Magnetic Resonance Deep Learning Radiomic Model Based on Distinct Metastatic Vascular Patterns for Evaluating Recurrence-Free Survival in Hepatocellular Carcinoma.

BACKGROUND: The metastatic vascular patterns of hepatocellular carcinoma (HCC) are mainly microvascular invasion (MVI) and vessels encapsulating tumor clusters (VETC). However, most existing VETC-related radiological studies still focus on the prediction of VETC status. PURPOSE: This study aimed to build and compare VETC-MVI related models (clinical, radiomics, and deep learning) associated with recurrence-free survival of HCC patients. STUDY TYPE: Retrospective. POPULATION: 398 HCC patients (349 male, 49 female; median age 51.7 years, and age range: 22-80 years) who underwent resection from five hospitals in China. The patients were randomly divided into training cohort (n = 358) and test cohort (n = 40). FIELD STRENGTH/SEQUENCE: 3-T, pre-contrast T1-weighted imaging spoiled gradient recalled echo (T1WI SPGR), T2-weighted imaging fast spin echo (T2WI FSE), and contrast enhanced arterial phase (AP), delay phase (DP). ASSESSMENT: Two radiologists performed the segmentation of HCC on T1WI, T2WI, AP, and DP images, from which radiomic features were extracted. The RFS related clinical characteristics (VETC, MVI, Barcelona stage, tumor maximum diameter, and alpha fetoprotein) and radiomic features were used to build the clinical model, clinical-radiomic (CR) nomogram, deep learning model. The follow-up process was done 1 month after resection, and every 3 months subsequently. The RFS was defined as the date of resection to the date of recurrence confirmed by radiology or the last follow-up. Patients were followed up until December 31, 2022. STATISTICAL TESTS: Univariate COX regression, least absolute shrinkage and selection operator (LASSO), Kaplan-Meier curves, log-rank test, C-index, and area under the curve (AUC). P < 0.05 was considered statistically significant. RESULTS: The C-index of deep learning model achieved 0.830 in test cohort compared with CR nomogram (0.731), radiomic signature (0.707), and clinical model (0.702). The average RFS of the overall patients was 26.77 months (range 1-80 months). DATA CONCLUSION: MR deep learning model based on VETC and MVI provides a potential tool for survival assessment. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Association between Early Immune-Related Adverse Events and Survival in Patients Treated with PD-1/PD-L1 Inhibitors.

BACKGROUND: Immune-related adverse events (irAEs) are side effects that reflect the activation of patients' immune systems after treatment with immune checkpoint inhibitors (ICIs). However, there is no meta-analysis on the effect of early irAEs on patient survival. Thus, we assessed the association between early irAEs and the survival of patients treated with ICIs. METHODS: PubMed, Embase, and Web of Science were searched from May 2010 to May 2020 for all the retrospective and prospective comparative studies to evaluate the hazard ratios (HRs) for death. A random-effects model was used to calculate the pooled HR for death, and heterogeneity was assessed using I² statistics. The main outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 11 reports with 2077 patients were included. A significant association was observed between early irAEs and a favorable clinical outcome. Patients with early irAEs had prolonged OS (HR: 0.62, 95% confidence interval (CI): 0.53-0.74, p < 0.001) and PFS (HR: 0.53, 95% CI: 0.41-0.66, p < 0.001) compared to those without; these results were confirmed using a sensitivity analysis. The irAE types, malignancy types, and sample size were correlated with patients' clinical outcomes. CONCLUSIONS: Early irAEs, especially cutaneous irAEs, correlated with a better clinical outcome in patients treated with ICIs.

Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study.

PURPOSE: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). PATIENTS AND METHODS: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety. RESULTS: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups. CONCLUSION: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

Development and Validation of a Model Including Distinct Vascular Patterns to Estimate Survival in Hepatocellular Carcinoma.

