Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Hepatology. Author manuscript; available in PMC Sep 23, 2008.
Published in final edited form as:
PMCID: PMC2547491
NIHMSID: NIHMS60349

Cholangiocarcinoma: Advances in Pathogenesis, Diagnosis, and Treatment

Cholangiocarcinoma (CCA) is an epithelial cancer originating from the bile ducts with features of cholangiocyte differentiation.1 CCA is the second most common primary hepatic malignancy, and epidemiologic studies suggest its incidence is increasing in Western countries.2 Advanced CCA has a devastating prognosis, with a median survival of <24 months.3 The only curative therapy is surgical extirpation or liver transplantation, but unfortunately the majority of patients present with advanced stage disease, which is not amenable to surgical therapies. Anatomically, CCA is classified into extrahepatic and intrahepatic forms of the disease. The extrahepatic form is more common, accounting for 80% to 90% of CCAs. It is further divided into proximal or perihilar and distal subsets depending on the location of the cancer within the extrahepatic biliary system. Perihilar disease is also frequently referred to as a Klatskin tumor. Three different growth patterns of extrahepatic CCA can be observed: (1) periductal infiltrating, (2) papillary or intraductal, and (3) mass forming.4 Intrahepatic CCA typically presents as an intrahepatic mass. In addition to their distinct morphology and clinical presentations, intrahepatic and extrahepatic CCAs differ in etiopathogenesis, molecular signatures, and management. In the last several years there have been significant new insights into the molecular pathogenesis of CCA. New diagnostic and therapeutic modalities have also been developed, resulting in improved detection rates and outcomes. In addition, we have now entered the era of targeted therapies for human cancers. Therefore, it is timely and topical to review these advances with a focus on promising targeted therapies for this disease. An additional goal is to stimulate further interest in this disease with the hope of improving outcomes for this still highly lethal malignancy.

Epidemiology of CCA

Hepatobiliary malignancies account for 13% of the 7.6 million annual cancer-related deaths worldwide and for 3% of the 560,000 annual cancer-related deaths in the United States. CCA accounts for 10% to 20% of the deaths from hepatobiliary malignancies. The prevalence of CCA shows a wide geographic variability, with the highest rates in Asia and the lowest in Australia.5 In the United States, the incidence of CCA has been reported to be 0.95/100,000 for intrahepatic forms and 0.82/100,000 for extrahepatic forms of the disease.5 Its prevalence in different racial and ethnic groups is heterogeneously distributed, with the highest age-adjusted prevalence in Hispanics (1.22/100,000) and the lowest in African Americans (0.17-0.5/100,000).6 In the last 4 decades, United States incidence rates of intrahepatic CCA have increased by 165%, whereas the extrahepatic CCA incidence has remained stable.7,8 The significant increase in age-adjusted incidence of intrahepatic CCA was confirmed after correction for a prior misclassification of hilar CCA as intrahepatic CCA.2 Similarly, increasing incidence rates of intrahepatic CCA have also been reported in Western Europe and Japan.9,10 The cause for the increasing incidence has not been identified. We speculate that increased lipid mediators such as oxysterols may contribute to the current increased incidence in Western societies.11 In Western nations, the median age at presentation is >65 years, and it is only rarely diagnosed in patients <40 years of age except in patients with primary sclerosing cholangitis (PSC).5 There is a slight male predominance for CCA.

Etiology of CCA

In the majority of cases, the etiology of CCA remains obscure. However, several conditions associated with inflammation and cholestasis have been identified as risk factors for CCA (Table 1). PSC is a common risk factor. The prevalence of CCA in this condition is 5% to 15%, and the annual incidence rate is 0.6% to 1.5%.12,13 The majority of PSC patients who develop CCA do so within the first 2.5 years following the diagnosis of PSC.12,13 Thus, the symptomatic patient who presents with their first diagnosis of PSC should be carefully screened for CCA. Hepatobiliary flukes—especially the species Opisthorchis viverrini and Clonorchis sinenesis—are risk factors for CCA.14 They are endemic in portions of East Asia, where ingesting undercooked fish is common. Several case–control studies as well as animal models have confirmed the correlation between liver fluke infection and CCA.1517 Another risk factor more commonly found in Asia than in Western countries is hepatolithiasis, for which an incidence rate of 10% for CCA has been described. 1820 Biliary malformations such as Caroli’s disease and choledochal cysts carry a 10% to 15% risk for developing CCA.2123 Hepatitis C and cirrhosis have also been reported as possible risk factors for CCA.24 Biliary–enteric drainage procedures are associated with CCA in the presence of recurrent cholangitis.25,26 Finally, compounds such as thorotrast and dioxins have been correlated with an increased risk for CCA.27 Although most patients have no identifiable overt risk factors for CCA, it remains possible that subclinical biliary tract inflammation underlies the pathogenesis of CCA in most patients.

Table 1
CCA Risk Factors

Pathogenesis of CCA

CCA likely results from malignant transformation of cholangiocytes, although transformation of epithelial cells within peribiliary glands and/or biliary stem cells may also contribute to its development. There is also evidence that subsets of CCA and mixed hepatocellular carcinoma/CCA originate from hepatic stem/progenitor cells.28,29 Etiologic and experimental evidence implicates inflammation and cholestasis as key factors in the pathogenesis of CCA. They create an environment that promotes damage in DNA mismatch repair genes/proteins, proto-oncogenes, and tumor suppressor genes.30 Cytokines, growth factors, and bile acids, found in increased concentrations in inflammation and cholestasis, contribute to these molecular changes and augment the growth and survival of altered cells. Cytokines stimulate expression of inducible nitric oxide synthase (iNOS) expression in epithelial cells, and iNOS up-regulation is present in inflammatory cholangiopathies and CCA.31 Increased iNOS activity results in generation of nitric oxide and reactive nitrogen oxide species (RNOS) known to interact with cellular DNA and proteins. The interaction between RNOS and the cellular genome results in mutations and DNA strand breaks. Mutagenesis is further promoted by interaction between nitric oxide and RNOS with DNA repair enzymes such as human 8-oxoguanine glycosylase, which is directly inactivated by S-nitrosylation of its active site cysteine residues.32 A variety of oncogenic mutations have been identified in human CCA tissues. Their frequency depends on tumor stage, tumor type, anatomical location, etiology, and ethnic population. Although dysregulation of the proto-oncogene k-ras and the tumor suppressor gene p53 is commonly observed in malignancies, mutations of k-ras have only been described in 20% to 54% of intrahepatic CCA. This is in sharp distinction to pancreatic ductal carcinoma where k-ras mutations are present in >90% of cancers.33,34 Thus, despite shared developmental ontology between the pancreatic ducts and the biliary tree, their adult cancers are different. Nuclear accumulation of p53 and up-regulation of the related protein mdm-2 and WAF-1 have been reported in 21.7% to 76% of CCAs.3542 Other inactivated tumor suppressor genes include p16INK4a, DPC4/Smad4, and APC.4345 Correlation between these markers and prognosis varies among studies. Other dysregulated genes/factors involved in cell cycle regulation and found in CCA are listed in Table 2. The majority of these genetic changes were described in intrahepatic CCA. Given the paucicellular, desmoplastic nature of extrahepatic bile ducts, genetic analysis of these tumors will require careful laser capture microdissection of the CCA cellular elements—a tedious process that has seldom been applied to this tumor.

