IL-6-induced cGGNBP2 encodes a protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma.

BACKGROUND AND AIMS: IL-6-induced tumor progression has been well established through the induction of antiapoptotic and proliferative genes. However, whether other mechanisms such as IL-6 regulation of circular RNAs (circRNAs) may also contribute to tumor development remains unknown. APPROACH AND RESULTS: High-throughput RNA sequencing was used to identify the differentially expressed circRNAs on IL-6 stimulation in intrahepatic cholangiocarcinoma (ICC) cells. CircRNA GGNBP2 (derived from ggnbp2 gene, termed as cGGNBP2) was up-regulated by IL-6 treatment in a time and concentration-dependent manner. The biogenesis of cGGNBP2 was regulated by RNA-binding protein DEx-H Box Helicase 9, which was also mediated by IL-6 exposure. Mass spectrometry and western blotting identified a protein cGGNBP2-184aa encoded by cGGNBP2. cGGNBP2-184aa promoted ICC cell proliferation and metastasis in vitro and in vivo. Mechanistically, cGGNBP2-184aa directly interacted with signal transducers and activators of transduction-3 (STAT3), phosphorylated STAT3Tyr705 , and played a positive regulatory role in modulating IL-6/STAT3 signaling. IL-6/cGGNBP2-184aa/STAT3 formed a positive feedback loop to sustain constitutive activation of IL-6/STAT3 signaling. Elevated cGGNBP2 expression was correlated with poor prognosis of patients with ICC and was identified as an independent risk factor for patient prognosis. CONCLUSIONS: Our study demonstrates that cGGNBP2-184aa, a protein encoded by IL-6-induced cGGNBP2, formed a positive feedback loop to facilitate ICC progression and may serve as an auxiliary target for clinical IL-6/STAT3-targeting treatments in ICC.

NIR to MIR ultra-broadband supercontinuum laser source based on all-silica fibers.

We demonstrated an ultra-broadband supercontinuum (SC) laser source with a wavelength range spanning the near-infrared (NIR) to mid-infrared (MIR) region. The SC spectrum was generated in a very short piece of highly nonlinear silica fiber (HNLF) which has a zero-dispersion wavelength (ZDW) of 1.55 µm. The pump source used has a spectral coverage of 1.5∼2.4 µm which covers the ZDW of HNLF, resulting in a dramatic blue and red shift of the spectrum through strong non-linear effects. As the pump laser pulse launched into HNLF, a SC spectrum with broadband range of 0.92∼2.92 µm and maximum average power of 5.09 W was achieved, which sets record coverage of HNLF-based watts magnitude SC laser sources for now, to the best of the authors' knowledge. The setup consists of silica fiber that can be considered easy-to-implement and with a cost-effectiveness scheme for ultra-broadband SC generation that could be easily applied to optical fiber sensing and spectral imaging technology.

Long noncoding RNA TLNC1 promotes the growth and metastasis of liver cancer via inhibition of p53 signaling.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in cancer development and progression. However, their biological roles and function mechanisms in liver cancer remain largely unknown. METHODS: RNA-seq was performed with clinical hepatoma tissues and paired adjacent normal liver tissues to identify differentially expressed lncRNAs. qPCR was utilized to examine the expression levels of lncRNAs. We studied the function of TLNC1 in cell growth and metastasis of hepatoma with both cell and mouse models. RNA-seq, RNA pull-down coupled with mass spectrometry, RNA immunoprecipitation, dual luciferase reporter assay, and surface plasmon resonance analysis were used to analyze the functional mechanism of TLNC1. RESULTS: Based on the intersection of our own RNA-seq, TCGA RNA-seq, and TCGA survival analysis data, TLNC1 was identified as a potential tumorigenic lncRNA of liver cancer. TLNC1 significantly enhanced the growth and metastasis of hepatoma cells both in vitro and in vivo. TLNC1 exerted its tumorigenic function through interaction with TPR and inducing the TPR-mediated transportation of p53 from nucleus to cytoplasm, thus repressing the transcription of p53 target genes and finally contributing to the progression of liver cancer. CONCLUSIONS: TLNC1 is a promising prognostic factor of liver cancer, and the TLNC1-TPR-p53 axis can serve as a potential therapeutic target for hepatoma treatment.

CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma.