Importance: Because of tumor heterogeneity, traditional clinical variables remain insufficient to predict recurrence, which impairs long-term survival among patients undergoing radical hepatectomy for hepatocellular carcinoma (HCC). Vessels encapsulating tumor clusters (VETC) constitute a novel vascular pattern distinct from microvascular invasion (MVI), representing biological aggressiveness of HCC. Objective: To establish a model to estimate individualized recurrence-free survival (RFS) in HCC by integrating VETC and MVI. Design, Setting, and Participants: This prognostic study included 498 patients undergoing radical hepatectomy for HCC from 5 academic centers in China from January 1, 2013, to December 31, 2016, and consisted of 3 cohorts: training (243 [48.8%]), internal validation (122 [24.5%]), and external validation (133 [26.7%]). Follow-up was completed on March 30, 2020, and the data were analyzed from December 1 to 31, 2020. Exposures: VETC, MVI, tumor number, and maximum tumor size. Main Outcomes and Measures: The primary end point was RFS. The risk score for relative recurrence and nomogram for absolute RFS probability were derived from the final model, which contained variables recommended by multivariate least absolute shrinkage and selection operator Cox proportional hazards regression analysis. Their performance was quantified using the Harrell concordance index (C index), the time-dependent area under the receiver operating characteristic curve, and calibration curves and was compared with 6 prognostic systems. Recurrence-free survival was estimated by the Kaplan-Meier method, and RFS curves were compared using a log-rank test. Results: Among the 498 patients, 432 (86.7%) were men; the mean (SD) age at diagnosis was 51.4 (11.3) years. Independent predictors for RFS identified included VETC, MVI, tumor number, and maximum tumor size, which were incorporated into the multivariate model (VMNS model). The C index (0.702; 95% CI, 0.653-0.752) for the VMNS score of the training cohort was significantly higher than those of 6 conventional systems (0.587 [95% CI, 0.535-0.638] to 0.657 [95% CI, 0.606-0.708]). Different recurrence risk groups defined by the VMNS score showed significantly different 2-year RFS (low-risk group, 81.4% [SE, 0.036]; medium-risk group, 62.1% [SE, 0.054]; high-risk group, 30.1% [SE, 0.079]; P < .001). Calibration curves of the VMNS nomogram showed good agreement between the nomogram-predicted RFS probability and actual RFS proportion. The internal and external validation cohorts confirmed the results. Conclusions and Relevance: The VMNS model enabled individualized prognostication of RFS in patients with HCC undergoing curative resection.

Comparison of the Prognostic Value of Inflammation-Based Scores in Patients with Hepatocellular Carcinoma After Anti-PD-1 Therapy.

BACKGROUND: Inflammatory response is related to cancer progression and patient survival. However, the value in predicting survival in hepatocellular carcinoma (HCC) patients who received anti-PD-1 therapy has not been elucidated. This study aimed to compare the predictive ability of inflammation-based scores for the prognosis of HCC patients after anti-PD-1 therapy. METHODS: A total of 442 patients who received anti-PD-1 therapy were included in the study. Representative inflammation-based prognostic scores, including the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein (CRP) ratio (LCR), lymphocyte-to-monocyte ratio (LMR), systemic immune inflammation index (SII), CRP-to-albumin ratio (CAR), prognostic nutritional index (PNI), Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), and prognostic index (PI), were assessed for prediction accuracy using Kaplan-Meier survival curves, time-dependent receiver operating characteristic (ROC) and Harrell's concordance index (C-index) analyses. RESULTS: All the inflammation-based prognostic scores exhibited good discriminatory ability in overall survival (OS) (all P < 0.01), while the PNI score was a unique independent predictor for OS in multivariate analysis (hazard ratio, 1.770; confidence interval, 1.309-2.393; P < 0.001). The areas under the ROC curves at 6, 12, 18 and 24 months and the C-index (0.65) demonstrated that the predictive accuracy of the PNI score was superior to that of the other inflammation-based scores. CONCLUSION: The PNI score is a discriminatory prognostic indicator for OS in HCC patients with anti-PD-1 therapy and is superior to the other inflammation-based prognostic scores in terms of predictive ability.

The predictive value of vessels encapsulating tumor clusters in treatment optimization for recurrent early-stage hepatocellular carcinoma.

