Management Of Bile Duct Cancer Research Articles

Current epidemiology and management of bile duct cancer

Current epidemiology and management of bile duct cancer

Diagnostic-therapeutic management of bile duct cancer.

Biliary tract cancer, or cholangiocarcinoma, comprises a heterogeneous group of malignant tumors that can emerge at any part of the biliary tree. This group is the second most common type of primary liver cancer. Diagnosis is usually based on symptoms, which may be heterogeneous, and nonspecific biomarkers in serum and biopsy specimens, as well as on imaging techniques. Endoscopy-based diagnosis is essential, since it enables biopsy specimens to be taken. In addition, it can help with locoregional staging of distal tumors. Endoscopic retrograde cholangiopancreatography is a key technique for the evaluation and treatment of malignant biliary tumors. Correct staging of cholangiocarcinoma is essential in order to be able to determine the degree of resectability and assess the results of treatment. The tumor is staged based on the TNM classification of the American Joint Committee on Cancer. The approach will depend on the classification of the tumor. Thus, some patients with early-stage disease could benefit from surgery; complete surgical resection is the cornerstone of cure. However, only a minority of patients are diagnosed in the early stages and are suitable candidates for resection. In the subset of patients diagnosed with locally advanced or metastatic disease, chemotherapy has been used to improve outcome and to delay tumor progression. The approach to biliary tract tumors should be multidisciplinary, involving experienced endoscopists, oncologists, radiologists, and surgeons.

Simvastatin enhances the chemotherapeutic efficacy of S-1 against bile duct cancer

Simvastatin has inhibitory effects on cancers. The present study aimed to investigate the interactive effects between simvastatin and S-1 against bile duct cancer and its mechanisms. The effects of simvastatin and 5-fluorouracil (5-FU) alone or in combination on the growth and apoptosis of the human cholangiocarcinoma cell line EGI-1 and the gallbladder carcinoma cell line Mz-ChA-1 cells were evaluated in vitro. Real-time PCR and western blot were used to determine E2F-1 and thymidylate synthase (TS) expressions in the treated cells. Tumoricidal efficacy of simvastatin and S-1 was further investigated in a subcutaneous bile duct cancer model in NOD/SCID mice. Simvastatin enhanced the cytotoxicity of 5-FU on bile duct cancer cells in vitro. IC50 of 5-FU alone was 4.34 μmol/l for EGI-1 and 13.9 μmol/l for MZ-ChA-1, whereas it decreased markedly to 0.90 and 2.95 μmol/l, respectively, when combined with simvastatin. The Chou and Talalay combination index of 5-FU and simvastatin was 0.41 and 0.40 at IC50 for EGI-1 and MZ-ChA-1, respectively. Simvastatin alone or plus 5-FU significantly suppressed E2F-1 and TS expressions in EGI-1 and MZ-ChA-1. Simvastatin plus 5-FU induced greater proportion of apoptotic cells on both EGI-1 and MZ-ChA-1, with an increase in cleaved caspase-3 levels, compared with simvastatin or 5-FU alone (all P < 0.05). Simvastatin plus S-1 induced greater tumor inhibition than simvastatin or S-1 alone with E2F-1/TS downregulation in vivo (all P < 0.05). Simvastatin and S-1 exerted synergistic effects against bile duct cancer, which might be mediated by E2F-1/TS downregulation. The combination could be a reasonable regimen in the management of bile duct cancer.

