Immunochemo-embolization therapy of hepatocellular carcinoma]

To increase antitumor effects of transcatheter arterial embolization therapy (TAE) for hepatocellular carcinoma (HCC), immunochemo-embolization therapy via hepatic artery was performed with a mixture of doxorubicin and iodized oil (LPD) following a mixture of gamma-IFN, OK-432 and gelatin sponge, and then a mixture of actinomycin D and gelatin sponge. Three patients with HCC were treated by this procedure. One patient had tumor thrombus in inferior vena cava (IVC). The serum alpha fetoprotein (AFP) levels before this procedure ranged from 66 ng/ml to 8,360 ng/ml. Following this procedure, the serum AFP levels began to decrease for 1-3 months, then increased for 3-6 months, and again suddenly decreased under 10 ng/ml in two cases after initial procedure. The serum AFP levels of two cases revealed under 10 ng/ml for 9-18 months. CT after 2 weeks to 3 months of this procedure showed a low-density area around LPD-uptaking tumor and after 1-8 months decreased tumor in size with diminishing of the low-density area. Therapy for the main tumor of one case with tumor thrombus of IVC proved to be effective, but it was not effective for tumor thrombus of IVC. The reasons that the serum AFP level increased after decreasing for 1-3 months and then fell below 10 ng/ml following this procedure, may be some kinds of immunological antitumor effects produced by endogenous cytokines.     

Value of serum alpha-fetoprotein and ferritin in the diagnosis of hepatocellular carcinoma

Alpha-fetoprotein (AFP) and ferritin in the serum were determined by radioimmunoassay and enzyme immunoassay, respectively, in 224 healthy subjects, 55 patients with benign hepatic disease and 44 patients with hepatocellular carcinoma (HCC). The AFP levels in the serum were significantly higher in patients with HCC than in healthy subjects and in patients with benign hepatic disease, but this level was not a satisfactory indicator of small HCC since it was elevated in only 75.0% of the patients with a tumor of less than 3.0 cm in its greatest diameter. Although serum ferritin was elevated in only 56.8% of the patients with HCC, the combination of these two tests raised the diagnostic rate of HCC from 65.9% by serum AFP measurement alone to 88.6% with no appreciable decrease in the specificity for HCC. In particular, it raised the diagnostic rates of lesions of less than 3.0 cm in the greatest diameter from 75.0% by measuring AFP alone to 100%. Thus the combination of AFP and ferritin measurement in the serum is useful for the early detection of HCC.     

CYFRA21—1、CA199、AFP联合检测对原发性肝癌的诊断价值

目的：探讨血清CYFRA21—1、CA199、AFP联合检测对原发性肝癌（PHC）的诊断价值。方法：对PHC患者65例、肝良性疾病组47例,应用电化学发光免疫分析技术检测其血清AFP、CYFRA21—1、CA199水平。结果：PHC患者血清AFP、CYFRA21—1、CA199阳性率分别为72．3％、44．6％,41．5％;AFP、CYFRA21—1、CA199联合检测阳性率显著提高,达93．8％,与单项AFP检测阳性率相比有显著性差异（P〈0．05）。结论：AFP、CYFRA21—1和CA199联合检测对原发性肝癌的诊断具有良好的临床应用意义。     

