Shun-Jun Fu

A novel and accurate predictor of survival for patients with hepatocellular carcinoma after surgical resection: the neutrophil to lymphocyte ratio (NLR) combined with the aspartate aminotransferase/platelet count ratio index (APRI)

BackgroundThe occurrence and development of hepatocellular carcinoma (HCC) depends largely on such non-tumor factors as inflammatory condition, immune state, viral infection and liver fibrosis. Various inflammation-based prognostic scores have been associated with survival in patients with HCC, such as the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR) and the prognostic nutritional index (PNI). The aspartate aminotransferase/platelet count ratio index (APRI) is thought to be a biomarker of liver fibrosis and cirrhosis. This study aims to evaluate the ability of these indices to predict survival in HCC patients after curative hepatectomy, and probe the increased prognostic accuracy of APRI combined with established inflammation-based prognostic scores.MethodsData were collected retrospectively from 321 patients who underwent curative resection for HCC. Preoperative NLR, PLR, PNI, APRI and clinico-pathological variables were analyzed. Univariate and multivariate analyses were performed to identify the predictive value of the above factors for disease-free survival (DFS) and overall survival (OS).ResultsUnivariate analysis showed that NLR, PLR, PNI and APRI were significantly associated with DFS and OS in HCC patients with curative resection. Multivariate analysis showed that NLR and APRI were superior to PLR and PNI, and both were independently correlated with DFS and OS. Preoperative NLR >2 or APRI >1.68 predicted poor prognosis of patients with HCC after hepatectomy. Furthermore, the predictive range of NLR combined with APRI was more sensitive than that of either measure alone.ConclusionsPreoperative NLR and APRI are independent predictors of DFS and OS in patients with HCC after surgical resection. Higher levels of NLR or APRI predict poorer outcomes in HCC patients. Intriguingly, combining NLR and APRI increases the prognostic accuracy of testing.

Prognostic significance of glypican-3 in hepatocellular carcinoma: a meta-analysis

BackgroundsGlypican-3(GPC3) has been implicated in tumor development and progression for several years. However, the prognostic significance of GPC3 expression in patients with hepatocellular carcinoma (HCC) is controversial. We performed a meta-analysis of available studies to assess whether GPC3 can be used as a prognostic factor in patients with HCC.MethodsWe searched PubMed and Ovid EBM Reviews databases and evaluated the reference list of relevant articles for studies that assessed the prognostic relevance of GPC3 in patients with HCC. Meta-analysis was performed using hazard ratio (HR) or odds ratio (OR) and 95% confidence intervals (95% CIs) as effect measures.ResultsA meta-analysis of eight studies included 1070 patients was carried out to evaluate the association between GPC3 and overall survival (OS) and disease-free survival (DFS) in HCC patients. The relation between GPC3 and tumor pathological features was also assessed. Our analysis results indicated that high GPC3 expression predicted poor OS (HR: 1.96, 95% CI: 1.51–2.55) and DFS (HR: 1.99, 95% CI: 1.57-2.51) of patients with HCC. GPC3 overexpression was significantly associated with high tumor grade (OR: 3.30, 95% CI: 2.04–5.33), late TNM stage (OR: 2.26, 95% CI: 1.00–5.12), and the presence of vascular invasion (OR: 2.43, 95% CI: 1.23–4.82).ConclusionsGPC3 overexpression indicates a poor prognosis for patients with HCC, and it may also have predictive potential for HCC invasion and metastasis.

Prognostic significance of preoperative aspartate aminotransferase to neutrophil ratio index in patients with hepatocellular carcinoma after hepatic resection

Objectives Various inflammation-based prognostic scores have been associated with poor survival in patients with hepatocellular carcinoma (HCC), and neutrophils display important roles. However, few studies have illuminated the relationship between preoperative aspartate aminotransferase (AST) to neutrophil ratio index (ANRI) and poor prognosis of HCC. We aimed to clarify the prognostic value of ANRI and evaluate the ability of different inflammation-based prognostic scores such as ANRI, AST to lymphocyte ratio index (ALRI), AST to platelet count ratio index (APRI), neutrophil-lymphocyte ratio index (NLR), and platelet-lymphocyte ratio index (PLR). Methods Data were collected retrospectively from 303 patients who underwent curative resection for HCC. Preoperative ANRI, ALRI, APRI, NLR, PLR and clinico-pathological variables were analyzed. Univariate, multivariate and Kaplan-Meier analyses were performed to identify the predictive value of the above factors for disease-free survival (DFS) and overall survival (OS). Results ANRI was correlated with presence of HBsAg, AST, presence of cirrhosis, tumor size, PVTT, cancer of the liver Italian program (CLIP) score, recurrence. Univariate analysis showed ANRI, ALRI, APRI, NLR, PLR were significantly associated with DFS and OS in HCC patients with curative resection. After multivariate analysis, ANRI was demonstrated to be superior to ALRI, APRI, NLR, PLR, which were independently correlated with DFS and OS. Survival analysis showed that preoperative ANRI > 7.8 predicted poor prognosis of patients with HCC after hepatectomy. preoperative ANRI also showed different prognostic value in various subgroups of HCC. Furthermore, the predictive range was expanded by the combination of ANRI and NLR. Conclusions preoperative ANRI is an independent effective predictor of prognosis for patients with HCC, higher levels of ANRI predict poorer outcomes and the combining ANRI and NLR increases the prognostic accuracy of testing.

