Tumor Encapsulation Research Articles

Efficacy of traditional herbal medicine versus transcatheter arterial chemoembolization in postsurgical patients with hepatocellular carcinoma: A retrospective study

BackgroundRecurrence is a major obstacle to improve the prognosis of hepatocellular carcinoma (HCC) patients. Transcatheter arterial chemoembolization (TACE) has been routinely used as an adjuvant therapy in treating HCC, but efficacy of TACE in preventing the recurrence of HCC remains unsatisfactory. This study aimed to compare the efficacy of a traditional herbal medicine (THM) therapy and TACE in preventing tumor recurrence and improving survival in postsurgical patients with HCC. Materials and methodsA total of 1506 HCC patients were enrolled from January 2008 to June 2017, including 262 patients who received THM therapy and 1244 patients who were treated with TACE. All patients were followed up until the occurrence of outcome event or June 30th, 2019. The recurrence-free survival (RFS) and overall survival (OS) were calculated by the Kaplan-Meier method, and the differences of RFS and OS between THM group and TACE group were analyzed by the log-rank test. Factors affecting the RFS or OS among these patients were assessed by the Cox proportional hazard regression model. A nomogram was built with the factors based on the Cox regression analysis to predict the prognosis. ResultsThe 1-, 3-, and 5-year RFS were 91.0%, 68.3%, and 49.7%, respectively, in the THM group and 79.4%, 38.6%, and 19.3%, respectively, in the TACE group. The RFS in the THM group was significantly higher than that of the TACE group (P = 6.2 × 10−11). The 1-, 3-, and 5-year OS were significantly improved in the THM group as compared to those in the TACE group (94.3%, 65.2%, and 41.4% vs. 82.7%, 46.0%, and 25.4%, P = 2.2 × 10−11). Multivariate analysis revealed that serum AFP level ≥400 ng/mL, HBV DNA load ≥500 copies/mL, TNM stage III-IV, tumor diameter ≥5 cm, presence of MVI, and multiple tumor nodules were independent risk factors for RFS, while complete tumor encapsulation and THM therapy were protective factors for RFS and OS. The nomogram demonstrated good accuracy in predicting RFS and OS, with the adjusted C-index of 0.748 and 0.796, respectively. ConclusionThe efficacy of THM therapy was superior to that of TACE in preventing recurrence and improving survival for HCC patients after hepatectomy.

Decreased expression of serum semaphorin 3B is associated with poor prognosis of patients with hepatocellular carcinoma.

Semaphorin 3B (SEMA-3B), which belongs to the semaphorin family, has an important role in cell apoptosis and inhibition of angiogenesis. A previous study by our group revealed that SEMA-3B was downregulated in tumor tissues of patients with hepatocellular carcinoma (HCC) and exerts anti-motility and anti-invasion effects on tumor cells. However, the serum levels of SEMA-3B and their clinical significance have remained elusive; therefore, the aim of the present study was to monitor its expression in HCC and investigate its clinical significance. ELISA was used to determine the serum levels of SEMA-3B in 132 patients with HCC and 57 healthy individuals. The association between SEMA-3B and clinicopathological parameters was investigated. Serum SEMA-3B was indicated to be significantly decreased in patients with HCC as compared with that in the controls (P<0.05) and it was negatively associated with tumor size (P=0.039), encapsulation (P=0.002) and TNM stage (P=0.034). The prognosis of patients with low expression of SEMA-3B was poor. In conclusion, the results of the present study revealed that serum SEMA-3B is decreased in HCC and is negatively associated with prognosis; therefore, it may be used as a prognostic marker in HCC.

HRC promotes anoikis resistance and metastasis by suppressing endoplasmic reticulum stress in hepatocellular carcinoma

Histidine-rich calcium binding protein (HRC) is markedly overexpressed in hepatocellular carcinoma (HCC) and is significantly correlated with metastasis. Anoikis resistance and endoplasmic reticulum (ER) stress may have a critical effect on survival before metastasis. However, the potential functions of HRC in anoikis resistance in HCC remain unknown. Here, we uncovered the clinical value of HRC and its functional significance on anoikis in HCC. The positive expression of HRC was observably correlated with tumor size, tumor encapsulation, and tumor-node-metastasis (TNM) stage. The expression of HRC increased in HCC cells cultured in suspension. HRC enhanced the anoikis resistance of HCC, and promoted the HCC metastasis in vivo. Mechanistically, the anoikis resistance was probably dependent on endoplasmic reticulum stress. Modulating HRC level changed the ERS to affect anoikis resistance by acting protein kinase RNA-like ER kinase (PERK)-eIF2a-ATF4-CHOP signaling axis. In conclusion, we define HRC as a novel candidate oncogene involved in anoikis resistance and HCC metastasis, and provide a new potential therapeutic target for HCC.