Table 2
Molecular Pathology of CCA

Interleukin-6 (IL-6) appears to be a critical signaling molecule in the pathogenesis of human cancers.46 For example, IL-6 has recently been reported to promote cancer stem cell survival in human breast cancer by up-regulating expression of the stem cell survival regulator Notch-3.47 In human lung cancer, epidermal growth factor receptor (EGFR)-activating mutations enhance IL-6 expression, promoting its autocrine/paracrine growth-promoting and survival properties.48 Thus, IL-6 can be upstream or downstream of other potent oncogenes. IL-6 is also a key cytokine in the pathogenesis of CCA. It is a known mitogen, and its proliferative effect has been confirmed in CCA.49 IL-6 is produced at high levels by CCA cells, and elevated IL-6 serum concentrations have been reported in CCA patients.50,51 IL-6 secretion by CCA cells is further enhanced by other inflammatory cytokines. 52 In addition to autocrine and paracrine IL-6 stimulation, CCA cells overexpress the IL-6 receptor subunit gp130.51 The usual negative feedback regulation of IL-6 signaling is blocked by epigenetic silencing of suppressors of cytokine signaling 3 (SOCS-3).53 Uninhibited IL-6 stimulation results in up-regulation of the antiapoptotic Bcl-2 protein Mcl-1, rendering CCA resistant to cytotoxic therapies.5355 IL-6 has also been shown to increase telomerase activity in CCA resulting in inhibition of telomere shortening and thereby evasion of cell senescence. 5661 In CCA cells, IL-6 activates p44/p42 and p38 mitogen-activated protein kinases (MAPKs), both shown to be critical for CCA cell proliferation.52 Activated p38 MAPK decreases cyclin-dependent kinase inhibitor p21WAF1/CIP1, a known negative cell cycle regulator.62 There is also cross-communication between IL-6 and other pathways (for example, IL-6–mediated overexpression of EGFR).63 Mechanisms of IL-6 signaling in human CCA are depicted in Fig. 1.

Fig. 1
IL-6 signaling and therapeutic targets in CCA. A schematic overview of IL-6 signaling and its downstream effectors as well as examples of potential therapeutic interventions is depicted. IL-6 binds to its receptor, which consists of the common receptor ...

Receptor tyrosine kinases, which can be targeted pharmaceutically, are overexpressed in many cancers and modulate cancer biology. For example, inhibition of EGFR signaling has been shown to significantly suppress CCA cell growth.64 EGFR can directly be activated by bile acids and promote CCA cell proliferation, a potential explanation for the tropism exerted by CCA for the biliary tree.65,66 EGFR activation is sustained in CCA by failure to internalize the ligand–receptor complex, a homeostatic mechanism essential for receptor inactivation.64 EGFR phosphorylation results in activation of the downstream kinases p42/44 MAPK and p38 MAPK, which in turn increase cyclooxygenase 2 (COX-2) expression in CCA cells.66 COX-2 plays an important role in CCA carcinogenesis through inhibition of apoptosis and growth stimulation. 6772 Additional induction of COX-2 is mediated by bile acids, oxysterols, and iNOS.11,66,70 Other COX-2–inducing molecules include the tyrosine kinase ErbB-2, which is overexpressed in CCA and involved in CCA carcinogenesis and progression.73,74 It is an EGFR homologue and is able to homodimerize or heterodimerize with other members of the EGF superfamily, resulting in activation or the Raf/MAPK-pathway. Also, hepatocyte growth factor and its receptor c-met are frequently over-expressed in CCA.51,74,75 Hepatocyte growth factor is mitogenic, and its increased secretion by CCA cells together with the overexpression of its receptor represents an autocrine mechanism for sustained growth stimulation by CCA.76 In addition to the enhancement of these growth-promoting pathways, loss of growth inhibition has been demonstrated in CCA. Response to transforming growth factor-β1 is aberrant in CCA, resulting in increased proliferative rates. In the presence of IL-6, CCA cells are also resistant to activin-mediated growth inhibition.51 In summary, there is a complex net of different factors and pathways involved in CCA development, growth, and propagation.

