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.

Development and Validation of a Novel Nomogram for Predicting Vessels that Encapsulate Tumor Cluster in Hepatocellular Carcinoma.

BACKGROUND: Vessels that encapsulate tumor cluster (VETC) is associated with poor prognosis in hepatocellular carcinoma (HCC). Vessels that encapsulate tumor cluster estimation before initial treatment is helpful for clinical doctors. We aimed to construct a novel predictive model for VETC, using preoperatively accessible clinical parameters and imagine features. METHODS: Totally, 365 HCC patients who received curative hepatectomy in the Sun Yat-Sen University Cancer Center from 2013 to 2014 were enrolled in this study. Vessels that encapsulate tumor cluster pattern was confirmed by immunochemistry staining. 243 were randomly assigned to the training cohort while the rest was assigned to the validation cohort. Independent predictive factors for VETC estimation were determined by univariate and multivariate logistic analysis. We further constructed a predictive nomogram for VETC in HCC. The performance of the nomogram was evaluated by C-index, receiver operating characteristic (ROC) curve, and calibration curve. Besides, the decision curve was plotted to evaluate the clinical usefulness. Ultimately, Kaplan-Meier survival curves were utilized to confirm the association between the nomogram and survival. RESULTS: Immunochemistry staining revealed VETC in 87 patients (23.8%). lymphocyte to monocyte ratio (>7.75, OR = 4.06), neutrophil (>7, OR = 4.48), AST to ALT ratio (AAR > .86, OR = 2.16), ALT to lymphocyte ratio index (BLRI > 21.73, OR = 2.57), alpha-fetoprotein (OR = 1.1), and tumor diameter (OR = 2.65) were independent predictive factors. The nomogram incorporating these predictive factors performed well with an area under the curve (AUC) of .746 and .707 in training and validation cohorts, respectively. Calibration curves indicated the predicted probabilities closely corresponded with the actual VETC status. Moreover, the decision curve proved our nomogram could provide clinical benefits with patients. Finally, low probability of VETC group had significantly longer recurrence free survival (RFS) and overall survival (OS) than the high probability of the VETC group (all P < .001). CONCLUSION: A novel predictive nomogram integrating clinical indicators and image characteristics shows strong predictive VETC performance and might provide standardized net clinical benefits.

Immune-related adverse events predict responses to PD-1 blockade immunotherapy in hepatocellular carcinoma.

Immune checkpoint blockade has demonstrated remarkable efficacy in hepatocellular carcinoma (HCC) but is also commonly accompanied by immune-related adverse events (irAEs). However, the association between irAEs and antitumor efficacy in HCC patients remains unknown. All patients with HCC treated with anti-PD-1 antibodies from July 2018 to November 2019 were analyzed and divided into different groups according to their irAEs' status. In total, 101 HCC patients, including 21 (20.8%) patients who presented with irAEs (irAEs+ ), were enrolled. Among the adverse events, rash (n = 9, 8.9%) was the most frequent irAE, followed by mucositis (n = 3, 3.0%) and thyroiditis (n = 3, 3.0%). Patients in the irAEs+ group showed a higher tumor response rate than those in the irAEs- group (overall response rate: 28.6% vs 6.3%, P = .011; disease control rate: 85.7% vs 60.0%, P = .028). The median progression-free survival (PFS) times were 14.8 months in the irAEs+ group and 4.1 months in the irAEs- group (P < .001). Further analysis based on the presence or absence of rash showed that the PFS of the patients in the irAEs+ /rash+ group was better than that of those in the irAEs+ /rash- or irAEs- group (all P < .05). Multivariate analysis showed that irAEs were an independent prognostic factor for PFS (hazard ratio [HR]: 0.22, P = .002). Thus, the occurrence of irAEs, especially rash, was associated with markedly improved PFS. Awareness of irAEs may help classify the subtype of HCC patients with an unprecedented survival benefit from anti-PD-1 antibodies.

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.

Induced CD10 expression during monocyte-to-macrophage differentiation identifies a unique subset of macrophages in pancreatic ductal adenocarcinoma.