BACKGROUND: The predictive value of vessels encapsulating tumor clusters (VETC) in recurrent early-stage hepatocellular carcinoma (HCC) remains unclear. Therefore, the aim of the present study was to investigate the prognostic significance of VETC in patients with recurrent early-stage HCC after repeat hepatic resection (RHR) or radiofrequency ablation (RFA). METHODS: From December 2005 to December 2016, 138 patients receiving RHR and 188 patients receiving RFA were recruited. VETC was evaluated by immunohistochemical staining for CD34. The survival outcomes of patients with VETC pattern or not were investigated. RESULTS: There was no significant difference between the RHR and RFA groups in disease-free survival (DFS) or overall survival (OS) as determined by the univariate analysis of the whole cohort. In the subgroup analysis of the VETC-positive cohort, the patients in the RHR group showed a longer median DFS time in contrast to those in the RFA group (15.0 vs. 5.0 months, p = 0.001). Similarly, the patients in the RHR group showed a longer median OS time in contrast to those in the RFA group (39.5 vs. 19 months, p = 0.001). In the VETC-negative cohort, no significant differences in DFS and OS rates between the RHR and RFA groups were observed (p > 0.05). CONCLUSIONS: The results of our study suggested that RHR was relatively safe and superior to RFA in improving survival outcomes for recurrent early-stage HCC after initial hepatectomy. Furthermore, the VETC pattern may represent a reliable marker for selecting HCC patients who may benefit from RHR.

Prognostic Value of the Preoperative Lymphocyte-C-Reactive Protein Ratio in Hepatocellular Carcinoma Patients Treated with Curative Intent: A Large-Scale Multicentre Study.

PURPOSE: This study aimed to evaluate the prognostic value of the lymphocyte-C-reactive protein ratio (LCR) score, a novel inflammation-based score based on lymphocytes and C-reactive protein, in hepatocellular carcinoma (HCC) patients treated with curative intent. PATIENTS AND METHODS: A total of 1158 HCC patients undergoing surgical resection or radiofrequency ablation with curative intent were recruited from 3 different centres and divided into a primary cohort (n=716) and a validation cohort (n=442). Univariate and multivariate analyses were performed to identify variables associated with overall survival (OS). The discriminatory accuracy of seven inflammation-based scores was compared by using the concordance index (C-index). RESULTS: The LCR score differentiated HCC patients into two groups with distinct prognoses (1-, 3-, and 5-year OS rates and median OS: 92.9%, 81.9%, 73.3% and 99.2 months and 79.8%, 56.6%, 49.7% and 69.1 months; P<0.001). Multivariate analysis showed that LCR score, AFP, ALBI score, tumour size, and TNM stage were independently associated with OS. When patients were stratified according to different disease states, the LCR score could still differentiate HCC patients into two groups with distinct prognoses (all P<0.005). The LCR score demonstrated a markedly superior C-index of 0.621 compared with the other inflammation-based scores (0.503-0.590). These findings were supported by the validation cohort. CONCLUSION: The preoperative LCR score is a novel, stable, and clinically feasible prognostic marker for patients with HCC, independent of liver function, tumour characteristics, and treatment allocation and is superior to other inflammation-based scores in terms of its prognostic ability.

Selecting an Optimal Staging System for Intermediate-Stage Hepatocellular Carcinoma: Comparison of 9 Currently Used Prognostic Models.

PURPOSE: It remains unknown which staging system is best in predicting the survival of patients with intermediate stage hepatocellular carcinoma (HCC). We aimed to investigate the performance of nine currently used HCC staging systems. PATIENTS AND METHODS: Between 2005 and 2014, a large cohort of 880 consecutive patients with intermediate stage HCC and sufficient data for utilization in all staging systems were enrolled. The prognostic performance of each staging system was compared. Independent prognostic variables were also identified. RESULTS: Multivariate analysis revealed that alkaline phosphatase (ALP), aspartate aminotransferase (AST), etiology, alpha-fetoprotein (AFP), Child-Pugh stage, tumor size, and tumor number were independent prognostic factors for survival. In the entire cohort, the Hong Kong Liver Cancer (HKLC) staging system was associated with the highest Harrell's c-index and lowest Akaike information criterion value in comparison with other systems. In subgroup analysis according to treatment strategy, the HKLC staging system remained the best prognostic model in patients undergoing hepatic resection (n=222) or transarterial chemoembolization (n=658). Additional prognostic factors of AST, ALP, etiology, and AFP improved the discriminatory ability of HKLC. CONCLUSION: The HKLC staging system is stable and consistently the best prognostic model in all patients with intermediate-stage HCC and in patients subjected to different treatment strategies. Selecting an optimal staging system is helpful in improving the design of future clinical trials in intermediate stage HCC.

