The Prediction Of Circulating AFPmRNA And The Effect Of INF-α On The Recurrence And Metastasis After Resection In Patients With Huge HCC(≥10cm)

Background:Hepatocellular carcinoma is one of the most common malignancies in the world. With the improvements on the hepatic technology and the imaging technology of the liver, and the increased experiences of the perioperative management, the rate of hepatic resection has been increasing, the early prognosis of patients who underwent hepatectomy for HCC is well acceptable, and even some authors reported that the peri-operative mortality can be near-zero. However, the actual 5-year recurrence rate following hepatectomy is still up to 35%-75%, which is one of the main causes of post-resectional death. Postoperative recurrence is categorized into early (<2 years) and late (>2 years) recurrence. Generally, early recurrence is attributed to the residual tumor cells from the resected tumor, and when the residual tumor cells advanced into the clinically obvious foci, it is often too late to effectively manage the recurrent foci, because of its large size and/or distant metastasis. Therefore, to detect postoperative residual tumor cells as soon as possible may bring benefits to postoperative treatment strategy.Tumor cells may be shed into the circulation spontaneously or iatrogenically to form metastatic foci. Using the PCR to detect tumor-specific gene transcript (mRNA/circulating DNA), we can sensitively detect the isolated tumor cell (ITC) in a small blood sample. Many studies reported that ITC may be a surrogate marker of postoperate prognosis. AFPmRNA is generally accepted as a liver-specific and tumor-specific marker. Clinical studies have demonstrated that peripheral blood AFPmRNA is associated with blood stream dissemination of HCC, and is a predictor for those patients with HCC who have undergone hepatectomy or experienced percutaneous ethanol injection or transarterial chemoemolization. However, to our knowledge, no studies have reported that the peripheral blood AFPmRNA is present or absent, and its relationship with the postoperative prognosis of patients with huge HCC(diameter≥10cm) in the present study, we try to measure the postoperative peripheral blood AFPmRNA to determine its value in detecting postoperative early recurrence and/or distant metastasis.The large size of HCC larger than 10cm indicates that the lesion is already advanced, with a greater possibility of tumor spread, including the existence of statllite nodules or macro-/micro-vascular invasion. Such advanced tumor carries a higher risk of recurrence, even after potentially curative resection. It is reported that postoperative 1-year recurrence rate is highly up to 35%-70%in patients with huge HCC, which leads to the poor prognosis. Therefore, to suppress early recurrence is the key to improve the postoperative prognosis.Up to now, many studies have reported that postoperative adjuvant or neoadjuvant therapy may reduce recurrence. Postoperative adjuvant therapy included transarterial chemoemolization, chemotherapy,acyclic retinoid therapy, immuno--therapy and interferon therapy. Interferon therapy is a hot topic in the last decade. Interferons are cytokines possessing a variety of biologic properties, including antiviral, immunomodulatory, antiproliferative, and antiengiogenic effects. In resent year, several clinical trials have suggested that adjuvant IFN-a treatment could obviously influence recurrence and survival of HCC patients after resection, while reresults in these trials were inconsistent. As far as early recurrence was concerned, some reported that IFN-αcould suppress early recurrence, but others reported the opposite. As for survival, there were also discordant results, some demonstrated that IFN-a could improve survival, but other denied. No report have demonstrated the effects of postoperative IFN-αtreatment on the recurrence and survival in patients with huge HCC(diameter≥10cm).Methods:1. RT-PCR to detect peripheral blood AFPmRNAThe patients were classified into hepatic resection group(n=178, all HCC patients, diameter≥10cm), and control group (n=60,20 volunteers, and 40 non-HCC in-hospital patients).5ml blood was sampled from peripheral vein preoperatively and postoperatively, respectively, and to detect AFPmRNA using RT-PCR;2. To record the clinicopathological parameters of all the 178 patients and to follow up them at regular time following resection, to timely detect the recurrence and record their survival;3. To determine the value of peripheral blood AFPmRNA in detecting early recurrence/metastasis by using the statistics analysis;4. IFN-a intramascular injection as postoperative adjuvant therapy for postoperative patients with huge HCC(diameter≥10cm);Sixty patients with huge HCC(diameter>10cm) and postoperative positive AFPmRNA were randomly classified into IFN-a treatment group(n=30) and control group(n=30). Between the fifth and sixth week after resection, in the IFN-αtreatment group, patients received IFN-a injection, which was started at a pilot dose of 3 million units two times a week by intramascular injection for two weeks, then 5 million units three times a week for 18 months;5. By using statistics analysis, to determine the effect of postoperative IFN-a treatment on the recurrence and survival in patients with huge HCC and positive postoperative AFPmRNA.Results:1. By using RT-PCR, peripheral blood HCC-specific AFPmRNA can be detected;2. Preoperative and postoperative peripheral blood AFPmRNA is negative in all patients in the control group;3. In the hepatic resection group,44.9%(80/178) and 38.8%(69/178) patients had positive AFPmRNA, preoperatively and postoperatively, respectively:4. In 37 patients with postoperative positive AFPmRNA.1-,2-,3-year disease-free survival rate is 64.6%,33.9% and 0%,respectively. In 92 patients with postoperative negative AFPmRNA,1-,2-,3-year disease-free survival rate is 80.0%,62.1% and 29.1%. The disease-free survival rate in the AFPmRNA(+) patients was significantly lower than that in the AFPmRNA(-) patients;5. The statistics analysis showed that peripheral blood AFPmRNA is an independent factor influencing disease-free survival;6. In the IFN-αtreatment group,1-,2-,3-year disease-free survival rate is 50.0%,33.3%,28.3%, respectively, which is higher than that in the control group but without statistical significance;7. In the IFN-a treatment group, the overall survival rate is 82.5%, 71.2% and 49.8%, respectively. In the control group, the overall survival rate is 53.3%,33.8% and 22.6%, respectively. The former is significantly higher than the later;8. The statistics analysis showed that IFN-αtreatment is an independent factor influencing overall survival.Conclusions:1. Peripheral blood AFPmRNA can be detected preoperatively and postoperatively in patients with huge HCC 2. Peripheral blood AFPmRNA may be a marker predicting the early recurrence in patients with huge HCC3. Postoperative IFN-a treatment may improve the disease-free survival rate, with no statistical significance compared to the control.4. Postoperative IFN-a treatment may significantly improve the 1-,2, 3-year overall survival.