参桃软肝方对中晚期肝癌保肝抑瘤的临床及实验研究
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摘要
研究目的
1.整理原发性肝癌中医病症证文献资料,重点阐述肝癌中医病症证理论。收集临床首诊中晚期原发性肝癌患者病例为研究对象,总结原发性肝癌中医病症证运用规律及病症证相互关系,探索中晚期肝癌的中医药诊疗思路。其次,分析中晚期肝癌临床预后影响因素,观察参桃软肝方对中晚期原发性肝癌保肝抑瘤的临床研究,初步探讨中医病症证三联诊疗思路在原发性肝癌治疗中的临床应用,探索应用中医药综合治疗中晚期肝癌的最佳方案以指导临床。
2.探讨参桃软肝方对H_(22)肝癌小鼠模型的抑瘤作用及对瘤组织VEGF表达影响的实验研究,为参桃软肝方的临床应用奠定实验基础。研究方法
一临床研究
1.纳入2007年1月～2009年1月期间广州中医药大学附属第一医院门诊及住院的首次就诊154例中晚期肝癌患者,在初步确定原发性肝癌诊断标准的基础上,采用回顾性对照的研究方法,对临床收集病例进行调查、统计,分析肝癌患者临床疾病资料;根据四诊概括,收集病人主要症状与体征,统计常见症状及体征出现率,提供辨证依据;结合病机种类及脏腑辨证,将纳入病例辨证分型,统计常见临床中医证型出现率。
2.对临床收集154例中晚期肝癌的临床分期、肝功能分级与常见中医主症、中医证型作相关性病症证分析。
3.154例中晚期肝癌病例随访,分析生存期,并对性别、年龄、临床分期、治疗方法、治疗前瘤体大小、治疗前卡氏评分、中医证型、AFP水平、Child-Pugh分级等9项临床预后影响因素统计中晚期肝癌生存期的预后影响因素。
4.154例中晚期肝癌病例中选取符合纳入标准和排除标准47例患者,分为中医组(全程中医治疗)15例和中西组(同期采用TACE、消融治疗同时配合中医治疗)32例两组。广州药学院附属第一医院肿瘤科同期收治采用介入治疗或消融治疗的肝癌患者为西医组21例。中医组采用辨病、辨证、随症相结合的治疗方法,辨病治疗采用参桃软肝方合并槐耳颗粒口服,辨证治疗按照辨证分型的基础上随症加减。比较三组治疗前后瘤体病灶大小、卡氏评分改变、肝功能改善等情况。
二实验研究
以肝癌H_(22)小鼠模型为研究对象,共建立皮下实体瘤小鼠移植模型40只。按照完全随机的分组方法将SPF级雄性昆明小鼠分为4组:模型组、中药低剂量组、中药高剂量组和CTX组(阳性对照组),各10只。自造模第2天开始灌胃,模型组予等量生理盐水,中药低、高剂量组根据小鼠与人体表面积比例,按0.86g/kg、1.34g/kg不同浓度中药溶液灌胃,CTX组予CTX腹腔注射20mg/kg/日,连续14天。给药结束后24h,各组小鼠颈椎脱臼法处死,称重及测量肿瘤体积,计算抑瘤率。肿瘤组织常规HE染色,观察形态变化。免疫组化法测定瘤体VEGF表达。
研究结果
一临床研究
1.中医病症证资料分析:不同治疗方法在年龄方面有显著性差异(P＜0.05),在不同性别方面中医组和其他两组无显著性差异(P＞0.05),在临床分期方面无显著性差异(P＞0.05),在肝功能分级方面有显著性差异(P＜0.05),而且肝功能A级与B级比较有显著性差异(P＜0.05)。不同Child-Pugh分级在年龄方面无显著性差异(P＞0.05),在性别方面有显著性差异(P＜0.05),在临床分期方面有显著性差异(P＜0.05),而且Ⅲ期与Ⅳ期(Ⅳa、Ⅳb)比较有显著性差异(P＜0.05)。中晚期肝癌临床最常见症状:上腹肿块、胸胁疼痛、全身消瘦、神疲倦怠、脉弦。中医证型中以肝郁脾虚证型常见(71.43%)。
2.中医病症证相关性分析:中医各证型同主症相关性无统计学意义(P＞0.05)。主症上腹肿块与临床分期呈正相关(P=0.008),余主症与临床分期相关性无统计学意义(P＞0.05)。上腹肿块与肝功能分级好坏呈正相关(P=0.000),全身消瘦、神疲倦怠与肝功能分级好坏呈正相关(P=0.047,P=0.001),中医各证型与临床分期相关性无统计学意义(P＞0.05)。肝胆湿热型与肝功能分级呈正相关(P=0.041),余中医证型与肝功能分级相关性无统计学意义(P＞0.05)。
3.肝癌预后分析:154例原发性肝癌患者,平均生存期548天,中位生存期为380天。3月、6月、1年生存率分别为73.4%、63.0%和47.2%。分析9项与生存期有关因素进行预后分析,单因素分析显示:临床分期、治疗方法、中医证型、治疗前AFP水平、Child-Pugh分级等5项因素有统计学意义,多因素分析仅Child-Pugh分级有统计学意义,得出与预后相关因素为Child-Pugh分级。
