Development Of Bile Duct Cancer Research Articles

BCLAF1 is Expressed as a Potential Anti-oncogene in Bile Duct Cancer.

Validating the role of BCLAF1 in the development of Bile Duct Cancer. Differential expression of BCLAF1 in Bile Duct Cancer and normal tissues was analyzed bioinformatically, and immuno-infiltration analysis was performed by R. We also derived the correlation between the expression of BCLAF1 and HIF-1α by bioinformatics analysis and validated it by Western Blotting, qRT-PCR and scratch assays before and after hypoxia. Through bioinformatics analysis, we found that BCLAF1 mRNA was significantly higher in the tumor tissues of Bile Duct Cancer. The high expression of BCLAF1 implied a more advanced stage but a lower mortality rate. KEGG and GO enrichment analysis showed that BCLAF1 overexpression in Bile Duct Cancer was mainly associated with histone modification, peptidyl lysine modification, and macromolecular methylation. We used the TIMER algorithm to show that BCLAF1 expression in Bile Duct Cancer is associated with immune cell infiltration, which affects tumor progression and patient prognosis. We confirmed by normoxia and hypoxia qRT-PCR, Western Blotting and scratch assays that BCLAF1 and HIF-1α expression are positively correlated and that BCLAF1 may be expressed as anti-oncogene in Bile Duct Cancer. These findings demonstrate that BCLAF1 may act as anti-oncogene in Bile Duct Cancer and may be involved in immune cell infiltration in Bile Duct Cancer, suppressing the expression of HIF-1α.

Orally Administered Bacillus Spores Expressing an Extracellular Vesicle-Derived Tetraspanin Protect Hamsters Against Challenge Infection With Carcinogenic Human Liver Fluke.

The human liver fluke Opisthorchis viverrini is a food-borne trematode that causes hepatobiliary disease in humans throughout Southeast Asia. People become infected by consuming raw or undercooked fish containing metacercariae. Development of a vaccine to prevent or minimize pathology would decrease the risk of severe morbidity, including the development of bile duct cancer. We produced an oral vaccine based on recombinant Bacillus subtilis spores expressing the large extracellular loop (LEL) of O. viverrini tetraspanin-2 (Ov-TSP-2), a protein that is abundant on the surface of O. viverrini secreted extracellular vesicles (EVs). Recombinant spores expressing Ov-TSP-2-LEL were orally administered to hamsters prior to challenge infection with O. viverrini metacercariae. Vaccinated hamsters generated serum IgG as well as bile IgG and IgA responses to Ov-TSP-2-LEL, and serum IgG from vaccinated hamsters blocked the uptake of fluke EVs by a human bile duct epithelial cell line. Vaccinated hamsters had 56% reductions in both adult flukes and fecal eggs compared to the control group. These findings indicate that oral vaccination of hamsters with recombinant B. subtilis spores expressing Ov-TSP-2-LEL is efficacious at reducing infection intensity and could form the basis of a vaccine for control of carcinogenic liver fluke infection in humans.

Development of bile duct cancer as a long-term complication of biliary-enteric anastomosis for benign diseases: a report of five patients