MiR-631 Inhibits Intrahepatic Metastasis of Hepatocellular Carcinoma by Targeting PTPRE.

MicroRNAs (miRNAs) have been reported to play critical roles in the pathological development of hepatocellular carcinoma (HCC), one of the most common cancers in the world. Our study aims to explore the expression, function and mechanism of miR-631 in HCC. Our findings are that expression of miR-631 is significantly down-regulated in HCC tissue compared with that in adjacent non-cancerous tissue, and low expression of miR-631 in HCC tissue is associated with cirrhosis, multiple tumors, incomplete tumor encapsulation, poor tumor differentiation, and high TNM stage. Our test results showed that miR-631 could inhibit migration, invasion, epithelial–mesenchymal transition (EMT) and intrahepatic metastasis of HCC. Receptor-type protein tyrosine phosphatase epsilon (PTPRE) as a downstream target of miR-631 could promote migration, invasion and EMT of HCC cells. Besides, the expression of PTPRE had a negative correlation with the expression of miR-631 both in vivo and in vitro, and increasing expression of PTPRE could reverse inhibitory effects of miR-631 in HCC cells. In sum, our study first demonstrated that miR-631 targeted PTPRE to inhibit intrahepatic metastasis in HCC. We gain insights from these findings into the mechanism of miRNAs regulation in HCC metastasis and further introduce a novel therapeutic target for HCC treatment.

Percutaneous Radiofrequency Ablation Combined With Transarterial Chemoembolization Plus Sorafenib for Large Hepatocellular Carcinoma Invading the Portal Venous System: A Prospective Randomized Study.

BackgroundHepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) portends a worse prognosis. The objective of this study was to compare the efficacy of percutaneous radiofrequency ablation (RFA) combined with transarterial chemoembolization (TACE) plus sorafenib to that of the most commonly utilized regimen of TACE plus sorafenib in large HCCs with type I/II PVTT.MethodsAn open-label, single-center, prospective, randomized trial of participants with tumors ≥5 cm and type I/II PVTT was performed. Participants with previously untreated HCCs were divided into two groups: RFA + cTACE + sorafenib (study group, n = 40) and cTACE + sorafenib (control group, n = 40). The primary endpoint was the objective response rate (ORR), the secondary endpoints included the overall survival (OS); time to progression (TTP); and toxicity. Prognostic factors were analyzed using cox-regression analysis.Results80 patients were enrolled into this study with integrated clinical data. Under a median follow-up of 506 days, the median age was 57.5 years (range: 28–80 years). The ORR of study group was higher than control group (70% vs 22.5%, p<0.001). Furthermore, the median OS of study group was superior to that of control group (468 days vs 219 days, HR: 0.44 [95% CI: 0.25–0.78], P = 0.005). Adverse events occurred with 100% probability in both groups (p>0.99), but no treatment-related deaths were recorded. Tumor encapsulation and attaining treatment response predict favorable OS in a multivariate Cox model. The rates of adverse events in both groups were 100% (p>0.99). There were no treatment-related deaths.ConclusionsRFA combined with TACE plus sorafenib is a safe, well-tolerated three-modality treatment for large HCCs with types I/II PVTT, and it demonstrated better efficacy than TACE plus sorafenib alone.

SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET.