OBJECTIVE: Tumor associated macrophages (TAMs) promoted pancreatic ductal adenocarcinoma (PDAC) initiation and progression. In this study we aimed to evaluate CD10 expression by monocytes/macrophages and its clinical significance in PDAC. METHODS: Human CD14+ peripheral blood monocytes were isolated and cultured for 6-7 days to differentiate into macrophages in vitro. Monocytic THP-1 cells were cultured and treated with 100 ng/ml phorbol 12-myristate 13-acetate (PMA) for 72 h to induce macrophage differentiation. Reverse transcription-quantitative PCR, immunohistochemistry, immunofluorescence, multiplex immunohistochemical staining and flow cytometry were performed to detect CD10 expression. In addition, the correlations between CD10 expression and immune cells infiltration were investigated through TIMER or GEPIA. Finally, Kaplan-Meier plotter and GEPIA databases were adopted to evaluate the influence of CD10 on clinical prognosis. RESULTS: Our results indicated that CD10 was expressed by a subset of human monocytes and many more cells expressed CD10 after differentiation into macrophages in vitro (13.19% vs. 41.39%; P < 0.0001). As for PDAC tissues, CD10 was correlated with immune cells infiltration and was expressed by a subset of TAMs. For THP-1 cells, PMA could induce CD10 expression through the MAPK pathway. The Kaplan-Meier plotter results suggested that CD10 expression had an impact on the prognosis of PDAC. CONCLUSIONS: In this study we demonstrated that CD10 was expressed by human primary monocytes, human monocyte-derived macrophages and TAMs, and was correlated with poor prognosis in PDAC, suggesting CD10 to be a potential therapeutic target in PDAC.

Postoperative Adjuvant Transarterial Infusion Chemotherapy with FOLFOX Could Improve Outcomes of Hepatocellular Carcinoma Patients with Microvascular Invasion: A Preliminary Report of a Phase III, Randomized Controlled Clinical Trial.

BACKGROUND: Microvascular invasion (MVI) is a risk factor for tumor recurrence after hepatectomy in hepatocellular carcinoma (HCC) patients. OBJECTIVE: This study aimed to investigate the efficacy and safety of postoperative adjuvant transarterial infusion chemotherapy (TAI) with the FOLFOX regimen for HCC patients with MVI. METHODS: In this prospective, phase III, randomized, open-label, controlled clinical trial, HCC patients with histologically confirmed MVI were randomly assigned (1:1) after hepatectomy to receive either one to two cycles of adjuvant TAI (AT group) or follow-up without any adjuvant treatment (FU group). The primary endpoint was disease-free survival (DFS), while secondary endpoints were overall survival (OS) and safety. RESULTS: Between June 2016 and April 2019, 127 patients were randomly assigned to the AT group (n = 63) or FU group (n = 64). Clinicopathological characteristics of the two groups were well-balanced. The 6-, 12-, and 18-month OS rates for the AT group were 100.0%, 97.7%, and 97.7%, respectively, and 94.5%, 89.6%, and 78.5% for the FU group, respectively. The 6-, 12-, and 18-month DFS rates for the AT and FU groups were 84.7%, 61.8%, and 58.7%, and 62.9%, 48.1%, and 38.6%, respectively. OS and DFS were significantly better in the AT group than in the FU group (p = 0.037 and 0.023, respectively). No patients in the AT group experienced grade 3 or more severe adverse events. CONCLUSIONS: Adjuvant TAI after hepatectomy may bring survival benefits to HCC patients with MVI. TRIAL REGISTRATION: Trial number: NCT03192618.

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.

Hepatic Arterial Infusion Chemotherapy vs Transcatheter Arterial Chemoembolization as Adjuvant Therapy Following Surgery for MVI-Positive Hepatocellular Carcinoma: A Multicenter Propensity Score Matching Analysis.

Background: Microvascular invasion (MVI) is a significant pathological feature in hepatocellular carcinoma (HCC), adjuvant hepatic arterial infusion chemotherapy (a-HAIC) and adjuvant transcatheter arterial chemoembolization (a-TACE), are commonly used for HCC patients with MVI. This study aims to evaluate the efficacies of two adjuvant therapies after surgical treatment for HCC, compare them, and identify the significant factors. Methods: Clinical data from two randomized controlled trials involving HCC patients with MVI after surgical treatment were retrospectively reviewed. Propensity score matching (PSM) analysis was performed to balance baseline differences between patients who received a-HAIC or a-TACE, and control groups who underwent hepatectomy alone. Disease-free survival (DFS) and overall survival (OS) rates were compared. Results: In total of 549 patients were collected from two randomized controlled trials. Using the PSM and Kaplan-Meier method, the median DFS of the a-HAIC, a-TACE, and control groups was 63.2, 21.7, and 11.2 months (P<0.05). The a-HAIC group show significantly better 1-, 3-, and 5-year OS rates compared to the a-TACE and control groups (96.3%, 80.0%, 72.8% vs 84.4%, 57.0%, 29.8% vs 84.5%, 62.8%, 53.4%, P<0.05). But the OS rates of a-TACE and control groups showed no significant difference (P=0.279). Multivariate analysis identified a-HAIC (HR=0.449, P=0.000) and a-TACE (HR=0.633, P=0.007) as independent protective factors. For OS, a-HAIC (HR=0.388, P=0.003) was identified as an independent protective factor, too. Conclusion: Compared to a-TACE and the control group, a-HAIC demonstrated greater benefits in preventing tumor recurrence and improving survival in HCC patients with MVI.

