High Visceral Adipose Tissue Density Correlates With Unfavorable Outcomes in Patients With Intermediate-Stage Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

Objectives: This study aimed to evaluate the association between different body composition features with prognostic outcomes of intermediate stage hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE). Methods: The areas and density of skeletal muscle area (SM) and adipose tissue [subcutaneous (SAT); visceral (VAT)] were calculated on the pre-TACE CT scans. Overall survival (OS) and progression-free survival (PFS) curves were calculated using the Kaplan-Meier method and compared with log-rank test. The discrimination and performance of body composition features were measured by area under time-dependent receiver operating characteristic (ROC) curve. Univariate and multivariate Cox proportional hazard analyses were applied to identify the association between body composition parameters and outcomes. Results: A significant prolonged OS and PFS was displayed by Kaplan-Meier curve analysis for HCC patients with VAT HU below -89.1 (25.1 months, 95% CI: 18.1-32.1 vs. 17.6 months, 95% CI: 16.3-18.8, p < 0.0001, 15.4 months, 95% CI: 10.6-20.2 vs. 6.6 months, 95% CI: 4.9-8.3, p < 0.0001, respectively). The 1-, 2-, 3-, and 5-year OS area under the curve (AUC) values of the VAT HU were higher than the other body composition parameters. Meanwhile, it is also found that 3-, 6-, 9-, and 12-month PFS AUC values of VAT HU were the highest among all the parameters. Univariate and multivariate Cox-regression analysis suggested a significant association between VAT density and outcomes (OS, HR: 1.015, 95% CI: 1.004-1.025, p = 0.005, PFS, HR: 1.026, 95% CI: 1.016-1.036, p < 0.0001, respectively). Conclusion: The VAT density could provide prognostic prediction value and may be helpful to stratify the intermediate stage HCC patients.

Corrigendum: Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Predictors of Outcomes in Patients With Unresectable Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Plus Sorafenib.

[This corrects the article DOI: 10.3389/fmolb.2021.624366.].

Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Predictors of Outcomes in Patients With Unresectable Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Plus Sorafenib.

Objectives: To investigate the predictive value of inflammatory biomarkers in patients with unresectable hepatocellular carcinoma (HCC) for outcomes following the combination treatment of transarterial chemoembolization (TACE) plus sorafenib. Materials and Methods: A total of 314 (270 male and 44 female) treatment-naïve patients with unresectable HCC treated by TACE plus sorafenib between January 2011 and December 2018 were enrolled in the retrospective study. The primary outcome was overall survival (OS). The secondary outcome was progression-free survival (PFS). Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were obtained within 3-7 days before the initial TACE and the median value of the NLR and PLR was considered as the cut-off value. Results: The median value of NLR and PLR was 2.42 and 100, respectively. The median OS and PFS of the entire cohort were 18.7 months (95% CI: 16.8-20.6) and 9.1 months (95% CI: 8.5-9.8), respectively. The low NLR and PLR group showed improved OS and PFS compared with the high NLR and PLR group [21.8 months (95% CI: 15.2-28.5) vs. 15.4 months (95% CI: 12.4-18.3), p < 0.0001; 21.6 months (95% CI: 15.8-27.5) vs. 14.9 months (95% CI: 11.9-17.8), p = 0.00027, respectively]. In addition, the low NLR and PLR group also provided a longer PFS than the high NLR and PLR group [10.4 months (95% CI: 8.9-12.0) vs. 8.1 months (95% CI: 7.1-9.2), p = 0.00022; 10.3 months (95% CI: 8.6-11.9) vs. 8.2 months (95% CI: 7.2-9.2), p < 0.0001, respectively]. High NLR and PLR at baseline were predictive factors of poor OS (p = 0.02 and p = 0.004) and PFS (p = 0.045 and p = 0.005). Conclusion: This study showed the prognostic value of quantitative inflammatory biomarkers in correlation with OS and PFS in unresectable HCC patients undergoing TACE plus sorafenib treatment.

Random Survival Forests to Predict Disease Control for Hepatocellular Carcinoma Treated With Transarterial Chemoembolization Combined With Sorafenib.

