| 1.Background and ObjectivePrimary liver cancer,mainly refers to hepatocellular carcinoma(HCC),accounting for the third leading cause of death of cancer in the world.According to statistics,about 55% of the new cases of HCC in the world are in China.A number of guidelines domestic and foreign indicate that surgery is still the first choice for the treatment of HCC,but the recurrence rate is as high as 80% in 5 years after radical resection of HCC.There have been many studies on preventing recurrence after radical resection of HCC at home and abroad,but there is still no recognized treatment.Therefore,it is still an important topic in the field of diagnosis and treatment of HCC to explore a new therapy to prevent recurrence of HCC after operation.In recent years,many studies have been reported on the relationship between neural regulation and the occurrence and development of cancer,among which sympathetic nerve regulation is the most important pathway.Long-term chronic stress has been shown to promote metastasis of malignant tumors such as ovarian cancer by activating the sympathetic nervous system.Studies have also shown that sympathetic adrenergic beta blockers can significantly reduce the risk of postoperative recurrence and distant metastasis of breast cancer.Previous studies on cell biology and animal experiments in our research group have been confir med that sympathetic adrenergic beta receptor pathway can significantly reduce the incidence,invasion and metastasis of hepatocellular carcinoma.At the same time,beta-blocker can prevent recurrence and metastasis of HCC after operation.This project is designed on the basis of the basic research results of the research group,and it is the clinical transformation medicine research.In this study,a prospective randomized controlled trial was conducted to investigate the effects of sympathetic adrenergic beta blockers on tumor recurrence,tumor-free survival and overall survival after radical resection of HCC.At the same time,the relationship between postoperative recurrence of HCC and chronic stress was discussed in order to find a new method to prevent postoperative recurrence of HCC,and to improve the 5-year survival rate of HCC.This study is based on many basic research results published by our research group,and to explore a new approach to the treatment of HCC from a new perspective of neural regulation.2.Methods and Results2.1 In accordance with the criteria for the inclusion and exclusion of patients in the research programme,patients who meet the criteria were randomized into groups.Patients with HCC in experimental group after operation treated with propranolol,a beta-blocker,to prevent recurrence.The specific regimen was to start taking propranolol about 5 days after operation,the initial dose was 10 mg twice daily,the heart rate and blood pressure were monitored daily,the daily dose of 10 mg was gradually increased,and the dose was increased once a day from 2 to 3 days.Until the maximum tolerated dosage is reached(each subject has a different maximum tolerance dose,until the resting HR was reduced by 25% or was less than 55 beats per minute),continue to take the maximum tolerated dose until the end of the follow-up,and if the drug withdrawal should be reduced by at least 2 weeks.The patients in the control group were not given any drugs to prevent recurrence after operation(except for anti-hepatitis virus drugs).The clinical,surgical and pathological data of each patient with HCC were collected.Perceived Stress Scale,stress score,cortisol concentration in hair were measured on the 5th day,1 month and 3 month after operation to evaluate the patients' chronic stress level.The blood routine,liver and kidney functions,blood AFP and liver contrast enhanced ultrasound were measured every 3 months,and liver tumor-specific MRI or the upper abdominal enhanced CT was performed every 6 months.The recurrence was judged according to the criteria in the study scheme,and the survival of the patients was recorded.The effects of beta-blockers on postoperative recurrence rate and tumor-free survival were analyzed,and the effects of different chronic stress states on the early recurrence rate of HCC were discussed.Kaplan-meier method was used for survival analysis.The difference between the two groups in early postoperative recurrence rate and early postoperative disease-free survival rate was analyzed by Log-rank test.The results showed that there was no statistical difference between the two groups.At the same time,the stress score of the patients was measured by heart rate