4.瘤体评价疗效:中医组瘤体缓解率为0%,稳定率为53.33%,其中Ⅲ期稳定率最高,达100%。中西组瘤体缓解率为15.63%,稳定率为81.25%,其中Ⅲ期稳定率最高,达90%。西医组瘤体缓解率为14.28%,稳定率为80.95%,其中Ⅲ期稳定率最高,达85.71%。
5.卡氏评分评价:中医组改善率60%,与治疗前比较,无显著性差异(P=0.334＞0.05)。中西组改善率59.38%,与治疗前比较,无显著性差异(P=0.462＞0.05)。西医组改善率33.33%,与治疗前比较,无显著性差异(P=0.095＞0.05)。
6.肝功能分级评价:中医组和中西组治疗后,肝功能分级与治疗前比较有显著性差异(P＜0.05)。西医组治疗后,肝功能分级与治疗前比较无显著性差异(P＞0.05)。
7.肝功能指标评价:中医组治疗中和治疗后,ALT、AST、ALP、GGT、TB、IB、TBA、AFU与治疗前比较,均无显著性差异(P＞0.05),ALB较治疗前降低,有显著性差异(P＜0.05),治疗后DB较治疗前升高、PA较治疗前降低,有显著性差异(P＜0.05)。中西组介入术后1周和4周ALT、AST、ALP、GGT、TB、DB、IB、TBA、AFU与治疗前比较,均无显著性差异(P＞0.05),ALB较术前降低,有显著性差异(P＜0.05)。介入术后4周PA较术前降低,有显著性差异(P＜0.05)。西医组介入术后1周和4周ALP、GGT、DB、IB、TBA、AFU与治疗前比较,均无显著性差异(P＞0.05)。介入术后1周ALT、AST、TB较术前升高、PA较术前降低,有显著性差异(P＜0.05),ALB较术前降低,无显著性差异(P＞0.05)。介入术后4周ALT、AST、TB、PA与治疗前比较,均无显著性差异(P＞0.05),ALB较术前降低,有显著性差异(P＜0.05)。
二实验研究
1.本课题所有小鼠造模均接种成功,全部成瘤,成功率为100%,皮下移植肝癌模型制作成功。
2.中药低、高剂量组均有不同程度的抑瘤作用,抑瘤率分别为32.9%、38.9%,各组瘤重与模型组相比均有显著性差异(P＜0.05)。
3.各组HE染色显示:中药高、低剂量组肿瘤组织存在不同程度上的细胞坏死区,肿瘤细胞核分裂相对减少,癌巢间及周围微血管相对减少。
4.应用免疫组织化学方法,检测荷瘤小鼠瘤块VEGF表达情况,结果显示:CTX组及中药低剂量、高剂量组VEGF染色评分均显著低于模型组(P＜0.05)。与CTX组比较,中药低剂量组和中药高剂量组VEGF染色评分均无显著性差异(P＞0.05)。中药低剂量组与中药高剂量组之间亦无显著性差异(P＞0.05)。
研究结论
1.肝癌病症证相结合的诊疗模式是中西医临床实践经验的结晶,是中西医肿瘤学优于单一学科治疗方式的理论基础,体现了循证医学、个体化治疗的肿瘤治疗新思维。
2.参桃软肝方治疗中晚期肝癌的优势体现在稳定瘤体、提高生存质量、与西医配合能减轻介入或消融等侵入性治疗手段所致的肝损害,提高耐受性及延长生存期。
3.参桃软肝方具有直接抑制肿瘤生长和减轻瘤重的作用,并对荷瘤小鼠肿瘤组织VEGF的表达有显著抑制作用,VEGF可能是参桃软肝方抗肿瘤作用机制之一,减少肿瘤细胞新生血管的生成,从而减缓肿瘤的侵袭和转移。
Objective
1)To make retrospective analysis about primary Hepatocellular Carcinoma(HCC) about disease,symptom and syndrome from literature sources;To summarize the theory of HCC about diease、symptom and syndrome;To explore the relationship between diease、symptom and syndrome.To identify the influence of some clinical factors on prognosis and to observe the therapeutic effect Shentao Ruangan Recipe(STR) in the treatment of stageⅢorⅣof HCC.