BACKGROUND: Considerable evidence shows that circular RNAs (circRNAs) play an important role in tumor development. However, their function in intrahepatic cholangiocarcinoma (ICC) metastasis and the underlying mechanisms are incompletely understood. METHODS: circNFIB (hsa_circ_0086376, termed as cNFIB hereafter) was identified in human ICC tissues through circRNAs sequencing. The biological role of cNFIB was determined in vitro and in vivo by gain or loss of functional experiments. Fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were conducted to analyze the interaction of cNFIB with dual specificity mitogen-activated protein kinase kinase1 (MEK1). Duolink in situ proximity ligation assay (PLA) and coimmunoprecipitation (co-IP) assay were used to investigate the effects of cNFIB on the interaction between MEK1 and mitogen-activated protein kinase 2 (ERK2). Finally, a series of in vitro and in vivo experiments were performed to explore the influences of cNFIB on the anti-tumor activity of trametinib (a MEK inhibitor). RESULTS: cNFIB was significantly down-regulated in human ICC tissues with postoperative metastases. The loss of cNFIB was highly associated with aggressive characteristics and predicted unfavorable prognosis in ICC patients. Functional studies revealed that cNFIB inhibited the proliferation and metastasis of ICC cells in vitro and in vivo. Mechanistically, cNFIB competitively interacted with MEK1, which induced the dissociation between MEK1 and ERK2, thereby resulting in the suppression of ERK signaling and tumor metastasis. Moreover, we found that ICC cells with high levels of cNFIB held the potential to delay the trametinib resistance. Consistently, in vivo and in vitro studies demonstrated that cotreatment with trametinib and lentivirus vector encoding cNFIB showed greater inhibitory effect than isolated trametinib treatment. CONCLUSIONS: Our findings identified that cNFIB played a key role in ICC growth and metastasis by regulating MEK1/ERK signaling. Given the efficacy of cNFIB modulation on ICC suppression and trametinib sensitivity, cNFIB appears to be a potential therapeutic molecule for ICC treatment.

Predicting microvascular invasion in hepatocellular carcinoma: A dual-institution study on gadoxetate disodium-enhanced MRI.

BACKGROUND & AIMS: Microvascular invasion (MVI) is an important risk factor in hepatocellular carcinoma (HCC), but its diagnosis mandates postoperative histopathologic analysis. We aimed to develop and externally validate a predictive scoring system for MVI. METHODS: From July 2015 to November 2020, consecutive patients underwent surgery for HCC with preoperative gadoxetate disodium (EOB)-enhanced MRI was retrospectively enrolled. All MR images were reviewed independently by two radiologists who were blinded to the outcomes. In the training centre, a radio-clinical MVI score was developed via logistic regression analysis against pathology. In the testing centre, areas under the receiver operating curve (AUCs) of the MVI score and other previous MVI schemes were compared. Overall survival (OS) and recurrence-free survival (RFS) were analysed by the Kaplan-Meier method with the log-rank test. RESULTS: A total of 417 patients were included, 195 (47%) with pathologically-confirmed MVI. The MVI score included: non-smooth tumour margin (odds ratio [OR] = 4.4), marked diffusion restriction (OR = 3.0), internal artery (OR = 3.0), hepatobiliary phase peritumoral hypointensity (OR = 2.5), tumour multifocality (OR = 1.6), and serum alpha-fetoprotein >400 ng/mL (OR = 2.5). AUCs for the MVI score were 0.879 (training) and 0.800 (testing), significantly higher than those for other MVI schemes (testing AUCs: 0.648-0.684). Patients with model-predicted MVI had significantly shorter OS (median 61.0 months vs not reached, P < .001) and RFS (median 13.0 months vs. 42.0 months, P < .001) than those without. CONCLUSIONS: A preoperative MVI score integrating five EOB-MRI features and serum alpha-fetoprotein level could accurately predict MVI and postoperative survival in HCC. Therefore, this score may aid in individualized treatment decision making.

Genetic variants in epithelial-mesenchymal transition genes as predictors of clinical outcomes in localized prostate cancer.

