| Part Ⅰ: The Value of Peripheral Circulating Tumor Cells in Predicting Hepatocellular Carcinoma with Microvascular InvasionObjectives: Microvascular invasion(MVI)is associated with poor prognosis after hepatectomy for primary liver cancer.Preoperative prediction of MVI in advance is helpful to the planning of surgical boundary and surgical margin,and reduce the risk of postoperative recurrence.This study screened out the indicators for predicting MVI,and explored the value of preoperative circulating tumor cells(CTC)in predicting MVI by establishing a prediction model.Methods: One hundred and thirty-seven patients were recuited in the study who were diagnosed with HCC and underwent hepatectomy in the Hepatic Surgery Department of Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology on November 2016-November 2018.Peripheral blood CTC were collected and detected before surgery,during surgery,postoperative one week,one month,two months,three months,six months and one year.The “7-zones” method for disposing pathological materials was used to identify the MVI.Kaplan-Meier method was used to draw survival curves of MVI positive group and MVI negative group,and Log-Rank(Mantel-Cox)method was used to test statistic difference.Logistic regression model was used to determine the independent risk factors for MVI.Receiver operating characteristic curve(ROC)was established to evaluate the capability of CTC for predicting MVI.Results: The mean follow-up time was 43.5 ± 6.8 months(median 43.1 months,range,30.2-54.4 months).Median recurrence free survival(RFS)in MVI positive group was 14.0months [95% confidence interval(CI)11.5-16.6],which was shorter than 25.1 months(95%CI 17.6-32.6)in MVI negative group(P = 0.003).Similarly,the median overall survival(OS)in MVI positive group was 25.2 months(95%CI 21.9-28.5),which was shorter than that in MVI negative group 48.1 months(95%CI 41.8-54.4)(P = 0.01).Logistic regression analysis showed that preoperative CTC,preoperative alpha-fetoprotein(AFP)and tumor diameter were independent risk factors for MVI.When CTC,AFP,tumor diameter and combined parameters were included,ROC model analysis showed that when CTC was 5,the sensitivity and specificity of MVI prediction was 78.5% and 88.0%respectively,area under curve(AUC)was 0.8245(95%CI 0.7511-0.8980)and Youden index was 0.665;when AFP was 297.3 ng/m L,the sensitivity and specificity of MVI prediction was 87.3% and 53.5% respectively,AUC was 0.6997(95%CI 0.6082-0.7912)and Youden index was 0.408;when tumor diameter was 3.7 cm,the sensitivity and specificity of MVI prediction was 57.0% and 75.9% respectively,AUC was 0.6854(95%CI0.5954-0.7754)and Youden index was 0.329 and the sensitivity and specificity of the combined parameters were 77.9% and 93.3%,respectively,the AUC was 0.8657(95%CI0.8026-0.9288)and Youden index was 0.712.Conclusion: MVI positive patients had a worse prognosis after hepatectomy than MVI negative patients.Preoperative CTC was better than preoperative AFP and tumor diameter indicators in predicting the existence of MVI,and the combination of the three indicators had the highest accuracy in predicting MVI.Effective prediction of MVI had practical significance for surgical resection planning and prognosis evaluation.Part Ⅱ: Relationship Between Dynamic Changes of Peripheral Circulating Tumor Cells and Postoperative Recurrence or Extrahepatic Metastasis of Hepatocellular Carcinoma after HepatectomyObjectives: Repeated sampling and dynamic detection are one of the advantages of liquid biopsy.Circulating tumor cells(CTC)were considered objective evidence of the presence of tumors in the blood,which can be used to dynamically monitor tumor recurrence and metastasis.The purpose of this study was to explore the relationship between the dynamic changes of CTC before,during and after surgery and the early recurrence,non-early stage,and extrahepatic metastasis.Methods: A total of 137 patients who were diagnosed with hepatocellular carcinoma(HCC)and underwent hepatectomy in the Hepatic Surgery Department of Tongji Hospital,Tongji Medical College of Huazhong University of Science