2)To investigate the regulatory effect of STR on the growth of H_(22) tumor and the expression of vascular endothelial growth factor(VEGF) in transplanted H_(22) tumor of mice.
Methods
Clinincal study
1)154 cases of inpatients and outpatients of stageⅢorⅣof HCC in the first affiliated hospital of Guangzhou University of TCM were enrolled between January 2007 and January 2009.Based on diagnostic criteria for HCC,clinical investigation cases were collected,clinical common symptoms and signs were analysed,occurrence of TCM types were summarized.
2)154 cases of stageⅢorⅣof HCC were analyzed about the relationship among diease、symptom and syndrome.
3)154 cases of stageⅢorⅣof HCC were followed up,prognosis influence of nine clinical prognostic factors such as gender,age,clinical stage, treatment methods,pre-treatment tumor size,Karnofsky score before treatment, TCM Syndrome,AFP level and Child-Pugh classification were analyzed using Kaplan-Meier's method and COX model.
4)47 cases were divided into 15 cases of TCM group and 32 cases of combined group.TCM group was treated by oral taking of STR and Huaier-granula and it also was accomplished with diagnosis and treatment based on an overall analysis of the illness and the patients condition.While combined group was treated with TACE(chemoembolization) and ablation combined with TCM.21 cases of Western group were enrolled in the first affiliated hospital of Guangdong College of pharmacy which treated only interventional method.The clinical efficacy of treatment in the three groups was evaluated by the change of tumor size reducing rate and KPS scores and the liver function.
Experimental study
The transplant tumor model of H_(22) hepatocarcinoma in mice was established.Forty mice were randomly divided into four groups,the CTX group,the STR low group, the STR high group and the control group,they were treated respectively with imtraperitoneal injection of CTX 20mg/kg/day,oral administration of STR in a dose of 0.86g/kg,1.34g/kg and equal volume of saline,the medication was given for 14 times totally.Twenty-four hours after the last administration, we calculated the tumor volume;The weight of the transplanted tumor mass were detected to work out the inhibitory rate;The histological and ultra structural changes in tumor tissue were observed by Hematoxylin-eosin(HE) staining; VEGF expression in tumor tissue was detected by S-P immunohistochemistry method.
Results
Clinincal study
1)Date analysis:Different treatment in terms of age with significant difference(P＜0.05);in terms of genger between TCM group and the other groups with no significant difference(P＞0.05);in terms of clinical stages with no significant difference(P＞0.05);in terms of liver function classification with significant difference(P＜0.05).the liver function class A and B with significant difference(P＜0.05).Different Child-Pugh class in terms of age with no significant difference(P＞0.05);in terms of genger with significant difference(P＜0.05);in terms of clinical stages with significant difference (P＜0.05),periodⅢandⅣwith significant difference(P＜0.05).The most common symptoms of stageⅢorⅣof HCC were upper abdominal mass,liver pain, body weight loss,fatigue,pulse string.Common TCM syndrome type was weak spleen and strong liver functions type(71.43%).