金龙胶囊配合肝动脉化疗栓塞术治疗原发性肝癌的疗效及机制分析

目的 观察金龙胶囊配合肝动脉化疗栓塞(TACE)术治疗原发性肝癌的疗效及机制分析.方法 将116例原发性肝癌患者,按数字表法随机分为对照组和治疗组,每组各58例;对照组采取单纯肝动脉化疗栓塞术(每4~10周重复治疗,最多治疗次数为12次)治疗,治疗后进行常规保肝治疗;治疗组在对照组基础上给予金龙胶囊(4粒/次,3次/d)内服治疗,连续服用3年;检测两组治疗后1周和1个月患者血清癌胚抗原(CEA)和甲胎蛋白(AFP)水平;比较两组临床疗效;检测两组外周血T淋巴细胞亚群变化.结果 两组患者治疗后1周血清CEA和AFP水平均略低于术前;治疗后1个月,治疗组患者血清CEA和AFP水平均明显低于对照组,(P<0.01);治疗组近期总缓解率为67.24%,对照组为41.38%,治疗组优于对照组(χ2=6.809,P<0.01);治疗后3个月,治疗组CD3+和CD4+值均明显高于对照组,而CD8+值明显低于对照组,比较差异均有统计学意义(P<0.01).结论 金龙胶囊联合TACE治疗原发性肝癌能明显降低患者血清CEA和AFP水平,提高患者免疫功能,其临床疗效优于单纯TACE治疗.     

血清AFP、CA125、CA199和CEA联合检测在原发性肝癌诊断中的价值

目的 通过联合检测血清AFP、CA125、CA199、CEA四种肿瘤标志物的含量,观察其对原发性肝癌(PHC)的诊断价值.方法 运用电化学发光免疫分析的方法,检测PHC组68例、良性肝病组50例及健康对照组58例血清中AFP、CA125、CA199、CEA的含量,分析各肿瘤标志物的灵敏度、特异性、准确度及联合检测的临床意义.结果 单独检测AFP、CA125、CA199、CEA对PHC的诊断阳性率分别为76.4%、35.3%、44.1%、29.4%;联合检测四种肿瘤标志物的阳性率为94.1%.结论 四种肿瘤标志物的联合检测有助于提高PHC患者的诊断阳性率.     

Clinical significance of serum alpha-fetoprotein in patients with liver cirrhosis

The clinical significance of serum alpha-fetoprotein (AFP) was studied in 114 patients with liver cirrhosis, who were followed for more than one year. Out of 114 patients, serum HBs antigen (HBsAg) was positive in 49 (43%). The mean follow-up period was 4.3 years (from 1 to 13 years). Serial determinations of AFP by RIA were performed once a month in all patients. The pattern of serial changes of AFP levels could be divided into three characteristic types: 1) fluctuation of AFP levels to greater than 20ng/ml was observed in 39 cases (Type I); 2) a transient rise of AFP levels to greater than 50ng/ml was observed in 20 cases (Type II); 3) in the remaining 55 cases, AFP levels were always less than 20ng/ml. During the follow-up period, liver cell carcinoma (LCC) developed in 29 cases (25%) and hepatic failure in 11 cases (10%). The incidence of LCC was significantly higher in Type I (18/39, 46%) than in Type II (3/20, 15%) and Type III (8/55, 15%). It is concluded that cirrhotic patients with fluctuation of AFP levels should be included in the high-risk group for LCC.     

肝癌及肝硬化患者可溶性endoglin的临床意义*

目的:本研究拟探讨肝癌及肝硬化患者血清中可溶性endoglin 的表达及其临床意义。方法:采用酶联免疫吸附实验（ELISA）方法检测87例肝癌患者、30例肝硬化患者及28例健康对照组血清endoglin 的浓度,分析肝癌患者血清endoglin 表达与肝癌分期、门脉癌栓及远处转移等临床指标的关系。结果:肝癌合并肝硬化患者血清endoglin 浓度显著高于肝硬化组（P<0.001）及正常对照组（P<0.001）,肝硬化患者血清endoglin 浓度显著高于正常对照组（P=0.016）。 进一步研究发现,肿瘤最大径>5cm,有远处转移,有门脉癌栓、AFP>400ng/mL、肝癌临床分期Ⅲ期的患者血清endoglin 的浓度均明显升高（P<0.05）,ROC 分析发现endoglin和AFP 联合检测后敏感性提高,曲线下面积较前增加。结论:我们在国内首次阐明可溶性endoglin 在肝癌及肝硬化患者中的临床意义,血清endoglin 可作为评估乙肝肝硬化进展为肝癌的补充诊断指标,可能有一定早期诊断、预测复发转移及预测预后的价值。      

Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC), a common cancer worldwide, has a dismal outcome partly due to the poor identification of early-stage HCC. Currently, one third of HCC patients present with low serum alpha-fetoprotein (AFP) levels, the only clinically available diagnostic marker for HCC. The aim of this study was to identify new diagnostic molecular markers for HCC, especially for individuals with low serum AFP. EXPERIMENTAL DESIGN: We used the microarray technique to determine the expression profiles of 218 HCC specimens from patients with either high or low serum AFP. From the microarray study, we selected five candidate genes (i.e., GPC3, PEG10, MDK, SERPINI1, and QP-C), which were overexpressed in HCCs. Using quantitative real-time PCR analyses, we validated the expression of these five genes in 50 AFP-normal and 8 AFP-positive HCC specimens and 36 cirrhotic noncancerous hepatic specimens, which include 52 independent specimens not used in microarray analysis. RESULTS: A significant increase in the expression of the five candidate genes could be detected in most of the HCC samples, including those with normal serum AFP and small tumors. GPC3, MDK, and SERPINI1 encode known serum proteins. Consistently, a significant increase in serum midkine, encoded by MDK, was associated with HCC patients, including those with normal serum AFP. Using prediction analysis of microarray, we showed that a combined score of these five genes can accurately classify noncancerous hepatic tissues (100%) and HCC (71%). CONCLUSIONS: We suggest that a diagnostic signature approach using a combined score of these five biomarkers rather than a single marker may improve the prediction accuracy of HCC patients, including those with normal serum AFP and smaller-sized tumors.     

Hepatic arterial injection chemotherapy with cisplatin suspended in an oily lymphographic agent for hepatocellular carcinoma

A method to prepare cisplatin suspended in an oily lymphographic agent, Lipiodol (LPS), has been established to deliver cisplatin to hepatocellular carcinoma (HCC) by the hepatic artery. Seventy-one patients, one Stage I, 16 Stage II, 16 Stage III, and 38 Stage IV, were treated with LPS therapy. A partial response was obtained in 33 cases (46.5%), a minor response in 20 cases (28.2%), and no change in 18 cases (25.3%). In 34 patients whose serum alpha-fetoprotein (AFP) levels were greater than 400 ng/ml, the serum AFP levels decreased in 31 patients (91.2%). The AFP decreased by more than 50% in 25 cases (73.5%) and more than 75% in 19 cases (55.9%). The plasma des-gamma-carboxy prothrombin (DCP) levels decreased in all of the 26 DCP-positive patients. The survival rate was 77% at 6 months and the 1-year survival rate was estimated to be 55%. The patients treated with LPS therapy survived longer compared with patients given Lipiodol containing neocarzinostatin by the hepatic artery. Complications such as acute gastroduodenal mucosal lesions (24%), cholecystitis (2.8%), pancreatitis (7%), delayed jaundice (7%), and hepatic encephalopathy (4.2%) were observed after therapy. The peak plasma platinum (Pt) concentrations determined as ultrafilterable Pt occurred 5 to 20 minutes, and 5 to 60 minutes as total Pt after the end of LPS injection. The Pt concentrations in the tumor tissues were 42 times higher in four operated cases and 7.1 times higher in six autopsy cases than those in the nontumorous tissue. These results suggest that LPS selectively accumulates in the HCC, is long-lasting and gradually releases the drug. In addition it is effective as a new anti-cancer therapy for hepatocellular carcinoma.     

Hepatocellular carcinoma with extrahepatic malignancies]

A clinical investigation of 16 hepatocellular carcinoma (HCC) patients with extrahepatic malignancies (13 male, 3 female) has been conducted. The age of these patients ranged from 55 to 76 years. Three of these double cancer cases were hemocronous, and 13 were heterochronous. The duration between the occurrence of the cancers ranged from 2 years and 4 months to 22 years. As for the site of the other cancer, the stomach was the most common organ (12 cases). In nine cases out of 16, the HCC was resected, whereas the other cases were treated with a TAE and hepatic artery ligation because the cancer were far advanced stages. Early detection of an HCC by AFP or an ultrasonographic examination, and a subsequent surgical resection in cases of a postoperative cancer patient with a liver dysfunction may lead to a more favorable prognosis.     

