Cryptogenic hepatocellular carcinoma: characteristics, outcome, and prognostic role of albumin-bilirubin (ALBI) grade vs easy ALBI grade.

BACKGROUND: The characteristics and prognosis of cryptogenic hepatocellular carcinoma (HCC) remain unclear. The albumin-bilirubin (ALBI) grade and its updated version, the easy ALBI (EZ-ALBI) grade, are important prognostic predictors for HCC. We aimed to investigate the long-term survival of patients with cryptogenic HCC and the prognostic role of ALBI and EZ-ALBI grade in these patients. METHODS: A prospective cohort of 2,937 HCC patients with viral or cryptogenic etiology were retrospectively analyzed. The multivariate Cox model was used to determine prognostic predictors. RESULTS: Cryptogenic HCC patients were often older and diabetic, had lower serum ɑ-fetoprotein (AFP) levels, larger tumor burden, poor performance status, advanced cancer stage, and received non-curative treatments compared with hepatitis B or C-related HCC. The Cox analysis showed that age > 65 years, serum AFP > 400 ng/mL, presence of vascular invasion or distant metastasis, presence of ascites, performance status 2-4, ALBI grade 2 and 3, EZ-ALBI grade 2 and 3, and non-curative treatment, were independent predictors of decreased survival in cryptogenic HCC (p < .001). Significant survival differences were found across ALBI grade and EZ-ALBI grade in cryptogenic HCC and subgroup patients receiving curative or non-curative treatments. The Cancer of Liver Italian Program was the best staging system for patients with cryptogenic HCC. CONCLUSIONS: Patients with cryptogenic HCC have a larger tumor burden and advanced cancer stage at disease presentation compared with those with viral HCC. The ALBI and EZ-ALBI score are robust models to evaluate liver functional reserve for these patients independent of treatment modality.

Albumin-Based Liver Reserve Models vs. MELD 3.0 in Prognostic Prediction for Hepatocellular Carcinoma Patients with Renal Insufficiency.

The severity of liver functional reserve is an important prognostic predictor in hepatocellular carcinoma (HCC). The albumin-bilirubin (ALBI), easy (EZ)-ALBI, platelet-albumin-bilirubin (PALBI), platelet-albumin (PAL) score, and MELD 3.0 score are used to evaluate the severity of liver dysfunction. However, their prognostic role in HCC patients, specifically with renal insufficiency (RI), is unclear. We aimed to investigate the predictive accuracy of the five models in these patients. A total of 1120 newly diagnosed HCC patients with RI were enrolled. A multivariate Cox proportional analysis was used to identify independent predictors associated with survival. In the Cox model, older age, an α-fetoprotein ≥20 ng/mL, vascular invasion, a medium and high tumor burden score, poor performance status, a higher ALBI grade, an EZ-ALBI grade, a PALBI grade, a PAL grade, and MELD 3.0 score were all independently associated with decreased overall survival (all p < 0.001). Among the five liver reserve models, the ALBI grade is the best surrogate marker to represent liver functional reserve in terms of outcome prediction. The albumin-based liver reserve models (ALBI, EZ-ALBI, PALBI, and PAL) and MELD 3.0 are all feasible prognostic markers to indicate liver injury, specifically in HCC patients with RI. Among them, the ALBI grade is the most robust tool for survival prediction in these patients.

Dual hepatitis B and C-associated hepatocellular carcinoma: clinical characteristics, outcome, and prognostic role of albumin-bilirubin grade.

BACKGROUND: Albumin-bilirubin (ALBI) grade is used to evaluate the outcome of patients with hepatocellular carcinoma (HCC) which is often associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. This study aimed to investigate the clinical characteristics, outcome, and prognostic role of ALBI grade in dual HBV/HCV-related HCC. METHODS: A total 3341 HCC patients with viral etiology were prospectively enrolled and retrospectively analyzed. Multivariate Cox proportional hazards model was used to identify independent prognostic predictors. RESULTS: Of all patients, 2083 (62%), 1068 (32%), and 190 (6%) patients had HBV, HCV, and dual HBV/HCV infection, respectively. The mean age of HBV, HCV, and dual virus group was 60, 68, and 64 years (p < 0.001), respectively. There was no significant survival difference between HBV, HCV, and dual HBV/HCV-related HCC group (p = 0.712). Multivariate Cox analysis in dual HBV/HCV-related HCC showed that multiple tumors [hazard ratio (HR): 1.537, p = 0.044], tumor size >3 cm (HR 2.014, p = 0.044), total tumor volume (TTV) >50 cm3 (HR 3.050, p < 0.001), vascular invasion (HR 3.258, p < 0.001), performance status 2-4 (HR 2.232, p < 0.001), ALBI grade 2-3 (HR 2.177, p < 0.001), and BCLC stage B-D (HR 2.479, p < 0.001) were independent predictors of poor survival. CONCLUSIONS: Dual viral infection does not accelerate the development of HCC in HBV carriers. Patient survival is similar between dual HBV/HCV-related HCC and single HBV- or HCV-related HCC group. The ALBI grade is a robust prognostic model in dual virus-related HCC to discriminate patient long-term survival.