2)Correlation analysis:The correlation between syndrome type and symptom had no significant difference(P＞0.05).Upper abdominal mass had positively correlated with clinincal stage(P=0.008),The correlation between the other symptoms and clinical stage had no significant difference(P＞0.05).Upper abdominal mass had positively correlated with Child-Pugh classification(P =0.000),Body weight loss and fatigue had positively correlated with Child-Pugh classification(P=0.047,P=0.001).The correlation between syndrome type and clinical stage had no significant difference(P＞0.05). Dampness-heat of liver and gallbladder had positively correlated with Child-Pugh classification(P=0.041).The correlation between the other syndrome type and Child-Pugh classification had no significant difference.
3)Prognosis analysis:The average survival time of 154 patients of HCC was 548 days,the overall median survival time(MST) of was 380 days,3 months, 6 months and one year survival rate was 73.4%,63.0%and 47.2%respectively.9 potential factors were analyzed:single-factor analysis showed that five factors such as clinical stage,treatment modalities,TCM syndrome type, AFP level before treatment,Child-Pugh classification were statistically significant.Multi-factor analysis showed that Child-Pugh grade of liver function was significant for survival.
4)Tumor efficacy evaluation:The tumor size reducing rate was 0%and the tumor size stabilizing rate was 53.33%in TCM group,the tumor size stabilizing rate of theⅢperiod reaching 100%was the highest.While those in combined group was 15.63%,81.25%respectively,the tumor size stabilizing rate of theⅢperiod reaching 90%was the highest.While those in western group was 14.28%,80.95%respectively,the tumor size stabilizing rate of theⅢperiod reaching 85.71%was the highest.
5)The quality of life score evaluation:The improve rate in TCM group was 60 %,compared with before treatment,the difference was no significant(P＞0.05).combined group was 59.38%,compared with before treatment,the difference was no significant(P＞0.05).Western group was 33.33%,compared with before treatment,the difference was no significant(P＞0.05).
6)Liver function classification evaluation:After treated,TCM group and combined group,compared with before treatment,the difference was significant (P＜0.05).Western group,compared with before treatment,the difference was no significant(P＞0.05).
7)Liver function evaluation:TCM group:in the middle of treatment and after treatment of ALT、AST、ALP、GGT、TB、IB、TBA、AFU,compared with before treatment, the difference was no significant(P＞0.05).ALB was decreased,the difference was significant(P＜0.05).After treated,DB increased,PA decreased,the difference was significant(P＜0.05).Combined group:After Intervention 1 week and 4 weeks of ALT、AST、ALP、GGT、TB、DB、IB、TBA、AFU,compared with those before treatment,the difference was no significant(P＞0.05).ALB was decreased,the difference was significant(P＜0.05).After Intervention 4 weeks of PA was decreased,the difference was significant(P＜0.05).Western group: After Intervention 1 week and 4 weeks of ALP、GGT、DB、IB、TBA、AFU,compared with those before treatment,the difference was no significant(P＞0.05).After intervention 1 week of ALT、AST、TB was increased,PA decreased,the difference was significant(P＜0.05).After Intervention 4 weeks of ALT、AST、TB、PA, compared with those before treatment,the difference was no significant (P＞0.05).
Experimental study
1)All mice model were inoculated successful,the tumors success rate was 100 %.liver transplantation subcutaneous model was successfully completed.
2)STR groups and the model group had significant effect on inhibiting the tumor weight(P＜0.05),when compared with the model group.The tumor inhibition rate was 32.9%in the low STR group;the tumor inhibition rate was 38.9%in the high STR group.
3)HE staining results showed that there were different degree of cell necrosis zones,split-phase reduction of tumor cell in tumor tissues of high-dose group and low-dose group.
4)The expression of VEGF:The results showed that the positive rate of VEGF of high-dose group and low dose group and CTX group were significantly lower than model group(P＜0.05).High-dose group and low dose group,compared with CTX group were no significant difference(P＞0.05).High-dose group and low-dose group also were no significant difference(P＞0.05).
Conclusion
1)Shentao Ruangan Recipe can stable tumor,improve KPS score and prolong the survival time of stageⅢorⅣof HCC.It can also reduce the damage to liver function caused by invasive treatment such as interventional and ablation.
2)STR could obviously inhibit the growth of H_(22) hepatocarcinoma and its mechanism may be related to the down-regulation of the protein expression of VEGF in tumor tissue.
