BACKGROUND: Convincing evidence has indicated that an alteration in telomere length is involved in tumorigenesis. In epidemiologic studies, a strong correlation also has been observed consistently between relative telomere length (RTL) in peripheral blood leukocytes (PBLs) and susceptibility of many cancers. However, whether leukocyte RTL can be used as a predictor of risk for hepatocellular carcinoma (HCC) remains to be determined. METHODS: The RTL in PBLs was determined by measuring the telomere repeat copy number to single-copy gene number ratio in each sample compared with a reference DNA sample using a polymerase chain reaction-based method in this case-control study. The study participants included 240 patients with HCC (cases), a group of 240 healthy individuals (controls), and 120 noncancer controls with chronic liver disease (CLD). RESULTS: HCC cases exhibited a significantly longer RTL (median, 0.57; range, 0.21-3.3) than CLD controls (median, 0.46; range, 0.15-1.99; P < .001) and healthy controls (median, 0.39; range, 0.13-2.69; P < .001). Compared with individuals who had short RTL, individuals who had long RTL had a significantly increased risk of HCC when either healthy controls (adjusted odds ratio [OR], 7.28; 95% confidence interval, 4.46-11.88) or CLD controls (adjusted OR, 2.86; 95% confidence interval, 1.74-4.70) were used as the reference group. A significant dose-response relation was observed between HCC risk and long RTL (P trend < .001 for both control groups). In addition, there was a significantly positive RTL correlation between PBLs and normal liver tissues (r ¼ 0.78; P < .001) or cirrhotic liver tissues (r ¼ 0.67; P ¼ .001). Furthermore, a significant joint effect on the risk of HCC was noted between RTL and smoking status or alcohol use. CONCLUSIONS: The current study produced the first epidemiologic evidence linking long RTL in PBLs to an increased risk of HCC. The authors concluded that these findings warrant further investigation in other populations. Cancer 2011;117:4247-

BackgroundAsialoglycoprotein receptor (ASGPR)-ligand-based separation combined with identification with Hep Par 1 or pan-cytokeratin (P-CK) antibody have been demonstrated to detect circulating tumor cells (CTCs) in hepatocellular carcinoma (HCC). The aim of this study was to develop an improved enrichment and identification system that allows the detection of all types of HCC CTCs.MethodsThe specificity of the prepared anti-ASGPR monoclonal antibody was characterized. HCC cells were bound by ASGPR antibody and subsequently magnetically isolated by second antibody-coated magnetic beads. Isolated HCC cells were identified by immunofluorescence staining using a combination of anti-P-CK and anti-carbamoyl phosphate synthetase 1 (CPS1) antibodies. Blood samples spiked with HepG2 cells were used to determine recovery and sensitivity. CTCs were detected in blood samples from HCC patients and other patients.ResultsASGPR was exclusively expressed in human hepatoma cell line, normal hepatocytes and HCC cells in tissue specimens detected by the ASGPR antibody staining. More HCC cells could be identified by the antibody cocktail for CPS1 and P-CK compared with a single antibody. The current approach obtained a higher recovery rate of HepG2 cells and more CTC detection from HCC patients than the previous method. Using the current method CTCs were detected in 89% of HCC patients and no CTCs were found in the other test subjects.ConclusionsOur anti-ASGPR antibody could be used for specific and efficient HCC CTC enrichment, and anti-P-CK combined with anti-CPS1 antibodies is superior to identification with one antibody alone in the sensitivity for HCC CTC detection.

Sorafenib is a multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4–11.0) versus 8.0 months (95% CI, 6.6–9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1–27.3] vs. 15.7 months [13.0–20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Background: Somatic mutations of mitochondrial DNA (mtDNA) have been extensively identified mainly by traditional Sanger sequencing technology in various cancer types. However, low detection sensitivity of traditional methods greatly limits the comprehensive profiling of mtDNA somatic mutations in cancers, especially in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Moreover, the functional roles of mtDNA mutation in HBV-related hepatocarcinogenesis have not been systematically revealed.Patients and methods: Next-generation sequencing (NGS) platform was applied to profile the somatic mtDNA mutations of HCC and paired paratumor (non-HCC) tissues from a large cohort of 156 HBV-HCC patients.Results: Our data revealed the common existence of mtDNA mutation in both inflammatory and cancer tissues with significantly different mutation pattern. The mutation density (mutation number/region length) of D-loop region was much higher than that of other regions in both HCC and non-HCC tissues. Unexpectedly, the average mutation number in D-loop region of HCC tissues was significantly less than that of non-HCC tissues. In contrast, the heteroplasmy level of D-loop region mutations was significantly increased in HCC tissues, implying that the D-loop mutations might be positively selected in HCC tissues. Furthermore, our results indicated that the patients with D-loop mutations had a significantly lower mtDNA copy number and were more likely to relapse. In vitro experiments demonstrated that proliferation, invasion and metastasis ability of HCC cells with D-loop region mutations were significantly higher than those without D-loop region mutations. Conclusion:These results emphasize the critical contributing role of somatic mtDNA D-loop mutations in HBV-related hepatocarcinogenesis.