Metastasis is the main reason for high mortality in hepatocellular carcinoma (HCC) patients and the molecular mechanism remains unclear. Therefore, it is important to elucidate the mechanism underlying HCC metastasis. Here, we report a novel role of SIX homeobox 4 (SIX4), one of the SIX gene family, in promoting HCC metastasis. The elevated expression of SIX4 was positively correlated with loss of tumor encapsulation, microvascular invasion, higher TNM stage, and poor prognosis in human HCC. SIX4 expression was an independent and significant risk factor for the recurrence and survival in HCC patients. Upregulation of SIX4 promoted HCC invasion and metastasis, whereas downregulation of SIX4 decreased HCC invasion and metastasis. SIX4 transactivated Yes1 associated transcriptional regulator (YAP1) and MET proto-oncogene, receptor tyrosine kinase (MET) expression through directly binding to their promoters. Knockdown of YAP1 and c-MET inhibited SIX4-medicated HCC metastasis, while the stable overexpression of YAP1 and c-MET reversed the decreased metastasis induced by SIX4 knockdown. Hepatocyte growth factor (HGF), the specific ligand of c-MET, upregulated SIX4 expression through ERK/NF-κB pathway. Knockdown of SIX4 significantly decreased HGF-enhanced HCC metastasis. In human HCC tissues, SIX4 expression was positively correlated with nuclear YAP1, c-MET and HGF expression. Patients with positive coexpression of SIX4/ nuclear YAP1, SIX4/c-MET or HGF/SIX4 had the poorest prognosis. Moreover, the combination treatment of YAP1 inhibitor Verteporfin and c-MET inhibitor Capmatinib significantly suppressed SIX4-mediated HCC metastasis. In conclusion, SIX4 is a prognostic biomarker in HCC patients and targeting the HGF-SIX4-c-MET positive feedback loop may provide a promising strategy for the treatment of SIX4-driven HCC metastasis.

ERCC6L promotes the progression of hepatocellular carcinoma through activating PI3K/AKT and NF-\u03baB signaling pathway

BackgroundExcision Repair Cross-Complementation group 6-like (ERCC6L) has been shown to exhibit carcinogenic effect in several malignant tumors. However, the function and molecular mechanism of the ERCC6L in hepatocellular carcinoma (HCC) have not been investigated extensively.MethodsImmunohistochemistry analyses were used to detect ERCC6L expression in a HCC tissue microarray, and the Chi-square test was used to assess the correlation between ERCC6L expression and patients’ clinicopathological features. shRNA was used to down-regulation ERCC6L expression in HCC cell lines. MTT assay, plate clone formation assay, flow cytometry, caspase 3/7 activity and migration assays were performed to evaluate the impact of ERCC6L on HCC cells in vitro. Nude mice xenograft models were used to assess the role of ERCC6L in vivo. The regulatory of mechanism of PI3K/AKT pathway was evaluated by western blotting.ResultsERCC6L was highly expressed in HCC tissue compared with tumor adjacent tissues in 90 paired samples. ERCC6L expression positively correlated with gender, tumor encapsulation, and pathological stage. Patients with low ERCC6L expression had significantly longer OS than those with high ERCC6L expression. Knockdown of ERCC6L expression significantly inhibited proliferation, invasion and metastasis in vitro and tumor growth in vivo, and it promoted cell cycle arrest and apoptosis. Mechanistic analyses revealed that PI3K/AKT and NF-κB signaling pathway were inhibited by silencing ERCC6L.ConclusionThese results demonstrate that ERCC6L plays a critical role in HCC progression, and thereby might be a potential therapeutic target for HCC patients.

Surgical margin for phosphaturic mesenchymal tumors in soft tissues: An analysis of the radiological histopathological correlation

BackgroundPhosphaturic mesenchymal tumors primarily cause tumor-induced osteomalacia, a rare paraneoplastic syndrome, and half occur in soft tissues. There are few reports about the surgical margins of these tumors. This study aimed to clarify the optimal surgical margin for phosphaturic mesenchymal tumors by analyzing radiological and histopathological features. MethodsThis study included eight cases, seven primary and one recurrent, of tumor-induced osteomalacia caused by soft-tissue phosphaturic mesenchymal tumors that were surgically treated between January 2000 and January 2019. We evaluated the radiological and histopathological features of all tumors and investigated the correlation of these features, the surgical margin, and recurrence of hypophosphatemia. ResultsThe tumors were located in superficial (n = 5) and deep (n = 3) tissues. Six of the eight tumors had a clear boundary, but five had an irregular margin. Three tumors had a hypointense rim on T2-weighted images, indicating fibrous tumor encapsulation. Histopathological analysis revealed infiltrative growth in six of the eight tumors, which correlated with an irregular margin seen on imaging. Although there was no recurrence in patients treated with an intended wide margin >1 cm, one of the three patients treated with marginal tumor resection experienced a recurrence of hypophosphatemia, with histopathological analysis showing infiltration of subcutaneous fat. In contrast, two tumors with clear boundaries, regular margins, and fibrous capsule seen on imaging, had no infiltrative growth and were cured by marginal resection. In one recurrent case, tumor infiltration was observed in the previous surgical scar, which was not detected on preoperative imaging. ConclusionsSoft-tissue phosphaturic mesenchymal tumors with an irregular boundary seen on imaging tend to be infiltrative, especially into subcutaneous fat, and should be treated by at least a 1-cm wide margin resection. Tumors with a fibrous capsule with clear and regular margins are cured by marginal margin resection. These findings could inform surgeons' decisions regarding the resection of soft-tissue phosphaturic mesenchymal tumors.

