[Abstract] OBJECTIVE: To discuss the difficulties of liver transplantation for refractory recurrent liver tumors and considerations for perioperative management. Methods: To summarize 31 liver transplantation cases performed in our department from September 2003 to June 2005, including 15 cases of refractory recurrent liver tumors (group A) and the remaining 16 cases without any invasive treatment before surgery (group B), and to analyze the preoperative treatment, intraoperative exploration, time to free the diseased liver, time to liver-free period, intraoperative bleeding, use of blood transfusion and hemostatic drugs, operative mortality, postoperative adrenal Glucocorticoid withdrawal and chemotherapy. RESULTS: The intraoperative time to free the diseased liver and the duration of the hepatolithiasis stage were significantly longer in group A than in group B. The amount of bleeding, blood transfusion and hemostatic drugs used were significantly greater than in group B. The two cases of surgical death were both in group A. All surviving hepatocellular carcinoma cases were treated with systemic chemotherapy and adrenal glucocorticoids were discontinued within 3 months. There are 2 cases of recurrent hepatocellular carcinoma and pulmonary metastasis so far, and both cases had hepatic vein cancer embolism before transplantation. Conclusion: Liver transplantation for refractory recurrent liver tumor is more difficult than general liver transplantation and requires higher requirements for the operator, and intraoperative monitoring and supplementation of coagulation factors are extremely important. Perioperative anti-tumor therapy and early postoperative withdrawal of adrenal glucocorticoids are of positive significance for postoperative tumor-free survival. Keywords] Liver tumor; recurrence; liver transplantation; chemotherapy Hepatocellular carcinoma and some benign liver tumors recur after surgical resection, and there is no other effective treatment option after various methods of treatment, which are classified as refractory recurrent liver tumors. From September 2003 to June 2005, 31 cases of liver transplantation were performed in our department, including 15 cases of refractory recurrent liver tumors. After the statistics of intraoperative liver free time, liver-free period, bleeding, blood transfusion and use of hemostatic drugs, and operative mortality, it was found that liver transplantation for refractory recurrent liver tumors is difficult and the risk is significantly higher than that of liver transplantation for other end-stage liver diseases. After preliminary exploration, it was found that liver transplantation for refractory recurrent liver tumors is the only effective treatment method. 1. Data and Methods 1.1 General Data From September 2003 to June 2005, 31 cases of liver transplantation were performed in our department, including 1 case of recurrent multiple hepatic adenoma, 1 case of Wilson’s disease, 1 case of biliary cirrhosis, 3 cases of post-hepatitis cirrhosis, 11 cases of primary liver cancer, and 14 cases of recurrent liver cancer. The diagnosis was based on clinical manifestations, imaging data, serum AFP and pathological findings. One case of recurrent hepatic adenoma that had received 2 hepatectomies before transplantation and 14 cases of recurrent hepatocellular carcinoma after various treatments were included in the group of refractory recurrent liver tumors (group A), with 14 males and 1 female, aged 44.5±12.3 years, 12 cases of liver function ChildA grade and 3 cases of B grade. The 16 cases that did not receive invasive treatment before transplantation were used as the control group (Group B), 15 males and 1 female, aged 46.6±12.5 years, with 8 cases of liver function ChildA grade and 8 cases of B grade. The above cases were divided into two groups for statistical analysis, and the general conditions are shown in Table 1. 1.2 Treatment 1.2.1 Surgery 26 cases were treated with classical in situ liver transplantation and 5 cases were treated with back pack in situ liver transplantation. 3 cases were placed with biliary T-tubes. In both groups, one biliary-intestinal anastomosis was performed to reconstruct the bile duct, and an anastomotic support tube was placed for external drainage through the jejunal collar tunnel; 1.2.2 Preoperative chemotherapy All 14 cases of hepatocellular carcinoma were given capecitabine 1.0 orally 2/day and continued to be administered until liver transplantation; 1.2.3 Intraoperative chemotherapy The liver-free phase was treated with 5-fluorouracil 0.5 intravenously and mitomycin 10 mg intravenously; 1.2.4 Postoperative chemotherapy Systemic chemotherapy was started 3 weeks after surgery. The chemotherapy regimen for hepatocellular carcinoma is: oxaliplatin 85mg/m2 + 5% GS 500ml for 4 hours, fluid flushing followed by