Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial.

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .

Outcomes of intrahepatic cholangiocarcinoma with portal vein tumor thrombus following hepatic resection.

BACKGROUND AND AIM: Portal vein tumor thrombus (PVTT) is not commonly used in the treatment of intrahepatic cholangiocarcinoma (ICC), and its impact on the prognosis of ICC is unclear. We aimed to assess the outcomes of ICC with or without PVTT after hepatic resection. METHODS: From January 2000 to December 2005, the data from all consecutive patients with ICC who underwent hepatic resection at our hospital were retrospectively analyzed. According to the Cheng's PVTT Classification (types I-IV), we compared the survival outcomes of ICC patients (with or without PVTT) and prognosis of patients with ICC with different types of PVTT. RESULTS: Three hundred and three patients with ICC were enrolled in this study (59 with PVTT). The incidence of PVTT was 19.4% (59/303). The median survival times were 12.68 and 28.91 months for ICC patients with and without PVTT, respectively (P < 0.001). The multivariate analysis demonstrated that PVTT (hazard ratio [HR] 1.783; confidence interval 95% [1.279; 2.487]) was an independent risk factor for overall survival. Patients with type I PVTT exhibited significantly better survival than those with types II and III PVTT. CONCLUSION: The ICC patients with PVTT exhibit a poorer prognosis compared with ICC patients without PVTT after hepatic resection.

Elevated core-fucosylated IgG is a new marker for hepatitis B virus-related hepatocellular carcinoma.

Immunoglubulin G (IgG) and its abnormal glycosylations are associated with carcinogenesis. The present study investigates the relationship between cancer-derived IgG and clinicopathological characteristics in hepatocellular carcinoma (HCC) and assesses the value of serum N-glycosylated IgG in diagnosing and monitoring hepatitis B virus (HBV)-related HCC. Tissue microarray analysis of 90 HCC tissues showed that HCC patients with IgG immunopositivity had higher levels of core-fucosylated α fetoprotein (AFP-L3), larger tumors, and a higher incidence of portal vein tumor thrombus. HCC-derived IgG stimulated the growth of liver cancer cells in vitro. HCC patients presented a significantly increased fraction of Lens culinaris agglutinin binding IgG (core-fucosylated IgG, IgG-L3) among total serum IgG. The clinical diagnostic performance of serum IgG-L3% was evaluated in 3 case-control studies (1 training set and 2 validation cohorts), including 293 patients with HCC, 131 with liver cirrhosis, 132 HBV carriers, and 151 healthy controls. IgG-L3% had better general diagnostic performance than AFP in the training set and validation cohort 1 (accuracy: 81.33-85.11% versus 63.33-78.61%). In validation cohort 2, where we aimed to assess the efficiency of IgG-L3% in patients with AFP-negative HCC, the diagnostic accuracy of IgG-L3% was 72.54-73.60%. Finally, a longitudinal evaluation based on 31 HCC patients demonstrated that IgG-L3% decreased in 24 patients after curative surgery. The remaining 7 patients showed elevated IgG-L3% and post-operative recurrence. HCC patients with higher IgG-L3% had poor survival during a 3-year follow up. We conclude that HCC-derived IgG is correlated with progressive behavior of HCC. Therefore, elevated core-fucosylated IgG is a new diagnostic and prognostic marker in HBV-related HCC.

All-trans retinoic acid potentiates the chemotherapeutic effect of cisplatin by inducing differentiation of tumor initiating cells in liver cancer.

BACKGROUND & AIMS: Systemic chemotherapy serves as an adjuvant treatment for post-operation patients with hepatocellular carcinoma (HCC), and provides curative option for the patients with unresectable HCC. However, its efficiency is largely limited because of the high incidence of chemo-resistance. Increasing evidence has shown that tumor initiating cells (TICs) not only have the ability to self-renew and drive the initiation and progression of cancer, but also exhibit greater resistance to conventional chemo- and radio-therapies than non-TICs. It was the aim of this study to investigate the effects of ATRA with and without cisplatin on TIC differentiation and apoptosis in human HCC. METHODS: In the present study, we evaluated the TICs of HCC cell differentiation induced by all-trans retinoic acid (ATRA), and developed a novel chemotherapeutic approach to HCC, by characterizing the function of combinatorial treatment with cis-diammineplatinum(II) (cisplatin) and ATRA in vitro and in vivo. RESULTS: ATRA effectively induced differentiation of TICs, which potentiated the cytotoxic effects of cisplatin. The combinatorial treatment of ATRA acid and cisplatin reduced protein kinase B (AKT) (Thr308) phosphorylation, and promoted apoptosis of HCC cells more significantly than treatment with cisplatin alone. In addition, the combined treatment with the two drugs exerted stronger inhibition on either HCC cell migration in vitro or metastasis in vivo, when compared to the treatment with either drug alone. CONCLUSIONS: These results indicated that ATRA could significantly improve the effect of cisplatin, which is at least partially attributed to ATRA-induced differentiation of HCC TICs, and the subsequent decrease in this chemo-resistant subpopulation.

