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Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas
Ymera Pignochino, Ivana Sarotto, Caterina Peraldo-Neia, Junia Y Penachioni, Giuliana Cavalloni, Giorgia Migliardi, Laura Casorzo, Giovanna Chiorino, Mauro Risio, Alberto Bardelli, Massimo Aglietta, Francesco Leone
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-631
Abstract: Immunohistochemistry, FISH and mutational analysis were performed on 49 BTC samples of intrahepatic (ICCs), extrahepatic (ECCs), and gallbladder (GBCs) origin. The effect on cell proliferation of different EGFR/HER2 pathway inhibitors as single agents or in combination with gemcitabine was investigated on BTC cell lines. Western blot analyses were performed to investigate molecular mechanisms of targeted drugs.EGFR is expressed in 100% of ICCs, 52.6% of ECCs, and in 38.5% of GBCs. P-MAPK and p-Akt are highly expressed in ICCs (>58% of samples), and to a lower extent in ECCs and GBCs (<46%), indicating EGFR pathway activation. HER2 is overexpressed in 10% of GBCs (with genomic amplification), and 26.3% of ECCs (half of which has genomic amplification). EGFR or its signal transducers are mutated in 26.5% of cases: 4 samples bear mutations of PI3K (8.2%), 3 cases (6.1%) in K-RAS, 4 (8.2%) in B-RAF, and 2 cases (4.1%) in PTEN, but no loss of PTEN expression is detected. EGI-1 cell line is highly sensitive to gemcitabine, TFK1 and TGBC1-TKB cell lines are responsive and HuH28 cell line is resistant. In EGI-1 cells, combination with gefitinib further increases the antiproliferative effect of gemcitabine. In TFK1 and TGBC1-TKB cells, the efficacy of gemcitabine is increased with addiction of sorafenib and everolimus. In TGBC1-TKB cells, lapatinib also has a synergic effect with gemcitabine. HuH28 becomes responsive if treated in combination with erlotinib. Moreover, HuH28 cells are sensitive to lapatinib as a single agent. Molecular mechanisms were confirmed by western blot analysis.These data demonstrate that EGFR and HER2 pathways are suitable therapeutic targets for BTCs. The combination of gemcitabine with drugs targeting these pathways gives encouraging results and further clinical studies could be warranted.Biliary tract carcinomas (BTCs) are rare primary malignancies originating from the epithelium of the biliary tree and lead to intrahepatic (ICCs), extrahepatic (E
The Professional Medical Journal , 2007,
Abstract: Surgical complication after biliary tract injury are serious complications of Hepatobiliary surgery. Theincidence of iatrogenic bile duct injuries has increased significantly since the number of cholecystectomy operationshave increased, laparoscopic cholecystectomy became the "gold standard", mini-cholecystectomy established for thetreatment of cholelithiasis. Intraoperative hemorrhage can be life-threatening or may lead the death. The common usesof laparoscopic cholecystectomy and mini-cholecystectomy have made the young surgeons less familiar with opencholecystectomy procedure and the approaches to manage the biliary tract injuries. Uncommonly the patient had toundergo hepatic transplantation secondary to biliary tract surgery with several vessel injuries or biliary cirrhosis.Postoperative bile leakage can be managed by effective drainage as soon as possible. These complications uncommonwith the expert surgeons, but common with comparatively inexperienced surgeons. There is no substitute of experienceand caution in biliary surgery for optimization technique.
Viral infections of the biliary tract  [cached]
Gupta Ekta,Chakravarti Anita
Saudi Journal of Gastroenterology , 2008,
Abstract: Bacterial infections of the biliary tract are often considered to be an important cause of acute cholangitis. Viral infections of the biliary tract however, are very often mistaken as viral hepatitis. This article highlights various viral causes of common biliary tract infections. Viral cholangitis is both less common and less discussed than viral hepatitis. Hepatotropic viruses (A, B, C, and E) are generally regarded as hepatocellular pathogens, yet cholangitic manifestations are now well described in association with these diseases. Systemic viral diseases also lead to cholangitis in varying proportion to hepatitis. Human immunodeficiency virus is associated with protean hepatic complications, including cholangitis due to several causes. Other systemic viruses, most notably those of the herpes virus family, also cause hepatic disease including cholangitis and possibly ductopenia in both immunocompromised and immunocompetent patients.
