Purpose:Tumor growth and metastasis depend on angiogenesis, which is regulated by stimulating and inhibitory factors. Evaluation of angiogenesis of tumor is of value in predicting prognosis, and anti angiogenic therapy is a promising treatment of cancer. Genetic bases for angiogenesis control and search for new angiogenesis inhibitory factors remain to be studied in the future. Studies on relationship between angiogenic factors, such as vascular endothelial growth factors and basic fibroblast growth factors, and angiogenesis induced by hepatocellular carcinoma(HCC) are summarized in this paper. Experimental studies imply that anti angiogenic therapy will become a new modality in the treatment of HCC.

ular perfusion in tumors objectively, which is potential in monitoring tumor vascular response to antiangiogenic therapy.

Objective To investigate the relationship between hemodynamic parameters from quantitative analysis of contrast-enhanced ultrasonography (CEUS) on hepatocellular carcinoma (HCC) and pathological tumor differentiated grades. Methods Seventy-seven HCC lesions were examinated and off-line analyzed with dynamic images. Quantitative parameters such as slope of decrease to half of peak (SD), increased signal intensity (ISI), area under the curve (AUC) and blood flow coefficient (BF) were acquired, and the standardized values (sISI, sAUC and sBF) included the ratio of parameters from tumor to those from hepatic parenchyma. These quantitative parameters were correlated with tumor grades according to Edmonson criteria. Results There was significant difference (P＜0.05) of SD, AUC and BF, as well as standardized values (sISI, sAUC and sBF) between different grades of HCC. AUC, BF, sISI, sAUC and sBF were negative correlated with differentiated grades, respectively (P＜0.05). Well-differentiated HCC had significantly higher perfusion values than HCC of other grades (P＜0.05). Conclusion Quantitative analysis of CEUS can assess differentiation of HCC indirectly, and might reveal biological behavior of malignant tumors.

Objective: To explore the clinical significance of transcription factor Sp1 expression in hepatocellular carcinoma (HCC) and association between Sp1 expression and survival in HCC patients. Methods:With the use of immunoreactivity, Sp1 expres-sion and its correlation with other clinicopathological characteristics were examined in a tissue microarray that contains samples from 98 HCC patients. Results:HCC tissues expressed markedly higher levels of Sp1 than did adjacent normal liver tissues. Sp1 expression was closely associated with microvascular invasion, which suggests that HCC with more microvascular invasion is prone to have in-creased Sp1 expression. Overexpression of Sp1 correlates with significantly shorter overall survival and higher recurrence rates in HCC patients after curative resection. Conclusion:Transcription factor Sp1 may be an independent prognostic factor for both overall surviv-al and cumulative recurrence rate.

Objective To investigate the feasibility of contrast-enhanced ultrasonography(CEUS) in quantitative assessment of angiogenesis in patients with hepatocellular carcinoma(HCC).Methods Thirtythree patients with HCCs confirmed by pathology underwent CEUS in one week preoperatively.The presets and contrast dosage were fixed in all the studies.The new quantitative software with GAMMA fitting technique was used to analyze the dynamic images offline.The quantitative parameters such as baseline intensity,increased signal intensity(ASI),decent curvature(a2),up slope rate(a3),arrive time(AT), time to peak(TTP), accelerate time(ACT),peak intensity(PI),and area under curve(AREA) were calculated.The pathological specimen was stained with CD34 antibady and microvessel density (MVD) was calculated automatically.The correlation between parameters of CEUS and MVD was analyzed statistically.Results The parameters of ASI, a2, a3, AT, TTP, PI and ACT in the tumor were significantly different from those in liver parenehyma ( P＜0.01 ).The value of a2 in the tumor was correlated with MVD, the standardized ASI and AREA were correlated with MVD (P＜0.05).Conclusions The quantitative analysis with CEUS reflects the microvascular perfusion flow objectively.It provides a noninvasive imaging method to assess the angiogenesis in HCCs.

Objective To summarize the techniques of anatomical liver resection for the treatment of hepatocellular carcinoma(HCC).Methods The clinical data of 125 patients with solitary HCC who underwent anatomical liver resection at the Zhongshan Hospital from January 2005 to December 2006 were retrospectively analysed.The inflow and outflow of hepatic segments to be resected were selectively clamped,then the main branches of portal vein and hepatic artery were ligated,and the ischemic hepatic segments were resected en bloc.Kelly forceps were used to crash and clamp the liver cut surface.The stumps of left and right hepatic ducts were continuously sutured with Prolene sutures.For tumors with the size above 10 cm in diameter,hepatectomy with anterior approach and liver hanging maneuver were adopted.Bile leakage was checked by injecting methylene blue or covering a gauze on the liver cut surface.Results The mean blood loss of all patients was 250 ml(100-6000 ml),and 32 of them needed blood transfusion.The morbidity was 23%(29/125).No patient died within 30 days after the operation,and 6%(5/83)of patients were found with residual tumor by postoperative arteriography.Conclusion Anatomical liver resection may improve the safety of operation,prevent the injury of great vessels and thus improve the efficacy.