Objective To study the association, clinical presentation, and diagnosis and treatment of bile duct cancer as a late complication of biliary-enteric anastomoses for benign diseases. Methods A retrospective study was carried out on 5 patients and the medical literature was reviewed. Results They were 3 males and 2 females. The average age was (66.0±0.7) years. The average time period was (14.0±6.1) years after biliary-enteric anastomosis. The clinical presentations included right upper quadrant pain, fever, chills and jaundice. CA19-9, CT and MRI were valuable in diagnosis. There were two patients with distal and three patients with perihilar cholangiocarcinomas (type IIIa, n=2, and type IV, n=1). Local resection with lymphadenectomy was carried out in one patient. Another patient underwent pancreaticoduodenectomy. The remaining three patients only underwent percutaneous transhepatic cholangial drainage (PTCD). The 2 patients who underwent surgery died of progressive tumor disease at 8 and 13 months postoperatively. The other three patients who underwent palliative biliary drainage died within 6 months of PTCD. There was no significant difference between the two types of treatment (P>0.05). Conclusions Chronic cholangitis caused by reflux and bacterial infection was properly a predisposing factor leading to late development of bile duct cancer after biliary-enteric anastomosis for benign diseases. Patients treated with biliary-enteric anastomosis should be closely monitored for late development of cholangiocarcinoma. Some procedures such as choledochoduodenostomy and jejunum interposition choledochoduodenostomy should be abandoned because of their poor outcomes and severe complications. Proper indications of biliary-enteric anastomosis should strictly be followed and the Oddi's sphincter should be protected if possible to prevent late development of bile duct cancer. Key words: Biliary tract diseases; Biliary tract surgical procedures; Bile duct neoplasms; Biliary-enteric anastomosis; Postoperative complication; Treatment outcome

Pancreaticobiliary maljunction and choledochal cysts: from embryogenesis to therapeutics aspects.

Pancreaticobiliary maljunction (PBM) and choledochal cysts (CC) are rare and little-known diseases. Several definitions have been proposed for the PBM, but the most widely accepted is an excessive length of the common pancreaticobiliary duct due to the abnormal convergence of the pancreatic and biliary ducts out of the duodenal wall. This anomaly, thought to develop during embryogenesis, is associated with a loss of regulation of the Oddi's sphincter leading to a pancreaticobiliary or biliopancreatic backflow. This reflux could be responsible, or associated with cystic dilatation of the bile ducts and biliary tract cancers, to various biliary or pancreatic events such as cholangitis or pancreatitis. For the diagnosis of PBM, magnetic resonance cholangiopancreatography has now become the gold standard as a noninvasive imaging tool. However, the main risk of PBM is the development of bile duct cancer, most often on a distended area. PBM without CC increase the occurrence of gallbladder cancer and require a preventive cholecystectomy. Surgical treatment of PBM with concomitant CC is more complex and depends on localization of the dilatation(s) as reported in the Todani's classification. This review describes the pathogenesis, embryogenesis, clinical features, investigation and management of PBM and CC.

Hepatobiliary and Pancreatic: Cystic bile duct remnant after surgery for a choledochal cyst

Choledochal cysts are congenital anomalies of the bile duct that result in dilatation of the extrahepatic bile duct, the intrahepatic bile ducts or both components of the biliary system. Although several forms of dilatation have been described including bile duct diverticula, the most common is diffuse dilatation of the extrahepatic bile duct. The majority of these patients also have an anomalous junction of the bile duct and main pancreatic duct creating a “long common channel”. At least 50% of patients are diagnosed before the age of 10 years because of abdominal pain, jaundice, pancreatitis or a palpable abdominal mass. However, 25% of patients present as adults, usually with abdominal pain, pancreatitis or abnormal liver function tests. The diagnosis is readily made on an ultrasound study but additional investigations can include computed tomography (CT) scans, magnetic resonance imaging (MRI) scans and endoscopic retrograde cholangiopancreatography. The treatment of choice is usually surgical excision of the cyst with a biliary reconstruction using a choledochojejunostomy. Complications of untreated choledochal cysts include biliary cirrhosis, portal hypertension and the development of cholangiocarcinoma. Complications after surgery can include a cystic bile duct remnant as illustrated below. The patient was a 48-year-old woman who was admitted to our hospital with upper abdominal pain. Her past history included excision of a choledochal cyst at the age of 8 years. She was investigated with an enhanced CT scan, MRI scan (T2 weighted) and magnetic resonance cholangiopancreatography (MRCP). The CT scan (Figure 1, left) and MRCP (Figure 1, right) show a cystic structure in the head of the pancreas with a filling-defect, 15 mm in diameter. Various tumor markers were within the reference range. At laparotomy, there was a dilated remnant of the bile duct in the head of the pancreas (Figure 2, left). This was resected down to the junction with the main pancreatic duct. The bile duct remnant contained a calculus (Figure 2, right) while histological examination of the wall of the sac only revealed chronic inflammatory tissue. The patient has been followed for 12 months since surgery and is currently painfree. The management of enlarged but asymptomatic bile duct remnants is less clear although there are case reports of the development of bile duct cancer.