Diagnosis of CCA

In the majority of cases, CCA is clinically silent, with symptoms only developing at an advanced stage. Once symptomatic, the clinical presentation depends on tumor location and growth pattern. Ninety percent of patients with extrahepatic ductal CCA present with painless jaundice, and 10% of patients present with cholangitis.77,78 Unilobar biliary obstruction with ipsilateral vascular encasement results in atrophy of the affected lobe and hypertrophy of the unaffected lobe.79 Upon physical examination, this “atrophy–hypertrophy complex” phenomenon presents as palpable prominence of one hepatic lobe. Intrahepatic mass-forming CCA presents with symptoms typical for hepatic masses, including abdominal pain, malaise, night sweats, and cachexia. The tumor markers CA-125 and CEA can be elevated in CCA; however, they are nonspecific and can be increased in other gastrointestinal or gynecologic malignancies or cholangiopathies. 80 CA 19-9 is the most commonly used tumor marker for CCA.81 Its sensitivity and specificity for detection of CCA in PSC are 79% and 98%, respectively, at a cutoff value of 129 U/mL. Other investigators have identified a higher cutoff of >180 U/mL to achieve this degree of specificity.82 A change from baseline of >63 U/L has a sensitivity of 90% and specificity of 98% for CCA.83 In patients without PSC, its sensitivity is 53% at a cutoff of >100 U/L and its negative predictive value is 76% to 92%.84 CA 19-9 can also be elevated in bacterial cholangitis and other gastrointestinal and gynecologic neoplasias; patients lacking the blood type Lewis antigen (10% of individuals) do not produce this tumor marker.8588 Ultrasound and computed tomography (CT) are only of limited value for detection of intrahepatic and extrahepatic CCA due to their low sensitivity and specificity, as well as their low accuracy in estimating tumor extent of intrahepatic and extrahepatic CCA.78,8991 Their main role in CCA is detection of bile duct obstruction, vascular compression or encasement, tumor staging, and preoperative planning. For evaluation of tumor location and intraductal extent, cholangiography is the most important diagnostic modality, especially for extrahepatic CCA.92 Endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), or percutaneous transhepatic cholangiography (PTC) can be used for this purpose.78 ERCP and PTC allow therapeutic interventions (for example, placement of biliary stents) as well as collection of tissue samples for pathologic and cytologic analysis. MRCP/magnetic resonance imaging (MRI) provides information about intrahepatic location and tumor dimensions of intrahepatic CCA, ductal as well as periductal tumor extent of extrahepatic CCA, vascular involvement, and metastases (Fig. 2). Its sensitivity and imaging quality of tumor tissue can be increased significantly with ferumoxide enhancement.93,94 The most sensitive method for evaluation of regional lymphadenopathy is endosonography. Biopsy of lymph nodes via fine needle aspiration for further pathologic analysis can also be performed during the endosonographic procedure. 95 However, biopsy of hilar lesions during endosonography is discouraged, because it can result in tumor seeding.96 In indeterminate cases, establishment of a diagnosis can be attempted with positron emission tomography (PET) with [18F]-2-deoxy-glucose.78,90 Sensitivity and specificity of integrated PET/CT in the identification of primary lesions has been reported as 93% and 80% for intrahepatic CCA and 55% and 33% for extrahepatic CCA.97 For regional lymph node metastases, the sensitivity of PET/CT was 12% and the specificity was 96%.97 False positive PET scans have been reported in the setting of chronic inflammation.98 A recent report suggested that PET scanning in non-PSC patients can change management and therefore is useful in staging.99

Fig. 2
Imaging of CCA. A gadolinium-enhanced MRI scan of the liver with ferumoxide of a patient with hilar CCA is depicted. The arrow inserted into the T2-weighted MRI scan points out the biliary tumor.

The pathologic diagnosis of CCA can be challenging due to the paucicellular desmoplastic nature of the periductal infiltrating form of CCA. Moreover, a cellular diagnosis of CCA is confounded by common reactive changes in PSC, resulting in highly variable sensitivity and specificity of this technique in this patient population. Using a basket device may increase the diagnostic yield of conventional cytology compared with a brush.100 Also, measurements of bile insulin-like growth factor can help distinguish malignant from benign strictures.101 The introduction of digital image analysis (DIA) and fluorescence in situ hybridization (FISH) have significantly increased the diagnostic yield of brush cytology. Both techniques depend on the identification of aneuploidy. The sensitivity and specificity of DIA for extrahepatic CCA are 39% and 77% compared with 18% and 98% with conventional cytology.102 In PSC patients, the sensitivity and specificity of DIA for CCA are 43% and 87%. FISH has a sensitivity of 47% and a specificity of 100% for detection of CCA in PSC. However, FISH analysis is complicated, and three subsets of chromosomal amplification occur: (1) trisomy 7, (2) tetrasomy or duplication of all chromosomes labeled, and (3) polysomy or amplification of at least three chromosomes. Trisomy 7 can occur in inflammatory diseases of the biliary tree, especially PSC.103 This is a true amplification of chromosome 7, because EGFR, which is also located on this chromosome, is amplified. We do not consider trisomy 7 to be diagnostic of CCA, although it likely places the patient at risk for the development of CCA. Whether EGFR inhibitors can reverse this lesion or prevent subsequent CCA in PSC patients remains to be studied. Tetrasomy must be interpreted with caution, because high mitotic rates will yield tetrasomy during the M phase of the cell cycle. Polysomy remains diagnostic of cancer in the appropriate clinical context (for example, a biliary stricture). Recently, diagnostic modalities such as endoscopic/percutaneous flexible cholangioscopy, intraductal ultrasound, and radiolabeled imaging have become available. However, they are not part of the standard diagnostic algorithm and should be reserved for cases in which other techniques have failed to demonstrate CCA but the level of suspicion is high. In particular, the emerging role of choledochoen-teroscopy will need to be validated prospectively, and tissue/cytologic diagnosis will still remain the gold standard. In summary, the diagnosis of CCA is challenging and should be undertaken in a multimodality approach that includes clinical context and laboratory as well as radiologic and pathologic analysis. A diagnostic approach for ductal CCA is proposed in Fig. 3.

Fig. 3
Diagnostic evaluation of hilar CCA. In patients with clinical suspicion of hilar CCA, CA 19-9 serum analysis, endoscopic retrograde cholangiopancreatography, and conventional as well as molecular cytologic analysis of endoscopically obtained biliary brushings ...

Staging of CCA

CCA has been classified using the International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) TNM (tumor-node-metastasis) system (Table 3). This classification is a pathologic staging system and therefore often requires surgical acquisition of the tissue. An optimal staging system should provide detailed information about disease extent, vascular involvement, and metastases without subjecting the patient to surgical treatment. It should also take into account treatment options, performance status, and age and correlate with meaningful clinical outcomes. There is an urgent need for such a validated staging system in hilar CCA. Without a staging system, stratification of patients for clinical trials is currently hampered.