Anti-PD-1 Immunotherapy Improves the Efficacy of Hepatic Artery Infusion Chemotherapy in Advanced Hepatocellular Carcinoma.

BACKGROUND: Hepatic artery infusion chemotherapy (HAIC) and anti-programmed cell death protein-1 (PD-1) immunotherapy have shown promising outcomes in patients with advanced hepatocellular carcinoma (HCC), respectively. However, the combination of the two treatments has not been reported. In this study, we compared the efficacy of HAIC combined with anti-PD-1 immunotherapy (HAICAP) and HAIC in patients with advanced HCC. METHODS: Between November 2018 and December 2019, advanced HCC patients that were treated with either HAICAP or HAIC were retrospectively recruited and reviewed for eligibility. Efficacy was evaluated according to tumor response and survival. RESULTS: As a result, 229 patients were included in this study. Patients were divided into HAICAP group (n = 81) and HAIC group (n = 148) accordingly. The follow-up time ranged from 1.0 to 21.6 months, with a median of 11.0 months. The median overall survival was 18.0 months in the HAICAP group and 14.6 months in the HAIC group (p = 0.018; HR = 0.62; 95% CI 0.34-0.91). The median progression-free survival was 10.0 months in the HAICAP group and 5.6 months in the HAIC group (p = 0.006; HR = 0.65; 95% CI 0.43-0.87). The disease control rate in overall response (83% vs 66%; p = 0.006) and intrahepatic response (85% vs 74%, respectively; p = 0.045) were higher in the HAICAP group than in the HAIC group. CONCLUSION: In comparison to HAIC, HAICAP was associated with a better treatment response and survival benefits for patients with advanced HCC.

The lymphocyte-C-reactive protein ratio as the optimal inflammation-based score in patients with hepatocellular carcinoma underwent TACE.

The lymphocyte-C-reactive protein ratio (LCR) is a recently described inflammation-based score, and it remains unclear which is the optimal inflammation-based score among patients with hepatocellular carcinoma (HCC) who underwent transarterial chemoembolization (TACE). A large cohort of HCC patients (n=1625) who underwent TACE as the initial treatment were enrolled in the present study. Inflammation-based scores, including the Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), high-sensitivity modified Glasgow Prognostic Score (Hs-mGPS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), and LCR, were all related to the survival of HCC patients, but only the LCR score was a significant and independent predictor in multivariate analysis (hazard ratio: 1.45; 95% confidence interval: 1.27-1.65; P<0.001). Further analysis showed that the LCR score stably and consistently differentiated subgroup patients with distinct prognoses. The predictive accuracies of the LCR score (0.70, 0.68, and 0.68 for 1-, 3-, and 5-year C-index, respectively) were superior to the other inflammatory-based scores (0.60-0.64, 0.58-0.62, and 0.58-0.62 for 1-, 3-, and 5-year C-index, respectively). The LCR score was an independent prognostic indicator for HCC patients who underwent TACE, and it was superior to the other inflammation-based scores in prognostic ability.

Lymphocyte-C-reactive protein ratio as a novel prognostic index in intrahepatic cholangiocarcinoma: A multicentre cohort study.