Development of bile duct cancer in a 26-year-old man after resection of infantile choledochal cyst

Anomalous arrangement of the pancreaticobiliary duct is considered to be a high-risk factor for biliary tract malignancy. We report a case of intrahepatic cholangiocarcinoma in a 26-year-old man after total resection of choledochal cyst with anomalous arrangement of the pancreaticobiliary duct at the age of 5 months. He had been doing well after total resection of the choledochal cyst; however, he suddenly presented with a spiky fever and abdominal pain in the right upper quadrant at the age of 26 years. Computed tomographic scan and percutaneous transhepatic cholangioscope revealed multiple stones and stenosis of the hepatic duct and the left intrahepatic bile duct. Histologic examination of a biopsy specimen obtained from the stenotic site showed adenocarcinoma of the intrahepatic bile duct. Left lobectomy with re-reconstruction by right hepaticojejunostomy was performed, and his postoperative course was uneventful. One year after the operation, however, he died of carcinomatous peritonitis with recurrence of cholangiocarcinoma. This report warns us that bile stasis owing to stenosis of the intrahepatic bile duct and repeated cholangitis with multiple stones are high-risk factors for carcinogenesis of the intrahepatic bile duct even after total resection of the infantile choledochal cyst.

Immunohistochemical study of characteristics of bile duct dysplasia evaluated on the basis of expression of metastasis/invasion-related factors and p53

Bile duct carcinoma still continues to have an unfavorable prognosis, despite an improved rate of curative resection and the development of surgical techniques. We evaluated the expression of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and intercellular adhesive factors (E-cadherin, alpha-catenin, beta-catenin) in cancer, dysplastic lesions, and normal (nonatypical) epithelia (glandulous ducts) in patients with bile duct carcinoma. Positivity rates for these factors were compared among the three histological types to examine the characteristics of bile duct dysplasia. Among 89 patients with bile duct carcinoma resected at our hospital during the past 10 years, we studied 18 patients who concurrently had a cancerous lesion, dysplastic lesion, and normal (nonatypical) epithelia adjoining each other in excised specimens. The immunohistochemical expressions of MMPs, TIMPs, E-cadherin, alpha-catenin, and beta-catenin were investigated. Positivity rates for MMP-9, TIMP-1, TIMP-2, membrane type (MT) 1-MMP, MT2-MMP, and E-cadherin were significantly higher in cancerous than in normal epithelium. Only the positivity rate for MT1-MMP was significantly higher in dysplasia than in normal epithelium. Positivity for MMP-related factors correlated with the degree of atypia of the bile duct epithelium. Differences between cancer and dysplasia were slightly greater than those between dysplasia and normal epithelium. Likelihood ratios between cancer and dysplasia, cancer and normal epithelium, and dysplasia and normal epithelium were higher than 5 for all metastasis-related factors and higher than 10 for most factors. This finding suggests that a normal-dysplasia-carcinoma sequence underlies the development of bile duct cancer accompanied by dysplasia. The phenotypic characteristics of dysplasia are closer to those of normal epithelium than to those of cancerous epithelium. A normal-dysplasia-carcinoma sequence is apparently involved in the development of bile duct cancer accompanied by dysplastic cells.