and Technology on November2016-November 2018 were recruited.Peripheral blood CTC levels were collected and detected before surgery,during surgery,postoperative one week,one month,two months,three months,six months and one year.At the end of follow-up,according to the time of recurrence,the patients were divided into three groups: early recurrence group(within one year after surgery),non-early recurrence group(one year later),and non-recurrence group,and the difference of the dynamic changes of CTC in each group was compared.Cox proportional regression analysis were used to evaluate independent risk factors for early recurrence.Results: The mean follow-up time was 43.5 ± 6.8 months(median 43.1 months,range,30.2-54.4 months).42 cases(30.7%)had early recurrence,50 cases(36.5%)had non-early recurrence,and 45 cases(32.8%)had non-recurrence.Compared with preoperative,intraoperative CTC of the three groups had no significant increase(7.3 ± 6.9 vs.7.5 ± 5.8,P = 0.714;5.0 ± 3.6 vs.5.6 ± 5.8,P = 0.176;3.4 ± 2.6 vs.3.6 ± 2.8,P = 0.460).In the early recurrence group,the postoperative CTC level did not decrease at 1 week after surgery compared with the intraoperative level(7.5 ± 5.8 vs.7.6 ± 5.1,P = 0.950)and was persistently high level after operation.However,the number of CTC in patients with non-early recurrence decreased significantly 1 week after surgery(5.6 ± 5.8 vs.2.0 ± 4.1,P= 0.002),and remained at a low level.In the non-recurrence group,CTC decreased significantly one week after hepatectomy(3.6 ± 2.8 vs.1.2 ± 2.3,P < 0.001),and then continued to decline until it reached zero.Portal vein tumor thrombus(PVTT)[hazard ratio(HR)8.569,95% confidence interval(CI)2.687-20.264],Barcelona Clinic Liver Cancer(BCLC)stage B or C(HR 5.268,95%CI 1.5744-10.336),microvascular invasion(MVI)(HR 3.245,95%CI 1.247-5.698),CTC ≥ 4(HR 10.855,95%CI 3.678-32.036)were independent risk factor for early recurrence.Preoperative CTC level was significantly higher in patients with extrahepatic metastasis than in patients without extrahepatic metastasis(12.7 ± 10.8 vs.4.5 ± 3.0,P < 0.001).However,there was no significant difference in intraoperative CTC compared with preoperative CTC in recurrence without extrahepatic metastasis group and recurrence with extrahepatic metastasis group(5.5 ± 4.9vs.4.5 ± 3.0,P = 0.178;12.8 ± 8.2 vs.12.7 ± 10.8,P = 0.957).Conclusion: The change of postoperative CTC was closely related to recurrence.The continuous high level of postoperative CTC suggested the possibility of early recurrence,while the continuous decrease of postoperative CTC indicated a low risk of recurrence.The occurrence of extrahepatic metastasis was associated with high preoperative CTC level,but not with intraoperative CTC change.Following the principle of “no-touch” in surgery did not lead to the increase of intraoperative CTC level.Part Ⅲ: Clinical Research of PD-1/PD-L1 Combined with TKIs in the Treatment of Advanced Primary Liver CancerObjectives: A retrospective analysis was performed on 235 patients with unresectable primary liver cancer(PLC)who received programmed cell death protein-1/ligand inhibitors(PD-1/PD-L1)combined with tyrosine kinase inhibitors(TKIs).To compare the therapeutic effects of PD-1/PD-L1 inhibitors combined with TKIs between initially diagnosed unresectable PLC and recurrent unresectable PLC after hepatectomy.Methods: A retrospective analysis was performed on 235 patients with unresectable PLC treated in Department of Hepatic Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology from January 2019 to June 2021.Patients were divided into two groups: initially diagnosed unresectable PLC(143 cases)and recurrent unresectable PLC after hepatectomy(92 cases).Tumor therapeutic response was evaluated according to the modified response evaluation criteria in solid tumors(m RECIST).The main outcomes were objective response rate(ORR),disease control rate(DCR),duration of response(DOR)and overall survival(OS),while the secondary outcomes were to the time of remission(TTR).The survival curve was drawn by Kaplan-Meier method,and Log-Rank(Mantel-Cox)method was used to test