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Preoperative platelet-albumin–bilirubin grades predict the prognosis of patients with hepatitis B virus-related hepatocellular carcinoma after liver resection

Abstract Minimal information is available concerning platelet-albumin–bilirubin (PALBI) grades in patients with hepatocellular carcinoma (HCC) following liver resection. This study aimed to investigate the predictive ability of PALBI grades in patients with a Child–Pugh class A score and hepatitis B virus-related (HBV-related) HCC after liver resection. The data of patients with HBV-related HCC who underwent liver resection from 2010 to 2017 at our center were reviewed (n = 785). Cox regression was used to determine factors independently associated with postoperative recurrence and mortality. The area under the receiver operating characteristic curve (AUC) was used to estimate the predictive accuracy of different tools. During the follow-up period, 505 (64.3%) patients experienced recurrence, and 374 (47.6%) patients died. Multivariate analysis revealed that the tumor-node-metastasis (TNM) stage (HR = 1.591, 95%CI = 1.414–1.789, P < .001), PALBI grade (HR = 1.326, 95%CI = 1.139–1.544, P < .001), a high AFP level (HR = 1.382, 95%CI = 1.158–1.649, P < .001) and transfusion (HR = 1.364, 95%CI = 1.087–1.712, P = 0.007) were independently associated with recurrence. Additionally, microvascular invasion (HR = 1.674, 95%CI = 1.292–2.169, P < .001), beyond the Milan criteria (HR = 0.477, 95%CI = 0.346–0.657, P < .001), PALBI grade (HR = 1.356, 95%CI = 1.151–1.598, P < .001), a high AFP level (HR = 1.542, 95%CI = 1.252–1.900, P < .001), and transfusion (HR = 1.548, 95%CI = 1.199–1.999, P = 0.001) adversely impacted the overall survival. The AUCs of the PALBI grades for postoperative recurrence and mortality were significantly higher than the albumin–bilirubin grade and Child–Pugh score. The prognostic significance of the PALBI grade for postoperative recurrence and mortality was maintained when stratified by the TNM stage. The preoperative PALBI grade is a surrogate marker for the postoperative prognosis in patients with HBV-related HCC after liver resection.


Introduction
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and third most frequent cancer-related cause of death worldwide. [1] Every year, over 700,000 new HCC cases are diagnosed, with a similar number of deaths due to its highly aggressive behavior. [1] Unfortunately, more than 50% of new cases and deaths occur in China because of the high prevalence of hepatitis B virus (HBV) infection. [1] Liver resection is a widely used treatment for patients with HCC and well-preserved liver function. However, the long-term outcomes of HCC patients after liver resection remain unsatisfactory because of a high incidence of postoperative recurrence. Previous investigations reported a postoperative recurrence rate of 70% at 5 years, even in patients with early stage HCC. [2] Liver function plays a key role in liver resection for HCC. Several investigations have reported that liver function not only contributed to surgical safety but was also associated with postoperative recurrence and long-term survival following liver resection. [3,4] Currently, the Child-Pugh score is the most commonly used system to evaluate liver function in patients. However, the Child-Pugh score includes some subjective factors, including encephalopathy and ascites. Moreover, the interrelationship between ascites and albumin can confound the Child-Pugh score. In 2015, the albumin-bilirubin (ALBI) grade was proposed to assess a patient's liver function, and it only includes 2 objective factors (albumin and total bilirubin). [5] Since it was introduced, a number of investigations have confirmed that the ALBI grade was better than the Child-Pugh score in predicting a patient's liver function as well as in predicting a patient's prognosis following liver resection and radioembolization. [3,6,7] However, the ALBI grade does not incorporate portal hypertension, which is considered to be an unfavorable factor for longterm survival of HCC patients. [8,9] Recently, based on the ALBI grade, the platelet-albumin-bilirubin (PALBI) grade was developed to assess a patient's liver function. This grade incorporates blood platelet count as a surrogate maker of portal hypertension. [10] Both ALBI and PALBI include only objective factors. Despite some external validations of the ALBI and PALBI grades, whether the PALBI score could predict a HCC patient's outcome after liver resection remains unclear. [10][11][12] In this study, we attempted to clarify this issue.

Patients and methods
The data of patients with HBV-related HCC who underwent liver resection at West China Hospital between 2010 and 2017 were reviewed. Patients who met the following criteria were excluded: re-resection, ruptured HCC, no history of HBV infection, coinfection with hepatitis C virus, received preoperative antitumor treatment, a positive surgical margin, and the presence of other types of tumors. HCC was confirmed by postoperative pathological examination. The hepatitis B surface antigen was detected in all patients. This study was approved by the ethics committee of West China Hospital.

Follow-up
All preoperative blood tests were performed 2 days before the operation. After liver resection, patients were regularly followed up at one month post-op, every 3 months during the first postoperative 3-year period, and every 6 months thereafter. Before and after the operation, antiviral drugs (entecavir or lamivudine) were conventionally administered to patients who were positive for hepatitis B virus-DNA (HBV-DNA). During follow-up, blood cell tests, liver function tests, serum alphafetoprotein (AFP) measurement, HBV-DNA tests, visceral ultrasonography, computed tomography or magnetic resonance imaging, and chest radiography were performed for all patients. Bone scintigraphy was performed whenever HCC recurrence was suspected. Postoperative recurrence was defined as positive imaging findings compared with preoperative examination values or confirmation by biopsy or resection. [13]

Statistical analysis
All statistical analyses were performed using SPSS 21.0 (SPSS Company, Chicago, IL) for Windows. All continuous variables were shown as the means ± standard deviation and compared using one-way analysis of variance. Categorical variables were analyzed using the x 2 test or Fisher's exact test. Recurrence-free survival (RFS) and overall survival (OS) were determined using the Kaplan-Meier method, and comparisons were determined using the logrank test. Independent risk factors for RFS and OS were identified using Cox regression analysis. Potential risk factors with a Pvalue < .05 in the univariate analysis were included in the multivariate analysis. The area under the receiver operating characteristic curve (AUC) was used to estimate the predictive accuracy of the PALBI grade, ALBI grade and Child-Pugh score. A P-value of < .05 was considered statistically significant.