1.整理原发性肝癌中医病症证文献资料,重点阐述肝癌中医病症证理论。收集临床首诊中晚期原发性肝癌患者病例为研究对象,总结原发性肝癌中医病症证运用规律及病症证相互关系,探索中晚期肝癌的中医药诊疗思路。其次,分析中晚期肝癌临床预后影响因素,观察参桃软肝方对中晚期原发性肝癌保肝抑瘤的临床研究,初步探讨中医病症证三联诊疗思路在原发性肝癌治疗中的临床应用,探索应用中医药综合治疗中晚期肝癌的最佳方案以指导临床。
2.探讨参桃软肝方对H_(22)肝癌小鼠模型的抑瘤作用及对瘤组织VEGF表达影响的实验研究,为参桃软肝方的临床应用奠定实验基础。研究方法
一临床研究
1.纳入2007年1月～2009年1月期间广州中医药大学附属第一医院门诊及住院的首次就诊154例中晚期肝癌患者,在初步确定原发性肝癌诊断标准的基础上,采用回顾性对照的研究方法,对临床收集病例进行调查、统计,分析肝癌患者临床疾病资料;根据四诊概括,收集病人主要症状与体征,统计常见症状及体征出现率,提供辨证依据;结合病机种类及脏腑辨证,将纳入病例辨证分型,统计常见临床中医证型出现率。
2.对临床收集154例中晚期肝癌的临床分期、肝功能分级与常见中医主症、中医证型作相关性病症证分析。
3.154例中晚期肝癌病例随访,分析生存期,并对性别、年龄、临床分期、治疗方法、治疗前瘤体大小、治疗前卡氏评分、中医证型、AFP水平、Child-Pugh分级等9项临床预后影响因素统计中晚期肝癌生存期的预后影响因素。
4.154例中晚期肝癌病例中选取符合纳入标准和排除标准47例患者,分为中医组(全程中医治疗)15例和中西组(同期采用TACE、消融治疗同时配合中医治疗)32例两组。广州药学院附属第一医院肿瘤科同期收治采用介入治疗或消融治疗的肝癌患者为西医组21例。中医组采用辨病、辨证、随症相结合的治疗方法,辨病治疗采用参桃软肝方合并槐耳颗粒口服,辨证治疗按照辨证分型的基础上随症加减。比较三组治疗前后瘤体病灶大小、卡氏评分改变、肝功能改善等情况。
二实验研究
以肝癌H_(22)小鼠模型为研究对象,共建立皮下实体瘤小鼠移植模型40只。按照完全随机的分组方法将SPF级雄性昆明小鼠分为4组:模型组、中药低剂量组、中药高剂量组和CTX组(阳性对照组),各10只。自造模第2天开始灌胃,模型组予等量生理盐水,中药低、高剂量组根据小鼠与人体表面积比例,按0.86g/kg、1.34g/kg不同浓度中药溶液灌胃,CTX组予CTX腹腔注射20mg/kg/日,连续14天。给药结束后24h,各组小鼠颈椎脱臼法处死,称重及测量肿瘤体积,计算抑瘤率。肿瘤组织常规HE染色,观察形态变化。免疫组化法测定瘤体VEGF表达。
研究结果
一临床研究
1.中医病症证资料分析:不同治疗方法在年龄方面有显著性差异(P＜0.05),在不同性别方面中医组和其他两组无显著性差异(P＞0.05),在临床分期方面无显著性差异(P＞0.05),在肝功能分级方面有显著性差异(P＜0.05),而且肝功能A级与B级比较有显著性差异(P＜0.05)。不同Child-Pugh分级在年龄方面无显著性差异(P＞0.05),在性别方面有显著性差异(P＜0.05),在临床分期方面有显著性差异(P＜0.05),而且Ⅲ期与Ⅳ期(Ⅳa、Ⅳb)比较有显著性差异(P＜0.05)。中晚期肝癌临床最常见症状:上腹肿块、胸胁疼痛、全身消瘦、神疲倦怠、脉弦。中医证型中以肝郁脾虚证型常见(71.43%)。
2.中医病症证相关性分析:中医各证型同主症相关性无统计学意义(P＞0.05)。主症上腹肿块与临床分期呈正相关(P=0.008),余主症与临床分期相关性无统计学意义(P＞0.05)。上腹肿块与肝功能分级好坏呈正相关(P=0.000),全身消瘦、神疲倦怠与肝功能分级好坏呈正相关(P=0.047,P=0.001),中医各证型与临床分期相关性无统计学意义(P＞0.05)。肝胆湿热型与肝功能分级呈正相关(P=0.041),余中医证型与肝功能分级相关性无统计学意义(P＞0.05)。
3.肝癌预后分析:154例原发性肝癌患者,平均生存期548天,中位生存期为380天。3月、6月、1年生存率分别为73.4%、63.0%和47.2%。分析9项与生存期有关因素进行预后分析,单因素分析显示:临床分期、治疗方法、中医证型、治疗前AFP水平、Child-Pugh分级等5项因素有统计学意义,多因素分析仅Child-Pugh分级有统计学意义,得出与预后相关因素为Child-Pugh分级。