pushing calcium folinic acid 300mg, and then 5-fluorouracil 750mg for 8-10 hours, once every 2 weeks, for a total of 6 times. The chemotherapy regimen for cholangiocarcinoma is: gemcitabine hydrochloride 1000mg IV and 5-fluorouracil 1000mg IV push once a week for 3 times; 1.2.5 Hormone reduction and withdrawal Total methylprednisolone 200mg IV on day 1 after liver transplantation, decreasing by 40mg daily, change to oral prednisone tablets 20mg daily after 1 week for malignancy, prednisone tablets 15mg daily after 2 weeks, 1 month later to 10mg, 2 months later to 5mg, full 3 months to stop the hormone, and benign disease after transplantation hormone use full 1 year; 1.3 Observation index Compare the intraoperative diseased liver free time, liver-free period time, bleeding volume and dosage of hemostatic drugs and surgical mortality between the two groups; 1.4 Statistical treatment The t-test was used to compare the measurement data between the two groups. 2. Results 2.1 Intraoperative exploration in group A was accompanied by extensive abdominal adhesions, severe establishment of collateral circulation and different degrees of anatomical alterations; 2.2 Intraoperative diseased liver free time was 190.7±41.5 min in group A and 130±13.6 min in group B. (p<0.05); intraoperative liver-free phase time was 104.7±30.8 min in group A and 76±12.5 min in group B. (p<0.05); intraoperative liver-free phase time was 104.7±30.8 min in group A and 76±12.5 min in group B. (p<0.05). (p<0.05); 2.3 Intraoperative bleeding was 8637.3±5311.4 ml in group A and 2135±706.3 ml in group B. (p<0.05); 2.4 Intraoperative hemostatic drug dosage in both groups; 2.5 Two patients in group A died of acute renal failure and infectious shock secondary to multiple organ failure at 1 and 3 weeks postoperatively, respectively. All surviving patients with hepatocellular carcinoma had completed or were about to undergo postoperative chemotherapy, and the longest case had survived tumor-free for more than 14 months. Two cases developed recurrent hepatocellular carcinoma and pulmonary metastases more than 1 month and 2 months after transplantation, respectively, and both cases had hepatic vein thrombosis before transplantation. Another case of recurrent hepatic adenoma did not show tumor recurrence. The majority of recurrent liver tumors are hepatocellular carcinoma, and the 5-year tumor-free survival rate after resection of hepatocellular carcinoma has been recently reported to be only 10.5% [1]. The high recurrence rate of hepatocellular carcinoma directly affects the prognosis of hepatocellular carcinoma. Recurrent hepatocellular carcinoma has become increasingly ineffective after multiple hepatectomies, hepatic artery chemoembolization and anhydrous alcohol injections, and further treatment becomes a very difficult problem as the tumor is difficult to control and liver function deteriorates. Nowadays, with the maturity and popularity of liver transplantation technology, liver transplantation has become one of the important treatment means for liver tumors. Martinez AD et al [2] reported that the operative mortality rate of liver transplantation for hepatocellular carcinoma was 27.5% and the recurrence rate of hepatocellular carcinoma was 18.8%. . However, there are not many reports related to liver transplantation for recurrent liver tumors after various repeated treatments, which may be related to the complexity of such cases, the multiple tumors, the difficulty of surgery, and the poor prognosis. For this group of patients, liver transplantation is the only last effective treatment. Fifteen cases in this group had been treated with preoperative hepatic resection, hepatic artery chemoembolization, and anhydrous alcohol injection, but the tumors were still uncontrollable, and the expected survival time for all of them had no more than 2 months for hepatocellular carcinoma. The authors concluded that the indications for liver transplantation for recurrent liver tumor are: (1) recurrent tumor with liver function loss and no other effective treatment; (2) recurrent hepatocellular carcinoma with portal vein thrombus not invading the main portal vein; (3) clear absence of extrahepatic metastases; (4) failure of other treatment methods. The difficulties of liver transplantation for refractory recurrent liver tumor can be seen from the intraoperative exploration and the comparison of bleeding volume: (1) multiple surgeries, hepatic artery chemoembolization and anhydrous alcohol injection resulted in extensive and dense perihepatic adhesions, severe liver function impairment, poor compensation and high portal pressure, so it was difficult to free the diseased liver, large trauma and more bleeding, therefore, the time for freeing the diseased liver in group A was significantly longer than that in group B. Group A required more