Clinical significance of herpes virus entry mediator expression in hepatitis B virus-related hepatocellular carcinoma.

Herpes virus entry mediator (HVEM) is overexpressed in several malignancies, including hepatocellular carcinoma (HCC). However, to the best of our knowledge, the clinical significance of HVEM in hepatitis B virus (HBV)-related HCC remains unclear. Thus, the present study aimed to explore the clinical significance of HVEM in HBV-related HCC. In the present study, HVEM expression was evaluated in HCC cell lines and HCC frozen samples. The prognostic value of HVEM was assessed in a cohort of 221 patients with HBV-related HCC, following radical resection. B- and T-lymphocyte attenuator (BTLA) expression in subsets of CD8+ T cells was determined via flow cytometry analysis. The results demonstrated high HVEM expression in HCC cell lines, and in HCC tissues compared with paired non-cancerous liver tissues. HVEM expression was demonstrated to be significantly associated with tumor encapsulation and vascular invasion. Furthermore, tumor HVEM status was significantly associated with infiltration of regulatory T cells, but not with CD8+ T cells. Notably, high HVEM expression in HCC was determined to be an independent predictor of an unfavorable outcome of patients with HCC following radical resection. Higher BTLA expression (the receptor of HVEM) was observed in both HCC-infiltrating CD8+ effector memory (CCR7- CD45RA-) and CD45RA+ effector memory (CCR7- CD45RA+) T cells in HCC tissues and blood compared with those in paired peritumor tissues or peripheral blood. Taken together, the results of the present study suggest that HVEM may serve a critical role in HBV-related HCC, most likely by promoting tumor progression and tumor immune evasion, thus the HVEM/BLTA signaling pathway may be a potential target in tumor immunotherapy.

CFL1 to promote proliferation and invasiveness and to regulate NF-κB-mediated inflammatory factors in hepatocellular carcinoma.

e16669 Background: Cofilin1 (CFL1) is an actin-binding protein that plays an essential role in cytoskeleton regulation. However, its function in hepatocellular carcinoma (HCC) is largely unknown. The aim of study was to investigate the role of CFL1 in HCC. Methods: We used qRT-PCR and western blot assays to detect CFL1 expression. The role of CFL1 in regulating HCC cell growth and invasion were assessed by forced expression and downregulation. A tissue microarray study containing 189 HCC cases was conducted to evaluate the clinical relevance and prognostic significance of CFL1. Results: The expression level of CFL1 in high metastasis cell lines was significantly higher than that in low metastasis lines ( P &lt; 0.05). Knockdown of CFL1 reduced the proliferation and invasion activities of Huh7 and MHHC97H cells ( P &lt; 0.05). Western blot revealed that the cytoplasmic level of the p65 subunit of NF-κB was significantly elevated along with reduced nuclear levels and NF-κB-targeted genes MMP9, BCL2, EZH2, COX2 and VCAM1 levels significantly inhibited n HCC cells silenced for CFL1. Immunohistochemistry in a primary tissue array revealed that CFL1 expression correlated with Tumor encapsulation and microvascular invasion ( P &lt; 0.05). High CFL1 expression patients had significantly higher recurrence and deaths rates (recurrence: 72.9% vs. 42.9%, death: 20.8% vs. 51.1%) than low CFL1 expression patients ( P &lt; 0.001). Conclusions: CFL1 regulate the proliferation and dissemination of HCC and TNF-α induced NF-κB nuclear translocation. CFL1 may serve as a prognostic marker in HCC and might be a promising therapeutic target for suppressing metastasis.

Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis.