BACKGROUND & AIMS: The lymphocyte-C-reactive protein ratio (LCR) is a novel inflammatory-based score, based solely on the lymphocyte and C-reactive protein. We aimed to clarify the prognostic value of the LCR score in intrahepatic cholangiocarcinoma (ICC) patients after resection. METHODS: We compared the prognostic accuracy of the LCR score with other inflammatory-based scores in this large, multicentre cohort study. The independent variables associated with overall survival (OS) were explored in both the primary (n = 228) and validation cohorts (n = 135). Harrell's concordance index (C-index) was used to compare the predictive ability of all the assessed inflammatory-based scores. RESULTS: The LCR score was differentiated two groups of ICC patients with distinct prognoses (1-, 3-, and 5-year OS rates: 94.4%, 66.3%, and 59.3%; and 66.6%, 45.6%, and 32.7%, respectively) (P < .001). Multivariate analysis showed that the LCR score, as well as the TNM stage and preoperative CA19-9 level, were independently associated with OS. The predictive accuracy of the LCR score (c score: 0.634) was superior to that of the other inflammatory-based scores (c scores: 0.508-0.615). These findings were supported by the external validation cohort. CONCLUSION: The LCR score is stable and consistently the best prognostic score and may offer as a simple, objective and discriminatory method in facilitating the risk stratification of ICC patients.

Tumor necrosis as a poor prognostic predictor on postoperative survival of patients with solitary small hepatocellular carcinoma.

BACKGROUND: Small hepatocellular carcinoma (sHCC) is a special subtype of HCC with the maximum tumor diameter ≤ 3 cm and excellent long-term outcomes. Surgical resection or radiofrequency ablation provides the greatest chance for cure; however, many patients still undergo tumor recurrence after primary treatment. To date, there is no clinical applicable method to assess biological aggressiveness in solitary sHCC. METHODS: In the current study, we retrospectively evaluated tumor necrosis of 335 patients with solitary sHCC treated with hepatectomy between December 1998 and 2010 from Sun Yat-sen University Cancer Center. RESULTS: The presence of tumor necrosis was observed in 157 of 335 (46.9%) sHCC patients. Further correlation analysis showed that tumor necrosis was significantly correlated with tumor size and vascular invasion (P = 0.026, 0.003, respectively). The presence of tumor necrosis was associated closely with poorer cancer-specific overall survival (OS) and recurrence-free survival (RFS) as evidenced by univariate (P <  0.001; hazard ratio, 2.821; 95% CI, 1.643-4.842) and multivariate analysis (P = 0.005; hazard ratio, 2.208; 95% CI, 1.272-3.833). Notably, the combined model by tumor necrosis, vascular invasion and tumor size can significantly stratify the risk for RFS and OS and improve the ability to discriminate sHCC patients' outcomes (P <  0.0001 for both). CONCLUSIONS: Our results provide evidence that tumor necrosis has the potential to be a parameter for cancer aggressiveness in solitary sHCC. The combined prognostic model may be a useful tool to identify solitary sHCC patients with worse outcomes.

Novel Value of Preoperative Gamma-Glutamyltransferase Levels in the Prognosis of AFP-Negative Hepatocellular Carcinoma.

BACKGROUND: Gamma-glutamyltransferase (GGT) is involved in tumor development and progression, but its prognostic value in α-fetoprotein- (AFP-) negative (AFP < 25 ng/mL) hepatocellular carcinoma (HCC) patients remains unknown. METHODS: A large cohort of 678 patients with AFP-negative HCC following curative resection who had complete data were enrolled in this study. The optimal cutoff value for the preoperative level of GGT was determined by the X-tile program. Independent prognostic factors for overall survival (OS) and disease-free survival (DFS) were also identified. RESULTS: The optimal cutoff values for the preoperative levels of GGT were 37.2 U/L and 102.8 U/L, which were used to divide all patients into three subgroups (group 1, GGT < 37.2 U/L (n = 211, 31.1%); group 2, GGT ≥ 37.2 and <102.8 U/L (n = 320, 47.2%); group 3, GGT ≥ 102.8 U/L (n = 147, 21.7%)), with distinct OS times (58.5 vs. 53.5 vs. 44.4 months, P < 0.001) and DFS times (47.9 vs. 40.3 vs. 30.1 months, P < 0.001). Elevated preoperative GGT levels were associated with an unfavorable tumor burden (larger tumor size, multiple tumors, and microvascular invasion) and were selected as independent predictors of a worse OS (group 2 vs. group 1, HR: 1.73 (1.13-2.65), P = 0.011; group 3 vs. group 1, HR: 3.28 (2.10-5.13), P < 0.001) and DFS (group 2 vs. group 1, HR: 1.52 (1.13-2.05), P = 0.006; group 3 vs. group 1, HR: 2.11 (1.49-2.98), P < 0.001) in multivariable analysis. CONCLUSIONS: Elevated preoperative GGT levels are associated with an unfavorable tumor burden and serve as an independent prognostic marker for worse outcomes in AFP-negative HCC patients following resection.