4.瘤体评价疗效:中医组瘤体缓解率为0%,稳定率为53.33%,其中Ⅲ期稳定率最高,达100%。中西组瘤体缓解率为15.63%,稳定率为81.25%,其中Ⅲ期稳定率最高,达90%。西医组瘤体缓解率为14.28%,稳定率为80.95%,其中Ⅲ期稳定率最高,达85.71%。
5.卡氏评分评价:中医组改善率60%,与治疗前比较,无显著性差异(P=0.334＞0.05)。中西组改善率59.38%,与治疗前比较,无显著性差异(P=0.462＞0.05)。西医组改善率33.33%,与治疗前比较,无显著性差异(P=0.095＞0.05)。
6.肝功能分级评价:中医组和中西组治疗后,肝功能分级与治疗前比较有显著性差异(P＜0.05)。西医组治疗后,肝功能分级与治疗前比较无显著性差异(P＞0.05)。
7.肝功能指标评价:中医组治疗中和治疗后,ALT、AST、ALP、GGT、TB、IB、TBA、AFU与治疗前比较,均无显著性差异(P＞0.05),ALB较治疗前降低,有显著性差异(P＜0.05),治疗后DB较治疗前升高、PA较治疗前降低,有显著性差异(P＜0.05)。中西组介入术后1周和4周ALT、AST、ALP、GGT、TB、DB、IB、TBA、AFU与治疗前比较,均无显著性差异(P＞0.05),ALB较术前降低,有显著性差异(P＜0.05)。介入术后4周PA较术前降低,有显著性差异(P＜0.05)。西医组介入术后1周和4周ALP、GGT、DB、IB、TBA、AFU与治疗前比较,均无显著性差异(P＞0.05)。介入术后1周ALT、AST、TB较术前升高、PA较术前降低,有显著性差异(P＜0.05),ALB较术前降低,无显著性差异(P＞0.05)。介入术后4周ALT、AST、TB、PA与治疗前比较,均无显著性差异(P＞0.05),ALB较术前降低,有显著性差异(P＜0.05)。
二实验研究
1.本课题所有小鼠造模均接种成功,全部成瘤,成功率为100%,皮下移植肝癌模型制作成功。
2.中药低、高剂量组均有不同程度的抑瘤作用,抑瘤率分别为32.9%、38.9%,各组瘤重与模型组相比均有显著性差异(P＜0.05)。
3.各组HE染色显示:中药高、低剂量组肿瘤组织存在不同程度上的细胞坏死区,肿瘤细胞核分裂相对减少,癌巢间及周围微血管相对减少。
4.应用免疫组织化学方法,检测荷瘤小鼠瘤块VEGF表达情况,结果显示:CTX组及中药低剂量、高剂量组VEGF染色评分均显著低于模型组(P＜0.05)。与CTX组比较,中药低剂量组和中药高剂量组VEGF染色评分均无显著性差异(P＞0.05)。中药低剂量组与中药高剂量组之间亦无显著性差异(P＞0.05)。
研究结论
1.肝癌病症证相结合的诊疗模式是中西医临床实践经验的结晶,是中西医肿瘤学优于单一学科治疗方式的理论基础,体现了循证医学、个体化治疗的肿瘤治疗新思维。
2.参桃软肝方治疗中晚期肝癌的优势体现在稳定瘤体、提高生存质量、与西医配合能减轻介入或消融等侵入性治疗手段所致的肝损害,提高耐受性及延长生存期。
3.参桃软肝方具有直接抑制肿瘤生长和减轻瘤重的作用,并对荷瘤小鼠肿瘤组织VEGF的表达有显著抑制作用,VEGF可能是参桃软肝方抗肿瘤作用机制之一,减少肿瘤细胞新生血管的生成,从而减缓肿瘤的侵袭和转移。
Objective
1)To make retrospective analysis about primary Hepatocellular Carcinoma(HCC) about disease,symptom and syndrome from literature sources;To summarize the theory of HCC about diease、symptom and syndrome;To explore the relationship between diease、symptom and syndrome.To identify the influence of some clinical factors on prognosis and to observe the therapeutic effect Shentao Ruangan Recipe(STR) in the treatment of stageⅢorⅣof HCC.
