Emerging drugs for biliary cancer

Biliary cancer comprise carcinoma of the gallbladder as well as the intrahepatic, hilar and extrahepatic bile ducts. Furthermore, many different etiologies and risk factors are contributing to the inhomogeneity of this disease. It is often diagnosed at an advanced stage when potentially curative resection is not feasible. Due to the lack of randomised Phase III studies, there is no standard regimen for chemotherapy in biliary cancer. Recent investigations into the underlying molecular mechanisms involved in biliary carcinogenesis and tumour growth have contributed greatly to our understanding of biliary cancer. Through a better understanding of these mechanisms, improved and more specific diagnostic, therapeutic and preventive strategies may be developed. Although fluoropyrimidines and gemcitabine remain the backbone of routine chemotherapy in advanced disease, new agents such as epidermal growth factor receptor blockers and angiogenesis inhibitors may hold promise for improving the outcome for patients with biliary cancer.     

肝门胆管癌的术前减黄问题

临床上习惯将恶性肿瘤直接侵及或压迫肝外胆道致胆汁排出受阻而引起的黄疸称为恶性梗阻性黄疸,根据阻塞部位一般可分为高位胆道梗阻和低位胆道梗阻.高位胆道梗阻多指高位胆管癌,即肝门胆管癌,部分胆囊癌向肝管方向浸润发展,也可致胆道梗阻;后者系壶腹周围恶性肿瘤所致的梗阻,通常包括胰头癌、胆总管下端癌及壶腹癌等.低位胆道肿瘤的经典手术方式为胰十二指肠切除术,外科处理原则相对比较统一,而肝门胆管癌因其解剖部位特殊、切除范围不同、机体受累状态和相应的术前准备不同,以及术者技术经验等差异,在临床实际处理上存在着颇多问题和争议.本文结合国内外文献和我们的临床经验,拟就肝门胆管癌的术前相关准备尤其减黄问题作一讨论.     

Expression of p53 in adenocarcinoma of the gallbladder and bile ducts

Abstract: Point mutation of the p53 tumor suppressor gene appears to be an important event in tumor development and progression, and overexpression of the p53 gene product has been widely studied in a variety of neoplasms. Some point mutations of the p53 gene lead to an increase in half-life in the gene product, which accumulates in the nucleus and can be detected by immunohistochemical means. We studied overexpression of p53 protein in specimens from 12 patients with adenocarcinoma of the gallbladder, two gallbladders with epithelial dysplasia without carcinoma, eight carcinomas of the common bile duct, 13 hilar cholangiocarcinomas, and six peripheral cholangiocarcinomas. The monoclonal antibody Ab-2 (Oncogene Science) was used in conjunction with citrate microwave antigen retrieval. Nuclear staining was scored as positive (graded 1 to 3, depending on number of positive nuclei) or negative. Overexpression of p53 protein was present in 7/12 (58%) gallbladder carcinomas, and was seen more often in moderately or poorly differentiated tumors. Intramucosal carcinoma adjacent to invasive carcinoma was positive in three cases, although fewer cells stained than in the carcinoma. Two cases of low-grade dysplasia not associated with carcinoma were negative. Expression of p53 was not an independent prognostic factor when survival was related to grade and stage of tumor. Three of eight (38%) common bile duct carcinomas and 5/13 (38%) hilar cholangiocarcinomas were positive for p53. Slightly fewer (2/6, 33%) peripheral cholangiocarcinomas were positive. No difference in survival relative to p53 expression was demonstrated.     

What is the impact of coexistence of hepatolithiasis on cholangiocarcinoma?

BACKGROUND: Hepatolithiasis is a well-known etiology of cholangiocarcinoma. However, whether or not hepatolithiasis influences the presentation of cholangiocarcinoma is not very clear. To help clarify this, we conducted the present study to investigate the clinicopathological characteristics of cholangiocarcinoma with hepatolithiasis. As well, we made a comparison between the presence and absence of hepatolithiasis in patients with cholangiocarcinoma to determine the impact of hepatolithiasis. METHODS: Among 140 patients with histologically proven cholangiocarcinoma at the Taichung Veteran General Hospital between October 1982 and December 2000, 38 were found to have concomitant hepatolithiasis. Patients were evaluated on the basis of age, gender, presenting symptom, laboratory data, preoperative liver function (indocyanine green test), tumor markers, histological differentiation, lymph node involvement, and organ metastasis. Data were statistically analyzed using the chi-squared test and Student's t-test. Analysis of survival was performed using the Kaplan-Meier method, and univariate analysis and multivariate analyses for survival were performed by Cox proportional hazard model. RESULTS: The cholangiocarcinoma with hepatolithiasis group (CC + HL) was found to be predominantly female, with more common presentation of fever and less presentation of jaundice (P < 0.05). In addition, patients with cholangiocarcinoma without hepatolithiasis (CC - HL group) had higher serum bilirubin levels and more advanced histological differentiation (P < 0.05). As well, the percentage of resectability of the CC + HL group was higher than that of the CC - HL group, although it was not statistically significant. Univariate and multivariate analyses for overall survival showed that those patients with an age older than 65 years, hypoalbuminemia, poor histological differentiation, and a presence of hepatolithiasis were prone to a graver prognosis, albeit none of them were statistically significant. Resectability was the only independent predictor of a favorable prognosis with significant difference. CONCLUSIONS: The clinicopathological features of cholangiocarcinoma with concomitant hepatolithiasis showed few differences from that without hepatolithiasis. Resectability was the only predictor that favored a good prognosis.     