Easy albumin-bilirubin score as a new prognostic predictor in hepatocellular carcinoma.

BACKGROUND: Liver functional reserve is a major prognostic determinant in patients with hepatocellular carcinoma (HCC). The albumin-bilirubin (ALBI) score is an objective method to assess the severity of cirrhosis in this setting. However, calculation of the ALBI score is complex and difficult to access in clinical practice. Recently, the EZ (easy)-ALBI score was proposed as an alternative biomarker of liver injury. We aimed to evaluate the prognostic role of the EZ-ALBI score in HCC from early to advanced stages. METHODS: A total of 3794 newly diagnosed HCC patients were prospectively enrolled and retrospectively analyzed. Independent prognostic predictors were determined by using the multivariate Cox proportional hazards model. RESULTS: The EZ-ALBI score showed good correlation with the ALBI score (correlation coefficient, 0.965; p < 0.001). The correlation of the EZ-ALBI score was highly preserved in different Child-Turcotte-Pugh (CTP) classifications, treatment methods, and Barcelona Clinic Liver Cancer (BCLC) stages (correlation coefficients, 0.90-0.97). In the Cox multivariate analysis, age >65 years, male sex, serum α-fetoprotein >20 ng/ml, large or multiple tumors, total tumor volume >100 cm3 , vascular invasion or distant metastasis, ascites, poor performance status, EZ-ALBI grade 2 and 3, and noncurative treatments were independently associated with increased mortality (all p < 0.05). Moreover, EZ-ALBI grade can stratify long-term survival in patients with different CTP class, treatment strategy, and BCLC stage. CONCLUSIONS: The EZ-ALBI score is an easy and feasible method to evaluate liver functional reserve. As a new prognostic biomarker in HCC, the predictive power of the EZ-ALBI grade is independent across different cancer stages and treatments.

Tumor burden score as a new prognostic marker for patients with hepatocellular carcinoma undergoing transarterial chemoembolization.

BACKGROUND AND AIM: Size and number are major determinants of tumor burden in hepatocellular carcinoma (HCC). Patients with HCC undergoing transarterial chemoembolization (TACE) have variable outcomes due to heterogeneity of tumor burden. Recently, tumor burden score (TBS) was proposed to evaluate the extent of tumor involvement. However, the prognostic accuracy of TBS has not been well evaluated in HCC. This study aimed to assess its prognostic role in HCC patients undergoing TACE. METHODS: A total of 935 treatment-naïve HCC patients receiving TACE were retrospectively analyzed. Multivariate Cox proportional hazards model was used to determine independent prognostic predictors. RESULTS: Tumor burden score tended to increase with increasing size and number of tumors in study patients. The Cox model showed that serum creatinine ≥ 1.2 mg/dL (hazard ratio [HR]: 1.296, 95% confidence interval [CI]: 1.077-1.559, P = 0.006), serum α-fetoprotein ≥ 400 ng/dL (HR: 2.245, 95% CI: 1.905-2.645, P < 0.001), vascular invasion (HR: 1.870, 95% CI: 1.520-2.301, P < 0.001), medium TBS (HR: 1.489, 95% CI: 1.206-1.839, P < 0.001) and high TBS (HR: 2.563, 95% CI: 1.823-3.602, P < 0.001), albumin-bilirubin (ALBI) grade 2-3 (HR: 1.521, 95% CI: 1.291-1.792, P < 0.001), and performance status 1 (HR: 1.362, 95% CI: 1.127-1.647, P < 0.001) and status 2 (HR: 1.553, 95% CI: 1.237-1.948, P < 0.001) were associated with increased mortality. Patients with high TBS had poor overall survival in Barcelona Clinic Liver Cancer stage B/C and different ALBI grades. CONCLUSIONS: Tumor burden score is a feasible new prognostic surrogate marker of tumor burden in HCC and can well discriminate survival in patients undergoing TACE across different baseline characteristics.