The prognostic role of programmed death ligand-1 (PD-L1) expression in hepatocellular carcinoma (HCC) has been widely studied but the results are controversial. In this comprehensive meta-analysis, we elucidated the clinical value of PD-L1 in HCC. Relevant studies were systematically searched in the Cochrane Library, EMBASE, and PubMed until June 27, 2019. Eligible studies were validated for the prognostic effect of PD-L1 on the overall survival (OS), disease-free survival (DFS), and relapse-free survival (RFS) in HCC using a hazard ratio (HR) and its 95% confidence interval (95% CI). Twenty-three studies with 3529 patients were involved in this meta-analysis. The pooled results revealed that high membrane-bound PD-L1 (mPD-L1) expression was associated with poor OS (HR: 1.42; 95% CI: 1.12–1.80; P = 0.004) and had no significant correlation with RFS (HR: 1.14; 95% CI: 0.85–1.54; P = 0.39), and DFS (HR: 1.36; 95% CI: 0.81–2.28; P = 0.25). The results also indicated that high soluble PD-L1 (sPD-L1) levels were associated with worse OS (HR: 2.93; 95% CI: 2.20–3.91; P < 0.00001). In addition, high mPD-L1 expression was associated with high alpha-fetoprotein levels (AFP; OR = 1.46; 95% CI: 1.16–1.84; P = 0.001), hepatitis (OR = 0.72; 95% CI: 0.54–0.98; P = 0.03), poor tumor differentiation (OR = 0.68; 95% CI: 0.55–0.84; P = 0.03), and tumor-infiltrating lymphocytes (OR = 3.39; 95% CI: 1.06–10.91; P = 0.04). The mPD-L1 expression had no significant correlation with age, number of tumors, gender, tumor size, liver cirrhosis, vascular invasion, tumor encapsulation, or TNM stage. The study revealed that high mPD-L1 expression in the tumor tissue and high sPD-L1 levels were associated with shorter OS in HCC. Moreover, overexpression of mPD-L1 was significantly associated with poor tumor differentiation, hepatitis, AFP elevation, and tumor-infiltrating lymphocytes.

Actual long-term survival in HCC patients with portal vein tumor thrombus after liver resection: a nationwide study.

Liver resection for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) offers a chance of cure, although survival is often limited. The actual 3-year survival and its associated prognostic factors have not been reported. A nationwide database of HCC patients with PVTT who underwent liver resection with 'curative' intent was analyzed. The clinicopathologic characteristics, the perioperative, and survival outcomes for the actual long-term survivors were compared with the non-long-term survivors (patients who died within 3years of surgery). Univariable and multivariable regression analyses were performed to identify predictive factors associated with long-term survival outcomes. The study included 1590 patients with an actuarial 3-year survival of 16.6%, while the actual 3-year survival rate was 11.7%. There were 171 patients who survived for at least 3years after surgery and 1290 who died within 3years of surgery. Multivariable regression analysis revealed that total bilirubin > 17.1μmol/l, AFP > 400ng/ml, types of hepatectomy, extent of PVTT, intraoperative blood loss > 400ml, tumor diameter > 5cm, tumor encapsulation, R0 resection, liver cirrhosis, adjuvant TACE, postoperative early recurrence (< 1year), and recurrence treatments were independent prognostic factors associated with actual long-term survival. One in nine HCC patients with PVTT reached the long-term survival milestone of 3years after resection. Major hepatectomy, controlling intraoperative blood loss, R0 resection, adjuvant TACE, and 'curative' treatment for initial recurrence should be considered for patients to achieve better long-term survival outcomes.

High expression levels of CLEC4M indicate poor prognosis in patients with hepatocellular carcinoma.

The identification of novel and accurate biomarkers is important to improve the prognosis of patients with hepatocellular carcinoma (HCC). C-Type lectin domain family 4 member M (CLEC4M) is involved in the progression of numerous cancer types. However, the clinical significance of CLEC4M in HCC is yet to be elucidated. The aim of the present study is to evaluate the involvement of CLEC4M in HCC progression. The expression level of CLEC4M was determined in tumor, and their corresponding adjacent non-tumor tissues derived from 88 patients with HCC, using immunohistochemistry, western blot and reverse transcription-quantitative PCR. The correlation between CLEC4M expression and certain clinicopathological characteristics was retrospectively analyzed. The results suggested that CLEC4M was specifically labeled in sinusoidal endothelial cells, in both HCC and non-tumor tissues. Moreover, the expression of CLEC4M in tumor tissues was significantly lower than that in non-tumor tissues (P<0.0001), which indicated its potential as a biomarker of the development of HCC. Subsequently, correlation analysis suggested that the relatively higher CLEC4M expression in HCC tissues was significantly associated with increased microvascular invasion (P=0.008), larger tumor size (P=0.018), absence of tumor encapsulation (P<0.0001) and lower tumor differentiation (P=0.019). Notably, patients with high CLEC4M expression levels in their tumor tissues experienced more frequent recurrence and shorter overall survival (OS) times compared with the low-expression group. Furthermore, CLEC4M expression in tumor tissues was identified as an independent and significant risk factor for recurrence-free survival and OS. The results of the present study suggest that CLEC4M may be a valuable biomarker for the prognosis of the patients with HCC, postoperatively.