The Professional Medical Journal , 2006,
Abstract: Objective:-To observe the rate of biliary tract injury and to prove theeffectiveness of mini-cholecystectomy in developing countries. Setting:- Department of Surgery, Nishtar Hospital,Multan. Design:- Descriptive study. Duration:- One year, starting from October 2002 to October 2003. Material andmethods: Total 50 patients were treated with mini-cholecystectomy. Follow up for complication was done for the periodof 6 months after procedure. Results: In 50 patients there was no bile duct injury. Biliary peritonitis and strictures wereseen in 2(4%) patients. Patients developed biliary leakage in which drain was not put at the time of operation and onlydrain was put and recovered. Conclusion: Mini-cholecystectomy is relatively economical method for the treatment ofgall stone disease which is associated with less patients discomfort and less incidence of postoperative complications,short hospital stay, good cosmetic results, early return to work, so it should always be preferred to conventionalcholecystectomy.
Targeted medical therapy of biliary tract cancer: Recent advances and future perspectives  [cached]
Michael H?pfner, Detlef Schuppan, Hans Scherübl
World Journal of Gastroenterology , 2008,
Abstract: The limited efficacy of cytotoxic therapy for advanced biliary tract and gallbladder cancers emphasizes the need for novel and more effective medical treatment options. A better understanding of the specific biological features of these neoplasms led to the development of new targeted therapies, which take the abundant expression of several growth factors and cognate tyrosine kinase receptors into account. This review will briefly summarize the status and future perspectives of antiangiogenic and growth factor receptor-based pharmacological approaches for the treatment of biliary tract and gallbladder cancers. In view of multiple novel targeted approaches, the rationale for innovative therapies, such as combinations of growth factor (receptor)-targeting agents with cytotoxic drugs or with other novel anticancer drugs will be highlighted.
Cystic diseases of the biliary tract and liver  [cached]
Nafiye Urganc?
Turk Pediatri Ar?ivi , 2008,
Abstract: Cystic diseases of liver are recognized in infancy and childhood initially. Cystic diseases of liver and biliary tract are choledocal cysts, autosomal recessive and autosomal dominant polycystic kidney disease, congenital hepatic fibrosis and Caroli disease (cystic dilatation of intrahepatic bile ducts). Choledochal cysts and Caroli disease do not allow biliary flow, cause chronic or obstructive cholestasis and progressive liver disease. In congenital hepatic fibrosis and polycystic kidney disease there is cystic formations at terminal interlobular bile ducts, but cholestasis is not seen. They don’t cause liver and biliary tract functional disturbances. (Turk Arch Ped 2008; 43: 40-5)
Targeted Therapy for Biliary Tract Cancer  [PDF]
Junji Furuse,Takuji Okusaka
Cancers , 2011, DOI: 10.3390/cancers3022243
Abstract: It is necessary to establish effective chemotherapy to improve the survival of patients with biliary tract cancer, because most of these patients are unsuitable candidates for surgery, and even patients undergoing curative surgery often have recurrence. Recently, the combination of cisplatin plus gemcitabine was reported to show survival benefits over gemcitabine alone in randomized clinical trials conducted in the United Kingdom and Japan. Thus, the combination of cisplatin plus gemcitabine is now recognized as the standard therapy for unresectable biliary tract cancer. One of the next issues that need to be addressed is whether molecular targeted agents might also be effective against biliary tract cancer. Although some targeted agents have been investigated as monotherapy for first-line chemotherapy, none were found to exert satisfactory efficacy. On the other hand, monoclonal antibodies such as bevacizumab and cetuximab have also been investigated in combination with a gemcitabine-based regimen and have been demonstrated to show promising activity. Furthermore, clinical trials using new targeted agents for biliary tract cancer are also proposed. This cancer is a relatively rare and heterogeneous tumor consisting of cholangiocarcinoma and gallbladder carcinoma. Therefore, a large randomized clinical trial is necessary to confirm the efficacy of chemotherapy, and international collaboration is important.