Imaging-based surrogate classification for risk stratification of hepatocellular carcinoma with microvascular invasion to adjuvant hepatic arterial infusion chemotherapy: a multicenter retrospective study.

BACKGROUND: Patients with microvascular invasion (MVI)-positive hepatocellular carcinoma (HCC) have shown promising results with adjuvant hepatic arterial infusion chemotherapy (HAIC) with FOLFOX after curative resection. We aim to develop an imaging-derived biomarker to depict MVI-positive HCC patients more precisely and promote individualized treatment strategies of adjuvant HAIC. MATERIALS AND METHODS: Patients with MVI-positive HCC were identified from five academic centers and utilized for model development (n=470). Validation cohorts were pooled from a previously reported prospective clinical study conducted (control cohort (n=145), adjuvant HAIC cohort (n=143)) (NCT03192618). The primary endpoint was recurrence-free survival (RFS). Imaging features were thoroughly reviewed, and multivariable logistic regression analysis was employed for model development. Transcriptomic sequencing was conducted to identify the associated biological processes. RESULTS: Arterial phase peritumoral enhancement, boundary of the tumor enhancement, tumor necrosis stratification, and boundary of the necrotic area were selected and incorporated into the nomogram for RFS. The imaging-based model successfully stratified patients into two distinct prognostic subgroups in both the training, control, and adjuvant HAIC cohorts (median RFS, 6.00 vs. 66.00 mo, 4.86 vs. 24.30 mo, 11.46 vs. 39.40 mo, all P<0.01). Furthermore, no significant statistical difference was observed between patients at high-risk of adjuvant HAIC and those in the control group (P=0.61). The area under the receiver operating characteristic curve at two years was found to be 0.83, 0.84, and 0.73 for the training, control, and adjuvant HAIC cohorts respectively. Transcriptomic sequencing analyses revealed associations between the radiological features and immune-regulating signal transduction pathways. CONCLUSION: The utilization of this imaging-based model could help to better characterize MVI-positive HCC patients and facilitate the precise subtyping of patients who genuinely benefit from adjuvant HAIC treatment.

Vessels encapsulating tumor clusters: a novel efficacy predictor of hepatic arterial infusion chemotherapy in unresectable hepatocellular carcinoma.

PURPOSE: Vessels encapsulating tumor clusters (VETC) is a novel vascular pattern structurally and functionally distinct from microvascular invasion (MVI) in hepatocellular carcinoma (HCC). This study aims to explore the prognostic value of VETC in patients receiving hepatic arterial infusion chemotherapy (HAIC) for unresectable HCC. METHODS: From January 2016 to December 2017, 145 patients receiving HAIC as the initial treatment for unresectable HCC were enrolled and stratified into two groups according to their VETC status. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were evaluated. RESULTS: The patients were divided into two groups: VETC+ (n = 31, 21.8%) and VETC- (n = 114, 78.2%). The patients in the VETC+ group had worse ORR and DCR than those in the VETC- group (RECIST: ORR: 25.8% vs. 47.4%, P = 0.031; DCR: 56.1% vs. 76.3%, P = 0.007; mRECIST: ORR: 41.0% vs. 52.6%, P = 0.008; DCR: 56.1% vs. 76.3%, P = 0.007). Patients with VETC+ had significantly shorter OS and PFS than those with VETC- (median OS: 10.2 vs. 21.6 months, P < 0.001; median PFS: 3.3 vs. 7.2 months, P < 0.001). Multivariate analysis revealed VETC status as an independent prognostic factor for OS (HR: 2.40; 95% CI: 1.46-3.94; P = 0.001) and PFS (HR: 1.97; 95% CI: 1.20-3.22; P = 0.007). CONCLUSION: VETC status correlates remarkably well with the tumor response and long-term survival in patients undergoing HAIC. It may be a promising efficacy predictor and help identify patients who will benefit from HAIC.

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.

Body mass index, as a novel predictor of hepatocellular carcinoma patients treated with Anti-PD-1 immunotherapy.

