We retrospectively analyzed the clinical data of HCC patients with compensated cirrhosis who received ablation therapy at Beijing You’an Hospital affiliated with Capital Medical University between January 1, 2014, and December 31, 2022. A total of 669 patients were included in the final analysis and these patients were randomly assigned to two groups in a ratio of 7:3, with 468 patients in the training set and 201 in the validation set ( Supplementary Figure S1 ). This study obtained approval from the Ethics Committee of Beijing You’an Hospital affiliated with Capital Medical University, and informed consent was waived due to the retrospective nature of the study.

Patients were diagnosed with HCC and cirrhosis according to the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) (17, 18). The early-stage of HCC was defined according to Barcelona Clinic Liver Cancer (BCLC) stage and Child-Pugh stage (19, 20). Compensated cirrhosis was defined as cirrhosis in the absence of clinical complications, including ascites, variceal bleeding, and hepatic encephalopathy.

The inclusion criteria were as follows: (1) age from 18 to 75 years; (2) BCLC stage 0 or A; (3) Child-Pugh stage A; (4) HCC patients with compensated cirrhosis. The exclusion criteria were as follows: (1) incomplete clinical or follow-up data; (2) with distant metastases or other malignancies; (3) insufficiency of vital organs; (4) bacterial or viral infections; (5) rheumatism or blood disorders that can cause platelet changes.

Demographics and laboratory data were collected from the electronic patient records, including age, gender, medical history (smoking, drinking, antiviral treatment, hypertension, diabetes mellitus), BCLC stage, tumor number, tumor size, red blood cell (RBC), hemoglobin (Hb), white blood cell (WBC), alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), neutrophils (Neu), lymphocytes (Lym), monocytes (Mon), albumin (Alb), globulin (Glob), prealbumin (Palb), prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), and international normalized ratio (INR). Meanwhile, we included the gamma-glutamyl transpeptidase to platelet ratio (GPR) in our analysis to increase the prognostic value of the proposed nomogram.

A close follow-up of all patients after local ablation was conducted, and it was completed via outpatient consultation or telephone calls. The typical follow-up was performed every 3 months in the first year and then every 6 months thereafter, which comprised physical examination, laboratory tests, and imaging examination. The last day of follow-up was July 1, 2023. Overall survival (OS), as the primary endpoint of this study, was defined as the interval from local ablation to either the occurrence of death or the last follow-up.

All enrolled patients were treated with local ablation, which was performed by qualified hepatologists and interventional radiologists. The specific process includes 5 items: (1) Appropriate position for ablation was determined by computed tomography (CT) or magnetic resonance imaging (MRI). (2) The ablation needle was inserted in the marked skin, and followed by image scanning to track the ablation process. (3) For the purpose of attaining complete ablation, operators should expand the ablative range and contemplate multiple sites, overlapping, or repeated ablation. (4) In order to prevent tumor implantation and postoperative bleeding, the needle track required to be heated in the final stage. (5) Following the ablation, all patients underwent imaging examinations to assess treatment efficacy and possible complications.

The methods of local ablation include radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation, among others. By introducing radiofrequency electrodes directly into the tumor tissue, RFA utilizes high-frequency electrical currents to generate heat, resulting in necrosis. While MWA uses microwave energy to generate heat and kill tumor cells. The characteristic of microwave energy is their ability to rapidly and evenly heat tissues. As for cryoablation, it utilizes extremely low temperature of medium (such as liquid nitrogen or argon gas) to freeze and destroy tumor cells. These ablation therapeutic modalities have specific advantages in the treatment of cancer, and the specific method was selected by clinical physicians in our study.

Continuous variables were presented as mean and standard deviation (mean ± SD) and analyzed by Student’s t-test or non-parametric test. Categorical variables were expressed as frequency (percentage) and contrasted using the Chi-square test.

In this research, patients were randomly split into the training set (n=468) and validation set (n=201) in a ratio of 7:3. The training cohort was utilized for building the nomogram, while the validation cohort was specifically employed to verify its performance. Concurrently, Lasso regression and multivariate Cox regression analysis were used to determine the independent risk factors associated with OS. Significant factors with p-values below the threshold of 0.05 were included in the nomogram. Subsequently, patients were categorized into low-risk group and high-risk group according to the scores calculated from the nomogram. Kaplan-Meier curves and log-rank tests were then employed to compare OS between the two groups. Additionally, the receiver operating characteristic (ROC) curves were plotted and the area under the ROC curves (AUCs) was calculated to evaluate the discriminative ability. Model calibration and clinical utility were assessed by calibration curves and decision curve analysis (DCA), respectively. At last, we used the ROC curve to observe the predictive ability of GPR and other risk factors.

All analyses were conducted using R statistical software (version 4.1.2) in this study. Statistical significance was set at p<0.05 (two-tailed).

During the period from January 1, 2014, to December 31, 2022, a total of 669 HCC patients with compensated cirrhosis after local ablation were recruited in this study and randomized into two groups with a 7:3 ratio. There were 468 patients constituted the training set, while 201 formed the validation set. All patients received ablation therapy without any combined treatments, and there were 150 (22.4%) patients died during the follow-up period. Our study concluded patients’ last follow-up on July 1, 2023, with a median follow-up duration of 52.4 months.