Elevated Preoperative Serum Gamma-glutamyltranspeptidase Predicts Poor Prognosis for Hepatocellular Carcinoma after Liver Transplantation

Gamma-glutamyltransferase (γ-GGT) is a membrane-bound enzyme that is involved in biotransformation, nucleic acid metabolism, and tumourigenesis. Elevated serum γ-GGT levels are related to an increased cancer risk and worse prognosis in many cancers. In the present study, we evaluated the prognostic value of preoperative serum γ-GGT in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). A total of 130 HCC patients after LT were included in the study. The optimal cut-off value of γ-GGT was 128U/L by receiver operating characteristic analysis, with a sensitivity and specificity of 60.0% and 72.9%, respectively. Elevated preoperative serum γ-GGT was significantly associated with high alpha-fetoprotein (AFP), large tumor size, and macro- and micro-vascular invasion. The 1-, 3-, 5-year disease-free survival (DFS) and overall survival (OS) rates of HCC patients in the γ-GGT > 128U/L group were poorer than those in the γ-GGT ≤ 128U/L group. Stratification analysis revealed that γ-GGT exhibited a greater predictive value for DFS and OS in HCC patients beyond the Milan criteria and no macro-vascular invasion. In conclusion, elevated preoperative serum γ-GGT was significantly associated with advanced tumor stage and aggressive tumor behaviors, and serum γ-GGT can be considered as a prognostic factor for HCC patients after LT, especially for patients beyond the Milan criteria or without macro-vascular invasion.

Prognostic value of combined preoperative lactate dehydrogenase and alkaline phosphatase levels in patients with resectable pancreatic ductal adenocarcinoma.

AbstractSerum enzymes, including lactate dehydrogenase (LDH) and alkaline phosphatase (ALP), have recently been reported to play important roles in tumor growth. Increases in LDH and ALP have been confirmed to predict poor prognosis in patients with various cancers. However, their prognostic value in pancreatic cancer has not been well studied. Therefore, we reviewed the preoperative data on LDH and ALP in 185 pancreatic ductal adenocarcinoma (PDAC) patients who underwent surgery between July 2005 and December 2010 to explore the prognostic value of these markers. The cutoff points were determined based on the upper limit of their normal values. The Chi-square test was used to analyze the relationships between LDH/ALP and clinical characteristics. Univariate and multivariate analyses were performed to identify the predictive value of the above factors for disease-free survival (DFS) and overall survival (OS). We found that elevation of LDH was related to carbohydrate antigen 19-9 (CA19-9), lymph node involvement, tumor size, TNM, distant metastasis, and recurrence. Additionally, ALP was correlated to perineural invasion. After multivariate analysis, LDH and ALP were identified as independent prognostic factors for DFS and OS, and elevation of LDH/ALP was correlated with poor DFS and OS. Notably, there was a positive correlation between LDH and ALP. The predictive power of LDH combined with ALP was more sensitive than that of either one alone. Therefore, we conclude that the preoperative LDH and ALP values are prognostic factors for PADC, and the prognostic accuracy of testing can be enhanced by the combination of LDH and ALP

MiR-486-5p negatively regulates oncogenic NEK2 in hepatocellular carcinoma

NEK2 is a member of the NIMA-related family of serine/threonine centrosomal kinases. We analyzed the relationship between differential expression of NEK2 and hepatocellular carcinoma (HCC) patient outcomes after liver transplants. We also studied the microRNAs that affect NEK2 expression. Analysis of multiple microarrays in the Oncomine database revealed that NEK2 expression was higher in HCC tissues than adjacent normal liver tissues. High NEK2 expression correlated with tumor size, pathological grade and macro- and microvascular invasion. Consequently, patients exhibiting high NEK2 expression had poorer prognosis. This was corroborated by our multivariate analysis that showed NEK2 to be an independent prognostic factor for HCC patient survival. Further, high NEK2 expression promoted proliferation, colony formation, migration and invasion of HCC cell lines. Tumor xenograft data from Balb/c nude mice demonstrated that HCC cells with high NEK2 expression formed larger tumors than those with low NEK2 expression. Finally, we showed that miR-486-5p suppressed NEK2 by directly binding to its transcript 3′UTR. We also demonstrated an inverse relationship between miR-486-5p and NEK2 expression in HCC patients. These findings suggest miR-486-5p negatively regulates NEK2, which is a critical prognostic indicator of HCC patient survival after liver transplantation.