Albumin-Bilirubin (ALBI) Grade-Based Nomogram for Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

BACKGROUND/AIM: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is highly heterogeneous because of variable characteristics of tumor burden and liver dysfunction. We aimed to propose and validate an albumin-bilirubin (ALBI) grade-based prognostic nomogram for HCC patients undergoing TACE. METHODS: A total of 1051 patients with HCC undergoing TACE were randomly assigned to derivation (n = 525) and validation (n = 526) set in this retrospective study based on prospective data. The multivariate Cox proportional hazards model in derivation set was used to generate the nomogram. The predictive accuracy of the nomogram was evaluated by discrimination and calibration tests. RESULTS: In multivariate analysis, presence of ascites, ALBI grade 2-3, serum ɑ-fetoprotein level ≥ 400 ng/mL, total tumor volume ≥ 396 cm3, presence of vascular invasion, and poor performance status were independently associated with decreased survival of patients in the derivation set. Each patient had an individualized score from 0 to 41 by adding up the points from these six prognostic predictors. The nomogram generated from the derivation set had a concordance index of 0.72 (95% confidence interval [CI] 0.63-0.82). Discrimination test in the validation set provided a good concordance index 0.72 (95% CI 0.62-0.81), and the calibration plots consistently matched the ideal 45-degree reference line for 3- and 5-year survival prediction. CONCLUSIONS: The ALBI grade-based prognostic model can well discriminate the survival in HCC patients undergoing TACE. The proposed easy-to-use nomogram may accurately predict the survival at 3 and 5 years for individual HCC patient in the precision medicine era.

Albumin-bilirubin grade-based nomogram of the BCLC system for personalized prognostic prediction in hepatocellular carcinoma.

BACKGROUND & AIMS: The prognostic accuracy of individual hepatocellular carcinoma (HCC) patient in each Barcelona Clinic Liver Cancer (BCLC) stage is unclear. We aimed to develop and validate an albumin-bilirubin (ALBI) grade-based nomogram of BCLC to estimate survival for individual HCC patient. METHODS: Between 2002 and 2016, 3690 patients with newly diagnosed HCC were prospectively enrolled and retrospectively analysed. Patients were randomly split into derivation and validation cohort by 1:1 ratio. Multivariate Cox proportional hazards model was used to generate the nomogram from tumour burden, ALBI grade and performance status (PS). The concordance index and calibration plot were determined to evaluate the performance of this nomogram. RESULTS: Beta coefficients from the Cox model were used to assign nomogram points to different degrees of tumour burden, ALBI grade and PS. The scores of the nomogram ranged from 0 to 24, and were used to predict 3- and 5-year patient survival. The concordance index of this nomogram was 0.77 (95% confidence interval [CI]: 0.71-0.81) in the derivation cohort and 0.76 (95% CI: 0.71-0.81) in the validation cohort. The calibration plots to predict both 3- and 5-year survival rate well matched with the 45-degree ideal line for both cohorts, except for ALBI-based BCLC stage 0 in the validation cohort. CONCLUSIONS: The proposed ALBI-based nomogram of BCLC system is a simple and feasible strategy in the precision medicine era. Our data indicate it is a straightforward and user-friendly prognostic tool to estimate the survival of individual HCC patient except for very early stage patients.

Differential Survival Impact of Diabetes Mellitus on Hepatocellular Carcinoma: Role of Staging Determinants.

BACKGROUND: Diabetes mellitus (DM) is common in patients with hepatocellular carcinoma (HCC) and may impact survival. Very few studies focused on the influence of DM in different clinical scenarios. We evaluated the prognostic impact of DM on HCC patients stratified by liver dysfunction, Milan criteria, and performance status defined in the Barcelona Clínic Liver Cancer staging parameters. METHODS: A prospective dataset of 3573 HCC patients between 2002 and 2016 was retrospectively analyzed. The multivariate Cox proportional hazards model was used to identify independent prognostic predictors. The Kaplan-Meier method with a log-rank test was applied to compare the survival distributions between different patient groups. RESULTS: Among all, DM was not an independent prognostic predictor in the Cox multivariate analysis (p = 0.1044). In the subgroup analysis, DM was not a significant prognostic predictor in Child-Turcotte-Pugh class A or class B/C patients. However, DM was associated with a decreased survival in patients within the Milan criteria (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.155-1.601, p = 0.0002) and in those with the performance status 0 (HR 1.213, 95% CI 1.055-1.394, p = 0.0067) in the multivariate Cox analysis, but not in those beyond the Milan criteria and poor performance status. CONCLUSIONS: DM is highly prevalent in HCC patients and has a distinct survival impact. DM is an independent survival predictor among patients within the Milan criteria and good performance status. These high-risk patients should be closely monitored, and aggressive anticancer treatment should be considered.

A New Prognostic Model Based on Albumin-Bilirubin Grade for Hepatocellular Carcinoma Beyond the Milan Criteria.