The baseline clinical characteristics of all patients were presented in Table 1 , which revealed no statistical differences between the two groups (p>0.05). Among these patients, the average age was 56.28 years, with 544 (81.3%) males and 125 (18.7%) females. Notably, 285 (42.6%) patients had a history of smoking and 215 (32.1%) had a history of drinking. Furthermore, 185 (27.7%) individuals were diagnosed with hypertension and 133 (19.9%) with diabetes mellitus. The training and validation cohorts both had a majority of patients in BCLC stage A (71.2% vs. 65.2%), with most solitary tumors (68.4% vs. 71.1%) and tumor size less than 3cm (65.6% vs. 60.1%).

Lasso regression, utilizing a loss function with L1 regularization to penalize model coefficients while minimizing the objective function, was employed to screen risk factors associated with OS ( Figure 1 ). The 10-fold cross-validation method was applied to select the optimal λ value, which was determined to be 0.0274 (Log λ = -1.562). Significant risk factors filtered by Lasso regression were GPR, age, gender, history of antiviral therapy, history of drinking, tumor number, tumor size, BCLC stage, Hb, and Palb. These variables were further incorporated into the multivariable Cox regression analysis, revealing that GPR (HR:1.257, 95% CI: 1.037-1.527), age (HR:1.025, 95% CI: 1.003-1.048), and Hb (HR:0.988, 95% CI: 0.978-0.999) as the independent prognostic factors for OS ( Table 2 ).

Based on these independent prognostic factors, we constructed a nomogram for predicting the OS of compensated cirrhotic HCC patients who received local ablation ( Figure 2 ). Every risk factor corresponds to a specific score according to its value on the nomogram. It was necessary to sum the scores of factors and draw a vertical line at the corresponding total point. After these steps, the vertical line intersects with three lines representing mortality risk, which forecast the 3-, 5-, and 8-year OS.

In the training cohort, patients were categorized into low-risk group (n=234) and high-risk group (n=234) in light of the nomogram. The Kaplan-Meier curve was plotted, indicating that the median OS was 92.0 months for the high-risk group, while it was not reached in the low-risk group ( Figure 3 ). The cumulative OS rates for 3-, 5-, and 8-year were 86.9%, 71.0%, and 49.5% in the high-risk group, while 94.0%, 87.3%, and 70.6% in the low-risk group. There existed an obvious distinction in OS among the two groups (p=0.00034).

Subsequently, the time-dependent ROC curve was drawn and the C-index in the training set was 0.695 (95% CI: 0.656-0.734). It showed that AUCs of 3-, 5-, and 8-year were 0.701, 0.755, and 0.768. The 1-specificity and sensitivity of 3-, 5-, and 8-year were (0.468, 0.862), (0.411, 0.913), and (0.331, 0.861), respectively ( Figure 4 ). These outcomes highlighted the advantageous discriminative ability. At last, a calibration curve ( Figure 5 ) and DCA curves ( Figure 6 ) were created, affirming that the nomogram demonstrated good calibration and clinical utility.

In order to further validate the reliability of this nomogram, we performed internal validation in our study. According to the nomogram, patients in the validation cohort were also classified into two groups by the Kaplan-Meier curve: low-risk group (n=100) and high-risk group (n=101) ( Figure 3 ). The median OS was 92.0 months for the high-risk group, while it was not reached in the low-risk group. The cumulative OS rates for 3-, 5-, and 8-year were 85.2%, 71.3%, and 49.8% in the high-risk group, while 95.2%, 86.5%, and 82.6% in the low-risk group. In concordance with the training cohort, there was also a statistically significant discrepancy in OS among the two groups (P=0.0021).

The C-index in the validation cohort was 0.679 (95% CI: 0.616-0.742) and the AUCs for 3-, 5-, and 8-year were 0.684, 0.707, and 0.778, which suggested the favorable diagnostic value. The 1-specificity and sensitivity of the ROC curve were (0.472, 0.832), (0.434, 0.844), and (0.351, 0.903) for 3-, 5-, and 8-year ( Figure 4 ). The calibration curve exhibited a good match ( Figure 5 ), and the DCA curves also had good clinical practicability ( Figure 6 ).

The discriminative ability of the GPR and other risk factors was assessed using ROC curve ( Supplementary Figure S2 ). The AUC values were 0.514 for age, 0.504 for hemoglobin, 0.580 for fibrosis 4 score (Fib-4), 0.614 for aspartate transaminase to platelet ratio index (APRI), and 0.652 for GPR, respectively. The outcome indicated that the GPR was observed to have better predictive ability compared with other risk factors. Moreover, we explored the AUC value of the combination of GPR and neutrophil to lymphocyte ratio index (NLR) based score (AUC=0.679), which showed improved discriminability compared to GPR alone. Thus, the predictive ability of GPR combined with NLR need more studies to investigate.

At last, our study used KM curves to analyze the predictive ability of the nomogram for disease-free survival (DFS). It was defined as the time from the date of local ablation to recurrence or last of follow-up. Although it underperformed in the validation cohort, there existed an obvious distinction among training cohort ( Supplementary Figure S3 ). In the training cohort, the median DFS was 18.0 months for the high-risk group, and 24.5 months for the low-risk group. The cumulative DFS rates for 1-, 3-, and 5-year were 66.2%, 24.6%, and 16.8% in the high-risk group, while 73.9%, 35.4%, and 26.0% in the low-risk group. These outcomes demonstrated that the nomogram had a certain predictive capability for DFS.