α-fetoprotein-producing rectal cancer: Calculated tumor marker doubling time

α-fetoprotein (AFP) production by rectal cancer is very rare. In the English literature there are only a few reported cases in which serum AFP level was >1,000 ng/ml. A 43-year-old Japanese man with rectal cancer and liver metastases had a high serum AFP level (941 ng/ml) when first evaluated. Three weeks later, the serum AFP level was extremely elevated (7,060 ng/ml). He underwent abdominoperineal excision of the rectum and biopsy of liver metastases. The placement of an intrahepatic-arterial infusion catheter into the proper hepatic artery via the right gastroepiploic artery was also performed. Immunohistochemically, AFP-positive cells were identified in both the rectal and liver tumors. Nine days postoperatively, the serum AFP level was 2,000 ng/ml. In spite of intensive chemoimmunotherapy, serum AFP level was increased and 14 weeks after surgery was extremely elevated (267,300 ng/ml). The patient succumbed to cancer 3 months after surgery. To our knowledge, this is the first case of an AFP-producing rectal cancer in which AFP doubling time could be calculated as 12.8 days. © Wiley-Liss, Inc.     

胃肠道恶性肿瘤患者血清AFP、CEA和CA19-9的表达特征探讨

目的:探讨血清肿瘤标志物AFP、CEA和CA19-9在胃肠道恶性肿瘤患者中的表达特征。方法:用罗氏全自动电化学发光分析仪测定126例胃肠道恶性肿瘤患者血清AFP、CEA和CA19-9的表达水平,并分析该3项指标与临床病理因素的关系。结果:血清CEA随着肿瘤浸润深度、临床分期增加以及远处转移而表达水平上升,差异有统计学意义(P0.05);血清CA19-9随着临床分期及远处转移表达水平上升,差异有统计学意义(P0.05)。血清AFP表达水平在不同临床病理因素间无统计学差异(P0.05)。结论:胃肠道恶性肿瘤患者血清CEA、CA19-9的表达水平与胃肠道恶性肿瘤患者的病情密切相关。     

Plasma carcinoembryonic antigen in the diagnosis and management of patients with hepatocellular carcinoma

The value of serial carcinoembryonic antigen (CEA) measurements as a marker of disease progression or in monitoring treatment was investigated in patients with hepatocellular carcinoma. Of 40 patients, including 16 with normal serum alpha-fetoprotein (AFP) concentrations, 29 (72.5%) had abnormal plasma CEA at presentation. Although this was more common in patients with pre-existing cirrhosis, the mean and range of plasma CEA were similar in patients with and without pre-existing hepatic disease. There was no correlation between plasma CEA and any biochemical parameter of hepatic function, although plasma CEA concentrations were significantly lower in patients with well-differentiated tumors. CEA concentrations increased in 71% of patients who had no response to cytotoxic drugs, but CEA also increased in 62.5% of those patients who did respond. Plasma CEA concentrations were elevated in 62.5% of patients with normal and 79% of patients with raised serum AFP on admission to the hospital. There was no correlation between individual AFP and CEA concentrations. Although elevated plasma CEA levels may be of diagnostic value in patients with hepatocellular carcinoma in the absence of pre-existing hepatic disease, and in those with normal serum AFP, our findings indicate that it does not behave as a true tumor marker.     

Alpha-1 antitrypsin (AAT) and alphafoetoprotein (AFP) in sera of patients with germ-cell neoplasms: value as tumour markers in patients with endodermal sinus tumour (yolk sac tumour).