Table 3
TNM Classification and UICC Staging System for Intrahepatic CCA

Long-term survival in patients with hilar CCA critically depends on complete tumor resection with negative tumor margins.104106 Therefore, evaluation for resectability of these tumors requires a staging system including parameters of biliary disease extent, vascular encasement, and hepatic lobar atrophy in addition to the information provided by a clinical TNM system. Such a staging system has been proposed by Memorial Sloan-Kettering Cancer Center (Table 4). Resectability, likelihood of curative or R0 resection, metastatic spread to N2 level lymph nodes, and survival correlated with the tumor stage of this modified classification.107

Table 4
Memorial Sloan-Kettering Cancer Center Staging System for Hilar CCA

Surgical Therapy of CCA

Surgical treatment is the only curative therapy for CCA and is therefore the treatment of choice if feasible. Solitary intrahepatic CCAs are managed by segmentectomy or lobectomy. Five-year survival rates are 22% to 44% and correlate with R0 (negative margin) resection, absence of lymph node metastases, and vascular invasion.108114 Survival rates after surgical treatment of intrahepatic as well as extrahepatic CCA have significantly improved in the last decade, possibly reflecting a more careful patient selection, thereby achieving higher rates of R0 resection.115 Surgical resection is also the treatment of choice for extrahepatic CCA in the absence of PSC. However, resection should only be attempted with curative intent, because there is no significant survival benefit of noncurative or debulking resection compared with patients not treated surgically.107 Exclusion criteria for surgical resection of hilar CCA are outlined in Table 5.116,117 Local lymph node metastases (N1) are not an absolute contraindication to surgical treatment, because they do not significantly influence outcomes in hilar CCA.107 Five-year survival rates after R0 resection for hilar CCA are 11% to 41% and for distal extrahepatic CCA are 27% to 37%.105,107,114,118120 However, overall R0 resection rates are <50%.118 Survival rates may be higher for en bloc resected patients; however, this approach is technically not feasible for cancers originating from or with significant involvement of the left hepatic duct.120 In PSC, outcomes of surgical resection are complicated by advanced liver disease in the majority of these patients, recurrent cholangitis with a biliary–enteric anastomosis, the multi-focal nature of the cancer, and their increased risk for further CCA. Because a biliary–enteric anastomosis is a risk factor for de novo CCA,25,26 creating a biliary–enteric anastomosis in a PSC patient should be viewed with caution, and informed consent regarding the potential development of additional CCA should be discussed. Patients with PSC plus CCA may be better evaluated as potential liver transplant candidates (vide infra). Perioperative morbidity following resection of hilar CCA is 31% to 85%, and postoperative mortality is 5% to 10% at major referral centers.107,121123 Several techniques have been evaluated for their potential to increase resectability, including preoperative portal vein embolization plus extended hepatectomy. 124,125 The goal of portal vein embolization is to induce hyperplasia of the nonembolized lobe increasing the volume of the remnant liver following an extended hepatectomy. This strategy achieved increased resectability in patients with hilar CCA and marginal remnant liver volumes.124,126 Adjuvant and neoadjuvant treatments for extrahepatic CCA—including chemotherapy, radiation therapy, and photodynamic therapy—cannot be recommended, because studies either failed to show significant effects or were statistically underpowered, nonrandomized, or restricted to short-term follow-up.127,128

Table 5
Exclusion Criteria for Surgical Resection of Hilar CCA

Results of liver transplantation for intrahepatic CCA are discouraging with 5-year survival rates of 0% to 18%, and therefore cannot be recommended.108,129132 Outcomes of liver transplantation for extrahepatic CCA were similarly disappointing, with 5-year survival rates of 23% to 26%.133,134 However, the development of new liver transplantation protocols for extrahepatic CCA at the Mayo Clinic and the University of Nebraska yielded highly promising results.135,136 Based on their initial experiences as well as on analysis of outcomes and correlated risk factors, strict selection criteria have been developed (Table 6), and neoadjuvant treatment has been optimized to its current form.137139 This protocol includes neoadjuvant therapy with external beam radiation therapy concurrent with 5-FU chemotherapy, followed by brachytherapy and chemotherapy with capecitabine. Prior to transplantation, patients undergo explorative laparotomy for restaging. Survival analysis of patients treated according to the Mayo Clinic protocol has yielded 1-and 5-year survival rates of 91% and 76%, respectively.138,140 Predictors for tumor recurrence include older age, CA 19-9 >100 U/mL on the day of transplantation, prior cholecystectomy, mass on cross-sectional imaging, residual tumor >2 cm in explant, tumor grade, and perineural invasion in explant.138 For highly selected patients with de novo perihilar CCA, unresectable CCA, and CCA superimposed on PSC, liver transplantation can be curative and is the treatment of choice.

Table 6
Mayo Clinic Criteria for Liver Transplantation for Hilar CCA

Palliative Treatments for CCA

CCA causes significant morbidity related to cholestasis and its complications, abdominal pain, cachexia, and bacterial cholangitis. Therefore, palliative therapies are quite important in the management of this disease. Endoscopic stent placement is as successful as surgical choledochojejunostomy or hepaticojejunostomy for restoration of biliary drainage and relief of cholestasis.141143 Unilateral hepatic duct stent placement has been shown to be equivalent to bilateral hepatic duct stenting for biliary drainage. 144 Metal stents have higher patency rates and are more cost-effective for patients, with an expected survival of >6 months. Plastic stents require exchange every 2 to 3 months due to occlusion, migration, or cholangitis and are preferred in patients who are candidates for surgical treatment or whose life expectancy is <6 months.78,145,146 In cases where endoscopic stent placement is not feasible, PTC can be employed for biliary drainage.

Photodynamic therapy (PDT) and radiation therapy have been evaluated as palliative therapies. Highly variable results have been reported with radiation therapy in largely uncontrolled studies, precluding a consensus opinion on the effectiveness of this modality. Radiation is also associated with significant morbidity, including gastrointestinal bleeding, biliary strictures, intestinal obstruction, and hepatic decompensation.147150 Therefore, radiation therapy cannot be unconditionally recommended for palliative or adjuvant therapy of intrahepatic and extrahepatic CCA. In PDT, a photosensitizing agent (such as hematoporphyrin) is administered followed by illumination at a wavelength corresponding to the absorption spectrum of the agent resulting in reactive oxygen species–induced cell death, tumor–vessel thrombosis, and tumor-specific immune reactions.151154 PDT treatment can reduce cholestasis and improve quality of life.155157 Complication rates are low and include sensitization to skin phototoxicity and acute cholangitis.158 Several studies including two randomized controlled trials indicate a survival benefit with PDT in hilar CCA.157,159162 In summary, PDT is a reasonable and recommendable approach for palliation of hilar CCA.163 Studies evaluating PDT as an adjuvant treatment have been uncontrolled, precluding a recommendation for PDT in this context.128,164

Medical Treatment for CCA

There are no curative medical therapies for CCA. The most studied chemotherapeutic drugs are 5-FU and gemcitabine; the latter was approved for CCA in 2002 by the U.S. Food and Drug Administration.165 Both drugs have been tested in combination with a variety of other drugs, including cisplatin, oxaliplatin, docetaxel, paclitaxel, mitomycin-C, doxorubicin, epirubicin, lomustine, and interferon-α.166177 However, none of the studies was randomized, and most studies were statistically underpowered, based on case reports, or demonstrated poor response rates. In conclusion, there is currently no randomized study showing a clear survival benefit for a specific chemotherapeutic regimen. With the advent of targeted therapies, it is apparent that survival is a more legitimate endpoint than response rates. For example, response rates with sorafenib for renal cell carcinoma are minimal, although life expectancy is prolonged.178 Given this evolving information, future trials will need to have a comparison arm. Randomized trials are urgently needed.