Association of a variant in MIR 196A2 with susceptibility to hepatocellular carcinoma in male Chinese patients with chronic hepatitis B virus infection.

MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. Recent studies have implicated that the rs11614913 SNP in MIR196A2 was associated with susceptibility of lung cancer, congenital heart disease, breast cancer and shortened survival time of nonsmall cell lung cancer. To assess whether this polymorphism is associated with susceptibility to and clinicopathologic characteristics of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), a total of 560 patients with chronic HBV infection and 391 healthy volunteers were enrolled, and MIR196A2 polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). In our study group, there was no significant association between MIR196A2 polymorphism and the risk of HBV-related HCC in all subjects, however, the risk of HCC was significantly higher with MIR196A2 rs11614913 CC genotype or C allele compared with those with the TT genotype or T allele in male patients. Furthermore, in a subsequent analysis of the association between this polymorphism and clinicopathologic characteristics, there was still no significant difference in both the distribution of genotype or allelic frequency. However, we observed that the T allele was significantly more frequent in male HCC patients with lymphatic metastasis. Our results suggested that MIR196A2 polymorphism was associated with susceptibility to HBV-related HCC in a male Chinese population.

N-glycan based models improve diagnostic efficacies in hepatitis B virus-related hepatocellular carcinoma.

The early diagnosis of hepatocellular carcinoma (HCC) is of great clinical desirable due to lack of specific and sensitive markers. Alterations in the sugar chains of glycoprotein synthesized by the liver contribute to the molecular basis of abnormalities in carcinogenesis. This study aims to construct and assess the diagnostic value of N-glycan based diagnostic model in HCC identification and follow-up. A total of 393 subjects including HBV-related HCC, liver fibrosis and healthy controls were recruited. Follow-up was carried out before and after surgical treatment in HCC. N-glycome of serum glycoprotein was profiled by DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE). Multiparameters diagnostic models were constructed based on N-glycan markers. The result found that 2 N-glycan structure abundances (NG1A2F, Peak 4; NA3Fb, Peak 9) were useful as N-glycan markers. The diagnostic efficacy of the log ratio [log(p9/4)] was similar to that of AFP in differentiating HCC from fibrosis. The accuracy and sensitivity of the diagnostic model combining AFP and N-glycan markers (Cscore B) were increased 7-10% compared with that of AFP. Log(p9/4) was more efficient in monitoring the progression of HCC with regarding to vascular invasion at improved specificity (16%) and accuracy (8%) compared with that of AFP. The N-glycan markers were found to be changed significantly after surgical resection in HCC follow-up. We conclude that the branching alpha (1,3)-fucosylated triantennary glycan and a biantennary glycan are promising as N-glycan markers. The diagnostic models based on the N-glycan markers and AFP improve the efficacy in HCC diagnosis and progression monitoring.

CTLA-4 +49A>G polymorphism is associated with the risk but not with the progression of colorectal cancer in Chinese.

PURPOSE: Colorectal cancer (CRC) is one of the most common malignancies in the world and a multipathway disease. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a potent immunoregulatory molecule that suppresses antitumor response by down-regulating T-cell activation. The most studied +49A>G polymorphism of CTLA-4 gene has been associated with several autoimmune or cancer diseases. Our aim was to investigate the association between this genetic variant and the risk as well as progression of colorectal cancer in Chinese. METHODS: We conducted a case-control study of 124 colorectal cancer cases and 407 healthy controls. DNA was extracted from blood specimens, and +49A>G polymorphism in the CTLA-4 gene was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). RESULTS: In our study group, the frequency of AG or GG or carrying at least one G allele at position +49 was significantly different in colorectal cancer patients and the control group, indicating that the risk of CRC was significantly higher among subjects with the AG or GG genotype or carrying at least one G allele at position +49 than among the subjects with the AA genotype. However, we observed no association between CTLA-4 +49A>G polymorphism and the progression of CRC. Interestingly, the CTLA-4 +49A allele was in non-significantly higher numbers in CRC patients with distant metastasis. CONCLUSIONS: Our results suggested that CTLA-4 +49A>G polymorphism was associated with an increased risk of colorectal cancer, but this polymorphism did not play an important role in the progression of CRC in Chinese.