BACKGROUND: Epithelial-mesenchymal transition (EMT) plays a pivotal role in the progression of prostate cancer (PCa). However, little is known about genetic variants in the EMT pathway as predictors of aggressiveness, biochemical recurrence (BCR) and disease reclassification in localized PCa. PATIENTS AND METHODS: In this multistage study, we evaluated 5186 single nucleotide polymorphisms (SNPs) from 264 genes related to EMT pathway to identify SNPs associated with PCa aggressiveness and BCR in the MD Anderson PCa (MDA-PCa) patient cohort (N = 1762), followed by assessment of the identified SNPs with disease reclassification in the active surveillance (AS) cohort (N = 392). RESULTS: In the MDA-PCa cohort, 312 SNPs were associated with high D'Amico risk (P < 0.05), among which, 14 SNPs in 10 genes were linked to BCR risk. In the AS cohort, 2 of 14 identified SNPs (rs76779889 and rs7083961) in C-terminal Binding Proteins 2 gene were associated with reclassification risk. The associations of rs76779889 with different endpoints were: D'Amico high versus low, odds ratio [95% confidence interval (CI)] = 2.89 (1.32-6.34), P = 0.008; BCR, hazard ratio (HR) (95% CI) = 2.88 (1.42-5.85), P = 0.003; and reclassification, HR (95% CI) = 2.83 (1.40-5.74), P = 0.004. For rs7083961, the corresponding risk estimates were: D'Amico high versus low, odds ratio (95% CI) = 1.69 (1.12-2.57), P = 0.013; BCR, HR (95% CI) = 1.87 (1.15-3.02), P = 0.011 and reclassification, HR (95% CI) = 1.72 (1.09-2.72), P = 0.020. There were cumulative effects of these two SNPs on modulating these endpoints. CONCLUSION: Genetic variants in EMT pathway may influence the risks of localized PCa's aggressiveness, BCR and disease reclassification, suggesting their potential role in the assessment and management of localized PCa.

Laparoscopic Caudate Lobectomy for Cholangiocarcinoma of Caudate Lobe Invading Middle Hepatic Vein.

BACKGROUND: Laparoscopic hepatectomy has gained popularity in the management of malignant liver lesions in the past decade. Its safety and feasibility, with faster recovery and comparable long-term outcomes, have been widely published. Nonetheless, laparoscopic isolated caudate lobectomy is still rare and technically demanding. We herein present a video on laparoscopic total caudate lobectomy for caudate cholangiocarcinoma. METHODS: The patient is a 61-year-old man who presented with epigastric distending discomfort. A contrast-enhanced magnetic resonance imaging was performed, showing a 4.6 × 3.9 cm tumor in the caudate lobe adjacent to the inferior vena cava, middle hepatic vein, right hepatic vein, as well as the bifurcation of the main trunk of the portal pedicle. The carbohydrate antigen was elevated to 54.58 U/ml (normal < 37 U/ml), and his liver function was normal. With the preoperative diagnosis of intrahepatic cholangiocarcinoma, laparoscopic caudate lobectomy was contemplated. RESULTS: The operative time was 300 min. The estimated intraoperative blood loss was 180 ml. The patient was discharged on the seventh postoperative day without any complications. Histopathological examination showed a 4.2 cm cholangiocarcinoma (T2N0M0) with a negative margin. He received a course of adjuvant chemotherapy. No recurrence was noted upon follow-up at 6 months after the operation. CONCLUSIONS: Laparoscopic resection for caudate lobe is a feasible and safe procedure. An experienced hepatobiliary surgeon could perform the procedure in selected cases, even with hepatic vein invasion.

A 5-microRNA signature identified from serum microRNA profiling predicts survival in patients with advanced stage non-small cell lung cancer.

Circulating microRNAs (miRNAs) are potential biomarkers for cancer diagnosis, screening and prognosis. This study aimed to identify serum miRNAs as predictors of survival in patients with advanced non-small cell lung cancer (NSCLC). We profiled serum miRNAs in a pilot set of four patients with good survival (>24 months) and four patients with poor survival (<6 months). We selected 140 stably detectable miRNAs and 42 miRNAs reported in literature for further analysis. Expression of these 182 miRNAs was measured using high-throughput polymerase chain reaction assay, and their association with 3-year survival in the discovery (n = 345) and validation (n = 177) cohorts was assessed. Five serum miRNAs (miR-191, miR-28-3p, miR-145, miR-328 and miR-18a) were significantly associated with 3-year overall survival in both cohorts. A combined 5-miRNA risk score was created to assess the cumulative impact of these miRNAs on risk of death. Quartile analysis of the risk score showed significant association with 3-year death risk, with a 4.6-, 6.8- and 9.3-month reduction in median survival time for the second, third and fourth quartiles, respectively. Survival tree analysis also identified distinct risk groups with different 3-year survival durations. Data from The Cancer Genome Atlas revealed all five miRNAs were differentially expressed (P < 0.0001) in paired tumor and normal tissues. Pathway analysis indicated that target genes of these five miRNAs were mainly enriched in inflammatory/immune response pathways and pathways implicated in resistance to chemoradiotherapy and/or targeted therapy. Our results suggested that the 5-miRNA signature could serve as a prognostic predictor in patients with advanced NSCLC.

KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3.

BACKGROUND: N6-methyladenosine (m6A) modification, the most abundant internal methylation of eukaryotic RNA transcripts, is critically implicated in RNA processing. As the largest known component in the m6A methyltransferase complex, KIAA1429 plays a vital role in m6A methylation. However, its function and mechanism in hepatocellular carcinoma (HCC) remain poorly defined. METHODS: Quantitative PCR, western blot and immunohistochemistry were used to measure the expression of KIAA1429 in HCC. The effects of KIAA1429 on the malignant phenotypes of hepatoma cells were examined in vitro and in vivo. MeRIP-seq, RIP-seq and RNA-seq were performed to identify the target genes of KIAA1429. RESULTS: KIAA1429 was considerably upregulated in HCC tissues. High expression of KIAA1429 was associated with poor prognosis among HCC patients. Silencing KIAA1429 suppressed cell proliferation and metastasis in vitro and in vivo. GATA3 was identified as the direct downstream target of KIAA1429-mediated m6A modification. KIAA1429 induced m6A methylation on the 3' UTR of GATA3 pre-mRNA, leading to the separation of the RNA-binding protein HuR and the degradation of GATA3 pre-mRNA. Strikingly, a long noncoding RNA (lncRNA) GATA3-AS, transcribed from the antisense strand of the GATA3 gene, functioned as a cis-acting element for the preferential interaction of KIAA1429 with GATA3 pre-mRNA. Accordingly, we found that the tumor growth and metastasis driven by KIAA1429 or GATA3-AS were mediated by GATA3. CONCLUSION: Our study proposed a complex KIAA1429-GATA3 regulatory model based on m6A modification and provided insights into the epi-transcriptomic dysregulation in hepatocarcinogenesis and metastasis.

Loss of Life Expectancy by 10 Years or More From Elevated Aspartate Aminotransferase: Finding Aspartate Aminotransferase a Better Mortality Predictor for All-Cause and Liver-Related than Alanine Aminotransferase.

OBJECTIVES: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are 2 commonly ordered liver function tests, and ALT has long been considered more liver-specific than AST. Between the 2, the one which is better in predicting liver or non-liver-related mortality remains unsettled. METHODS: The cohort, 416,122 adults, came from a self-paying comprehensive health surveillance program during 1994-2008 and was followed up till 2008. Mortality came from National Death Index, with 10,412 deaths identified. Hazard ratios (HRs), computed by Cox model, and life expectancy, by life table method, were presented for 5 levels of AST and ALT with elevated AST or ALT defined as ≥40 IU/L. Liver disease included liver cancer and other liver conditions. RESULTS: There were 3 times more elevated ALT (15.4%) than AST (5.7%). However, those with elevated AST had higher mortality for all-cause (HR = 2.44), for liver disease (HR = 27.2), and for liver cancer (HR = 47.6) than its ALT counterparts (HR = 1.69, 10.8, and 20.2, respectively). Elevated AST also lost more years of life expectancy (10.2) than those lost by ALT (5.2) and larger than most common risks. Elevated AST had increased mortality from all cancers (HR = 3.57), stroke (HR = 1.36), respiratory diseases (HR = 1.34), and injuries (HR = 1.82), other than just liver disease. All-cause mortality remained significantly increased, when high risk groups were excluded, such as frequent drinkers, hepatitis carriers, those died from nonmedical conditions, those died in the first 3 years, or advanced fibrosis index based on 4 factors or aspartate transaminase-to-platelet ratio index. Results were consistent between those returned for second visits and those analyzed in initial visits. DISCUSSION: Those with elevated AST (≥40 IU/L) had life expectancy cut short by 10.2 years, doubled the number of years lost with elevated ALT. For all-cause and for liver-related mortality, AST was an important predictor, better than ALT.