Targeted Therapy of CCA in Preclinical Studies

The growing understanding of the molecular pathogenesis of CCA opens new therapeutic options for molecular targeting. The majority of these strategies target antiapoptotic and growth-stimulating pathways. The use of methylation inhibitors is able to restore SOCS-3 expression, thereby reducing protein expression of the prosurvival bcl-2 family protein Mcl-1 and sensitizing CCA cells to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)-induced apoptosis.53,63 Other strategies for inhibiting Mcl-1 expression include the use of the multikinase inhibitor sorafenib and overexpression of mir-29 microRNA.179,180 Small molecules such as obatoclax are also in development to inhibit Mcl-1.181 Sensitization of CCA cells to TRAIL was also achieved through the use of a γ-secretase inhibitor to inhibit Notch signaling.182 Tyrosine kinase inhibitors have been used to target EGFR signaling and reduce tumor cell growth.64,183,184 Inhibition of IL-6 pathways by anti–IL-6 neutralizing antibodies or MAPK inhibitors results in growth inhibition of human CCA cell lines.52 Other strategies—including COX2 inhibitors, hepatocyte growth factor antagonists, ErbB-1/2 inhibition, and telomerase inhibition—achieved growth inhibition and/or induction or sensitization to apoptosis in vitro.61,68,69,185188 These examples show the promising potential of these new therapeutic approaches. However, the vast majority of these studies were conducted in vitro. Though the preliminary in vivo results are promising, the majority of in vivo studies have focused on tumor inhibition rather than on treatment of established tumors.187,189191 Better in vivo models of CCA will be necessary to study targeted therapies.16,60,73,192195

New In Vivo Models of CCA

In vivo evaluation of therapeutic compounds is an essential step in the preclinical development of effective antineoplastic therapies. Several subcutaneous xenograft systems have been described for CCA.183,196,197 However, preclinical data derived from these xenograft systems correlate only poorly with clinical outcomes, resulting in an increasing trend toward the use of organ-specific in vivo cancer models.198201 Early hepatobiliary CCA models were restricted to hamsters and rats, which develop tumors after treatment with carcinogens [N-nitrosobis(2-oxopropyl)amine, methylazoxymethyl acetate, dimethylnitrosamine, furan, thioacetamide] or infection with O. viverrini.16,60,192,193,202204 Recently, several new genetic CCA models have been described. Liver-specific combined deletion of the tumor suppressor genes Smad4 plus PTEN results in formation of CCA in mice.195 Another model of intrahepatic mass-forming CCA is achieved by treating p53-deficient mice with carbon tetrachloride (CCl4).205 Sirica and colleagues developed two models of CCA in which malignant transformation of explanted rat cholangiocytes followed by direct biliary inoculation of these cells resulted in CCA formation in 56% to 100% of animals.73,206 In summary, new models of CCA have been developed that resemble human CCA in many aspects. The majority of these models represent intrahepatic CCA, however, and genetic models of hilar CCA still need to be developed.

Potential Targeted Therapies for Human CCA

The chemoresistance of CCA is not completely understood. There is evidence that expression of multidrug resistance genes as well as up-regulation of antiapoptotic bcl-2 proteins are involved in the poor response rates of CCA to chemotherapeutics.207 New targeted therapies may overcome these barriers. Several drugs, targeting essential pathways in CCA pathogenesis, are already approved by the U.S. Food and Drug Administration and are in clinical use for other cancer types. Examples include EGFR inhibitors (Cetuximab, Erlotinib, and Gefitinib), Raf-kinase inhibitors (Sorafenib), Her-2–directed inhibitors (Trastuzumab and Lapatinib), and vascular endothelial growth factor–directed inhibition (Sorafenib and Bevacizumab). The National Institutes of Health reports several ongoing clinical trials evaluating the COX-2 inhibitor celecoxib and the receptor tyrosine kinase inhibitors Sorafenib, Erlotinib, and Bevacizumab as monotherapy or in combination with other agents in CCA.208 Other potential combinations that have not been evaluated yet include drugs inhibiting drug-resistance genes/proteins or agents down-regulating antiapoptotic signals. Glutathione-S-transferase-π inhibitor C16C2 decreased the IC50 of adriamycin and cyclophosphamide in vitro and enhanced the tumor suppressive potential in a CCA xenograft murine model.207 Another strategy involves sensitization to TRAIL-induced apoptosis by down-regulation of Mcl-1 (for example, by treatment with Sorafenib).209 These are just a few examples, but they represent the possibilities for targeting molecular pathways in human CCA.

Conclusion

Advances have been made in the diagnosis and management of CCA. From the clinical perspective, advanced cytologic techniques for the diagnosis of CCA have increased the use of brush cytology for the diagnosis of this neoplasm. En bloc surgical resection and liver transplantation have advanced the surgical treatment of this disease, and PDT has emerged as an important palliative therapy. The development of in vivo animal models for CCA will permit more rigorous development of targeted therapies for this disease. A clinical stratification system is necessary prior to the implementation of multicenter trials. Although progress on CCA has been continuous, more work is needed to cure and prevent this disease.

Acknowledgments

Supported by National Institutes of Health Grant DK59427, the Mayo Clinic Clinical Investigator Program, and the Mayo Foundation.

Abbreviations

CCA
cholangiocarcinoma
CT
computed tomography
DIA
digital image analysis
EGFR
epidermal growth factor receptor
ERCP
endoscopic retrograde cholangiopancreatography
FISH
fluorescence in situ hybridization
IL-6
interleukin-6
iNOS
inducible nitric oxide synthase
MAPK
mitogen-activated protein kinase
MRCP
magnetic resonance cholangiopancreatography
MRI
magnetic resonance imaging
PDT
photodynamic therapy
PET
positron emission tomography
PSC
primary sclerosing cholangitis
PTC
percutaneous transhepatic cholangiography
RNOS
reactive nitrogen oxide species
TRAIL
tumor necrosis factor–related apoptosis-inducing ligand

Footnotes

Potential conflict of interest: Nothing to report.