statistic difference.Results: The mean follow-up time was 19.5 ± 6.4 months(median 18.3 months;range 4.9to 34.7 months).Patients had an ORR of 34.9%,a DCR of 74.9%.The TTR was 2.5 ± 1.1months.The median DOR was 16.6 months [95% confidence interval(CI)12.7-20.5] for82 patients with confirmed remission,and the median OS was 18.9 months(95%CI16.5-19.4)for 235 patients.The incidence of grade 2 and above adverse events was 41.7%(98/235),and the incidence of severe adverse events(grade 4-5)was 4.7%(11/235).The combined therapeutic efficacy of initially diagnosed unresectable PLC group and recurrent unresectable PLC group after hepatectomy were compared.The ORR of the two groups were 33.6% and 37.0%(P = 0.595),and the DCR rates were 74.1% and 78.3%(P = 0.340),respectively.The DOR of the two groups were 15.0 months(95% CI 9.3-20.6)and 18.5months(95% CI 12.6-24.4),respectively(P = 0.25).The median OS of the two groups were 16.6 months(95% CI 14.2-19.1)and 21.1 months(95% CI 16.5-25.6),respectively(P= 0.31).Conclusion: PD-1/PD-L1 inhibitors combined with TKIs was safe,effective and well tolerated in the treatment of unresectable PLC.The efficacy of combination therapy in patients with recurrent unresectable PLC after hepatectomy was the same as that in patients with initially diagnosed unresectable PLC.Part Ⅳ: Comparison of Efficacy of TACE,PD-1/PD-L1 Inhibitor and TKIs in the Treatment of Unresectable Primary Liver CancerObjective: To retrospectively analyze and compare the prognosis differences of transcatheter arterial chemoembolization(TACE)(TACE group),programmed cell death protein-1/ligand inhibitors(PD-1/PD-L1)combined with tyrosine kinase inhibitors(TKIs)(PT group)and PD-1/PD-L1 inhibitors combined with TKIs combined with TACE(PTT group)in patients with unresectable primary liver cancer(PLC).Methods: From January 2019 to June 2021,281 patients with unresectable PLC admitted to the Department of Hepatic Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,were retrospectively analyzed.According to different therapeutic schemes,the patients were divided into three groups: TACE group(108 cases);PT group(74 cases)and PTT group(99 cases).Tumor therapeutic response was evaluated according to the modified response evaluation criteria in solid tumors(m RECIST).The main outcomes were objective response rate(ORR),disease control rate(DCR),duration of response(DOR)and overall survival time(OS),while the secondary outcomes were to the time of remission(TTR)and successful conversion rate.Kaplan-Meier method was used to draw survival curve,and Log-Rank(Mantel-Cox)method was used to test statistic difference.Results: PTT group had higher ORR(39.4% vs.13.9%,P < 0.001)and DCR(79.8% vs.45.4%,P < 0.001)than TACE group,but there was no statistic difference in ORR(39.4%vs.29.7%,P = 0.188)and in DCR(79.8% vs.71.6%,P = 0.211)between PTT group and PT group.The TTR of PTT group was shorter than that of PT group(1.9 ± 2.3 months vs.2.8 ± 3.1 months,P < 0.001);The TTR of PT group was shorter than that of TACE group(2.8 ± 3.1 months vs.3.2 ± 1.2 months,P = 0.002).The 1-year and 2-year survival rates were 90% and 46% in PTT group,86% and 26% in PT group and 50% and 17% in TACE group.The median OS of PTT group,PT group and TACE group were 21.9 months [95%confidence interval(CI)19.3-24.5)],17.5 months(95% CI 16.1-18.9)and 12.0 months (95% CI 10.7-13.3)(P < 0.001).The overall successful conversion rate of all patients was7.1%(20/281).The successful conversion rates of the three groups were13.1%,8.1% and <1% respectively.PTT group had higher successful conversion rate than TACE group(13.1% vs.< 1%,P < 0.001),and PT group also had higher successful conversion rate than TACE group(8.1% vs.< 1%,P = 0.019).Conclusion: The efficacy of PD-1/PD-L1 combined with TKIs combined with TACE was superior to TACE alone and PD-1/PD-L1 combined with TKIs in the treatment of unresectable PLC.PD-1/PD-L1 combined with TKIs combined with TACE had higher objective response rate,successful conversion rate,shorter to the time of remission and longer survival time. |
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