MATERIALS AND METHODS

Patients

The retrospective analysis obtained ethical approval and complied with the standards of the Declaration of Helsinki and current ethical guidelines. Informed consent was obtained from each patient before surgery for using their data for research. The CHC was histologically defined according to the WHO criteria,15 and two independent pathologists reassessed all these samples. The standard technique was adopted for hepatic resection.16 The probability of hilar lymph node metastasis was evaluated with preoperative contrast-enhanced computed tomography (CT) and (or) magnetic resonance imaging (MRI). The dissected lymphoid metastasis was routinely confirmed by pathology. Patients with no previous antitumor therapy, confirmed with CHC pathologically, no other malignancies and Child–Pugh class A or B were included in this study. The exclusion criteria were as follows: ICC or HCC proved by histopathology, tumors of uncertain origin, metastatic liver tumors, perioperative mortality and distant or intrahepatic metastasis. In the derivation cohort, 208 CHC patients who underwent liver resection, between April 1999 and December 2014, at Zhongshan Hospital of Fudan University were enrolled. Further, we included an external validation cohort with 101 patients, from September 2003 to January 2016, at Mengchao Hepatobiliary Hospital of Fujian Medical University. The study complied with the standards of the Declaration of Helsinki. The institutional review board of Zhongshan Hospital approved this study. All patients gave written informed consent.


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Laboratory test and data collection

The serum chemistries, blood cell count and tumor biomarkers (serum alpha-fetoprotein [AFP], carcinoembryonic antigen [CEA], carbohydrate antigen 19-9 [CA19-9]) were measured in routine examination according to standard laboratory procedures.17 Hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (HCV) were detected using standard test systems. To evaluate the potential risk predictors, all the data associated with demographic and pathological information were collected at the time of initial diagnosis.

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Follow-up and detection of recurrence

All patients underwent follow-up every 3 months in the first year and every 6 months thereafter until death or dropout. Abdominal ultrasound, liver function tests, serum AFP, CEA and CA19-9 levels were analyzed every 3 months, and abdominal MRI or CT scanning was performed every 6 months. According to standard guidelines for HCC,18 ICC19 or radiologic features of CHC described previously,20 recurrence was confirmed by contrast-enhanced imaging studies and tumor biomarkers.

Recurrent patients were managed with different therapeutic modalities, including radiofrequency ablation, repeated resection, transcatheter arterial chemoembolization (TACE) and supportive therapy. Overall survival (OS) was defined as the time period between the date of surgery and death and disease-free survival (DFS) was defined as the interval between the date of surgery and recurrence.

Statistical analysis

Continuous variables were reported as medians with IQR and categorical variables were as percentages. Pearson’s χ2 test and Fisher’s exact test were employed to compare categorical variables, whereas Wilcoxon test was used to evaluate continuous variables. Survival curves were computed with Kaplan–Meier methods and compared by using log-rank tests. Cox proportional hazards regression models were performed to determine univariate and multivariable HRs for predicting factors of CHC recurrence or survival. Predictors (P<0.10 in univariate analysis) were selected in the multivariate analysis. The final multivariate model was performed using a backward stepwise procedure for variable selection with a liberal P<0.05 as the retention criteria. According to the final multivariable model coefficients,21 the novel prognostic score was developed, assigning ordinal scores (0 or 1) to each of the selected factors. This simplified point scale could reflect the relative impact of risk covariables in the new model. And then, the relative value of each model component was summed to calculate the PECAR score. The PECAR score was tested and compared with AJCC 7th TNM system in the validation cohort. We used the C-index22 to assess model discrimination and absolute net reclassification index (NRI)23,24 to evaluate the improvement of model performance for CHC recurrence. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R software version 3.30 (R Foundation for Statistical Computing, Vienna, Austria). A P-value <0.05 was considered statistically significant.

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