Interleukin 1β-mediated HOXC10 Overexpression Promotes Hepatocellular Carcinoma Metastasis by Upregulating PDPK1 and VASP.

Rationale: Metastasis and recurrence are the primary reasons for the high mortality rate of human hepatocellular carcinoma (HCC) patients. However, the exact mechanism underlying HCC metastasis remains unclear. The Homeobox (HOX) family proteins, which are a highly conserved transcription factor superfamily, play important roles in cancer metastasis. Here, we report a novel role of HOXC10, one of the most upregulated HOX genes in human HCC tissues, in promoting HCC metastasis.Methods: The expression of HOXC10 and its functional targets was detected by immunohistochemistry in two independent human HCC cohorts. Luciferase reporter and chromatin immunoprecipitation assays were used to measure the transcriptional regulation of target genes by HOXC10. The effect of HOXC10-mediated invasion and metastasis were analyzed by Transwell assays and by an orthotopic metastasis model.Results: Elevated expression of HOXC10 was positively correlated with the loss of tumor encapsulation and with higher tumor-nodule-metastasis (TNM) stage and poor prognosis in human HCC. Overexpression of HOXC10 promoted HCC metastasis by upregulating metastasis-related genes, including 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and vasodilator-stimulated phosphoprotein (VASP). Knockdown of PDPK1 and VASP inhibited HOXC10-enhanced HCC metastasis, whereas upregulation of PDPK1 and VASP rescued the decreased metastasis induced by HOXC10 knockdown. Interleukin-1β (IL-1β), which is the ligand of IL-1R1, upregulated HOXC10 expression through the c-Jun NH2-terminal kinase (JNK)/c-Jun pathway. HOXC10 knockdown significantly reduced IL-1β-mediated HCC metastasis. Furthermore, Anakinra, a specific antagonist of IL-1R1, inhibited IL-1β-induced HOXC10 upregulation and HCC metastasis. In human HCC tissues, HOXC10 expression was positively correlated with PDPK1, VASP and IL-1R1 expression, and patients with positive coexpression of HOXC10/PDPK1, HOXC10/VASP or IL-1R1/HOXC10 exhibited the poorest prognosis.Conclusions: Upregulated HOXC10 induced by IL-1β promotes HCC metastasis by transactivating PDPK1 and VASP expression. Thus, our study implicates HOXC10 as a prognostic biomarker, and targeting this pathway may be a promising therapeutic option for the clinical prevention of HCC metastasis.

Glycol Chitosan: A Water-Soluble Polymer for Cell Imaging and Drug Delivery.

Glycol chitosan (GC), a water-soluble chitosan derivative with hydrophilic ethylene glycol branches, has both hydrophobic segments for the encapsulation of various drugs and reactive functional groups for facile chemical modifications. Over the past two decades, a variety of molecules have been physically encapsulated within or chemically conjugated with GC and its derivatives to construct a wide range of functional biomaterials. This review summarizes the recent advances of GC-based materials in cell surface labeling, multimodal tumor imaging, and encapsulation and delivery of drugs (including chemotherapeutics, photosensitizers, nucleic acids, and antimicrobial agents) for combating cancers and microbial infections. Besides, different strategies for GC modifications are also highlighted with the aim to shed light on how to endow GC and its derivatives with desirable properties for therapeutic purposes. In addition, we discuss both the promises and challenges of the GC-derived biomaterials.

Integrated Nomograms for Preoperative Prediction of Microvascular Invasion and Lymph Node Metastasis Risk in Hepatocellular Carcinoma Patients.

