liver Transplant Recipients with High-Risk Hepatocellular Carcinoma

Journal of Transplantation ◽

10.1155/2014/913634 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 14

Author(s):

Kirti Shetty ◽

Chiranjeev Dash ◽

Jacqueline Laurin

Keyword(s):

High Risk ◽

Adjuvant Therapy ◽

Therapy Group ◽

Treatment Protocol ◽

Milan Criteria ◽

Recurrence Rates ◽

Exact Test ◽

Sample Test ◽

Historical Controls ◽

Hcc Recurrence

The efficacy of liver transplantation (LT) for hepatocellular (HCC) is limited by tumor recurrence rates of 10–15%. We undertook this pilot study to examine the use of sorafenib as adjuvant therapy in high-risk LT recipients.Methods. We prospectively enrolled patients transplanted for HCC into a treatment protocol utilizing sorafenib if their explant examination showed evidence of viable tumor exceeding Milan criteria. We utilized as historical controls patients transplanted previously, whose explant tumor characteristics exceeded Milan criteria, but who were not “preemptively” treated with sorafenib. Wilcoxon two-sample test and Fisher’s exact test were used to compare survival and recurrence rates between the two groups.Results. Seven patients were treated with sorafenib and compared to 12 historical “controls.” Two of 7 treated patients suffered from HCC recurrence. Of the comparison group, 9 experienced HCC recurrence and all succumbed to disease. Dose reduction improved tolerance of drug. The overall rate of HCC recurrence was decreased in the adjuvant therapy group compared to historical controls (29% versus 75%,P=0.07). Disease free 1-year survival for the treated versus untreated group was 100% versus 66%, respectively.Conclusion. Adjuvant use of sorafenib is safe and decreases risk of HCC recurrence in high-risk LT recipients.

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SERUM ALPHA-FETOPROTEIN MODIFICATION (DELTA-AFP) IS A HIGHLY SPECIFIC TOOL TO SUSPECT HCC RECURRENCE AFTER LIVER TRANSPLANTATION

Digestive and Liver Disease ◽

10.1016/j.dld.2015.01.118 ◽

2015 ◽

Vol 47 ◽

pp. e54

Author(s):

F.R. Ponziani ◽

S. Bhoori ◽

M. Bongini ◽

M. Flores ◽

C. Muscarà ◽

...

Keyword(s):

Liver Transplantation ◽

Alpha Fetoprotein ◽

Serum Alpha Fetoprotein ◽

Hcc Recurrence

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Homocysteine: A novel prognostic biomarker in liver transplantation for alpha-fetoprotein- negative hepatocellular carcinoma

Cancer Biomarkers ◽

10.3233/cbm-201545 ◽

2020 ◽

Vol 29 (2) ◽

pp. 197-206

Author(s):

Modan Yang ◽

Winyen Tan ◽

Xinyu Yang ◽

Jianyong Zhuo ◽

Zuyuan Lin ◽

...

Keyword(s):

