Nomograms incorporating hsa_circ_0029325 highly expressed in exosomes of hepatocellular carcinoma predict the postoperative outcomes.

BACKGROUND: Liquid biopsies, for example, exosomal circular RNA (circRNA) can be used to assess potential predictive markers for hepatocellular carcinoma (HCC) in patients after curative resection. This study aimed to search for effective prognostic biomarkers for HCC in patients after surgical resection based on exosomal circRNA expression profiles. We developed two nomograms incorporating circRNAs to predict the postoperative recurrence-free survival (RFS) and overall survival (OS) of HCC patients. METHOD: Plasma exosomes isolated from HCC patients and healthy individuals were used for circRNA microarray analysis to explore differentially expressed circRNAs. Pearson correlation analysis was used to evaluate the correlation between circRNAs and clinicopathological features. Cox regression analysis was used to explore the correlation between circRNA and postoperative survival time as well as recurrence time. A nomogram based on circRNA and clinicopathological characteristics was established and further evaluated to predict prognosis and recurrence. RESULT: Among 60 significantly upregulated circRNAs and 25 downregulated circRNAs, hsa_circ_0029325 was selected to verify its power for predicting HCC outcomes. The high expression level of exosomal hsa_circ_0029325 was significantly correlated with OS (P = 0.001, HR = 2.04, 95% CI 1.41-3.32) and RFS (P = 0.009, HR = 1.62, 95% CI 1.14-2.30). Among 273 HCC patients, multivariate regression analysis showed that hsa_circ_0029325 (HR = 1.96, 95% CI 1.21-3.18), tumor size (HR = 2.11, 95% CI 1.33-3.32), clinical staging (HR = 2.31, 95% CI 1.54-3.48), and tumor thrombus (HR = 1.74, 95% CI 1.12-2.7) were independent risk factors for poor prognosis in HCC patients after radical resection. These independent predictors of prognosis were incorporated into the two nomograms. The AUCs under the 1-year, 3-year, and 5-year survival and recurrence curves of the OS and RFS nomograms were 0.755, 0.749, and 0.742 and 0.702, 0.685, and 0.642, respectively. The C-index, calibration curves, and clinical decision curves showed that the two prediction models had good predictive performance. These results were verified in the validation cohort with 90 HCC patients. CONCLUSION: Our study established two reliable nomograms for predicting recurrence and prognosis in HCC patients. We also show that it is feasible to screen potential predictive markers for HCC after curative resection through exosomal circRNA expression profile analysis.

Constraints for symptomatic radiation pneumonitis of helical tomotherapy hypofractionated simultaneous multitarget radiotherapy for pulmonary metastasis from hepatocellular carcinoma.

BACKGROUND AND PURPOSE: This study was aimed to identify the clinical and dosimetric parameters that predict symptomatic radiation pneumonitis (SRP, radiation pneumonitis≥2 grade) in patients with pulmonary metastasis from hepatocellular carcinoma (HCC) after helical tomotherapy (HT) hypofractionated simultaneous multitarget radiotherapy. MATERIALS AND METHODS: 62 patients with 407 pulmonary metastases from HCC were consecutively treated with HT. The median radiation dose was a 49.7Gy in 4.0Gy/fraction to 95% of the planning target volume (PTV). The associations between the clinical and dosimetric data and incidences of SRP were analyzed. The dose-pneumonitis relationship was analyzed based on Biologically Effective Dose (BED). RESULTS: Univariate analysis showed that the gross tumor volume (GTV), PTV, median lung dose (MLD), the number of pulmonary metastatic lesions (NPML), and the percentage of non-target normal lung (NTNL) volume receiving more than a BED of 3-50Gy (VBED3-50) were associated with SRP. Multivariate logistic regression analysis showed that VBED20 and NPML were significant parameters (both P<0.001) CONCLUSIONS: Our findings indicated that SRP can be predicted with NPML>5 and VBED20≥30.4% with the α/ß ratio of 3Gy.

Simultaneous multitarget radiotherapy using helical tomotherapy and its combination with sorafenib for pulmonary metastases from hepatocellular carcinoma.

We evaluated radiotherapy using helical tomotherapy (HT) combined with sorafenib for treatment of pulmonary metastases from hepatocellular carcinoma (HCC). We also analyzed potential prognostic factors and further validated the combination treatment. The objective response rate in the total cohort of 45 patients treated with HT (with or without sorafenib) was 66.7% (complete response, n = 1; partial response, n = 29), with no adverse events > grade 2 in severity. Median progression-free survival (PFS) and overall survival (OS) were 7.50 ± 0.53 and 26.40 ± 2.66 months, respectively. The addition of sorafenib was associated with increased PFS (11.80 ± 1.55 vs 5.80 ± 0.52 months, p = 0.006) and increased OS (29.60 ± 5.23 vs 21.90 ± 5.17 months, p = 0.007). After multivariate adjustment, the risk of disease progression associated with combination treatment was significantly lower (p = 0.022) compared with HT only, and survival was significantly longer (p = 0.014). Further validation confirmed the benefit of combination treatment. Prognostic factors were number of pulmonary metastases for PFS (19.00 ± 7.15 months for ≤3 lesions vs 5.80 ± 0.26 months for >3 lesions, p < 0.001) and intrahepatic tumor status for OS (28.50 ± 2.76 months for well-controlled tumors vs 15.60 ± 6.38 months for uncontrolled tumors, p = 0.011). In conclusion, radiotherapy with HT for pulmonary metastases is feasible without major complications, and its combination with sorafenib may be a promising approach in a subgroup of patients.