Resection vs. Sorafenib for Hepatocellular Carcinoma With Macroscopic Vascular Invasion: A Real World, Propensity Score Matched Analytic Study.

Background: Macroscopic vascular invasion (MVI) commonly occurs in patients with advanced hepatocellular carcinoma (HCC) for which resection and sorafenib are the common therapies prescribed. Here, we aimed to compare the survival outcomes of these two therapies in HCC patients with MVI. Methods: In total, 496 patients diagnosed with HCC and MVI without extrahepatic metastasis, treated with resection (resection-based group, n = 388) and sorafenib (sorafenib-based group, n = 108) were included in this study. A one-to-one propensity score-matching analysis (PSM) was performed to minimize the effect of potential confounders. Results: The median OS in the resection- and sorafenib-based group was 20.7 months (95% CI: 16.9-24.5) and 11.6 months (95% CI: 8.4-14.9) (p < 0.001), respectively. The median PFS was 4.7 months (95% CI: 3.8-5.5) in the resection-based group and 4.4 months (95% CI: 3.6-5.2) in the sorafenib-based group (p < 0.001). After PSM, 72 patients from each group were matched. The median OS was 27.2 months (95% CI: 16.4-38.0) in the resection-based group and 13.0 months (95% CI: 9.6-16.3) in the sorafenib-based group (p < 0.001). The median PFS was 5.3 months (95% CI: 3.2-7.4) in the resection-based group and 4.8 months (95% CI: 3.6-6.0) in the sorafenib-based group (p = 0.061). Conclusion: Findings from this study showed that, compared with sorafenib-based treatment, surgical resection might be associated with better survival benefits to HCC patients with MVI.

A Novel Prognostic Nomogram for Patients With Recurrence of Intrahepatic Cholangiocarcinoma After Initial Surgery.

Background: The prognosis of patients with post-operative recurrent intrahepatic cholangiocarcinoma (ICC) is at great variance. We aimed to propose a novel efficient prognostic nomogram in facilitating the risk stratification for post-operative recurrent ICC patients. Methods: From 2000 to 2016, a total of 237 post-operative recurrent ICC patients were enrolled in this study, and randomly divided into training (n = 178) and validation cohorts (n = 59) at a ratio of 3:1. The performance of this nomogram was assessed by discrimination, calibration, and clinical usefulness, and the results were compared with four other currently used ICC staging systems. Results: On multivariate analysis of the training cohort, serum CA 19-9, albumin-bilirubin grade at recurrence, time from primary resection to recurrence, tumor number at recurrence, and treatment for recurrence were selected for the model. The concordance index (C-index) of our model was 0.791 [95% confidence interval (CI), 0.736-0.846], which was statistically higher than the values of the following systems: American Joint Committee on Cancer (AJCC) 8th edition (0.610), Liver Cancer Study Group of Japan (0.613), Nathan (0.582), and Okabayashi (0.600; P < 0.001 for all). The nomogram performed well in terms of calibration when compared with actual observation. The findings were supported by the validation cohort. Conclusions: Compared with four currently used staging systems for ICC, our nomogram showed more promising clinical utility in improving individualized predictions of survival for post-operative recurrent ICC patients.

Treatment optimization for recurrent hepatocellular carcinoma: Repeat hepatic resection versus radiofrequency ablation.