Up-regulation of hTERT expression by low-dose cisplatin contributes to chemotherapy resistance in human hepatocellular cancer cells.

The telomerase is specifically activated in most malignant tumors but is usually inactive in normal somatic cells. It has been reported that telomerase has an anti-apoptotic role and up-regulation of telomerase helps cancer cells to be resistant to chemotherapeutic agent-induced cell death. The effect of cisplatin on telomerase activity is complex, and the exact mechanism remains largely unknown. In this study, we found that cisplatin activated telomerase activity and human telomerase reverse transcriptase (hTERT) expression in SMMC7721 human hepatocellular carcinoma cell line. Low-dose cisplatin up-regulated hTERT and NF-kappaB p65 expression and increased telomerase and NF-kappaB activity. Inhibition of NF-kappaB attenuated the hTERT expression and telomerase activity exposed to cisplatin, suggesting that NF-kappaB is responsible for the cisplatin-induced activation of the hTERT. Furthermore, preincubation of low-dose cisplatin which induced high expression of hTERT help hepatocellular carcinoma SMMC7721 cells survive under the high concentration of anti-cancer drugs. Inhibition of hTERT increased sensitivity of SMMC7721 cells to chemotherapy. Taken together, these results suggested that up-regulation of hTERT expression by low-dose cisplatin is NF-kappaB-dependent and contributes to chemotherapy resistance in human hepatocellular cancer cells.

[Exploration of indication of prophylactic transcatheter arterial chemoembolization on postoperative recurrence of hepatocellular carcinoma].

OBJECTIVE: To evaluate the efficacy of prophylactic transcatheter arterial chemoembolization (TACE) on postoperative recurrence of hepatocellular carcinoma. METHODS: A retrospective analysis was performed on clinicopathologic data of 260 hepatocellular carcinoma patients who underwent curative hepatectomy in Eastern Hepatobiliary Surgery Hospital, Second Military Medical University from January 2004 to June 2007. Among the 260 patients, 104 underwent postoperative prophylactic TACE and the other 156 were not. RESULTS: The overall survival rates at 1- and 2-years were 84.1% and 70.5% respectively. The overall disease-free survival rates at 1- and 2-years were 69.2% and 58.4% respectively. Of 260 overall patients, the disease-free survival rates at 1- and 2-years were 72.8% and 54.9% respectively in TACE group, and 66.9% and 59.7% respectively in non-TACE group, statistically significant difference of the cumulative disease-free survival rates at 1- and 2-years between TACE group and non-TACE group were not observed (P = 0.145, P = 0.405). Of 62 patients with tumor size >or= 10 cm, the disease-free survival rates at 1- and 2-years were respectively 66.6% and 48.7% in TACE group, and respectively 44.6% and 31.2% years between TACE group and non-TACE group were observed (P = 0.025, P = 0.025). Of 38 patients with vascular tumor thrombi, the disease-free survival rates at 1- and 2-years were respectively 33.0% and 0 in TACE group, and respectively 26.2% and 21.8% in non-TACE group, statistically significant difference of the cumulative disease-free survival rates at 1-years between TACE group and non-TACE group was observed (P = 0.025), and not at 2-years (P = 0.122). CONCLUSIONS: In non-TACE group, statistically significant difference of the cumulative disease-free survival rates at 1- and 2-Prophylactic TACE is preferred for hepatocellular carcinoma patients with high risk factors for recurrence such as tumor size >or= 10 cm and presented vascular tumor thrombi.

Genetic recombinant expression and characterization of human augmenter of liver regeneration.