2)To investigate the regulatory effect of STR on the growth of H_(22) tumor and the expression of vascular endothelial growth factor(VEGF) in transplanted H_(22) tumor of mice.
Methods
Clinincal study
1)154 cases of inpatients and outpatients of stageⅢorⅣof HCC in the first affiliated hospital of Guangzhou University of TCM were enrolled between January 2007 and January 2009.Based on diagnostic criteria for HCC,clinical investigation cases were collected,clinical common symptoms and signs were analysed,occurrence of TCM types were summarized.
2)154 cases of stageⅢorⅣof HCC were analyzed about the relationship among diease、symptom and syndrome.
3)154 cases of stageⅢorⅣof HCC were followed up,prognosis influence of nine clinical prognostic factors such as gender,age,clinical stage, treatment methods,pre-treatment tumor size,Karnofsky score before treatment, TCM Syndrome,AFP level and Child-Pugh classification were analyzed using Kaplan-Meier's method and COX model.
4)47 cases were divided into 15 cases of TCM group and 32 cases of combined group.TCM group was treated by oral taking of STR and Huaier-granula and it also was accomplished with diagnosis and treatment based on an overall analysis of the illness and the patients condition.While combined group was treated with TACE(chemoembolization) and ablation combined with TCM.21 cases of Western group were enrolled in the first affiliated hospital of Guangdong College of pharmacy which treated only interventional method.The clinical efficacy of treatment in the three groups was evaluated by the change of tumor size reducing rate and KPS scores and the liver function.
Experimental study
The transplant tumor model of H_(22) hepatocarcinoma in mice was established.Forty mice were randomly divided into four groups,the CTX group,the STR low group, the STR high group and the control group,they were treated respectively with imtraperitoneal injection of CTX 20mg/kg/day,oral administration of STR in a dose of 0.86g/kg,1.34g/kg and equal volume of saline,the medication was given for 14 times totally.Twenty-four hours after the last administration, we calculated the tumor volume;The weight of the transplanted tumor mass were detected to work out the inhibitory rate;The histological and ultra structural changes in tumor tissue were observed by Hematoxylin-eosin(HE) staining; VEGF expression in tumor tissue was detected by S-P immunohistochemistry method.
Results
Clinincal study
1)Date analysis:Different treatment in terms of age with significant difference(P＜0.05);in terms of genger between TCM group and the other groups with no significant difference(P＞0.05);in terms of clinical stages with no significant difference(P＞0.05);in terms of liver function classification with significant difference(P＜0.05).the liver function class A and B with significant difference(P＜0.05).Different Child-Pugh class in terms of age with no significant difference(P＞0.05);in terms of genger with significant difference(P＜0.05);in terms of clinical stages with significant difference (P＜0.05),periodⅢandⅣwith significant difference(P＜0.05).The most common symptoms of stageⅢorⅣof HCC were upper abdominal mass,liver pain, body weight loss,fatigue,pulse string.Common TCM syndrome type was weak spleen and strong liver functions type(71.43%).