Immunocheckpoint inhibitors have shown significant efficacy in the treatment of hepatocellular carcinoma (HCC), but there are individual differences. The aim of this study was to explore body mass index (BMI) as a predictor of anti-PD-1 efficacy in patients with HCC. We retrospectively analyzed 101 HCC patients who treated with anti-PD-1 at Sun Yat-sen University Cancer Center from July 2018 to November 2019 and divided them into overweight (BMI > 24.9) and non-overweight (BMI ≤ 24.9) groups based on baseline BMI levels. BMI > 24.9 accounted for 22 cases (21.8%) and BMI ≤ 24.9 accounted for 79 cases (78.2%) in the study cohort. Overweight patients had higher disease control rates than non-overweight patients (P = 0.019, respectively). The mean progression-free survival (PFS) in overweight patients (10.23 months) was significantly longer than that of non-overweight patients (6.85 months; P = 0.027). Among patients with immune-related adverse events (irAEs), the mean PFS was also significantly longer in overweight patients (7.72 months) than in non-overweight patients (5.31 months, P = 0.034). Multivariate analysis showed that BMI was an independent prognostic factor for PFS in HCC patients treated with anti-PD-1 (hazard ratio: 0.47, P = 0.044). Thus, higher BMI predicts a better prognosis among HCC patients treated with anti-PD-1. In clinical practice, patients' BMI can provide a useful tool for predicting the efficacy of anti-PD-1 therapy.

Long noncoding RNA TINCR facilitates hepatocellular carcinoma progression and dampens chemosensitivity to oxaliplatin by regulating the miR-195-3p/ST6GAL1/NF-κB pathway.

BACKGROUND: Long non-coding RNAs (lncRNA) have an essential role in progression and chemoresistance of hepatocellular carcinoma (HCC). In-depth study of specific regulatory mechanisms is of great value in providing potential therapeutic targets. The present study aimed to explore the regulatory functions and mechanisms of lncRNA TINCR in HCC progression and oxaliplatin response. METHODS: The expression of TINCR in HCC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration, invasion, and chemosensitivity were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and apoptosis assays. Luciferase reporter assays and RNA pulldown were used to identify the interaction between TINCR and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) via miR-195-3p. The corresponding functions were verified in the complementation test and in vivo animal experiment. RESULTS: TINCR was upregulated in HCC and associated with poor patient prognosis. Silencing TINCR inhibited HCC proliferation, migration, invasion, and oxaliplatin resistance while overexpressing TINCR showed opposite above-mentioned functions. Mechanistically, TINCR acted as a competing endogenous (ceRNA) to sponge miR-195-3p, relieving its repression on ST6GAL1, and activated nuclear factor kappa B (NF-κB) signaling. The mouse xenograft experiment further verified that knockdown TINCR attenuated tumor progression and oxaliplatin resistance in vivo. CONCLUSIONS: Our finding indicated that there existed a TINCR/miR-195-3p/ST6GAL1/NF-κB signaling regulatory axis that regulated tumor progression and oxaliplatin resistance, which might be exploited for anticancer therapy in HCC.

C-Reactive Protein Levels Predict Responses to PD-1 Inhibitors in Hepatocellular Carcinoma Patients.

Background: Serum C-reactive protein (CRP) is a biomarker of an acute inflammatory response and has been successfully used as a prognostic predictor for several malignancies. However, the clinicopathological significance of CRP levels in hepatocellular carcinoma (HCC) patients being treated with PD-1 inhibitors remains unclear. Methods: Serum CRP levels were measured for a total of 101 HCC patients that had been treated with PD-1 inhibitors from July 2018 to November 2019. The clinicopathological data was retrospectively analyzed to identify any clinical implications between CRP levels and responses to PD-1 inhibitors and patients' progression-free survival (PFS). Results: The median PFS was 8.87 months in the CRP-low subgroup and 3.67 months in the CRP-high subgroup (P = 0.009). Univariate and multivariate Cox regression analysis demonstrated that both serum CRP and AFP levels were independent risk factors for the PFS of HCC patients treated with PD-1 inhibitors (P < 0.05). Moreover, Cox regression analysis after Propensity Score Matching showed the similar results. A prognostic model combining CRP and AFP levels could significantly stratify HCC patients receiving PD-1 inhibitors into low-, intermediate-, and high-risk subgroups (P < 0.001). Patients in the risk subgroups reported similar overall response rates (P = 0.625) and significantly different disease control rates (low- vs. intermediate- vs. high-risk groups: 81.6% vs. 65.1% vs. 35%, respectively, P = 0.002). Conclusions: The results of this study support the association between high serum CRP levels with the response and PFS for HCC patients receiving PD-1 inhibitors. Furthermore, the levels of both CRP and AFP in an HCC patient before treatment initiation show great potential for determining the efficacy of PD-1 inhibitors.

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.

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.

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.