Molecular evidence for the synonymy of two species of Apatemon Szidat, 1928, A. gracilis (Rudolphi, 1819) and A. annuligerum () (Digenea: Strigeidae) parasitic as metacercariae in British fishes

The current study examined rDNA (internal transcribed spacer regions, ITS1 and ITS2) and cytochrome c oxidase subunit 1 (CO1) sequence data of Apatemon annuligerum (originating from two geographical locations) and A. gracilis metacercariae (originating from four natural piscine hosts) to determine the systematic status of these two strigeid digeneans. With the exception of short repeat motifs, the ITS1 regions sequenced demonstrated no intra- or inter-specific sequence variation. ITS2 sequences were 292 bp and CO1 sequences 366 bp in length and identical for both nominal Apatemon species. These sequence data provide strong evidence that the two species are con-specific and that A. annuligerum should be regarded as a junior synonym of A. gracilis.

Expression of tenascin in bile duct cancer of hamster liver by combined treatment of dimethylnitrosamine with Opisthorchis viverrini infections.

Tenascin is an extracellular matrix glycoprotein known to be an essential factor for the modulation of reciprocal interactions between the epithelium and mesenchyme during embryogenesis and tumourigenesis. The interactions between the expression of tenascin in the liver of Syrian golden hamster and the development of bile duct cancer in an Opisthorchis viverrini-associated cholangiocarcinoma model were investigated. The tenascin was expressed in connective tissues surrounding the dilated ducts, ductal rims and the stroma of cancers, and strongly in the stroma flame of necrotic cancer nodules. The mRNA signal for tenascin was also recognized in the stroma cells. The potential roles of tenascin as prognostic tumour markers are discussed.

Late development of bile duct cancer in patients who had biliary-enteric drainage for benign disease: a follow-up study of more than 1,000 patients.

To evaluate the correlation between biliary-enteric surgical drainage and the late development of cholangiocarcinoma of the biliary tract. In patients with biliary-enteric drainage, reflux of intestinal contents into the bile duct may occur and cause cholangitis, which is regarded as the most serious complication of these procedures. Lithiasis of the biliary tract and a previous biliary-enteric anastomosis have both been suggested to favor the late onset of cholangiocarcinoma. Consecutive patients (n = 1,003) undergoing three different procedures of biliary-enteric anastomosis (transduodenal sphincteroplasty, choledochoduodenostomy, and hepaticojejunostomy) between 1967 and 1997 were included in this study. The postoperative clinical course and long-term outcome were evaluated by a retrospective review of the hospital records and follow-up. Mean follow-up was 129.6 months. Fifty-five (5.5%) cases of primary bile duct cancer were found among the 1,003 patients at intervals of 132 to 218 months from biliary-enteric anastomosis. The incidence of cholangiocarcinoma in the three groups was 5.8% in transduodenal sphincteroplasty patients, 7.6% in choledochoduodenostomy patients, and 1.9% in hepaticojejunostomy patients. The incidence of malignancy related to the different underlying diagnosis was 5.9%, 7.2%, and 1.9% in patients with choledocholithiasis, sphincter of Oddi stenosis, and postoperative benign stricture, respectively. Although only one patient who developed cholangiocarcinoma had previous concurrent lithiasis of the biliary tract, 40 patients had experienced mostly severe, recurrent cholangitis. No case of malignancy occurred in patients scored as having no cholangitis in the early and long-term postoperative outcome. Univariate and multivariate analyses have shown the presence of cholangitis as the only factor affecting the incidence of cholangiocarcinoma. Chronic inflammatory changes consequent to biliary-enteric drainage should be closely monitored for the late development of biliary tract malignancies.