The aim of the present work is to develop and validate accurate preoperative nomograms to predict microvascular invasion (MVI) and lymph node metastasis (LNM) in hepatocellular carcinoma. A total of 268 patients with resected hepatocellular carcinoma (HCC) were divided into a training set (n = 180), in an earlier period, and a validation set (n = 88), thereafter. Risk factors for MVI and LNM were assessed based on logistic regression. Blood signatures were established using the least absolute shrinkage and selection operator algorithm. Nomograms were constructed by combining risk factors and blood signatures. Performance was evaluated using the training set and validated using the validation set. The clinical values of the nomograms were measured by decision curve analysis. The risk factors for MVI were hepatitis B virus (HBV) DNA loading, portal hypertension, Barcelona liver clinic (BCLC) stage, and three computerized tomography (CT) imaging features, namely tumor number, size, and encapsulation, while only BCLC stage, Child-Pugh classification, and tumor encapsulation were associated with LNM. The nomogram incorporating both risk factors and blood signatures achieved better performance in predicting MVI in the training and validation sets (C-indexes of 0.828 and 0.804) than the LNM nomogram (C-indexes of 0.765 and 0.717). Calibration curves also demonstrated a good fit. The decision curves indicate significant clinical usefulness. The novel validated nomograms for HCC patients presented herein are noninvasive preoperative tools that can effectively predict the individualized risk of MVI and LNM, and this predictive power can aid doctors in explaining the illness for patient counseling.

ITGBL1 Promotes Cell Migration and Invasion Through Stimulating the TGF-β Signalling Pathway in Hepatocellular Carcinoma

Integrin beta-like 1 (ITGBL1), a beta integrin-related protein, is involved in the development and progression of several cancers; however, its roles in the development and progression of hepatocellular carcinoma (HCC) are largely unknown. In the current study, we found that the expression level of ITGBL1 was significantly increased in HCC tissues, compared to the adjacent normal tissues. Patients with higher ITGBL1 expression were correlated with tumour encapsulation and poorer overall survival. ITGBL1 overexpression in the HepG2 and SMMC-7721 HCC cells promoted their migration and invasion, as assessed by the in vitro and in vivo models, whereas the knockdown or knockout of ITGBL1 in CSQT-2 cells significantly reduced their migration and invasion abilities. In HCC cells, ITGBL1 overexpression stimulates the epithelial-mesenchymal transition (EMT), along with the increased expression level of KRT17, Snail, Slug, and Vimentin, and the downregulation of Claudin-1 expression. ITGBL1 overexpression stimulates the TGF-β/Smad signalling pathway, while the inhibition of the TGF-β/Smad signalling pathway downregulates the ITGBL1-mediated EMT. These findings indicated that ITGBL1 stimulates metastasis in HCC by enhancing the TGF-β/Smad signalling pathway, which may serve a potential therapeutic target in HCC. Funding Statement:This work was supported by the Major National Projects for Infectious Diseases (2018ZX10302204-001-003), the National Natural Science Foundation of China (grant numbers: 81572047), the National Key R&D Program of China (grant nos. 2017YFC0907001 and 2018ZX10302205) and the Shanghai Municipal Commission of Health and Family Planning (20164Y0250) and the Shanghai Jiao Tong University Interdiscipline with Medicine Program (YG2016QN58). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Written informed consent was obtained from each patient, and the study protocol has been approved by the ethics committees and the institutional review board of the Second Military Medical University. All the animal experiments were approved by the animal experimentation ethics committee of the Ruijin Hospital, affiliated to the Shanghai Jiaotong University School of Medicine.

Tongue Schwannoma: A Clinicopathologic Study of 19 Cases.

Schwannomas commonly occur in the head and neck but infrequently involve the oral cavity and rarely affect the tongue. The clinical and pathologic features of 19 cases of schwannoma arising in the tongue were analyzed. There were 13 males and 6 females ranging in age from 12 to 82years (mean 34years; median 29years). The majority of tumors presented as an asymptomatic mass localized to the anterior two-thirds of the tongue. Histologically, 18 schwannomas exhibited characteristic Antoni A and B areas with the former pattern predominating. One tumor was composed exclusively of cellular Antoni A tissue and was classified as a cellular schwannoma. Tumor encapsulation was variable with nearly half of the lesions lacking a well-defined fibrous capsule. All were strongly and diffusely positive for S-100 protein. No recurrences were observed on clinical follow-up. Schwannoma of the tongue, although rare, should be separated from other types of lingual nerve sheath proliferations and tumors.