Risk Factors ◽

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Tumor Recurrence ◽

Prognostic Biomarker ◽

Milan Criteria ◽

Recurrence Free Survival ◽

Free Survival ◽

Independent Risk Factors ◽

Hcc Recurrence

BACKGROUND: Precise recipient selection optimizes the prognosis of liver transplantation (LT) for hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is the most commonly used biomarker for diagnosis and prognosis of HCC in the clinical context. As a crucial molecule in methionine cycle, homocysteine (Hcy) level has been proved to be related to HCC progression and metastasis. OBJECTIVE: We aimed to explore the prognostic capacity of pre-transplant serum Hcy level in LT for HCC. METHODS: This study retrospectively enrolled 161 HCC patients who had underwent LT from donation after cardiac death (DCD) in the First Affiliated Hospital of Zhejiang University from 2015.01.01 to 2018.09.01. Pre-transplant serum Hcy level was incorporated into statistical analysis together with other clinical parameters and pathological features. RESULTS: From an overall perspective, significant difference was observed in Hcy level between recurrence (n= 61) and non-recurrence group (n= 100) though subsequent analysis showed unsatisfactory predicting performance. In the whole cohort, multivariate analysis showed that lnAFP (p= 0.010) and Milan criteria (MC, p< 0.001) were independent risk factors of HCC recurrence after LT. MA score based on MC and lnAFP performed well in predicting post-LT tumor recurrence with the AUROC at 0.836 (p< 0.001) and 3-year recurrence-free survival rate at 96.8% (p< 0.001) in the low risk group (n= 69). According to the clinical practice, serum concentration lower than 20 μg/L is considered as normal range of AFP. Elevated pre-transplant serum AFP (> 20 μg/L) predicts high HCC recurrence after LT. We further divided the 161 recipients into AFP- group (n= 77, AFP ⩽ 20 μg/L) and AFP+ group (n= 84, AFP > 20 μg/L). MA score was still well presented in the AFP+ group and the AUROC for tumor recurrence was 0.823 (p< 0.001), whereas the predicting accuracy was reduced in AFP- group (AUROC: 0.754, P< 0.001). After subsequent analysis, we found that elevated pre-transplant Hcy level (> 12.75 μmol/L) predicted increased tumor recurrence risk in AFP- group. The 3-year recurrence-free survival rates were 92.0% and 53.7% (p< 0.001) in low Hcy subgroup (n= 40) and high Hcy subgroup (n= 37) respectively. Multivariate analysis showed that Hcy (p= 0.040) and Milan criteria (p= 0.003) were independent risk factors for post-transplant tumor recurrence in AFP- group. Further combination of Hcy level and Milan criteria identified a subgroup of AFP- recipients with acceptable outcomes even though beyond Milan criteria (3-year recurrence-free survival rate: 77.7%, p< 0.001). CONCLUSION: As a classic predictor in HCC prognosis, AFP performed well in our study cohort when combined with Milan criteria. Homocysteine was an effective prognostic biomarker in LT for AFP- hepatocellular carcinoma. In recipients exceeding Milan criteria, acceptable post-transplant outcome could be seen in those with low Hcy and AFP level.

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Elevation of CA 125 and CA 19–9 in patients with end-stage liver disease

The International Journal of Biological Markers ◽

10.5301/jbm.2012.9139 ◽

2012 ◽

Vol 27 (2) ◽

pp. 147-151 ◽

Cited By ~ 8

Author(s):

Ashish Singhal ◽

Elaine Lander ◽

Andreas Karachristos ◽

Ellen Daly ◽

Phyllis Dowling ◽

...

Keyword(s):

Liver Transplantation ◽

Liver Disease ◽

Serum Concentration ◽

Underlying Mechanism ◽

Meld Score ◽

Ca 125 ◽

End Stage Liver Disease ◽

Pathological Conditions ◽

The Mean ◽

End Stage

Background The serum tumor markers CA 19–9 and CA 125 are the serologic markers used for the monitoring of biliopancreatic and ovarian cancer, respectively. They are reported to be elevated in a variety of nonneoplastic clinical situations, including end-stage liver disease (ESLD). However, their prevalence and degree of elevation in patients with ESLD remained unclear. Aim To examine the prevalence and degree of elevation of CA 19–9 and CA 125 in patients with ESLD and to determine their association with severity of liver disease. Methods Retrospective analysis of 161 patients with ESLD that were evaluated for liver transplantation at our institution between March 2009 and December 2010. The mean age was 55.15 ± 8.75 years and 107 (66.4%) of the patients were men. Serum CA 19–9 and CA 125 levels were determined during evaluation of their candidacy for liver transplantation. Results Eighty-three (51.5%) patients had elevated CA 125 and 44 (53%) of them had a serum concentration >5 times the upper limit of normal (ULN). Elevated CA 125 was associated with alcoholic liver disease, high Model for End-Stage Liver Disease (MELD) score, and presence of ascites. Similarly, 37 (23%) patients had elevated CA 19–9 and 8 (21.6%) of them had a serum concentration >5 times ULN. Elevation of CA 19–9 was associated with high MELD score. Conclusions CA 125 and CA 19–9 concentrations were elevated in 51.5% and 23% of patients with ESLD, respectively. Although the definite etiology remained unclear, their elevation was associated with the pathological conditions associated with advanced liver disease. Further studies are needed to clarify the underlying mechanism(s) responsible for their increased levels.

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Addition of eGFR and Age Improves the Prognostic Absolute Renal Risk-Model in 1,134 Norwegian Patients with IgA Nephropathy

American Journal of Nephrology ◽

10.1159/000381403 ◽

2015 ◽

Vol 41 (3) ◽

pp. 210-219 ◽

Cited By ~ 15

Author(s):

Thomas Knoop ◽

Ann Merethe Vågane ◽

Bjørn Egil Vikse ◽

Einar Svarstad ◽

Bergrún Tinna Magnúsdóttir ◽

...