Surgical strategy for bile duct cancer: Advances and current limitations

The aim of this review is to describe recent advances and topics in the surgical management of bile duct cancer. Radical resection with a microscopically negative margin (R0) is the only way to cure cholangiocarcinoma and is associated with marked survival advantages compared to margin-positive resections. Complete resection of the tumor is the surgeon's ultimate aim, and several advances in the surgical treatment for bile duct cancer have been made within the last two decades. Multidetector row computed tomography has emerged as an indispensable diagnostic modality for the precise preoperative evaluation of bile duct cancer, in terms of both longitudinal and vertical tumor invasion. Many meticulous operative procedures have been established, especially extended hepatectomy for hilar cholangiocarcinoma, to achieve a negative resection margin, which is the only prognostic factor under the control of the surgeon. A complete caudate lobectomy and resection of the inferior part of Couinaud's segment IV coupled with right or left hemihepatectomy has become the standard surgical procedure for hilar cholangiocarcinoma, and pylorus-preserving pancreaticoduodenectomy is the first choice for distal bile duct cancer. Limited resection for middle bile duct cancer is indicated for only strictly selected cases. Preoperative treatments including biliary drainage and portal vein embolization are also indicated for only selected patients, especially jaundiced patients anticipating major hepatectomy. Liver transplantation seems ideal for complete resection of bile duct cancer, but the high recurrence rate and decreased patient survival after liver transplant preclude it from being considered standard treatment. Adjuvant chemotherapy and radiotherapy have a potentially crucial role in prolonging survival and controlling local recurrence, but no definite regimen has been established to date. Further evidence is needed to fully define the role of liver transplantation and adjuvant chemo-radiotherapy.

Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance.

The prognosis for patients with bile duct cancer (BDC) remains poor. Although BDC cells are essentially radioresistant, recent reports have suggested that radiation therapy, in addition to its palliative role in the management of BDC, may improve patient survival. A better understanding of the mechanisms that lead to cellular radioresistance may assist in the development of more effective BDC therapies based on radiotherapy in combination with radiosensitizing agents. The serine/threonine kinase AKT/protein kinase B, a downstream effector of phosphatidylinositol 3'-kinase, is a well-characterized kinase that is known to play a critical role in antiapoptotic signaling pathways. In this investigation, we sought to clarify the role of AKT signaling in the radioresistance in BDC cells. First, to examine whether activated AKT is expressed in BDCs, tumor specimens were obtained from 19 consecutive BDC cases. Immunohistochemical staining using an anti-phosphorylated-AKT antibody showed that phosphorylated (activated) AKT was expressed in cancer cells but not in neighboring normal mucosa in 16 cases (84.2%). Next, to evaluate the role of AKT activation in the regulation of BDC cell radiosensitivity, clonogenic assays were performed using the phosphatidylinositol 3'-kinase inhibitor LY294002 with and without irradiation. LY294002 inhibited AKT activation in BDC cells and, on irradiation, decreased clonogenic survival in a radiation dose-dependent manner. Only a small decrease in cell viability was observed in cells exposed to LY294002. Expression of constitutively active AKT in BDC cells resulted in decreased radiosensitivity, whereas a dominant-negative AKT increased radiosensitivity. Furthermore, constitutively active AKT also inhibited radiation-induced apoptosis. Collectively, these results indicate that activated AKT in BDC cells is associated with radioresistance and suggest that pharmacological or genetic modulation of AKT activity may have important therapeutic implications in BDC patients treated with radiation.

Surgical and endoscopic management of bile duct cancer

There is still considerable controversy regarding the value of surgical versus nonsurgical treatment for bile duct cancer. Therapeutic modalities vary from total hepatectomy and liver transplantation to percutaneous or endoscopic stent insertion. The aim of this study was to assess the results of the treatment of 118 patients presented with bile duct cancer in the Department of Surgery, University of Szeged, during the time period 1990-2002. The age, male/female ratio, postoperative morbidity and mortality were analyzed. The resectability rate was 18% (21/118). The mortality rate was 23.8% (5/21) after radical operations and 7% or 12.5% after the palliative procedures. 67 patients had palliative surgery following unsuccessful or recurrent jaundice after non-surgical palliation. The previously applied palliative methods have been transpapillary stenting, endoscopic pig-tail drainage, percutaneous transhepatic drainage or dilatation. Palliative surgery for jaundice caused by extrahepatic bile duct cancer is justified in cases with an unsuccessful attempt for endoscopic stenting or occlusion of endoscopically placed endoprothesis. Bilio-enteric bypass with a Roux-Y jejunal loop is superior than external drainage respecting desicterization, postoperative recovery, mortality, complication rate and quality of life.