BACKGROUND AND AIMS: The optimal treatment strategy for recurrent hepatocellular carcinoma (HCC) remains unclear. Therefore, we aimed to compare the outcomes of repeat hepatic resection (RHR) and radiofrequency ablation (RFA) for recurrent HCC. METHOD: From December 2004 to December 2015, 138 patients who underwent RHR and 194 patients who underwent RFA were enrolled. Propensity score matching (PSM) was performed to establish 1:1 RHR-RFA group matching. Clinical outcomes were compared before and after matching. RESULTS: Before matching, the 1-, 3-, and 5-year postrecurrence survival (PRS) rates were 91.8%, 82.0%, and 72.9% for the RHR group (n = 138) and 94.4%, 75.4%, and 61.7% for the RFA group (n = 194), respectively (P = .380). After matching, the PRS rates at 1, 3, and 5 years were 90.5%, 81.5%, and 71.8% for the RHR group (n = 120) and 91.0%, 61.0%, and 41.7% for the RFA group (n = 120), respectively (P = .002). In the subgroup analysis, the PRS rates for the RHR group were better than those for the RFA group for patients who relapsed within 2 years (P = .004) or patients with primary tumor burden beyond the Milan criteria (P = .004). Multivariate analysis showed that treatment allocation was identified as an independent prognostic factor for PRS. CONCLUSION: Compared with RFA, RHR provided a survival advantage for recurrent HCC, especially for patients who relapsed within 2 years and those with primary tumor burden beyond the Milan criteria.

A novel treatment strategy using indocyanine green for transarterial chemoembolization in BCLC stage C hepatocellular carcinoma.

PURPOSE: The aim of our study was to propose a strategy based on indocyanine green (ICG) (SBI) to provide better clinical guidelines for transarterial chemoembolization (TACE) treatments for Barcelona clinic liver cancer (BCLC) stage C hepatocellular carcinoma (HCC) patients. MATERIALS AND METHODS: From October 2005 to December 2012, 112 BCLC stage C HCC patients initially treated with TACE were investigated, randomly divided into a training cohort (n = 79) and validation cohort (n = 33). In training group, the patients were grouped based on their 15 minutes ICG retention rate (ICG R15), different chemo drugs and dose of lipidol in TACE. Overall survival (OS) and progression-free survival (PFS) were analyzed in subgroups. Strategy based on ICG was built and verified in validation group. RESULTS: For those patients with ICG R15 values >10%, the lipiodol ≤10 mL group showed better survival than the lipiodol >10 mL group. For those patients with ICG R15 values ≤10%, the group that received triple-drug chemotherapy treatments with lipiodol diameter ratio values between 1 and 3 showed better survival than the other group. Patients who conformed with the SBI had better survival times than those who did not conform with the SBI, in both the training cohort (median OS 10.3 vs 5.1 months; P < .001; median PFS, 3.3 vs 2.1 months; P = .006) and the validation cohort (median OS 8.9 vs 7.1 months; P = .087; median PFS, 6.6 vs 2.3 months; P < .001). CONCLUSIONS: The SBI is suitable and may provide survival benefits for TACE treatments in BCLC stage C HCC patients.

Risk factors of extra-hepatic progression after transarterial chemoembolization for hepatocellular carcinoma patients: a retrospective study in 654 cases.

Aim: To investigate the risk factors of extra-hepatic progression after TACE in HCC. Methods: The study population included 654 HCC patients who underwent TACE between October 2005 and September 2012. We collected and analyzed their clinical characteristics and survival information. TACE was performed as previously described with minor modifications. When necessary, superselective chemoembolization was performed through the segmental or subsegmental arteries, based on the tumor location and extent and hepatic function reserve. If stasis could not be achieved in a tumor-feeding artery, iodized oil was used solely in some patients. Embolization was then performed with injection of absorbable gelfoam particles (1-2 mm in diameter) through the angiographic catheter. Results: The tumor response to initial TACE was evaluated in 645 patients. The CR rate, response rate (RR), and disease control rate (DCR) were 9.92%, 25.89%, and 70.39%, respectively. The median overall survival (OS) period was 14.5 months. The 6-month, 1-, 2-, 3-, and 5-year OS rates were 75.5%, 55.0%, 33.9%, 22.8%, and 14.9%, respectively. The median progression-free survival (PFS) period was 4.3 months. The 6-month, 1-, 2-, 3-, and 5-year PFS rates were 40.7%, 27.1%, 16.7%, 13.9%, and 9.3%, respectively. One hundred and fifty patients developed extrahepatic progression during follow-up. We demonstrated that in the absence of radical treatment after initial TACE (p<0.001), the presence of extrahepatic metastasis before initial TACE (p<0.001), AST >45 U/L (p=0.024), ALB <35 g/L (p=0.012), and tumor response were evaluated as PD and SD after initial TACE (p<0.001) and were found to be independent predictors of a poorer prognosis of extrahepatic PFS. Conclusions: We identified risk factors for extrahepatic progression after TACE in HCC patients. Early combination treatment was strongly recommended in patients that met these risk factors.