Polymorphisms in genes related to epithelial-mesenchymal transition and risk of non-small cell lung cancer.

The epithelial-mesenchymal transition (EMT) process is a crucial step for tumor invasion and metastasis. Previous research investigating EMT has mostly focused on its role in cancer progression. Recent studies showed that EMT and EMT-driving transcription factor (EMT-TF) expression are early events in lung cancer pathogenesis, implying a potential association between EMT and lung cancer risk. In this study, we examined whether genetic variants in EMT-related genes are associated with risk of non-small cell lung cancer (NSCLC). We used data from a genome-wide association study of 1482 NSCLC cases and 1544 healthy controls as the discovery phase, in which we analyzed 1602 single-nucleotide polymorphisms (SNPs) within 159 EMT-related genes. We then validated the significant SNPs in another 5699 cases and 5815 controls from the National Cancer Institute lung cancer genome-wide association study. Cumulative effects were evaluated for validated SNPs, and a gene-based test was performed to explore gene-level association with disease risk. In the discovery phase, 174 SNPs demonstrated significant associations with NSCLC risk. In the validation phase, seven SNPs mapped to EGFR, NOTCH3, ADGRF1 and SMAD3 were confirmed. Cumulative effect analysis of the significant SNPs demonstrated increasing risk with the number of unfavorable genotypes in the discovery and validation datasets. Gene-based analysis implicated ADGRF1, NOTCH3 and CDH1 as significant for NSCLC risk. Functional prediction revealed several potential mechanisms underlying these associations. Our results suggest that EMT-related gene variants may be involved in susceptibility to NSCLC; if confirmed, they might help identify higher-risk individuals.

Hepatic trisectionectomy for hepatocellular carcinoma using the Glisson pedicle method combined with anterior approach.

BACKGROUND: Hepatic trisectionectomy is a challenge for surgeons. We describe a technique by combination of the Glisson pedicle method and anterior approach to perform hepatic trisectionectomy. METHODS: In this technique, the Glisson pedicles are isolated above the hilar plate without hilar dissection. After dividing these pedicles, the hepatic hilum can be lowered more easily. With the hepatic hilum brought down, the following step of hepatic parenchyma transection using the anterior approach can be performed safely, avoiding accidental injury to the vessels and hepatic duct in the hilar plate. CONCLUSIONS: This technique provides a safe, easy way to perform hepatic trisectionectomy without warm ischemia injury to the remnant liver.

Pancreatic injuries in earthquake victims: what have we learnt?

OBJECTIVE: To analyze the clinical characteristic and management of patients with pancreatic injuries from the Wen-Chuan and Lu-Shan earthquakes. METHODS: We retrospectively reviewed 39,784 patients from the Wen-Chuan earthquake and 1489 from the Lu-Shan earthquake. The demographics, clinical data, treatment strategies, and outcomes of patients with pancreatic injuries were recorded and compared between survivors of the two earthquakes. RESULTS: Pancreatic injury occurred only in a small proportion (0.2%) in patients with trauma on admission, and most (61%) patients had Grades I-II pancreatic injuries. Blunt trauma was the leading cause of pancreatic trauma. Most patients (95%) suffered multiple injuries, of which chest injuries (61%) were the most common. Elevated serum amylase levels were observed in 50 (86%) of 58 patients, and computed tomography (CT) identified pancreatic injuries in 32 (80%) of 40 patients. A significantly higher rate (p = 0.043) of pancreatic complication was present in patients with Grade III and IV injuries (38%) than in those with Grade I and II injuries (18%). Forty patients were initially treated by conservative management with 6 (15%) requiring delayed operations. Four (67%) pancreatic complications and 2 (33%) deaths occurred in patients with delayed operations. CONCLUSIONS: Repeated serum amylase analysis, CT, and laparoscopic exploration were reliable diagnostic modalities to diagnose pancreatic injury. Conservative management was safe in patients with Grade I and II injuries. Delayed operation, especially for Grade III patients, resulted in increased morbidity and mortality.

Parenchymal Sparing Laparoscopic Segmentectomy III and IV with Indocyanine Green Fluorescence Negative Stain Method Using Glisson Pedicle Approach.