2)Correlation analysis:The correlation between syndrome type and symptom had no significant difference(P＞0.05).Upper abdominal mass had positively correlated with clinincal stage(P=0.008),The correlation between the other symptoms and clinical stage had no significant difference(P＞0.05).Upper abdominal mass had positively correlated with Child-Pugh classification(P =0.000),Body weight loss and fatigue had positively correlated with Child-Pugh classification(P=0.047,P=0.001).The correlation between syndrome type and clinical stage had no significant difference(P＞0.05). Dampness-heat of liver and gallbladder had positively correlated with Child-Pugh classification(P=0.041).The correlation between the other syndrome type and Child-Pugh classification had no significant difference.
3)Prognosis analysis:The average survival time of 154 patients of HCC was 548 days,the overall median survival time(MST) of was 380 days,3 months, 6 months and one year survival rate was 73.4%,63.0%and 47.2%respectively.9 potential factors were analyzed:single-factor analysis showed that five factors such as clinical stage,treatment modalities,TCM syndrome type, AFP level before treatment,Child-Pugh classification were statistically significant.Multi-factor analysis showed that Child-Pugh grade of liver function was significant for survival.
4)Tumor efficacy evaluation:The tumor size reducing rate was 0%and the tumor size stabilizing rate was 53.33%in TCM group,the tumor size stabilizing rate of theⅢperiod reaching 100%was the highest.While those in combined group was 15.63%,81.25%respectively,the tumor size stabilizing rate of theⅢperiod reaching 90%was the highest.While those in western group was 14.28%,80.95%respectively,the tumor size stabilizing rate of theⅢperiod reaching 85.71%was the highest.
5)The quality of life score evaluation:The improve rate in TCM group was 60 %,compared with before treatment,the difference was no significant(P＞0.05).combined group was 59.38%,compared with before treatment,the difference was no significant(P＞0.05).Western group was 33.33%,compared with before treatment,the difference was no significant(P＞0.05).
6)Liver function classification evaluation:After treated,TCM group and combined group,compared with before treatment,the difference was significant (P＜0.05).Western group,compared with before treatment,the difference was no significant(P＞0.05).
7)Liver function evaluation:TCM group:in the middle of treatment and after treatment of ALT、AST、ALP、GGT、TB、IB、TBA、AFU,compared with before treatment, the difference was no significant(P＞0.05).ALB was decreased,the difference was significant(P＜0.05).After treated,DB increased,PA decreased,the difference was significant(P＜0.05).Combined group:After Intervention 1 week and 4 weeks of ALT、AST、ALP、GGT、TB、DB、IB、TBA、AFU,compared with those before treatment,the difference was no significant(P＞0.05).ALB was decreased,the difference was significant(P＜0.05).After Intervention 4 weeks of PA was decreased,the difference was significant(P＜0.05).Western group: After Intervention 1 week and 4 weeks of ALP、GGT、DB、IB、TBA、AFU,compared with those before treatment,the difference was no significant(P＞0.05).After intervention 1 week of ALT、AST、TB was increased,PA decreased,the difference was significant(P＜0.05).After Intervention 4 weeks of ALT、AST、TB、PA, compared with those before treatment,the difference was no significant (P＞0.05).
Experimental study
1)All mice model were inoculated successful,the tumors success rate was 100 %.liver transplantation subcutaneous model was successfully completed.
2)STR groups and the model group had significant effect on inhibiting the tumor weight(P＜0.05),when compared with the model group.The tumor inhibition rate was 32.9%in the low STR group;the tumor inhibition rate was 38.9%in the high STR group.
3)HE staining results showed that there were different degree of cell necrosis zones,split-phase reduction of tumor cell in tumor tissues of high-dose group and low-dose group.
4)The expression of VEGF:The results showed that the positive rate of VEGF of high-dose group and low dose group and CTX group were significantly lower than model group(P＜0.05).High-dose group and low dose group,compared with CTX group were no significant difference(P＞0.05).High-dose group and low-dose group also were no significant difference(P＞0.05).
Conclusion
1)Shentao Ruangan Recipe can stable tumor,improve KPS score and prolong the survival time of stageⅢorⅣof HCC.It can also reduce the damage to liver function caused by invasive treatment such as interventional and ablation.
2)STR could obviously inhibit the growth of H_(22) hepatocarcinoma and its mechanism may be related to the down-regulation of the protein expression of VEGF in tumor tissue.
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