Anatomical versus Non-anatomical Resection for Hepatocellular Carcinoma with Microscope Vascular Invasion: A Propensity Score Matching Analysis.

Background: The benefits of anatomical resection (AR) and non-anatomical resection (NAR) on hepatocellular carcinoma (HCC) patients with microscope vascular invasion (MVI) remain unknown. We aimed to investigate the prognostic outcomes of AR and NAR for HCC patients with MVI. Study Design: A total of 362 consecutive HCC patients diagnosed with MVI after hepatic resection between February 2005 and December 2013 were included in this study. The patient outcomes were compared, and a 1:2 propensity score matching (PSM) analysis was applied to eliminate selection bias. Results: Before PSM, compared to the NAR group, the AR group contained more patients that exceeded the Milan criteria, with larger, unilobar tumors and higher AST levels. After PSM, 100 patients were classified into the propensity-matched AR group (PS-AR), while 170 were classified into the propensity-matched NAR group (PS-NAR). Baseline data, including liver function and tumor burden measurements, were similar in the matched groups. The respective 1-, 3- and 5-year overall survival (OS) rates were 78.9%, 56.9%, and 51.5% in the PS-AR group and 76.2%, 53.0%, and 42.4% in the PS-NAR group (P = 0.301). The 1-, 3- and 5-year disease-free survival (DFS) rates were 51.1%, 44.7% and 42.0% in the PS-AR group and 44.9%, 34.3% and 26.4% in the PS-NAR group, respectively (P = 0.039). Multivariate analysis identified AR (P=0.025) as an independent favorable prognostic factor for DFS in HCC patients with MVI. Conclusions: Anatomical resection was superior to non-anatomical resection for improving DFS in hepatocellular carcinoma patients with microscope vascular invasion.

NCKAP1 improves patient outcome and inhibits cell growth by enhancing Rb1/p53 activation in hepatocellular carcinoma.

In our previous report, we identified miR-34c-3p as an independent factor contributing to the carcinogenesis of hepatocellular carcinoma (HCC) by targeting NCK Associated Protein 1 (NCKAP1). NCKAP1 has been known to promote the malignancy of cancer cells by disrupting the structural stability of WAS protein family member 1 (WASF1) and is correlated with poor prognosis of patients in several cancer types. Our results, however, show that NCKAP1 is correlated with a favorable outcome in HCC patients. The underlying mechanism of this contradictory phenomenon is unknown. The current study was designed to explore the mechanism of NCKAP1 in HCC. As a result, clinicopathological correlations and results from in vivo and in vitro models indicated that NCKAP1 was a tumor suppressor gene. Cell cycle analysis suggested that NCKAP1 inhibit cells from entering G2/M phase. Western blot analysis showed that WASF1 was barely expressed in HCC cell lines compared to that of breast cancer cell lines, which serve as positive controls. Furthermore, Rb1 and p53 expression was upregulated in cell lines overexpressing NCKAP1. Expression of several cell cycle regulating proteins also varied in the HCC cell lines. In conclusion, although previous studies have identified NCKAP1 as a cell invasion promoter by binding to WASF1, we found that NCKAP1 is a tumor suppress gene that modulates the cell cycle of HCC cell lines by targeting Rb1/p53 regulation.