variability,detection of hair cortisol concentration using high performance liquid chromatography tandem mass spectrometry and measurement the patient's PSS-10 score.The correlativity of PSS-10 score,stress score and hair cortisol concentration was analyzed and the best cut-off value of the above three indexes were calculated by X-tile software.The evaluation system of chronic stress state in patients with HCC after operation was established.The effect of different chronic stress states on postoperative recurrence of HCC was analyzed.Other factors related to the prognosis of HCC were also analyzed.2.2 There were 90 patients who diagnosed with HCC were enrolled at hepatobiliary surgery department of the First Affiliated Hospital of the Army Medical University from August 2017 to March 2019 in this study,including 45 patients in the experimental group and 45 patients in the control group.Until March 1,2019,the median follow-up period was 9 months(range,3 to 19 months).No patient lost follow-up.There was no statistical difference in Baseline heart rate,hcv infection,sex,child-pugh grade,HBV infection,AFP,portal vein diameter,ICGR-15,age,preoperative liver function,tumor diameter,tumor number,liver cirrhosis,portal hypertension,esophageal and gastric varices,splenomegaly,Child-pugh grade,BCLC stage between two groups,that indicates the two groups are comparable.The recurrence rate of the two groups was analyzed.The recurrence rate was 28.9%(13/45)in the experimental group,including 10 cases(22.2%)intrahepatic recurrence and 6.7%(3 / 45)abdominal cavity metastasis.The recurrence rate was 24.4%(11 / 45)in the control group,20.0%(9 / 45)was intrahepatic recurrence,4.4%(2 / 45)was abdominal cavity metastasis,2.2%(1 / 45)was lung metastasis.A total of 6 patients(6.7%)died in both groups,including 1 case of leukemia and 1 case of upper gastrointestinal hemorrhage.One case died in the experimental group,accounting for 2.2%(1 / 45),5 cases died in the control group,accounting for 11.1%(5 / 45).There was no significant difference in mortality between the two groups by Fisher exact test(p=0.203).The cumulative recurrence rate of test group and control group was 28.9% and 24.4% respectively in one year after operation by Kaplan-Meier method.There was no statistical difference in recurrence rate between the two groups by Log-rank test(p=0.634).The tumor-free survival time of the experimental group and the control group were 15 months and 8 months,respectively.The 1-year disease-free survival rates of the experimental group and the control group were 73.3% and 77.8%,respectively,there was no significant difference in the overall level,there was no significant difference in the overall level(p=0.330).Based on univariate factor analysis,Cox multivariate analysis showed that recurrence rate of HCC after operation was significantly correlated with stress perception scale(PSS-10),hair cortisol concentration,portal vein diameter and preoperative creatinine level and the early disease-free survival rate was significantly correlated with tumor diameter,NLR,positive rate of epithelial CTC and INR.2.3 The cut-off value of PSS-10 was 17,12 patients' PSS-10 > 17 and 78 patients' PSS-10 ? 17;45 patients' stress score > 50 and 45 patients' stress score? 50.The cut-off value of hair cortisol concentration was 20.3 pg/mg,38 patients' hair cortisol concentration >20.30 pg/mg,and 52 patients' hair cortisol concentration? 20.30 pg/mg.The PSS-10,stress score was significantly correlated with the hair cortisol concentration in patients with HCC.Combined with the three indexes,the chronic stress state of patients with HCC after operation can be well evaluated.Further analysis showed that the disease-free survival time of HCC patients with PSS-10 > 17,stress score > 50 and hair cortisol concentration > 20.30pg/mg was shorter.The pro gnosis of HCC patients with long-time chronic stress was poor.3.Conclusions3.1 The Perceived Stress Scale PSS-10,stress score and hair cortisol concentration were negatively correlated with the disease-free survival time of HCC patients.Long-term chronic stress status could promote the early recurrence of HCC after operation.Combined with the three indexes,the chronic stress state of patients with HCC after operation could be evaluated from both subjective and objective aspects.3.2 Because the sample size was not reached and the follow-up time was short,the positive results of sympathetic adrenergic ? receptor blocker for preventing recurrence of HCC were not obtained at present. |
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