Results
A total of 785 patients were included in the current study; 681 (86.8%) males and 104 (13.2%) females. The mean age was 50.8 ± 11.8 years.

Comparison of patients with different PALBI grades
As shown in Figure 1, the 1-,    (Table 3).

Comparison of the predictive ability of PALBI grade, ALBI grade and Child-Pugh score
The discriminatory capabilities of the PALBI grade, ALBI grade and Child-Pugh score were tested by the AUC methods. When we compared the AUC for the PALBI grade, ALBI grade and Child-Pugh score in predicting postoperative recurrence, the PABLI grade had the highest AUC (AUC = 0.590), followed by the ALBI grade (AUC = 0.534) and Child-Pugh score (0.518).

The prognostic significance of PALBI stratified by TNM stage
We analyzed the prognostic significance of PALBI when stratified by TNM stage. As shown in Figure 2, when we divided patients into 3 groups according to TNM stage, the prognostic significance of the PALBI grade for RFS and OS was maintained when stratified by TNM stage. Patients with a high PALBI grade had a higher incidence of recurrence and lower long-term survival than those with a low PALBI grade.

Discussion
Liver function plays an important role in predicting the prognosis in HCC patients. Traditionally, we have used the Child-Pugh score to assess a patient's liver function. However, the prognostic power of the Child-Pugh score was weakened when some subjective factors were included. Previous investigations confirmed that the ALBI grade was a simple, evidence-based and objective tool to evaluate a patient's liver function. [3,12] The ALBI grade did not involve factors related to portal hypertension. A number of studies have revealed that portal hypertension was associated with a high incidence of postoperative complications, recurrence and reduced long-term survival in HCC patients following liver resection. [14,15] The PALBI grade not only includes factors (total bilirubin and Table 3 Comparison of clinicopathological parameters of patients with different PALBI grades.  albumin) associated with liver function but also includes factors (platelet) reflecting portal hypertension. This may be an explanation for why the PALBI grade showed better predictive ability than other tools in the current study. We acknowledge that platelet count cannot exactly mirror portal hypertension. However, previous studies suggested a low platelet count negatively influences a patient's prognosis. For example, Shehta et al [16] confirmed that a preoperative low platelet count was related to a high HCC recurrence rate after liver resection. Maithel et al [17] revealed that a low preoperative platelet count was independently associated with increased postoperative major complications and mortality in liver resection in HCC patients. Recently, a metaanalysis that was performed by Zhang et al [18] also confirmed that a low platelet count was associated with poor RFS and OS in HCC patients after liver resection. There were some investigations concerning the PALBI score in predicting the prognosis of HCC. Liu et al [11] suggested that both ALBI and PALBI were good tools to assess liver dysfunction. In their study, Liu et al included patients with Child-Pugh class A, B, and C liver function who underwent liver resection, radiofrequency ablation and transarterial chemoembolization (TACE). [11] Recently, Hansmann et al [10] confirmed that PALBI was accurate in the survival metrics in high-risk HCC patients who received TACE. In their study, Hansmann et al involved patients with Child-Pugh class A, B, and C liver function. [10] In our study, we only included patients with Child-Pugh class A liver function who had liver resection, which was different from the abovementioned studies. [10,11] Wellpreserved liver function is very important for liver resection. Moreover, our study further identified the prognostic performance of TNM stage stratified by the PALBI grade. Our study confirmed that the PALBI grade can predict not only the OS but also the RFS for patients with HCC after liver resection.
Consistent with previous studies, in our study, a high AFP level, TNM stage, MVI, beyond Milan criteria and transfusion were suggested to be negative factors for prognosis. [19,20] Our study further suggested that the PALBI grade was an independent risk factor for both RFS and OS following liver resection. For patients in Child-Pugh class A, the Child-Pugh score has only 2 points (5 or 6). The ALBI grade also classifies these patients into 2 grades. However, the PALBI grade divides these patients into 3 grades. In our study, 223 patients with the Child-Pugh score 5 were classified into PALBI grade 2 or 3. In other words, the PALBI grade may be more useful in subdividing patients in the Child-Pugh class A than the Child-Pugh score. The subdivision of the Child-Pugh class A is useful for predicting a patient's prognosis. For instance, Okajima et al [21] confirmed that both the RFS and OS of patients with a Child-Pugh score 5 was better than that of patients with a Child-Pugh score 6, although all patients were designated as Child-Pugh class A. This finding may offer another potential explanation for why the PALBI grade showed good prognostic power in our study. Additionally, the PALBI grade only contains total bilirubin, albumin and platelets. These 3 paraments are objective and can be easily obtained from routine blood tests. Thus, the PALBI grade is an objective tool to assess liver function, and therefore is better than the Child-Pugh score.
There are some limitations in this study. This study is a singlecenter retrospective study. In the current study, we only included patients with HBV-related HCC. The predictive ability of the PALBI grade for other causes of HCC needs further investigation.
In conclusion, our study confirmed that the PALBI grade, an objective and evidence-based tool, is a surrogate marker for the prognosis in patients with HCC following liver resection.

Author contributions
LHM and CLP proposed this study. LHM and ZSZ collected the data. LHM, LC, and ZSZ analyzed the data.