Objectives: To use baseline variables to predict one-year disease control for patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) combined with sorafenib as initial treatment by applying a machine learning approach based on the random survival forest (RF) model. Materials and Methods: The multicenter retrospective study included 496 patients with HCC treated with TACE combined with sorafenib between January 2014 and December 2018. The independent risk factors associated with one-year disease control (complete response, partial response, stable disease) were identified using the RF model, and their predictive importance was determined using the Gini index. Tumor response was assessed according to modified Response Evaluation Criteria in Solid Tumors. Results: The median overall survival was 15.5 months. A total of 186 (37.5%) patients achieved positive one-year disease control. The Barcelona Clinic Liver Cancer (BCLC) stage (Gini index: 20.0), tumor size (≤7 cm, >7 cm; Gini index: 9.0), number of lobes involved (unilobar, bilobar; Gini index: 6.4), alpha-fetoprotein level (≤200 ng/dl, >200 ng/dl; Gini index: 6.1), albumin-bilirubin grade (Gini index: 5.7), and number of lesions (1, >1; Gini index: 5.3) were identified as independent risk factors, with the BCLC stage as the most important variable. The RF model achieved a higher concordance index of 0.724 compared to that for the logistic regression model (0.709). Conclusions: The RF model is a simple and accurate approach for prediction of one-year disease control for patients with HCC treated with TACE combined with sorafenib.

Prognosis Nomogram for Hepatocellular Carcinoma Patients with Portal Vein Invasion Undergoing Transarterial Chemoembolization Plus Sorafenib Treatment: A Retrospective Multicentre Study.

OBJECTIVES: To explore the outcomes of combined transarterial chemoembolization (TACE) with sorafenib in hepatocellular carcinoma (HCC) patients with portal vein tumour thrombus (PVTT) and to establish a prognostic prediction nomogram to differentiate target patients and stratify risk. MATERIALS AND METHODS: This multicentre, retrospective study consisted of 185 consecutive treatment-naïve patients with HCC and PVTT treated with TACE plus sorafenib from three institutions between January 1st, 2012 and December 31st, 2017. The primary outcome measurement of the study was overall survival (OS). The type of PVTT was classified by the Liver Cancer Study Group of Japan. The prognostic nomogram was established based on the predictors and was performed with interval validation. RESULTS: The median OS of the Vp1-3 and Vp4 groups was 12.4 months (11.7-18.9) and 8.5 months (7.6-11.2) (P = 0.00098), respectively, and there was a significant difference in the median OS between the Vp1-2 and Vp3 subgroups (16.4 months (12.2-27.9) vs. 10.9 months (8.4-18.1), P = 0.041). The multivariate Cox regression analysis suggested that tumour size, albumin-bilirubin grade, and PVTT type were independent prognostic factors. The C-index value of the nomogram based on these predictors in the entire cohort was 0.731 (0.628-0.833). CONCLUSIONS: After the combined therapy of TACE and sorafenib, advanced HCC patients with segmental or subsegmental PVTT showed better survival than those with main PVTT. The nomogram can be applied to identify advanced HCC patients with PVTT who may benefit most from the combination treatment and be helpful for making decision in clinical practice.

Imaging Changes and Clinical Complications After Drug-Eluting Bead Versus Conventional Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma: Multicenter Study.

BACKGROUND. Drug-eluting bead transarterial chemoembolization (DEB-TACE) has emerged as an alternative to conventional TACE (cTACE) for treatment of hepatocellular carcinoma (HCC), although selection between the approaches remains controversial. OBJECTIVE. The purpose of this study was to compare DEB-TACE and cTACE in the treatment of patients with unresectable HCC in terms of hepatobiliary changes on imaging and clinical complications. METHODS. This retrospective study included 1002 patients (871 men, 131 women; mean age, 59 ± 12 years) from three centers who had previously untreated unresectable HCC and underwent DEB-TACE with epirubicin (780 procedures in 394 patients) or cTACE with ethiodized oil mixed with doxorubicin and oxaliplatin (1187 procedures in 608 patients) between May 2016 and November 2018. Among these patients 83.4% had hepatitis B-related liver disease, 57.6% had Barcelona Clinic Liver Cancer (BCLC) stage A or B HCC, and 42.4% had three or more nodules. Mean tumor size was 6.3 ± 4.2 cm. Hepatobiliary changes and tumor response were evaluated with CT or MRI 1 month after TACE. Clinical records were reviewed for adverse events. RESULTS. Bile duct dilatation (p < .001) and portal vein narrowing (p = .006) on imaging and liver failure (p = .03) and grade 3 abdominal pain (p < .001) in clinical follow-up occurred at higher frequency in the DEB-TACE group (15.5%, 4.6%, 2.3%, and 6.1%) than in the cTACE (7.4%, 1.6%, 0.7%, and 2.1%) group. Higher frequency of bile duct dilation in patients who underwent DEB-TACE was observed in subgroup analyses that included patients with BCLC stage A or B HCC (p = .001), with cirrhosis (p < .001), without cirrhosis (p = .04), and without main portal vein tumor thrombus (p = .002). Total bilirubin level 1 month after treatment was 1.5 ± 2.4 mg/dL (95% CI, 1.2-1.8 mg/dL) for DEB-TACE versus 1.3 ± 2.0 mg/dL (95% CI, 1.1-1.5 mg/dL) for cTACE (p = .02). The cTACE and DEB-TACE groups did not differ in other manifestations of postembolization syndrome or systemic toxicity (p > .05). Local tumor disease control rates did not differ between the cTACE and DEB-TACE groups (1 month, 96.7% vs 98.5%, p = .06; 3 months, 81.8% vs 82.4%, p = .87), but overall DCR was significantly higher in the cTACE than in the DEB-TACE group (1 month, 87.5% vs 80.0%, p = .001; 3 months, 78.5% vs 72.1%, p = .02). CONCLUSION. Compared with cTACE, DEB-TACE was associated with greater frequency of hepatobiliary injury and severe abdominal pain. CLINICAL IMPACT. Greater caution and closer follow-up are warranted for patients who undergo DEB-TACE for unresectable HCC than for those who undergo cTACE.