Nitric Oxide-Mediated Inhibition of DNA Repair Potentiates Oxidative DNA Damage in Cholangiocytes

Chronic inflammation, a risk factor for the development of bile duct cancer, induces inducible nitric oxide synthase (iNOS) with nitric oxide (NO) generation, which promotes oxidative damage of DNA, a process that probably is important in the initiation and progression of malignancies. Because inhibition of DNA repair is required for accumulation of oxidative DNA lesions, our aim was to determine if NO also inhibits repair of oxidative DNA damage. A cholangiocarcinoma cell line and a cholangiocyte cell line were transfected with iNOS. Extracts from transfected but not untransfected cells were unable to repair 8-oxodeoxyguanine (8-oxodG); this effect was irreversible because addition of dithiothreitol to cell extracts had no effect. NO inhibition of 8-oxodG repair was blocked by NO scavengers but not by peroxynitrite scavengers or inhibitors of the soluble guanylyl cyclase/protein kinase G pathway. NO also potentiated hydrogen peroxide-induced DNA damage. Finally, immunohistochemistry in human liver samples uniformly demonstrated de novo expression of iNOS and the presence of 3-nitrotyrosine and 8-oxodG formation in the biliary epithelia of 30 patients with primary sclerosing cholangitis (a premalignant disease of the biliary tract) compared with controls. Collectively, these data implicate NO-mediated inhibition of 8-oxodG base excision DNA repair processes as a mechanism potentiating DNA damage in human inflammatory diseases involving the biliary tract.

Late development of bile duct cancer after sphincteroplasty: A ten- to twenty-two-year follow-up study

Background. Transduodenal sphincteroplasty is designed to destroy the sphincteric muscle fibers, producing a terminal choledochoduodenostomy. In the absence of Oddi 's sphincter, intestinal contents with both activated pancreatic juice and bacterial flora are refluxed into the bile duct and remain there for a prolonged time. The long-term effect of producing the reflux has not been evaluated to date. Methods. One hundred nineteen consecutive patients undergoing transduodenal sphincteroplasty between February 1973 and July 1984 were included in this study. Postoperative clinical courses of 108 patients could be evaluated by means of a retrospective review of the hospital records. Median follow-up was 18 years. Results. Eight cases (7.4%) of primary bile duct cancer were found among the 108 cases at intervals of 1 to 20 years after sphincteroplasty. Two patients had concurrent hepatolithiasis. The patency of sphincteroplasty was confirmed in all cases, and the bile was infected in seven cases. Pathologic specimens obtained demonstrated cholangiocarcinomas and various degrees of atypical hyperplastic lesions under the background of chronic cholangitis. Conclusions. Chronic cholangitis can be an important causative factor in late development of bile duct cancer after sphincteroplasty. Any patients treated with choledochoduodenostomy should be closely monitored for late cholangiocarcinoma.

Sclerosing cholangitis

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology that leads to progressive obliterative fibrosis of the biliary tree. It is strongly associated with ulcerative colitis. The disease progresses in most patients to death from liver failure or cholangiocarcinoma. Although the etiology remains unknown, it is clearly immune mediated, confirmed by the close association with the autoimmune haplotype HLA A1, B8, DR3, DR52a. In addition, in over 70% of cases, antineutrophil cytoplasmic antibody that does not disappear after liver transplantation circulates. The neutrophil antigen remains unknown. The gold standard for diagnosis remains endoscopic retrograde cholangiopancreatography. The clinical course is variable, and patients may be asymptomatic at presentation. Median survival ranges from 12 to 21 years. The diagnosis of cholangiocarcinoma in primary sclerosing cholangitis remains difficult to establish, although serum markers such as carcinoembryonic antigen and carbohydrate antigen CA 19–9, and histologic markers such as dysplasia may suggest the development of bile duct cancer. No medical treatment is of proven benefit, but ursodeoxycholic acid is the most promising therapy. Orthotopic liver transplantation remains the only effective treatment and the results are excellent, with a 5-year survival rate higher than 70%.

Hilar cholangiocarcinoma associated with clonorchiasis

Pathologic and epidemiologic evidence support the relationship between the liver fluke Clonorchis sinensis and the development of bile duct cancer. We report here a case of cholangiocarcinoma in a Laotian immigrant originally diagnosed with clonorchiasis. This case demonstrates the importance of early recognition and treatment of this disease to prevent subsequent morbidity and mortality. Diagnosis and treatment of clonorchiasis as well as the possible modes of cancer induction are discussed.