E. Tarcoveanu,C. Bradea,R. Moldovanu,G. Dimofte
Jurnalul de Chirurgie , 2005,
Abstract: Development of mini-invasive surgery determinates a rapid improvement in laparoscopic regional anatomy. As laparoscopy is becoming common in most surgical departments, basic laparoscopic anatomy is mandatory for all residents in general surgery. Successful general surgery starts in the anatomy laboratory. Successfully minim invasive surgery starts in the operative theatre with laparoscopic exploration. The initial laparoscopic view of the right upper quadrant demonstrates primarily the subphrenic spaces, abdominal surface of the diaphragm and diaphragmatic surface of the liver. The falciform ligament is a prominent dividing point between the left subphrenic space and the right subphrenic space. The ligamentum teres hepatis is seen in the free edge of the falciform. Upward traction on the gallbladder exposes the structures of Calot’s triangle and the hepatoduodenal ligament. The liver is divided into anatomic segments based on internal anatomy that is invisible to the laparoscopist. Surface landmarks include the falciform ligament and the gallbladder fossa. The surgical procedures performed laparoscopically currently include liver biopsy, wedge resection, fenestration of hepatic cysts, laparoscopic approach of the hidatid hepatic cyst, and atypical hepatectomy. We present the laparoscopic anatomy of extrahepatic biliary tract. Once the gallbladder is elevated, inspection reveals Hartmann’s pouch and the cystic duct. The typical angular junction of the cystic duct on the common duct actually occurs in a minority of patients and the length and course of the cystic duct are highly variable. The boundaries of Calot’s triangle are often not well seen. The cystic artery is often visible under the peritoneum as it runs along the surface of the gallbladder. The variations of the structures of the hepatoduodenal ligament may occur to injuries during laparoscopic cholecystectomy. Cholangiography increases the safety of dissection of biliary tract by providing a “road map” and generally precedes the dissection in cases of anatomical variations. Intraoperative evaluation represents a strong argument for above dates.
Worldwide trends in mortality from biliary tract malignancies
Tushar Patel
BMC Cancer , 2002, DOI: 10.1186/1471-2407-2-10
Abstract: Annual age-standardized rates for individual countries were compiled for deaths from biliary tract malignancies using the WHO database. These data were used to analyze gender and site-specific trends in mortality rates.An increasing trend for mortality from intrahepatic cholangiocarcinoma was noted in most countries. The average estimated annual percentage change (EAPC) in mortality rates for males was 6.9 ± 1.5, and for females was 5.1 ± 1.0. Increased mortality rates were observed in all geographic regions. Within Europe, increases were higher in Western Europe than in Central or Northern Europe. In contrast, mortality rates for extrahepatic biliary tract malignancies showed a decreasing trend in most countries, with an overall average EAPC of -0.3 ± 0.4 for males, but -1.3 ± 0.4 for females.There has been a marked global increase in mortality from intrahepatic, but not extra-hepatic, biliary tract malignancies.Biliary tract tumors have proven challenging to treat and manage due to their poor sensitivity to conventional therapies and our inability to prevent or to detect early tumor formation [1]. Furthermore, their etiology remains poorly understood. Within the biliary tract, tumors can arise from intrahepatic bile ducts (intrahepatic cholangiocarcinoma), extrahepatic bile ducts, or the gall bladder. Intrahepatic cholangiocarcinomas are highly prevalent in certain regions such as Thailand and Southeast Asia [2]. Because parasitic biliary tract infection is also endemic to these regions, liver fluke infection and chronic biliary tract inflammation have been identified as a strong risk factor for cholangiocarcinoma [3,4]. Nevertheless the precise etiology and pathogenesis of these tumors remain obscure [5].We have recently reported an increase in intrahepatic, but not extrahepatic biliary tract tumors in the U.S [6]. An increase in intrahepatic cholangiocarcinoma has also been reported in some other countries [7-9]. There have been few studies of the epidemiology o
Carcinogenesis and chemoprevention of biliary tract cancer in pancreaticobiliary maljunction  [cached]
Akihiko Tsuchida,Takao Itoi
World Journal of Gastrointestinal Oncology , 2010,
Abstract: Pancreaticobiliary maljunction (PBM) is a high risk factor for biliary tract cancer. In PBM, since the pancreatic duct and bile duct converge outside the duodenal wall beyond the influence of the sphincter of Oddi, pancreatic juice and bile are constantly mixed, producing a variety of harmful substances. Because of this, the biliary mucosa is repeatedly damaged and repaired, which causes an acceleration of cell proliferative activity and multiple gene mutations. Histological changes such as hyperplasia, metaplasia, and dysplasia ultimately result in a high incidence of carcinogenesis. In a nationwide survey by the Japanese Study Group on PBM, coexisting biliary tract cancer was detected in 278 of the 1627 registered cases of PBM (17.1%). Of these cases, in those with dilatation of the extrahepatic bile duct, cancer was often detected not only in the gallbladder but also in the bile ducts. More than 90% of cancer cases without dilatation of the extrahepatic bile duct develop in the gallbladder. Standard treatment for PBM is a cholecystectomy and resection of the extrahepatic bile duct. However, cholecystectomy alone is performed at nearly half of institutions in Japan. Conversely, reports of carcinogenesis in the remnant bile duct or pancreas after diversion surgery are steadily increasing. One of the causes for this is believed to be an accumulation of gene mutations which were present before surgery. Anticancer drugs are ineffective in preventing such carcinogenesis following surgery, thus the postoperative administration of chemopreventive agents may be necessary.
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