References

1. de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med. 1999;341:1368–1378. [PubMed]
2. Welzel TM, McGlynn KA, Hsing AW, O’Brien TR, Pfeiffer RM. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst. 2006;98:873–875. [PubMed]
3. Farley DR, Weaver AL, Nagorney DM. “Natural history” of unresected cholangiocarcinoma: patient outcome after noncurative intervention. Mayo Clin Proc. 1995;70:425–429. [PubMed]
4. Lim JH, Park CK. Pathology of cholangiocarcinoma. Abdom Imaging. 2004;29:540–547. [PubMed]
5. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24:115–125. [PubMed]
6. McLean L, Patel T. Racial and ethnic variations in the epidemiology of intrahepatic cholangiocarcinoma in the United States. Liver Int. 2006;26:1047–1053. [PubMed]
7. Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol. 2004;40:472–477. [PubMed]
8. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;33:1353–1357. [PubMed]
9. Mouzas IA, Dimoulios P, Vlachonikolis IG, Skordilis P, Zoras O, Kouroumalis E. Increasing incidence of cholangiocarcinoma in Crete 1992–2000. Anticancer Res. 2002;22:3637–3641. [PubMed]
10. Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress. Part 2: molecular pathology and treatment. J Gastroenterol Hepatol. 2002;17:1056–1063. [PubMed]
11. Yoon JH, Canbay AE, Werneburg NW, Lee SP, Gores GJ. Oxysterols induce cyclooxygenase-2 expression in cholangiocytes: implications for biliary tract carcinogenesis. Hepatology. 2004;39:732–738. [PubMed]
12. Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:523–526. [PubMed]
13. Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Loof L, Danielsson A, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol. 2002;36:321–327. [PubMed]
14. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg. 2002;89:962–970. [PubMed]
15. Kurathong S, Lerdverasirikul P, Wongpaitoon V, Pramoolsinsap C, Kanjanapitak A, Varavithya W, et al. Opisthorchis viverrini infection and cholangiocarcinoma. A prospective, case-controlled study. Gastroenterology. 1985;89:151–156. [PubMed]
16. Tesana S, Takahashi Y, Sithithaworn P, Ando K, Sakakura T, Yutanawiboonchai W, et al. Ultrastructural and immunohistochemical analysis of cholangiocarcinoma in immunized Syrian golden hamsters infected with Opisthorchis viverrini and administered with dimethylnitrosamine. Parasitol Int. 2000;49:239–251. [PubMed]
17. Parkin DM, Srivatanakul P, Khlat M, Chenvidhya D, Chotiwan P, Insiripong S, et al. Liver cancer in Thailand. I. A case-control study of cholangiocarcinoma. Int J Cancer. 1991;48:323–328. [PubMed]
18. Kubo S, Kinoshita H, Hirohashi K, Hamba H. Hepatolithiasis associated with cholangiocarcinoma. World J Surg. 1995;19:637–641. [PubMed]
19. Lesurtel M, Regimbeau JM, Farges O, Colombat M, Sauvanet A, Belghiti J. Intrahepatic cholangiocarcinoma and hepatolithiasis: an unusual association in Western countries. Eur J Gastroenterol Hepatol. 2002;14:1025–1027. [PubMed]
20. Su CH, Shyr YM, Lui WY, P’Eng FK. Hepatolithiasis associated with cholangiocarcinoma. Br J Surg. 1997;84:969–973. [PubMed]
21. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol. 1999;10 Suppl 4:308–311. [PubMed]
22. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease. A changing pattern of presentation. Ann Surg. 1994;220:644–652. [PMC free article] [PubMed]
23. Scott J, Shousha S, Thomas HC, Sherlock S. Bile duct carcinoma: a late complication of congenital hepatic fibrosis. Case report and review of literature. Am J Gastroenterol. 1980;73:113–119. [PubMed]
24. Shaib YH, El-Serag HB, Nooka AK, Thomas M, Brown TD, Patt YZ, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study. Am J Gastroenterol. 2007;102:1016–1021. [PubMed]
25. Tocchi A, Mazzoni G, Liotta G, Lepre L, Cassini D, Miccini M. 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. Ann Surg. 2001;234:210–214. [PMC free article] [PubMed]
26. Bettschart V, Clayton RA, Parks RW, Garden OJ, Bellamy CO. Cholangiocarcinoma arising after biliary-enteric drainage procedures for benign disease. Gut. 2002;51:128–129. [PMC free article] [PubMed]
27. Walker NJ, Crockett PW, Nyska A, Brix AE, Jokinen MP, Sells DM, et al. Dose-additive carcinogenicity of a defined mixture of “dioxin-like compounds” Environ Health Perspect. 2005;113:43–48. [PMC free article] [PubMed]
28. Nomoto K, Tsuneyama K, Cheng C, Takahashi H, Hori R, Murai Y, et al. Intrahepatic cholangiocarcinoma arising in cirrhotic liver frequently expressed p63-positive basal/stem-cell phenotype. Pathol Res Pract. 2006;202:71–76. [PubMed]
29. Sell S, Dunsford HA. Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma. Am J Pathol. 1989;134:1347–1363. [PMC free article] [PubMed]
30. Jaiswal M, LaRusso NF, Gores GJ. Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol. 2001;281:G626–G634. [PubMed]
31. Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res. 2000;60:184–190. [PubMed]
32. Jaiswal M, LaRusso NF, Nishioka N, Nakabeppu Y, Gores GJ. Human Ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide. Cancer Res. 2001;61:6388–6393. [PubMed]
33. Dergham ST, Dugan MC, Kucway R, Du W, Kamarauskiene DS, Vaitkevicius VK, et al. Prevalence and clinical significance of combined K-ras mutation and p53 aberration in pancreatic adenocarcinoma. Int J Pancreatol. 1997;21:127–143. [PubMed]
34. Z’Graggen K, Rivera JA, Compton CC, Pins M, Werner J, Fernandez-del Castillo C, et al. Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas. Ann Surg. 1997;226:491–498. [discussion: 498–500]. [PMC free article] [PubMed]