Keyword(s):

Iga Nephropathy ◽

Prognostic Model ◽

Risk Model ◽

Area Under The Curve ◽

Predicting Outcome ◽

The Mean ◽

Stage Renal Disease ◽

End Stage ◽

French Cohort

Background: Predicting outcome in individual patients with IgA nephropathy (IgAN) is difficult but important. For this purpose, the absolute renal risk (ARR) model has been developed in a French cohort to calculate the risk of end-stage renal disease (ESRD) and death. ARR (0-3) is scored in individual IgAN patients based on the presence of proteinuria ≥1 g/24 h, hypertension, and severe histopathological lesions (1 point per risk factor). We have validated the ARR model in a Norwegian cohort of IgAN patients and tested whether adding data on initial estimated glomerular filtration rate (eGFR) and age improved prediction. Methods: IgAN patients diagnosed between 1988 and 2012 were identified in the Norwegian Kidney Biopsy Registry, and endpoints were identified by record linkage with the Norwegian Renal Registry (ESRD) and the Population Registry (deaths). Results: We identified 1,134 IgAN patients. The mean duration of follow-up was 10.2 years (range 0.0 to 25.7 years). Two hundred and fifty one patients developed ESRD and there were 69 pre-ESRD deaths. The ARR model significantly stratified the IgAN cohort according to risk of ESRD/death. The inclusion of eGFR and age significantly improved the ARR prognostic model; in the receiver operator characteristics (ROC) analysis, area under the curve (AUC) at 10-years of follow-up increased from 0.79 to 0.89, p < 0.001. Conclusions: ARR is a suitable prognostic model for stratifying IgAN patients according to the risk of ESRD or death. Including initial eGFR and age in the model substantially improved its accuracy in our nationwide cohort.

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P0046 : Response to loco-ablative treatment of HCC prior to liver transplantation is associated with low recurrence rates in patients exceeding the milan criteria

Journal of Hepatology ◽

10.1016/s0168-8278(15)30252-x ◽

2015 ◽

Vol 62 ◽

pp. S309

Author(s):

A. Finkenstedt ◽

A. Vikoler ◽

K. Mülleder ◽

M. Portenkircher ◽

J. Peterson ◽

...

Keyword(s):

Liver Transplantation ◽

Milan Criteria ◽

Recurrence Rates

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Living Donor Liver Transplantation: The Optimal Curative Treatment for Hepatocellular Carcinoma Even Beyond Milan Criteria

Cancer Control ◽

10.1177/10732748211011960 ◽

2021 ◽

Vol 28 ◽

pp. 107327482110119

Author(s):

Altan Alim ◽

Yalcin Erdogan ◽

Murat Dayangac ◽

Yildiray Yuzer ◽

Yaman Tokat ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Prognostic Factors ◽

Vascular Invasion ◽

Living Donor ◽

Living Donor Liver Transplantation ◽

Alpha Fetoprotein ◽

Milan Criteria ◽

Donor Liver ◽

Donor Liver Transplantation

Introduction: Liver transplantation offers the most reasonable expectation for curative treatment for hepatocellular carcinoma. Living-donor liver transplantation represents a treatment option, even in patients with extended Milan criteria. This study aimed to evaluate the outcomes of hepatocellular carcinoma patients, particularly those extended Milan criteria. Materials and Patients: All HCC patients who received liver transplant for HCC were included in this retrospective study. Clinical characteristics including perioperative data and survival data (graft and patient) were extracted from records. Univariate and multivariate analyses was performed to identify significant prognostic factors for survival, postoperative complications and recurrence. Results: Two-hundred and two patients were included. The median age was 54.8 years (IQR 53-61). Fifty-one patients (25.3%) underwent deceased donors liver transplantation and 151 patients (74.7%) underwent living donor liver transplantation. Perioperative mortality rate was 5.9% (12 patients). Recurrent disease occurred in 43 patients (21.2%). The overall 1-year and 5-year survival rates were 90.7% and 75.6%, respectively. Significant differences between patients beyond Milan criteria compared to those within Milan criteria were not found. Alpha-fetoprotein level >300 ng/mL, vascular invasion, and bilobar tumor lesions were independent negative prognostic factors for survival. Conclusion: Liver transplantation is the preferred treatment for hepatocellular carcinoma and it has demonstrated an excellent potential to cure even in patients with beyond Milan criteria. This study shows that the Milan criteria alone are not sufficient to predict survival after transplantation. The independent parameters for survival prediction are Alpha-Fetoprotein-value and status of vascular invasion.

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