B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence.

B7-H3, a novel B7 family member, positively or negatively regulates T-cell responses. We investigated the clinical relevance and prognostic significance of B7-H3 in hepatocellular carcinoma (HCC). Western blotting showed B7-H3 upregulation in 17 of 24 (70.8 %) HCC tissues compared with nontumor liver tissues (p = 0.028). B7-H3 immunostaining on tissue microarrays containing 240 HCC patient samples indicated that 225 (93.8 %) tumors had aberrant B7-H3 expression, with strong intensity in 79 (32.9 %) cases, whereas B7-H3 expression in peritumor liver cells was weak in most cases (226; 94.2 %). Notably, patients with high/moderate tumor cell B7-H3 expression showed significantly poorer survival (p = 0.009) and increased recurrence (p = 0.002). After multivariable adjustment, high/moderate B7-H3 expression remained significant for an increased risk of recurrence (hazard ratio = 1.79; 95 % confidence interval = 1.19-2.70; p = 0.005). B7-H3 expression correlated with invasive phenotypes like vascular invasion and advanced tumor stage, and the metastatic potential of HCC cell lines. Flow cytometry showed that B7-H3 expression is inversely correlated with proliferation and interferon-γ production by infiltrating T cells. Interferon-γ stimulation significantly upregulated B7-H3 expression in HCC cells in vitro, implicating B7-H3 expression as a feedback mechanism to evade anti-tumor immunity. Importantly, the prognostic value of B7-H3 expression was validated in an independent cohort of 206 HCC patients. Collectively, our data suggest that B7-H3 was abundantly expressed in HCC and was associated with adverse clinicopathologic features and poor outcome. Thus, B7-H3 represents an attractive target for diagnostic and therapeutic manipulation in human HCC.

Expression of TREM-1 in hepatic stellate cells and prognostic value in hepatitis B-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a typical inflammation-related malignancy characterized by high postoperative recurrence and metastasis. Although several inflammatory cells and inflammatory signatures have been linked to poor prognosis, the inflammation-associated molecular mechanisms of HCC development and progression are largely unknown. Here we show that triggering receptor expressed in myeloid cells (TREM)-1, a transmembrane receptor expressing in myeloid cells, was also expressed in tumor-activated hepatic stellate cells (HSCs) and associated with the aggressive behavior of HCC cells. Enzyme-linked immunosorbent assay was used to measure the expression levels of soluble TREM-1 (sTREM-1) in activated hepatic stellate cells supernatant and 92 preoperative and postoperative plasmas of patients with malignancy and/or benign liver tumor/disease, respectively. Expression levels of TREM-1 were assessed by immunohistochemistry in tissue microarray from 240 patients with HCC. As a result, increased secretion of sTREM-1 from activated HSCs was observed after co-culture with HCC cell lines (P < 0.001), and conditioned medium collected from activated HSCs/cancer associated myofibroblasts (CAMFs) with or without agonist/inhibitor of TREM-1 significantly changed the migratory ability of HCC cells. The levels of sTREM-1 were significantly higher in patients with HCC than those with benign liver tumors (P < 0.005). Peritumoral density of TREM-1 was shown to be an independent prognosis predictor according to univariate (P < 0.001 for both overall survival and time to recurrence) and multivariate analysis (P = 0.008 for overall survival; P = 0.005 for time to recurrence). Thus, these observations suggest that TREM-1 is related to the aggressive tumor behavior and has potential value as a prognostic factor for HCC.

Overexpression of galectin-1 is associated with poor prognosis in human hepatocellular carcinoma following resection.

BACKGROUND AND AIM: The high expression of the galectin-1 predicts poor patient outcome in several tumors. The aim of this study was to investigate its prognostic value in patients with hepatocellular carcinoma (HCC) after resection. METHODS: Galectin-1 and tumor-infiltrating FoxP3(+) regulatory T cells (Tregs) were validated by tissue microarrays from HCC patients (n = 386) and statistically assessed for correlations with the clinical profiles and the prognosis of the patients. RESULTS: We found that galectin-1, which was prevalently upregulated in HCC, was significantly associated with tumor invasive characteristics (such as vascular invasion, incomplete encapsulation, poor differentiation, multiple number, and large tumor size). Patients with high galectin-1 expression had a significantly poorer tumor recurrence (P = 0.025) and overall survival (P = 0.021) than those with low galectin-1 expression. Even in early-stage disease, high galectin-1 expression was also independently associated with shortened survival (P < 0.001) and increased tumor recurrence (P = 0.005). Multivariate Cox proportional hazards analysis showed that galectin-1 was an independent marker for predicting the poor prognosis of HCC. The galectin-1 level was positively related to the number of tumor-infiltrating FoxP3(+) Tregs (r = 0.416, P < 0.001), and their combination served as a better prognosticator. The postoperative tumor recurrence and survival of HCC patients with galectin-1(high) and FoxP3(high) were significantly poorer than the other groups (both P < 0.001). CONCLUSIONS: Galectin-1 might be a new prognostic factor for HCC after resection and could potentially be a high-priority therapeutic target.