35. Boberg KM, Schrumpf E, Bergquist A, Broome U, Pares A, Remotti H, et al. Cholangiocarcinoma in primary sclerosing cholangitis: K-ras mutations and Tp53 dysfunction are implicated in the neoplastic development. J Hepatol. 2000;32:374–380. [PubMed]
36. Furubo S, Harada K, Shimonishi T, Katayanagi K, Tsui W, Nakanuma Y. Protein expression and genetic alterations of p53 and ras in intrahepatic cholangiocarcinoma. Histopathology. 1999;35:230–240. [PubMed]
37. Tannapfel A, Benicke M, Katalinic A, Uhlmann D, Kockerling F, Hauss J, et al. Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut. 2000;47:721–727. [PMC free article] [PubMed]
38. Ahrendt SA, Rashid A, Chow JT, Eisenberger CF, Pitt HA, Sidransky D. p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer. J Hepatobiliary Pancreat Surg. 2000;7:426–431. [PubMed]
39. Isa T, Tomita S, Nakachi A, Miyazato H, Shimoji H, Kusano T, et al. Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma. Hepatogastroenterology. 2002;49:604–608. [PubMed]
40. Watanabe M, Asaka M, Tanaka J, Kurosawa M, Kasai M, Miyazaki T. Point mutation of K-ras gene codon 12 in biliary tract tumors. Gastroenterology. 1994;107:1147–1153. [PubMed]
41. Tada M, Omata M, Ohto M. High incidence of ras gene mutation in intrahepatic cholangiocarcinoma. Cancer. 1992;69:1115–1118. [PubMed]
42. Levi S, Urbano-Ispizua A, Gill R, Thomas DM, Gilbertson J, Foster C, et al. Multiple K-ras codon 12 mutations in cholangiocarcinomas demonstrated with a sensitive polymerase chain reaction technique. Cancer Res. 1991;51:3497–3502. [PubMed]
43. Kang YK, Kim WH, Lee HW, Lee HK, Kim YI. Mutation of p53 and K-ras, and loss of heterozygosity of APC in intrahepatic cholangiocarcinoma. Lab Invest. 1999;79:477–483. [PubMed]
44. Hahn SA, Bartsch D, Schroers A, Galehdari H, Becker M, Ramaswamy A, et al. Mutations of the DPC4/Smad4 gene in biliary tract carcinoma. Cancer Res. 1998;58:1124–1126. [PubMed]
45. Taniai M, Higuchi H, Burgart LJ, Gores GJ. p16INK4a promoter mutations are frequent in primary sclerosing cholangitis (PSC) and PSC-associated cholangiocarcinoma. Gastroenterology. 2002;123:1090–1098. [PubMed]
46. Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 2005;41:2502–2512. [PubMed]
47. Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007;117:3988–4002. [PMC free article] [PubMed]
48. Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL, et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 2007;117:3846–3856. [PMC free article] [PubMed]
49. Okada K, Shimizu Y, Nambu S, Higuchi K, Watanabe A. Interleukin-6 functions as an autocrine growth factor in a cholangiocarcinoma cell line. J Gastroenterol Hepatol. 1994;9:462–467. [PubMed]
50. Goydos JS, Brumfield AM, Frezza E, Booth A, Lotze MT, Carty SE. Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker. Ann Surg. 1998;227:398–404. [PMC free article] [PubMed]
51. Yokomuro S, Tsuji H, Lunz JG, 3rd, Sakamoto T, Ezure T, Murase N, et al. Growth control of human biliary epithelial cells by interleukin 6, hepatocyte growth factor, transforming growth factor beta1, and activin A: comparison of a cholangiocarcinoma cell line with primary cultures of non-neoplastic biliary epithelial cells. Hepatology. 2000;32:26–35. [PubMed]
52. Park J, Tadlock L, Gores GJ, Patel T. Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology. 1999;30:1128–1133. [PubMed]
53. Isomoto H, Mott JL, Kobayashi S, Werneburg NW, Bronk SF, Haan S, et al. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology. 2007;132:384–396. [PMC free article] [PubMed]
54. Isomoto H, Kobayashi S, Werneburg NW, Bronk SF, Guicciardi ME, Frank DA, et al. Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology. 2005;42:1329–1338. [PubMed]
55. Kobayashi S, Werneburg NW, Bronk SF, Kaufmann SH, Gores GJ. Interleukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells. Gastroenterology. 2005;128:2054–2065. [PubMed]
56. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998;279:349–352. [PubMed]
57. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011–2015. [PubMed]
58. Ozaki S, Harada K, Sanzen T, Watanabe K, Tsui W, Nakanuma Y. In situ nucleic acid detection of human telomerase in intrahepatic cholangiocarcinoma and its preneoplastic lesion. Hepatology. 1999;30:914–919. [PubMed]
59. Itoi T, Shinohara Y, Takeda K, Takei K, Ohno H, Ohyashiki K, et al. Detection of telomerase activity in biopsy specimens for diagnosis of biliary tract cancers. Gastrointest Endosc. 2000;52:380–386. [PubMed]
60. Iki K, Tsujiuchi T, Majima T, Sakitani H, Tsutsumi M, Takahama M, et al. Increased telomerase activity in intrahepatic cholangiocellular carcinomas induced by N-nitrosobis(2-oxopropyl)amine in hamsters. Cancer Lett. 1998;131:185–190. [PubMed]
61. Yamagiwa Y, Meng F, Patel T. Interleukin-6 decreases senescence and increases telomerase activity in malignant human cholangiocytes. Life Sci. 2006;78:2494–2502. [PMC free article] [PubMed]
62. Tadlock L, Patel T. Involvement of p38 mitogen-activated protein kinase signaling in transformed growth of a cholangiocarcinoma cell line. Hepatology. 2001;33:43–51. [PubMed]
63. Wehbe H, Henson R, Meng F, Mize-Berge J, Patel T. Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res. 2006;66:10517–10524. [PubMed]
64. Yoon JH, Gwak GY, Lee HS, Bronk SF, Werneburg NW, Gores GJ. Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells. J Hepatol. 2004;41:808–814. [PubMed]
65. Werneburg NW, Yoon JH, Higuchi H, Gores GJ. Bile acids activate EGF receptor via a TGF-alpha-dependent mechanism in human cholangiocyte cell lines. Am J Physiol Gastrointest Liver Physiol. 2003;285:G31–G36. [PubMed]