BACKGROUND: To minimize the loss of functional liver volume in cases of severe cirrhosis and repeat hepatectomy for recurrence of hepatocellular carcinoma (HCC), anatomical hepatectomy is gradually extended from major to minor hepatectomy (Miyama et al. in Cancers (Basel):13, 2021; Ishizawa et al. in Ann Surg 256:959-964, 2012). For local located HCC, (sub)segmentectomy can yet be regarded as a choice instead of hemihepatectomy. Indocyanine green (ICG) has been used for tumor location, navigation of resected margin and liver segment, and identification of bile leakage. Negative stain that ICG dye was administered intravenously after occluding the target portal pedicle is more applicable to sectionectomy or hemihepatectomy, especially in cases where multiple target pedicles exist or portal vein puncture is difficult to carry out to achieve anatomic resection. Herein, we present a video of laparoscopic segmentectomy III and IV with ICG fluorescence negative stain using Glisson Pedicle approach. METHOD: A 49-year-old woman with hepatitis B related cirrhosis for 2 years was referred for treatment of a single nodule in segment IV invading the umbilical portion of left portal vein. The preoperative alpha-fetoprotein (AFP) was 442 ng/ml and protein induced by vitamin K absence or antagonist-II (PIVKA-II) was 122 mAu/ml. Liver function was Child-Pugh A and indocyanine green retention test at 15 min (ICG-R15) was 9.2%. The surgical procedure involved the following steps: (1) Extrahepatic Glisson pedicle dissection based on Laennec's s capsule (Sugioka et al. in J Hepatobiliary Pancreat Sci 24:17-23, 2017) was performed for isolation of the pedicles towards segments III and IV in the umbilical fossa. (2) Demarcation line was revealed and ICG (1 ml, 5 mg/l) was administered intravenously for the negative stain after dividing the target pedicles. (3) Parenchyma transection was performed along the border of the negative staining area in the cranial and caudal direction. RESULTS: Operative time was 220 min and blood loss was 150 ml with no transfusion. HCC sized 2.5 cm*1.7 cm*1.2 cm was confirmed in histopathology with a free margin and no microvascular invasion. The fibrosis of the liver parenchyma was S4 based on Ishak system. The patient was discharged on the postoperative day 6 without any complications. No recurrence in residual liver was noted on the CT scan at 9 months during follow-up. CONCLUSION: Laparoscopic segmentectomy III and IV is an effective procedure for HCC especially in cases with demands of hepatic parenchymal preservation. ICG navigation and Glisson Pedicle approach may be particularly helpful.

Effect of PIVKA-II and AFP secretion status on early recurrence of hepatocellular carcinoma after open and laparoscopic surgery.

BACKGROUND: Prothrombin induced by vitamin K absence-II (PIVKA-II) and Alpha-fetoprotein (AFP) have been widely used as diagnostic markers in hepatocellular carcinoma (HCC), but the prognostic values of the two serum markers and their clinical usefulness in patient selection for different surgical approaches remain largely unclear. METHODS: HCC patients received surgical treatment between 2015 and 2019 were included. Patients were divided into four statuses according to the serum PIVKA-II and AFP secretion status: PIVKA-II (-) AFP (-) (status 1); PIVKA-II (+) AFP (-) (status 2); PIVKA-II (-) AFP (+) (status 3); PIVKA-II (+) AFP (+) (status 4). Kaplan-Meier analyses were conducted to compare the survivals of the four groups and the HCC patients received different surgical interventions; time-dependent AUC curves were introduced to evaluate the prognostic value of the PIV-AFP status; Cox regression model was used to identify prognostic indexes for overall survival (OS) and recurrence-free survival (RFS). RESULTS: A total of 518 patients were included. Patients with PIVKA-II (+) and APF (+) presented significantly decreased OS and RFS comparing to the other statuses. The areas under ROC curves of PIV-AFP status in predicting OS and RFS were superior to the PIVKA-II or the AFP alone. The HCC patients in early stages with PIVKA-II (+) and APF (+) had worse RFS when received laparoscopic hepatectomy than those who received open hepatectomy, whereas there was no difference in other secretion statuses. The PIVKA-II (+) and AFP (+) secretion status was an independent risk factor for OS, RFS. CONCLUSIONS: The PIV-AFP secretion status is of favorable clinical utility in predicting the OS and RFS of the HCC patients; extra caution is needed when applicated the laparoscopic approach in the HCC patients with PIVKA-II (+) and AFP (+).

Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma.

BACKGROUND: Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its mechanism in detail. METHODS: 117 HCC and 29 non-HCC patients with focal liver lesions were collected and analyzed to assess the association between NRCAM and HCC metastasis. Single-cell RNA sequencing (scRNA-seq) was used to explore the biological characteristics of cells with high NRCAM expression in metastatic HCC. The role and mechanism of NRCAM in LCSC dissemination and metastasis was explored in vitro and in vivo using MYC-driven LCSC organoids from murine liver cells. RESULTS: Serum NRCAM is associated with HCC metastasis and poor prognosis. A scRNA-seq analysis identified that NRCAM was highly expressed in LCSCs with MYC activation in metastatic HCC. Moreover, NRCAM facilitated LCSC migration and invasion, which was confirmed in MYC-driven LCSC organoids. The in vivo tumor allografts demonstrated that NRCAM mediated intra-hepatic/lung HCC metastasis by enhancing the ability of LCSCs to escape from tumors into the bloodstream. Nrcam expression inhibition in LCSCs blocked HCC metastasis. Mechanistically, NRCAM activated epithelial-mesenchymal transition (EMT) and metastasis-related matrix metalloproteinases (MMPs) through the MACF1 mediated ß-catenin signaling pathway in LCSCs. CONCLUSIONS: LCSCs typified by high NRCAM expression have a strong ability to invade and migrate, which is an important factor leading to HCC metastasis.

Systemic therapies in hepatocellular carcinoma: Existing and emerging biomarkers for treatment response.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer-related death worldwide. Due to asymptomatic patients in the early stage, most patients are diagnosed at an advanced stage and lose the opportunity for radical resection. In addition, for patients who underwent procedures with curative intent for early-stage HCC, up to 70% of patients may have disease recurrence within 5 years. With the advent of an increasing number of systemic therapy medications, we now have more options for the treatment of HCC. However, data from clinical studies show that with different combinations of regimens, the objective response rate is approximately 40%, and most patients will not respond to treatment. In this setting, biomarkers for predicting treatment response are of great significance for precise treatment, reducing drug side effects and saving medical resources. In this review, we summarized the existing and emerging biomarkers in the literature, with special emphasis on the pathways and mechanism underlying the prediction value of those biomarkers for systemic treatment response.

Immune-Related Biomarkers Improve Performance of Risk Prediction Models for Survival in Patients With Hepatocellular Carcinoma.

Object: The prediction of hepatocellular carcinoma (HCC) prognosis faced great challenge due to tumor heterogeneity. The purpose of this study was to explore the correlation between the immune infiltrate and prognosis. Moreover, we aimed to establish a risk prediction model for survival in HCC patients based on clinicopathological and immune indicators. Methods: In this study, 316 patients with HCC who underwent radical resection in West China Hospital from 2009 to 2014 were included. Clinicopathological data and pathological specimens were collected. H&E staining and immunohistochemical staining were performed on the pathological tissue sections. The evaluation of tumor-infiltrating lymphocyte (TIL) density was based on H&E slices, and the assessment of the expressions of CD8, CD68, Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin domain and mucin domain-3 (TIM-3), Programmed Cell Death Protein 1 (PD-1), Programmed Cell Death Ligand 1 (PD-L1), OX40, CD66b, and Tryptase. was performed on the immunohistochemical slices. A risk prediction model for survival in HCC patients was established by integrating immune-related biomarkers and clinicopathological indicators. Results: The Barcelona Clinic Liver Cancer (BCLC) stage; the microvascular invasion status; the density of TILs; the expressing levels of CD66b, OX40, and PD-L1 in the immune cell; CD68; and CD8 were the predictors of patients' overall survival (OS). The BCLC stage; the density of TILs; and the expressions of OX40, CD68, and CD8 were associated with disease-free survival (DFS). The expressions of CD66b, CD68, OX40, and CD8 had a cumulative effect on prognosis. The area under the curve of the prediction model for OS based on clinicopathological features was improved from 0.62 to 0.74 by adding to CD8, OX40, CD68, CD66b, and TILs, whereas it was improved from 0.59 to 0.73 for the DFS prediction model. Conclusion: Our results, if confirmed, indicated that immune-related biomarkers should be taken into account or stratified in survival analysis for HCC.