Deep Learning Predicts Overall Survival of Patients With Unresectable Hepatocellular Carcinoma Treated by Transarterial Chemoembolization Plus Sorafenib.

OBJECTIVES: To develop and validate a deep learning-based overall survival (OS) prediction model in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) plus sorafenib. METHODS: This retrospective multicenter study consisted of 201 patients with treatment-naïve, unresectable HCC who were treated with TACE plus sorafenib. Data from 120 patients were used as the training set for model development. A deep learning signature was constructed using the deep image features from preoperative contrast-enhanced computed tomography images. An integrated nomogram was built using Cox regression by combining the deep learning signature and clinical features. The deep learning signature and nomograms were also externally validated in an independent validation set of 81 patients. C-index was used to evaluate the performance of OS prediction. RESULTS: The median OS of the entire set was 19.2 months and no significant difference was found between the training and validation cohort (18.6 months vs. 19.5 months, P = 0.45). The deep learning signature achieved good prediction performance with a C-index of 0.717 in the training set and 0.714 in the validation set. The integrated nomogram showed significantly better prediction performance than the clinical nomogram in the training set (0.739 vs. 0.664, P = 0.002) and validation set (0.730 vs. 0.679, P = 0.023). CONCLUSION: The deep learning signature provided significant added value to clinical features in the development of an integrated nomogram which may act as a potential tool for individual prognosis prediction and identifying HCC patients who may benefit from the combination therapy of TACE plus sorafenib.

Prognostic Performance of Albumin-Bilirubin Grade With Artificial Intelligence for Hepatocellular Carcinoma Treated With Transarterial Chemoembolization Combined With Sorafenib.

PURPOSE: To establish albumin-bilirubin (ALBI) grade-based and Child-Turcotte-Pugh (CTP) grade-based nomograms, as well as to develop an artificial neural network (ANN) model to compare the prognostic performance and discrimination of these two grades for hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) combined with sorafenib as an initial treatment. METHODS: This multicenter retrospective study included patients from three hospitals between January 2013 and August 2018. In the training cohort, independent risk factors associated with overall survival (OS) were identified by univariate and multivariate analyses. The nomograms and ANN were established and then validated in two validation cohorts. RESULTS: A total of 504 patients (319, 61, and 124 patients from hospitals A, B, and C, respectively) were included. The median OS was 15.2, 26.9, and 14.8 months in the training cohort and validation cohorts 1 and 2, respectively (P = 0.218). In the training cohort, both ALBI grade and CTP grade were identified as independent risk factors. The ALBI grade-based and CTP grade-based nomograms were established separately and showed similar prognostic performance and discrimination when validated in the validation cohorts (C-index in validation cohort 1: 0.799 vs. 0.779, P = 0.762; in validation cohort 2: 0.700 vs. 0.693, P = 0.803). The ANN model showed that the ALBI grade had higher importance in survival prediction than the CTP grade. CONCLUSIONS: The ALBI grade and CTP grade have comparable prognostic performance for HCC patients treated with TACE combined with sorafenib. ALBI grades 1 and 2 have the potential to act as a stratification factor for clinical trials on the combination therapy of TACE and systemic therapy.