Objective To study the risk factors of post-hepatectomy hepatic decompensation (PHD) in patients with hepatocellular carcinoma.MethodWe reviewed 562 patients with Child-Pugh A classification,who underwent partial hepatectomy for hepatocellular carcinoma at Zhongshan Hospital,Fudan University between July 1st 2007 to December 31st 2007,to study the risk factors of hepatic decompensation.ResultsPreoperative high total bilirubin (TB) and low prealbumin (PA) were independent risk factors of PHD by logistic multivariate analysis ROC analysis revealed the cut-offs of preoperative PA predicting PHD were 0.14 g/L (sensitivity 41.4％; specificity 83.1％).The incidence of PHD was 16.0％ when TB≥20.4 μmol/L and PA＜0.14 g/L(OR=7.276,P=0.002).ConclusionThe Child-Pugh A patients recovered well when the preoperative liver function was as follows:TB＜20.4 μmol/L and PA≥0.14 g/L.

Objective To investigate the risk factors influencing early and late recurrences after resection of primary clear cell carcinoma of the liver (PCCCL).Methods 214 PCCCL patients treated by curative resection from January 1996 to March 2006 were retrospectively analyzed.Recurrences were classified into early (≤1 year) and late (＞1 year) recurrences.Results 99 patients developed recurrences,with early recurrence in 28 patients and late recurrence in 71 patients.The 3-and 5-year overall survival (OS) rates for recurrent PCCCL were significantly worse than those with no recurrence (68.7％ and 46.2％ vs 72.2％ and 64.3％,P=0.003).The 1-,3-and 5-year OS rates for late recurrence were 100％,80.3％ and 54.6％,which were significantly better than those with early recurrence (85.7％,39.3％ and 25.0％,P=0.001).On multivariate analysis,aminoleucine transferase (ALT) level and vascular invasion were independent risk factors for early recurrence,while age was the only significant risk factor for late recurrence.Conclusions The time to recurrence was the main determinant for prognosis of recurrent PCCCL,Clarifying the different risk factors for early and late recurrences will help postoperative follow-up,early detection of recurrence,and hopefully will improve survival.

Objective To investigate the clinicopathologic characteristics and prognostic factors of primary clear cell carcinoma of the liver(PCCCL). Methods A total of 214 PCCCL patients treated by curative resection from January 1996 to March 2006 were retrospectively analyzed. Results The 1-,3-,and 5-year overall survival (OS) rates for PCCCL patients were significantly better than those of non-clear cell hepatocellular carcinoma ( NHCC ) patients ( 90.2％,70.6％,and 55.9％ vs 82.8％,62.7％ and 47.7％,P =0.001 ).Tumor size was significantly smaller in PCCCL group than in NHCC group ( x2 =4.37,P =0.04 ).Tumors of PCCCL group had a lower incidence of vascular invasion ( x2 =9.42,P =0.002) and a better differentiation than those of NHCC group ( x2 =4.30,P =0.04).Serum a-fetoprotein (AFP) level,tumor size,liver cirrhosis,and vascular invasion were independent risk factors impacting OS and disease-free survival (DFS) of PCCCL. Conclusions PCCCL is an uncommon subtype of HCC and has different clinicopathologic characteristics from NHCC. Complete surgical resection is the optimal treatment for PCCCL and its prognosis is much better than that of NHCC.