Indications for non-transplant surgery in primary sclerosing cholangitis

Primary sclerosing cholangitis (PCS) is a progressive disease leading to secondary biliary cirrhosis. Patients are at increased risk of developing cholangiocarcinoma, which is usually diagnosed at an advanced stage. Treatment of PCS includes medical therapy, endoscopic biliary dilation, percutaneous transhepatic stenting, extrahepatic biliary resection and liver transplantation. The most effective management of primary sclerosing cholangitis before the onset of cirrhosis remains unclear. Non-transplant surgical procedures have a limited but defined role in patients with PCS. Resection of the extrahepatic biliary tree in symptomatic non-cirrhotic patients improves hyperbilirubinaemia and prolongs both transplant-free and overall survival when compared with non-operative dilation and/or stenting. Surgical resection may also definitively establish or exclude a diagnosis of cholangiocarcinoma in patients with dominant extrahepatic or perihilar strictures. Extrahepatic bile duct resection may also reduce the risk of cholangiocarcinoma. Extrahepatic biliary resection should be considered in selected non-cirrhotic patients with symptomatic biliary obstruction and dominant extrahepatic and/or perihilar strictures. Those patients in whom cholangiocarcinoma is suspected should also undergo resection.     

胆道结石并发肝内胆管癌风险的Meta分析

目的 明确肝外胆管结石及胆囊结石并发肝内胆管癌(Intrahepatic cholangiocarcinoma,ICC)风险,为胆道结石的临床治疗提供参考.方法 计算机检索PubMed、EmBase以及CBM等数据库,查找胆道结石以及胆囊结石并发ICC风险的队列研究或者病例对照研究.应用STATA软件对所获得研究数据行Meta分析,根据研究间异质性选择固定效应模型或者随机效应模型.采用Egger检验评估发表偏倚.结果 共有6篇病例对照研究纳入分析,包括123 713例患者,其中ICC 4 753例,无瘤对照118 960例.Meta分析结果显示,胆管结石为ICC发病的高危因素(OR:17.64,95％ CI:11.14 ～27.95),除外肝内胆管结石,肝外胆管结石导致的ICC发病风险仍较高(OR:11.79,95％ CI:4.17～ 33.35).此外,胆囊结石也是ICC发病危险因素(OR:2.07,95％ CI:1.17 ～3.67).结论 肝外胆管结石与胆囊结石均为ICC发病的重要危险因素.     

Overexpression of Prdx1 in hilar cholangiocarcinoma: a predictor for recurrence and prognosis

Prdx1 is an important member of peroxiredoxins (Prdxs) regulating various cellular signaling and differentiation. Prdx1 confers an aggressive survival phenotype of cancer cells and drug-resistance, yet its role in hilar cholangiocarcinoma is not fully investigated. In present study, we detected the expression profile of Prdx1 in 88 hilar cholangiocarcinoma by tissue arrays and immunohistochemistry. Prdx1 level was down-regulated by specific Prdx1-shRNA in vitro and the possible mechanism was investigated. Overexpression of Prdx1 was observed in 53 of 88 cases (60.2%). Prdx1 expression was significantly associated with tumor invasion, nodal metastasis, advanced disease stage. Down-regulation of Prdx1 inhibited cell proliferation and colony formation of QBC939 cells and reduced the level of SNAT1 expression. Patients with Prdx1 overexpression had a shorter disease-free survival and overall survival than those without Prdx1 expression. Multivariate analysis showed that Prdx1 was an independent prognostic factor for patients with hilar cholangiocarcinoma. The data indicate that Prdx1 may contribute to the development and progression of hilar cholangiocarcinoma, partially through regulating SNAT1 expression, and may be used as a biomarker in predicting the outcome of patients with hilar cholangiocarcinoma.     

Prognostic significance of microRNA-203 in cholangiocarcinoma

MircroRNA functions as a tumor suppressor or a promoter in cholangiocarcinoma (CCA). Researchers have found that miR-203 functioned as tumor suppressor in many types of cancer. However, the role of miR-203 that plays in CCA remains to be clarified. We aimed to detect the expression level and the prognostic significance of miR-203 in CCA tissues. qRT-RCR was performed to examine the miR-203 expression levels in CCA tissue specimens and corresponding normal tissues. Our findings suggest that miR-203 expression was an independent poor prognostic factor for CCA patient overall survival. Therefore, miR-203 may serve as a valuable prognostic marker and promising treatment target for CCA.     

150例肝外胆管癌的临床病理与预后分析

目的：探讨肝外胆管癌的临床病理特点及预后分析。方法：选取2007年1月至2013年1月收治的150例肝外胆管癌患者,给予手术治疗,对患者术后的临床病理特点进行回顾性统计,选择Kaplan－Meier方法分析病理与预后的联系。结果：经过分析后得知,肝外胆管癌患者的1年生存率70．6％、2年生存率18．0％、3年生存率4．0％,平均生存时间18．5月。姑息性手术与根治性手术的生存率存在明显差异（ P＜0．05）。另外,肝管周围组织浸润阴性者预后效果明显优于阳性者（ P＜0．05）。肿瘤分化程度越好,患者预后效果越好。结论：针对肝外胆管癌患者,其术后预后因素主要包含肿瘤分化程度、肿瘤浸润和根治性手术,临床治疗时应考虑这些预后因素。