Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation

Miltiadous, Oriana; Sia, Daniela; Hoshida, Yujin; Fiel, M. Isabel; Harrington, Andrew N.; Thung, Swan N.; Tan, Poh Seng; Dong, Hui; Revill, Kate; Chang, Charissa; Roayaie, Sasan; Byrne, Thomas; Mazzaferro, Vincenzo; Rakela, Jorge; Florman, Sander; Schwartz, Myron; Llovet, Josep M.

doi:10.1016/j.jhep.2015.07.025

Cited by 69 publications

(57 citation statements)

References 47 publications

(66 reference statements)

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“…Therefore, as combination of morphological tumor parameters and serum HCC markers in the selection process is gaining increasing popularity among transplant centers78101316171819, the relevance of obtaining data on the presence of microvascular invasion appears to become far less important for the clinical practice. This observation corresponds to previous findings of other authors regarding no significant impact of microvascular invasion in multivariable analyses including these important features434445.…”

Section: Discussionsupporting

confidence: 92%

Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation

Grąt

Stypułkowski

Patkowski

et al. 2017

Sci Rep

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Microvascular invasion (MVI) is well known to negatively influence outcomes following surgical treatment of hepatocellular cancer (HCC) patients. The aim of this study was to evaluate the rationale for prediction of MVI before liver transplantation (LT). Data of 200 HCC patients after LT were subject to retrospective analysis. MVI was present in 57 patients (28.5%). Tumor number (p = 0.001) and size (p = 0.009), and alpha-fetoprotein (p = 0.049) were independent predictors of MVI used to create a prediction model, defined as: 0.293x(tumor number) + 0.283x(tumor size in cm) + 0.164xloge(alpha-fetoprotein in ng/ml) (c statistic = 0.743). The established cut-off (≥2.24) was associated with sensitivity and specificity of 72%. MVI was not an independent risk factor for recurrence (p = 0.307), in contrast to tumor number (p = 0.047) and size (p < 0.001), alpha-fetoprotein (p < 0.001) and poor differentiation (p = 0.039). Recurrence-free survival at 5 years for patients without MVI was 85.9% as compared to 83.3% (p = 0.546) and 55.3% (p = 0.001) for patients with false negative and true positive prediction of MVI, respectively. The use of both morphological and biological tumor features enables effective pre-transplant prediction of high-risk MVI. Provided that these parameters are combined in selection of HCC patients for LT, pre-transplant identification of all patients with MVI does not appear necessary.

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Section: Discussionsupporting

confidence: 92%

Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation

Grąt

Stypułkowski

Patkowski

et al. 2017

Sci Rep

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“…In despite of lacking simple, rigorous assays for defining the number of CSCs [29], measuring CSCs biomarkers potentially help clinicians to relist LT candidates. Llovet JM et al revealed that HCC patients without CSCs markers expression transplanted beyond Milan criteria achieved TFS rates similar as HCC patients transplanted within Milan criteria [30]. We investigated the role of FAM83D in CSCs.…”

Section: Discussionmentioning

confidence: 99%

FAM83D associates with high tumor recurrence after liver transplantation involving expansion of CD44+ carcinoma stem cells

et al. 2016

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To investigate the potential oncogene promoting recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT), throughput RNA sequencing was performed in a subgroup of HCC patients. The up-regulated FAM83D in HCC tissues was found and further verified in 150 patients by real-time PCR and immunohistochemistry. FAM83D overexpression significantly correlated with high HCC recurrence rate following LT and poor HCC characteristics such as high AFP, poor differentiation. Of cancer stem cells (CSCs) markers, CD44 expression was effectively suppressed when FAM83D was knocked down by siRNA. Meanwhile, the siRNA transfected cells suppressed formation of sphere and ability of self-renew. In a xenograft tumorigenesis model, FAM83D knockdown apparently inhibited tumor growth and metastasis. Microarray assays revealed that FAM83D promotes CD44 expression via activating the MAPK, TGF-β and Hippo signaling pathways. Furthermore, CD44 knockdown presented reverse effect on above signaling pathways, which suggested that FAM83D was a key activator of loop between CD44 and above signaling pathways. In conclusion, FAM83D promotes HCC recurrence by promoting CD44 expression and CD44+ CSCs malignancy. FAM83D provides a novel therapeutic approach against HCC recurrence after LT.

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“…Although whether RFA can be considered as a competitive alternative to resection is uncertain in early stage HCC, measurement of WFA-sialylated MUC1 may be helpful for selection of those patients suitable for RFA treatment. It has been reported that HCC patients transplanted beyond the Milan criteria without histochemical HPC feature achieved good survival, similar to those within the Milan criteria 13 . Therefore, WFA-sialylated MUC1 may support a limited expansion of liver transplantation indications.…”

Section: Discussionmentioning

confidence: 83%

“…Those subtypes of HCCs with HPC/biliary features have been associated with more aggressive biological characteristics, including recurrence and metastasis. Cytokeratin 19 (CK19) is known as a marker of HPC/biliary features and the expression of CK19 in HCC tissue has been linked to a poor prognosis 9–13 . Furthermore, mucin-1 (MUC1) is also known as a biliary marker in HCC tissues and the expression of MUC1 in HCC is also associated with a poor prognosis 14, 15 .…”

Section: Introductionmentioning

confidence: 99%

Serum Wisteria Floribunda Agglutinin-Positive Sialylated Mucin 1 as a Marker of Progenitor/Biliary Features in Hepatocellular Carcinoma

Tamaki

Kuno

Matsuda

et al. 2017

Sci Rep

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Histological molecular classification of hepatocellular carcinoma (HCC) is clinically important for predicting the prognosis. However, a reliable serum marker has not been established. The aim of this study was to evaluate the diagnostic value of serum Wisteria Floribunda agglutinin-positive sialylated mucin 1 (WFA-sialylated MUC1), which is a novel biliary marker, as a marker of HCC with hepatic progenitor cell (HPC)/biliary features and of prognosis. A total of 144 consecutive patients who underwent complete radiofrequency ablation of primary HCC were enrolled. A serum WFA-sialylated MUC1 level of 900 μL/mL was determined as the optimal cutoff value for prediction of immunohistochemical staining for HPC/biliary features [sialylated MUC1 and cytokeratin 19 (CK19)]. Positive staining rate of sialylated MUC1 and CK19 was significantly higher in patients with WFA-sialylated MUC1 ≥900 than those with WFA-sialylated MUC1 <900. Furthermore, cumulative incidence of HCC recurrence was significantly higher in patients with WFA-sialylated MUC1 ≥900 and on multivariate analysis, serum WFA-sialylated MUC1 levels was an independent predictor of HCC recurrence. These results revealed that serum WFA-sialylated MUC1 was associated with histological feature of HCC and recurrence after curative therapy and it could be a novel marker of HPC/biliary features in HCC and of prognosis.

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Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation

Abstract: HCC patients transplanted beyond Milan criteria without gene signatures of progenitor markers (CK19 and S2) achieved survival rates similar as those within Milan criteria. Once prospectively validated, these markers may support a limited expansion of LT indications.

Cited by 69 publications

References 47 publications

Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation

Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation

FAM83D associates with high tumor recurrence after liver transplantation involving expansion of CD44+ carcinoma stem cells

Serum Wisteria Floribunda Agglutinin-Positive Sialylated Mucin 1 as a Marker of Progenitor/Biliary Features in Hepatocellular Carcinoma

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