Objective:To investigate the clinical efficacy of the combination therapy of lenvatinib and programmed death-1 (PD-1) antibodies in unresectable or advanced hepatocellular carcinoma (HCC).Methods:The retrospective and descriptive study was conducted. The clinico-pathological data of 59 patients with unresectable or advanced HCC who were admitted to Zhongshan Hospital of Fudan University from September 2018 to January 2020 were collected. There were 54 males and 5 females, aged from 25 to 73 years, with a median age of 52 years. All 59 patients underwent combination therapy with lenvatinib and PD-1 antibodies including 43 cases undergoing first-line therapy and 16 cases who cannot tolerate first-line therapy or with tumor progressed after first-line therapy undergoing second-line therapy. Observation indicators: (1) clinical efficacy; (2) adverse drug reactions and treatment; (3) follow-up and survival. Follow-up was performed using outpatient examination or telephone interview to detect tumor diameter of the target lesion, overall survival and progression free survival of patients up to December 2020. Measurement data with skewed distribution were expressed as M ( P25,P75) or M (range). Count data were represented as absolute numbers and (or) percentages. The Kaplan-Meier method was used to calculate the median duration of response (DoR), median overall survival time, median progression free survival time, survival rates and draw survival curves. Results:(1) Clinical efficacy: the objective response rate (ORR), complete response rate (CR), partial response rate (PR), stable disease rate (SD), progression disease rate (PD), time to response (TTR) and median DoR of 59 HCC patients were 37.3%(22/59), 11.9%(7/59), 25.4%(15/59), 37.3%(22/59), 25.4%(15/59), 2.6 months(2.1 months, 4.0 months), 6.3 months[95% confidence interval ( CI) as 2.2 to 10.5 months], respectively. The ORR, CR, PR, SD, PD and TTR of 43 HCC patients undergoing first-line therapy were 41.9%(18/43), 16.3%(7/43), 25.6%(11/43), 37.2%(16/43),20.9%(9/43), 2.2 months(2.0 months, 3.5 months), respectively. The median DoR of 43 patients undergoing first-line therapy was not reached. The ORR, CR, PR, SD, PD, TTR and median DoR of 16 HCC patients undergoing second-line therapy were 4/16, 0, 4/16, 6/16, 6/16, 3.8 months (3.6 months, 4.1 months), 4.2 months(95% CI as 2.0 to 6.3 months), respectively. Six of 59 HCC patients underwent R 0 resection due to tumor converting to resectable HCC with the conversion and resection rate of 10.2%(6/59). Among the 6 patients, 5 cases undergoing first-line treatment had the conversion and resection rates of 11.6% (5/43) and 1 case undergoing second-line treatment had the conversion and resection rates of 1/16, respectively. (2) Adverse drug reactions and treatment: 25 of 59 HCC patients underwent 3 to 4 grade adverse drug reactions with the incidence of 42.4%(25/59). Among the 25 patients, 10 cases including 5 cases undergoing first-line therapy and 5 cases undergoing second-line therapy had the level of gamma glutamyltransferase >5×upper limit of normal (ULN), 9 cases including 4 cases undergoing first-line therapy and 5 cases undergoing second-line therapy had the level of aspartate aminotransferase >5×ULN, 5 cases including 4 cases undergoing first-line therapy and 1 case undergoing second-line therapy occurred gastrointestinal hemorrhage, 4 cases undergoing first-line therapy had the level of white blood cell count <2.0×10 9/L, 4 cases including 1 case undergoing first-line therapy and 3 cases under-going second-line therapy had the level of total bilirubin >3×ULN, 3 cases undergoing first-line therapy had the level of neutrophil count <1.0×10 9/L, 3 cases including 2 cases undergoing first-line therapy and 1 case undergoing second-line therapy occurred ascites, 2 cases including 1 case undergoing first-line therapy and 1 case undergoing second-line therapy had the level of platelet count <50.0×10 9/L, 2 cases undergoing first-line therapy had the level of alanine aminotransferase >5×ULN, 2 cases undergoing first-line therapy occurred hyponatremia, 2 cases including 1 case undergoing first-line therapy and 1 case undergoing second-line therapy occurred pulmonary infection, 2 cases including 1 case undergoing first-line therapy and 1 case undergoing second-line therapy occurred type 1 diabetes, 1 case undergoing first-line therapy occurred hypokalemia, 1 case undergoing first-line therapy occurred myocarditis, 1 case undergoing first-line therapy occurred hypophysistis, 1 case undergoing first-line therapy occurred bullous dermatitis, 1 case undergoing first-line therapy occurred hypertension. Three of 59 HCC patients underwent 5 grade adverse drug reactions ,with the incidence of 5.1%(3/59), including 1 case undergoing first-line therapy with immune hepatitis, 1 case undergoing second-line therapy with immune pneumonia and 1 case undergoing second-line therapy with immune enteritis. Some of patients underwent multiple adverse drug reactions at the same time. Twenty five patients undergoing 3 to 4 grade adverse drug reactions were relieved with the treatment of drug reduction, drug withdrawal, symptomatic treatment or hormone therapy. Three patients undergoing 5 grade adverse drug reactions died after being treated with high-dose hormone shock and hepatoprotective treatment. (3) Follow-up and survival: all 59 patients were followed up for 1.5 to 25.2 months, with a median follow-up time of 13.3 months. Of them, patients undergoing first-line therapy were followed up for 1.9 to 25.2 months, with a median follow-up time of 13.5 months. During follow-up,20 cases undergoing first-line therapy died with the fatality rate of 46.5%(20/43). Patients undergoing second-line therapy were followed up for 1.5 to 24.4 months, with a median follow-up time of 10.8 months. During follow-up, 10 cases undergoing second-line therapy died with the fatality rate of 10/16. Up to the latest follow-up, the tumor diameter of the target lesion in all 59 patients, in patients undergoing first-line therapy and in patients undergoing second-line therapy was 75 mm(38 mm, 125 mm), 74 mm(36 mm, 116 mm), 84 mm(48 mm,150 mm), respectively. The ratio of tumor diameter of the target lesion at latest follow-up to tumor diameter of the target lesion at baseline were -9.05%(-27.3%, 19.7%), -16.1%(-28.8%, 13.6%), 13.2%(-24.7%, 23.5%) for all 59 patients, patients undergoing first-line therapy and patients undergoing second-line therapy, respectively. The median overall survival time and median progression free survival time of patients undergoing first-line therapy and patients undergoing second-line therapy were 17.1 months(95% CI as 11.0 to 23.2 months), 10.8 months(95% CI as 5.0 to 16.6 months) and 10.8 months(95% CI as 9.2 to 12.4 months), 3.0 months(95% CI as 1.6 to 4.4 months), respectively. Conclusion:For unresectable or advanced HCC, combination therapy with lenvatinib and PD-1 antibodies can obtain effective antitumor activity and less incidence of adverse drug reactions.