Serum alphafoetoprotein (AFP) and serum alpha-1 antitrypsin (AAT) were determined in 24 patients with germ-cell neoplasms of the gonads and extragonadal sites and in two patients with hepatocellular carcinoma. In the majority of the patients serial determinations were performed. All seven patients with testicular seminoma and four patients without evidence of active disease had normal levels of serum AAT and AFP. The remaining 13 patients with germ-cell neoplasms had tumours containing endodermal sinus tumour (yolk-sac tumour) elemetns. All these 13 patients had elevated levels of serum AFP and the levels were high or very high in most cases. Nine of these 13 patients had raised serum AAT, although the elevation above normal levels was only slight in a number of cases. When serial determinations were performed serum AAT levels frequently followed the pattern of serum AFP levels, but the AAT levels were frequently within normal limits and therefore the interpretation of the results was difficult, and much less reliable as compared with those for serum AFP. The elevation of serum AAT levels following the recurrence of the tumour was found to occur much later and was much less marked than elevation of serum AFP, which occurred early, showed a large rise and was a reliable marker of tumour recurrence in patients with germ-cell neoplasms containing endodermal sinus tumour elements. It is therefore considered that, although there is good evidence that serum AAT is produced by endodermal sinus tumour elements, serum AAT is not a useful monitor of disease activity in these patients, especially when compared with serum AFP, the value of which is well recognized. Serum AAT may be a useful tumour marker in patients with hepatocellular carcinoma, and this aspect should be investigated further.     

肝动脉栓塞化疗治疗不能切除的原发性肝癌：（附44例报告）

肝动脉栓塞化疗是治疗中晚期原发性肝癌的一种有效方法。本院自1989年8月～1990年10月采用此方法治疗44例中晚期原发性肝癌患者。所有病例AFP均有不同程度的下降,14例(31.8％)下降显著。肿瘤缩小33～70％者6例,5例获二期切除。主要副反应和并发症为腹痛、发热、呕吐、肝功能损害以及胃十二指肠动脉栓塞所致的胃十二指肠溃烂、穿孔。     

中晚期肝癌肝动脉插管化疗合并碘油栓塞疗效观察

目的 探讨超液化碘油与抗肿瘤药物相混合行肝动脉栓塞化疗治疗不能手术切除及内科静脉化疗不佳的中晚期肝癌的方法和疗效。方法 经股动脉行Seldinger法插管肝动脉超选治疗96例,单次剂量为:丝裂霉素10mg,顺铂60mg,吡柔比星60mg,5-Fu 1500mg,法国产超液化碘油10～20ml。结果 原发性肝癌:治疗前82例甲胎蛋白都有不同程度升高,其高低范围为626～2565ng/ml,通过治疗后数值明显下降,范围在35ng/ml以下并可达到正常水平;转移性肝癌:治疗前甲胎蛋白虽无明显升高,但通过治疗后可显著改善临床症状。二者用CT或术中DSA造影对照,均见病灶明显缩小。82例原发性肝癌中有6例治疗后病灶已全部消失。96例患者生活质量得到提高,生存期延长。结论 对Child B,C级中晚期肝癌患者,抗肿瘤药物吡柔比星与碘油混合乳剂行肝动脉栓塞治疗,绝大多数患者都能耐受,且能控制肿瘤的发展,并有缩小肿瘤的疗效。     

Relationship of hepatitis B surface antigen to serum alpha-fetoprotein in nonmalignant diseases of the liver.

Serum alpha-fetoprotein (AFP) levels were measured by radioimmunoassay in 89 healthy adult Chinese, 170 patients with histologically verified non-malignant liver diseases, and 14 hepatitis B surface antigen (HBsAg) carriers with normal liver histology. In 97% of the healthy adults, AFP levels were under 20 ng/ml, which is then regarded as the normal upper limit. Cases with supranormally elevated AFP levels ranged from 15-51% in chronic hepatic disorders and were 33% in acute hepatitis. None of the healthy HBsAg carriers had abnormal AFP level. HBs antigenemia was found to be related to AFP elevation in chronic active hepatitis, cirrhosis, and acute hepatitis but not in chronic persistent hepatitis and healthy HBsAg carriers. The correlation could be demonstrated only when the sensitive third generation test was employed to define seropositivity of HBsAg. Events after hepatic injury induced by hepatitis B virus, rather than the HBs antigenemia itself, are probably responsible for the association. Whether the association of HBsAg and elevated serum AFP in these nonmalignant hepatic disorders contributes to the higher risk of subsequent development of hepatocarcinoma in Taiwan is unknown and requires further long-term longitudinal study.     