A solid lipid nanoparticle formulation of 4-(N)-docosahexaenoyl 2', 2'-difluorodeoxycytidine with increased solubility, stability, and antitumor activity.

Previously, we synthesized 4-(N)-docosahexaenoyl 2', 2'-difluorodeoxycytidine (DHA-dFdC), a novel lipophilic compound with a potent, broad-spectrum antitumor activity. Herein, we report a solid lipid nanoparticle (SLN) formulation of DHA-dFdC with improved apparent aqueous solubility, chemical stability, as well as efficacy in a mouse model. The SLNs were prepared from lecithin/glycerol monostearate-in-water emulsions emulsified with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and Tween 20. The resultant DHA-dFdC-SLNs were 102.2 ± 7.3 nm in diameter and increased the apparent solubility of DHA-dFdC in water to at least 5.2 mg/mL, more than 200-fold higher than its intrinsic water solubility. DHA-dFdC in a lyophilized powder of DHA-dFdC-SLNs was significantly more stable than the waxy solid of pure DHA-dFdC. DHA-dFdC-SLNs also showed an increased cytotoxicity against certain tumor cells than DHA-dFdC. The plasma concentration of DHA-dFdC in mice intravenously injected with DHA-dFdC-SLNs in dispersion followed a bi-exponential model, with a half-life of ~44 h. In mice bearing B16-F10 murine melanoma, DHA-dFdC-SLNs were significantly more effective than DHA-dFdC in controlling the tumor growth. In addition, histology evaluation revealed a high level of apoptosis and tumor encapsulation in tumors in mice treated with DHA-dFdC-SLNs. DHA-dFdC-SLNs represents a new DHA-dFdC formulation with improved antitumor activity.

An Eastern Hepatobiliary Surgery Hospital Microvascular Invasion Scoring System in Predicting Prognosis of Patients with Hepatocellular Carcinoma and Microvascular Invasion After R0 Liver Resection: A Large-Scale, Multicenter Study.

Microvascular invasion (MVI) is associated with poor postoperative survival outcomes in patients with hepatocellular carcinoma (HCC). An Eastern Hepatobiliary Surgery Hospital (EHBH) MVI scoring system was established to predict prognosis in patients with HCC with MVI after R0 liver resection (LR) and to supplement the most commonly used classification systems. Patients with HCC with MVI who underwent R0 LR as an initial therapy were included. The EHBH-MVI score was developed from a retrospective cohort from 2003 to 2009 to form the training cohort. The variables associated with overall survival (OS) on univariate analysis were subsequently investigated using the log-rank test, and the EHBH-MVI score was developed using the Cox regression model. It was validated using an internal prospective cohort from 2011 to 2013 as well as three independent external validation cohorts. There were 1,033 patients in the training cohort; 322 patients in the prospective internal validation cohort; and 493, 282, and 149 patients in the three external validation cohorts, respectively. The score was developed using the following factors: α-fetoprotein level, tumor encapsulation, tumor diameter, hepatitis B e antigen positivity, hepatitis B virus DNA load, tumor number, and gastric fundal/esophageal varicosity. The score differentiated two groups of patients (≤4, >4 points) with distinct long-term prognoses outcomes (median OS, 55.8 vs. 19.6 months; p < .001). The predictive accuracy of the score was greater than the other four commonly used staging systems for HCC. The EHBH-MVI scoring system was more accurate in predicting prognosis in patients with HCC with MVI after R0 LR than the other four commonly used staging systems. The score can be used to supplement these systems. Microvascular invasion (MVI) is a major determinant of survival outcomes after curative liver resection for patients with hepatocellular carcinoma (HCC). Currently, there is no scoring system aiming to predict prognosis of patients with HCC and MVI after R0 liver resection (LR). Most of the widely used staging systems for HCC do not use MVI as an independent risk factor, and they cannot be used to predict the prognosis of patients with HCC and MVI after surgery. In this study, a new Eastern Hepatobiliary Surgery Hospital (EHBH) MVI scoring system was established to predict prognosis of patients with HCC and MVI after R0 LR. Based on the results of this study, postoperative adjuvant therapy may be recommended for patients with HCC and MVI with an EHBH-MVI score >4. This score can be used to supplement the currently used HCC classifications to predict postoperative survival outcomes in patients with HCC and MVI.