AIMS: To establish a highly effective prokaryotic recombinant expression system for human augmenter of liver regeneration (hALR) and to characterize the recombinant hALR both in vitro and in vivo. METHODS: ALR cDNA was synthesized and inserted into expression vector pET28a+, the recombinant plasmid was transformed into BL21, and expression of hALR was induced by IPTG. Recombinant hALR (rhALR) was purified by sequential detergent wash, enterokinase (EK) digestion, gel-filtration, and chelating chromatography. The rhALR was identified by SDS-PAGE, immunoblotting, MALDI-TOF-MS, and N-terminal sequencer. Cell proliferative effect of rhALR on human hepatocytes was analyzed by MTT. The protective effect of rhALR on liver function was observed on CCl(4)-induced intoxicated mice. RESULTS: Recombinant expression plasmid of ALR [pET28(a+)-hALR] was confirmed by restriction enzyme digestion and DNA sequencing. The expressed rhALR constituted 30% of total bacterial protein. Molecular weight was 15,029 for monomer and 30,136 for dimer by mass determination. N-terminal was M-R-T-Q-Q, exactly the same as anticipated for hALR. The purified protein migrating at about 15 KD showed excellent antigenicity in immunoblotting. The rhALR also showed a strong stimulative effect on hepatocyte proliferation. ALT and AST levels, liver histological structure, as well as the survival rate of CCl(4)-intoxicated mice were significantly improved when rALR was administrated at 40 microg/kg or 200 microg/kg. CONCLUSIONS: The rhALR is successfully expressed highly effectively with anticipated MW, N-terminal, and antigenicity. It could play an important role in relieving acute hepatic injury and hepatic failure by promoting hepatic cell proliferation and improving liver function in CCl(4)-intoxicated mice.

[Treatment strategy for synchronous liver metastasis from colorectal cancer].

BACKGROUND & OBJECTIVE: The patients with synchronous liver metastasis from colorectal cancer might get long-term survival after liver resection. But the optimal timing of surgery is undefined. This study was to explore the treatment strategy for synchronous liver metastasis from colorectal cancer. METHODS: From 1995 to 2005, 83 patients with synchronous liver metastasis from colorectal cancer were treated with operation at Eastern Hepatobiliary Surgery Hospital. Of the 83 patients, 37 received simultaneous liver and colorectal resection, and 46 received staged resection. The occurrence rate of postoperative complications, mortality, blood loss, hospital duration, overall survival rate, median survival time, disease-free survival time and recurrence rate of the 2 groups were compared. RESULTS: The occurrence rates of postoperative complications were 24.3% in simultaneous resection group and 19.6% in staged resection group (P=0.601). No operation-related death occurred. The mean blood losses were 462 mL in simultaneous resection group and 574 mL in staged resection group (P=0.312). The mean hospital duration was 19 days in simultaneous resection group and 36 days in staged resection group (P=0.001). The 1-, 3-and 5-year overall survival rates were 86.5%, 54.1%, and 27.0%, respectively, in simultaneous resection group and 89.1%, 52.2%, and 23.9%, respectively, in staged resection group (P>0.05). The median survival time was 40 months in simultaneous resection group and 37 months in staged resection group (P=0.075)û the median disease-free survival time was 12 and 11 months, respectively (P=0.532). The recurrence rates were 35.1% in simultaneous resection group and 30.4% in staged resection group (P=0.650). CONCLUSION: Synchronous liver and colorectal resection is preferred for synchronous liver metastasis from colorectal cancer.

Prevention and management of pleural effusion following hepatectomy in primary liver cancer.

BACKGROUND: Postoperative pleural effusion occurs frequently after hepatectomy. The risk factors, prevention and management of postoperative pleural effusion in patients with primary liver cancer (PLC) who have undergone hepatectomy and the value of the argon beam coagulator (ABC) for the prevention of pleural effusion are studied. METHODS: A total of 523 patients with PLC at our institution who had had right hepatectomy from July 2000 to June 2004 were studied retrospectively. Comparative analysis was made to identify the factors contributing to postoperative pleural effusion and the efficacy of various managements. RESULTS: Of the 523 patients whose livers were dissociated using argon beam cutting and/or coagulation, 20(3.8%) developed pleural effusions; whereas in the other 467 patients underwent hepatectomy with suture ligation of the diaphragmatic secondary wound surface during the same period, 49(10.5%) had pleural effusion (P < 0.01). The factors contributing to postoperative pleural effusion included subphrenic collection, postoperative hepatic insufficiency with ascites, duration of hepatic occlusion and underlying cirrhosis. CONCLUSIONS: Dissociation of the liver by argon beam cutting and/or coagulation can save suture ligation of the diaphragmatic secondary wound surface and may also prevent postoperative pleural effusion. Pleural drainage using an indwelling central-venous-catheter (CVC) in the pleural cavity is safe and efficacious.