Reply to: Importance of Platelet Indices in Hepatocellular Carcinoma Prognosis

We thank Dr. Sertoglu and his colleagues for their thoughtful comments and suggestions submitted in response to our article. We appreciate the opportunity to respond to their letter. First, they think that it would be more appropriate to take into consideration the gender-dependent difference in the upper limit of normal (ULN) of AST in calculating the APRI score. In fact, aside from gender, the ULN of AST is influenced by many other factors, including age, race, alcohol intake, body mass index, serum cholesterol, and methods of assay. It would be impossible to take all these factors into account. By all means, the ULN represents 95th percentile of the target population. In our institution, the normal range of AST is defined as 1–37 U/L for both healthy men and women with no difference. Therefore, we are unable to make such an amendment for APRI, which we hope that institutions with sufficient conditions (including enough hepatocellular carcinoma (HCC) patients, gender dependent different ULN of AST) could have such verification. Second, a receiver operating characteristic (ROC) analysis was suggested to be performed to determine the most appropriate cutoff point for preoperative platelet count. Actually, a similar question was asked by one reviewer, because many patients with advanced liver disease have low platelet counts. The reviewer pointed out that a relatively high number of 300/mm was chosen. How would the results change if the cutoff value was 150/mm? In our clinical test, the normal limit for platelet is 100–300/ mm. Only when serious portal hypertension and hypersplenism occurs will the platelet number decreases to very low level. In this series of patients, 74.09% (246/332) of cases had a platelet higher than 150/mm. When the cutoff value was 150/mm (as used by Maithel), both the disease-free survival and overall survival had no differences between two groups of patients with high (C 150/mm) and low (\ 150/mm) platelet count. Meanwhile, we tried the ROC analysis while preparing this article. We had a cutoff value of 267/mm, which was very close to the ULN of 300/mm for platelet in our clinical test. Moreover, when the cutoff value changed from 267 to 300/mm, there was no significant change for its prognostic value. Therefore, we used 300/mm as the cutoff value for platelet count. As suggested by Dr. Sertoglu, we evaluated other platelet-related indices, including age-platelet index (API), spleen-platelet ratio index (SPRI), and age-spleen-platelet ratio index (ASPRI), in our series of patients. APRI showed the highest diagnostic accuracy for prediction of tumor recurrence [AUROC (area under ROC curve) = 0.588] than all of these indices (AUROC = 0.500, 0.476, 0.496, respectively). Surprisingly, in univariate analysis, none of the above three new indices were proven to be independent factor for prognosis of HCC. This showed that not all platelet-based indices could be used to predict of prognosis in HCC patients.We thank Dr. Sertoglu and his colleagues for their thoughtful comments and suggestions submitted in response to our article. We appreciate the opportunity to respond to their letter. First, they think that it would be more appropriate to take into consideration the gender-dependent difference in the upper limit of normal (ULN) of AST in calculating the APRI score. In fact, aside from gender, the ULN of AST is influenced by many other factors, including age, race, alcohol intake, body mass index, serum cholesterol, and methods of assay. It would be impossible to take all these factors into account. By all means, the ULN represents 95th percentile of the target population. In our institution, the normal range of AST is defined as 1–37 U/L for both healthy men and women with no difference. Therefore, we are unable to make such an amendment for APRI, which we hope that institutions with sufficient conditions (including enough hepatocellular carcinoma (HCC) patients, gender dependent different ULN of AST) could have such verification. Second, a receiver operating characteristic (ROC) analysis was suggested to be performed to determine the most appropriate cutoff point for preoperative platelet count. Actually, a similar question was asked by one reviewer, because many patients with advanced liver disease have low platelet counts. The reviewer pointed out that a relatively high number of 300/mm was chosen. How would the results change if the cutoff value was 150/mm? In our clinical test, the normal limit for platelet is 100–300/ mm. Only when serious portal hypertension and hypersplenism occurs will the platelet number decreases to very low level. In this series of patients, 74.09% (246/332) of cases had a platelet higher than 150/mm. When the cutoff value was 150/mm (as used by Maithel), both the disease-free survival and overall survival had no differences between two groups of patients with high (C 150/mm) and low (\ 150/mm) platelet count. Meanwhile, we tried the ROC analysis while preparing this article. We had a cutoff value of 267/mm, which was very close to the ULN of 300/mm for platelet in our clinical test. Moreover, when the cutoff value changed from 267 to 300/mm, there was no significant change for its prognostic value. Therefore, we used 300/mm as the cutoff value for platelet count. As suggested by Dr. Sertoglu, we evaluated other platelet-related indices, including age-platelet index (API), spleen-platelet ratio index (SPRI), and age-spleen-platelet ratio index (ASPRI), in our series of patients. APRI showed the highest diagnostic accuracy for prediction of tumor recurrence [AUROC (area under ROC curve) = 0.588] than all of these indices (AUROC = 0.500, 0.476, 0.496, respectively). Surprisingly, in univariate analysis, none of the above three new indices were proven to be independent factor for prognosis of HCC. This showed that not all platelet-based indices could be used to predict of prognosis in HCC patients.