原发性肝癌综合治疗后甲胎蛋白水平与预后的相关性分析

目的探讨中晚期原发性肝癌患者综合治疗后血清甲胎蛋白(AFP)水平与预后的相关性。方法选择57例AFP阳性(AFP>500 ng/ml)的中晚期原发性肝癌患者,综合治疗后定期检测血清AFP,治疗后AFP下降者为A组,治疗后AFP上升者分为B组,(判断治疗后AFP上升或下降的标准以治疗前AFP值差±10%以上)。结果 32例(A组)患者AFP有不同程度的降低,25例(B组)患者AFP有不同程度升高。A组患者的中位生存时间为10.6个月,而B组的中位生存时间为5.1个月,两组差异有统计学意义(P﹤0.01)。结论血清中AFP水平可以作为判断肝癌患者综合治疗后的预后指标。     

A simple prognostic scoring system for patients with unresectable hepatocellular carcinoma treated by chemo-embolization

BACKGROUND: Hepatocellular carcinoma (HCC) comprises heterogeneous groups of patients with differing outcomes. METHODS: In order to attempt to identify patient sub-sets, we retrospectively examined the records of 750 patients with biopsy-proven unresectable HCC, who were treated with hepatic artery chemo-embolization and were followed till death. We used the Cox proportional hazard model, as it was neutral with respect to prejudged cut-off between short and long survival. RESULTS: On univariate analysis, we found a shorter survival to be associated with male gender, presence of cirrhosis, portal hypertension, portal vein thrombosis and elevations of bilirubin, GGTP, ALKP, AFP, DCP, PT and albumin. Five factors were found to be statistically significant (p<0.05) on multivariate analysis, namely presence of cirrhosis or ascites and elevations of AFP, ALKP or GGTP. We developed a simplified scoring system based upon the sum of the hazard ratios of each of these five factors. By combining the two factors with the heaviest hazard ratios from our multivariable analysis, namely AFP (+ = >100 ng/mL) and ALKP (+ = >100 IU/mL), we found a simple parsimonious prognostic tool, which segregated the patients into survival groups, namely AFP- ALKP-; either AFP+ or ALKP+; and AFP+ ALKP+; these three groups corresponded to a 24-month survival of 70%, 32% and 12%, respectively. CONCLUSION: we found that only two lab functions, AFP and ALKP levels, in our large HCC patient cohort undergoing hepatic artery chemo-embolization, had prognostic significance.     

血清高尔基体蛋白73联合甲胎蛋白检测在原发性肝癌患者中的诊断价值

目的:探讨高尔基体蛋白73（golgiprotein 73,GP73）联合甲胎蛋白检测用于原发性肝癌诊断的临床意义。方法:收集2013年6 月至9 月天津医科大学肿瘤医院160 例血清,其中原发性肝癌患者46例,单纯肝硬化患者30例,其他消化系统肿瘤患者44例,健康者40例。应用酶联免疫吸附实验定量检测血清GP73水平,电化学发光免疫分析检测血清甲胎蛋白（alpha-fetoprotein ,AFP）水平。结果:GP73诊断原发性肝癌的敏感性达到73.9% ,与本研究中AFP 敏感性（56.5%）相比,前者有显著增高,差异有统计学意义（P<0.01）。 GP73和AFP 联合检测敏感性有显著提高,可以达到86.9% ,与单独一种相比敏感性有显著性差异（P<0.01）。 结论:GP73有可能作为原发性肝癌诊断的血清标志物之一,而GP73和AFP 的联合检测对原发性肝癌的诊断也有较好的应用价值。