time for trauma hemostasis than group B during the hepatocellular phase. (2) The anatomical structure and position of the posterior inferior vena cava and the first hepatic hilar change easily lead to intraoperative misinjury causing hemorrhage, in one case in group A, the scar adhesion of the second hepatic hilar caused unclear anatomical structure, and the lateral wall of the inferior vena cava was cut during the freeing of the superior hepatic vena cava, bleeding 1000 ml within 2 minutes, and the patient's blood pressure dropped rapidly to 60/40 mmHg, and blood pressure transfusion was given immediately in both directions, while The patient's blood pressure was rapidly reduced to 60/40 mmHg, and the patient was immediately given two pressure transfusions, while the distal end of the rupture was repaired by pinching the index thumb. The comparison of intraoperative bleeding also reflects that the difficulty and risk of surgery for refractory recurrent liver tumor is much greater than that of general liver transplantation, which requires not only skillful vascular anastomosis technique, but also rich experience in liver resection and a solid foundation in liver anatomy. The main problem of liver transplantation for refractory recurrent liver tumors is the difficulty of liver resection and the large amount of blood transfusion is often required because of heavy bleeding during liver resection. Timely supplementation of various coagulation factors and peptidases to improve coagulation and inhibit hyperfibrinolysis is especially important. Thrombinogen complex and fibrinogen are commonly used in clinical practice to stop bleeding, but it is often difficult to obtain significant hemostatic effect. The activated recombinant coagulation factor VII binds with tissue factor to activate coagulation factor X. The activated coagulation factor X triggers the conversion of prothrombin complex to thrombin, and then the conversion of fibrinogen to fibrin to form thrombus, which has obvious efficacy in controlling large amount of intraoperative bleeding. The role of peptidase is to inhibit the degradation of fibrin by fibrinolytic enzymes and reduce the lysis of thrombus. The combination of these drugs was effective in reducing the bleeding from large trauma areas. Because of the higher blood loss in group A, the supplementation of coagulation factors was correspondingly higher than that in group B. To reduce recurrence after liver transplantation for liver cancer, the authors performed perioperative chemotherapy in all liver cancer cases. There is no conclusive evidence whether preoperative TACE can prolong the survival time of patients after liver transplantation, and TACE may cause congestion and edema of the diseased liver, intimal damage of the hepatic artery, and increase postoperative complications of liver transplantation, so preoperative TACE was not administered again and replaced by oral capecitabine. Capecitabine is a new type of fluorouracil drug, which is effective for GI malignancies, convenient to administer and has less toxic side effects. No aggravation of liver function damage was found in our group of cases after preoperative administration of capecitabine. Intraoperative fluorouracil and mitomycin given intravenously via peripheral veins during the liver-free phase could kill tumor cells in circulating blood. Considering that most recurrent hepatocellular carcinomas have been treated with TACE preoperatively and may develop tumor resistance, we chose oxaliplatin, 5-fluorouracil, and calcium folinic acid for prophylactic chemotherapy after surgery. For patients with cholangiocarcinoma, postoperative chemotherapy was administered with gemcitabine, which is relatively sensitive. With these treatments, all patients survived tumor-free except for 2 cases of postoperative death and 2 cases of recurrent metastasis with hepatic vein carcinoma thrombosis before transplantation. Mazzaferre V et al [4] reported that the recurrence rate of hepatocellular carcinoma was lowest when steroid preparations were discontinued within 3 to 6 months after liver transplantation for hepatocellular carcinoma. The risk of hepatocellular carcinoma recurrence increases almost fourfold if long-term steroid therapy is received after surgery [5]. In our cases, glucocorticoids were reduced early and discontinued at 3 months postoperatively, and only 2 cases had recurrence or metastasis of hepatocellular carcinoma, and vascular cancer embolism had a great impact on this. The long-term efficacy of liver transplantation for refractory recurrent liver tumors needs further observation, and various measures to reduce the recurrence rate of tumors after transplantation are being explored. The authors concluded that liver transplantation is the only effective treatment for refractory recurrent liver tumors to date.