BACKGROUND: The survival of patients with advanced hepatocellular carcinoma (HCC) is highly variable due to heterogeneous tumoral characteristics. We proposed and validated an albumin-bilirubin (ALBI)-based model for HCC beyond Milan criteria, the ALBI-HOME, for these patients. METHODS: A total of 2186 patients were enrolled and randomly assigned to the derivation cohort (n = 1093) and validation cohort (n = 1093). Multivariate Cox proportional hazards model was used to determine significant prognostic factors in the derivation cohort. The performance of ALBI-HOME was evaluated in the validation cohort. RESULTS: In the Cox model, six factors were identified as independent predictors of poor survival: ALBI grade 2 [hazard ratio (HR) 1.848, 95% confidence incidence (CI) 1.556-2.195, p < 0.001], ALBI grade 3 (HR 3.266, 95% CI 2.531-4.215, p < 0.001), serum AFP ≥ 100 ng/ml (HR 1.482, 95% CI 1.279-1.717, p < 0.001), total tumor volume ≥ 250 cm3 (HR 1.503, 95% CI 1.294-1.746, p < 0.001), ascites (HR 1.400, 95% CI 1.187-1.561, p < 0.001), performance status 0-1 (HR 1.756, 95% CI 1.485-2.076 p < 0.001), and vascular invasion or metastasis (HR 2.110, 95% CI 1.809-2.0, p < 0.001). The ALBI-HOME is based on these six parameters, and the score ranges from 0 to 7. This model was associated with the best prognostic ability among different HCC staging systems to predict survival in patients beyond Milan criteria; its ability remained consistently stable in different treatment subgroups and viral etiologies. CONCLUSIONS: The proposed ALBI-HOME is a simple and feasible predictive model for HCC beyond Milan criteria. It demonstrates superior prognostic performance among the currently used staging systems and may help identify at-risk patients to undergo more aggressive treatments.

Using nomogram of the Barcelona Clinic Liver Cancer system for treatment selection in patients with stage C hepatocellular carcinoma.

BACKGROUND: The nomogram of the Barcelona Clinic Liver Cancer (BCLC) for hepatocellular carcinoma (HCC) has been used for outcome prediction. Patients with BCLC stage C HCC often undergo anti-cancer therapy against current treatment guidelines in real world practice. We aimed to use the nomogram to provide guidance on treatment selection for BCLC stage C patients. METHODS: A total of 1317 patients with stage C HCC were retrospectively analyzed and divided into four groups by nomogram points. One-to-one matched pairs between patients receiving different treatments were generated by the propensity score with matching model within these groups. Survival analysis was performed by Kaplan-Meier method with log-rank test. RESULTS: Patients with higher nomogram points were more often treated with targeted or supportive therapies (p <  0.001). Patients receiving targeted or supportive therapies had a decreased survival compared to patients undergoing aggressive treatments (surgical resection, ablation, transarterial chemo-embolization or transplantation) across all four groups (p <  0.001). After matching for baseline differences in the propensity model, patients receiving different treatments had comparable age, gender, etiology of liver disease, tumor burden, severity of cirrhosis and performance status. Survival analyses were re-performed and disclosed that patients with nomogram points < 15 had better overall outcome after aggressive treatments (p <  0.05). For patients with nomogram points > 15, there was no significant difference in survival between patients receiving two different treatment strategies. CONCLUSIONS: The nomogram of BCLC system is a feasible tool to help stage C HCC patients to select primary anti-cancer treatment in pursuance of better overall survival.

Metastasis in patients with hepatocellular carcinoma: Prevalence, determinants, prognostic impact and ability to improve the Barcelona Clinic Liver Cancer system.

BACKGROUND & AIM: Patients with hepatocellular carcinoma and metastasis are classified as advanced or terminal stage by the Barcelona Clinic Liver Cancer system. This study investigates the prevalence, determinants, and prognostic effect of metastasis and its ability to improve the Barcelona Clinic Liver Cancer system. METHODS: A total of 3414 patients were enrolled. The Kaplan-Meier and Cox regression methods were used to determine survival predictors. Akaike information criterion was used to compare the prognostic performance of staging systems. RESULTS: There were 357 (10%) patients having extrahepatic metastasis at the time of diagnosis. Metastases were associated with old age, alcoholism, hepatitis B, poorer liver function, higher α-foetoprotein level and larger tumour burden (all P < .05). Vascular invasion was associated with metastasis regardless of total tumour volume, and higher α-foetoprotein level and multiple tumours were associated with metastasis in patients with smaller tumour volume (all P < .05). Patients with both vascular invasion and metastasis had significantly worse outcome compared to patients with either vascular invasion or metastasis (P < .05). In the Cox proportional model, the co-existence of vascular invasion and metastasis was an independent predictor of decreased survival (P < .05). Re-allocating 181 Barcelona Clinic Liver Cancer stage C patients with both vascular invasion and metastasis into stage D was associated with lower Akaike information criterion, indicating enhanced prognostic power of the Barcelona Clinic Liver Cancer. CONCLUSIONS: Metastasis is not uncommon, and is strongly associated with tumoural factors and poor long-term survival in hepatocellular carcinoma. Modification of the Barcelona Clinic Liver Cancer system based on vascular invasion and metastasis may further improve its predictive accuracy in advanced stage patients.