66. Yoon JH, Higuchi H, Werneburg NW, Kaufmann SH, Gores GJ. Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line. Gastroenterology. 2002;122:985–993. [PubMed]
67. Endo K, Yoon BI, Pairojkul C, Demetris AJ, Sirica AE. ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. Hepatology. 2002;36:439–450. [PubMed]
68. Han C, Leng J, Demetris AJ, Wu T. Cyclooxygenase-2 promotes human cholangiocarcinoma growth: evidence for cyclooxygenase-2-independent mechanism in celecoxib-mediated induction of p21waf1/cip1 and p27kip1 and cell cycle arrest. Cancer Res. 2004;64:1369–1376. [PubMed]
69. Nzeako UC, Guicciardi ME, Yoon JH, Bronk SF, Gores GJ. COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cells. Hepatology. 2002;35:552–559. [PubMed]
70. Ishimura N, Bronk SF, Gores GJ. Inducible nitric oxide synthase upregulates cyclooxygenase-2 in mouse cholangiocytes promoting cell growth. Am J Physiol Gastrointest Liver Physiol. 2004;287:G88–G95. [PubMed]
71. Han C, Wu T. Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of the epidermal growth factor receptor and Akt. J Biol Chem. 2005;280:24053–24063. [PubMed]
72. Wu T, Han C, Lunz JG, 3rd, Michalopoulos G, Shelhamer JH, Demetris AJ. Involvement of 85-kd cytosolic phospholipase A(2) and cyclooxygenase-2 in the proliferation of human cholangiocarcinoma cells. Hepatology. 2002;36:363–373. [PubMed]
73. Lai GH, Zhang Z, Shen XN, Ward DJ, Dewitt JL, Holt SE, et al. erbB-2/neu transformed rat cholangiocytes recapitulate key cellular and molecular features of human bile duct cancer. Gastroenterology. 2005;129:2047–2057. [PubMed]
74. Aishima SI, Taguchi KI, Sugimachi K, Shimada M, Tsuneyoshi M. cerbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma. Histopathology. 2002;40:269–278. [PubMed]
75. Terada T, Nakanuma Y, Sirica AE. Immunohistochemical demonstration of MET overexpression in human intrahepatic cholangiocarcinoma and in hepatolithiasis. Hum Pathol. 1998;29:175–180. [PubMed]
76. Lai GH, Radaeva S, Nakamura T, Sirica AE. Unique epithelial cell production of hepatocyte growth factor/scatter factor by putative precancerous intestinal metaplasias and associated “intestinal-type” biliary cancer chemically induced in rat liver. Hepatology. 2000;31:1257–1265. [PubMed]
77. Olnes MJ, Erlich R. A review and update on cholangiocarcinoma. Oncology. 2004;66:167–179. [PubMed]
78. Khan SA, Davidson BR, Goldin R, Pereira SP, Rosenberg WM, Taylor-Robinson SD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51 Suppl 6:VI1–VI9. [PMC free article] [PubMed]
79. Hann LE, Getrajdman GI, Brown KT, Bach AM, Teitcher JB, Fong Y, et al. Hepatic lobar atrophy: association with ipsilateral portal vein obstruction. AJR Am J Roentgenol. 1996;167:1017–1021. [PubMed]
80. Chen CY, Shiesh SC, Tsao HC, Lin XZ. The assessment of biliary CA 125, CA 19-9 and CEA in diagnosing cholangiocarcinoma—the influence of sampling time and hepatolithiasis. Hepatogastroenterology. 2002;49:616–620. [PubMed]
81. Nehls O, Gregor M, Klump B. Serum and bile markers for cholangiocarcinoma. Semin Liver Dis. 2004;24:139–154. [PubMed]
82. Siqueira E, Schoen RE, Silverman W, Martin J, Rabinovitz M, Weissfeld JL, et al. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. Gastrointest Endosc. 2002;56:40–47. [PubMed]
83. Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci. 2005;50:1734–1740. [PubMed]
84. Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ. The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol. 2000;95:204–207. [PubMed]
85. Narimatsu H, Iwasaki H, Nakayama F, Ikehara Y, Kudo T, Nishihara S, et al. Lewis and secretor gene dosages affect CA19-9 and DU-PAN-2 serum levels in normal individuals and colorectal cancer patients. Cancer Res. 1998;58:512–518. [PubMed]
86. Vestergaard EM, Hein HO, Meyer H, Grunnet N, Jorgensen J, Wolf H, et al. Reference values and biological variation for tumor marker CA 19-9 in serum for different Lewis and secretor genotypes and evaluation of secretor and Lewis genotyping in a Caucasian population. Clin Chem. 1999;45:54–61. [PubMed]
87. Akdogan M, Sasmaz N, Kayhan B, Biyikoglu I, Disibeyaz S, Sahin B. Extraordinarily elevated CA19-9 in benign conditions: a case report and review of the literature. Tumori. 2001;87:337–339. [PubMed]
88. Albert MB, Steinberg WM, Henry JP. Elevated serum levels of tumor marker CA19-9 in acute cholangitis. Dig Dis Sci. 1988;33:1223–1225. [PubMed]
89. Robledo R, Muro A, Prieto ML. Extrahepatic bile duct carcinoma: US characteristics and accuracy in demonstration of tumors. Radiology. 1996;198:869–873. [PubMed]
90. Slattery JM, Sahani DV. What is the current state-of-the-art imaging for detection and staging of cholangiocarcinoma? Oncologist. 2006;11:913–922. [PubMed]
91. Foley WD, Quiroz FA. The role of sonography in imaging of the biliary tract. Ultrasound Q. 2007;23:123–135. [PubMed]
92. Gores GJ. Early detection and treatment of cholangiocarcinoma. Liver Transpl. 2000;6:S30–S34. [PubMed]
93. Braga HJ, Imam K, Bluemke DA. MR imaging of intrahepatic cholangiocarcinoma: use of ferumoxides for lesion localization and extension. AJR Am J Roentgenol. 2001;177:111–114. [PubMed]
94. Raman SS, Lu DS, Chen SC, Sayre J, Eilber F, Economou J. Hepatic MR imaging using ferumoxides: prospective evaluation with surgical and intraoperative sonographic confirmation in 25 cases. AJR Am J Roentgenol. 2001;177:807–812. [PubMed]
95. Gleeson FC, Rajan E, Levy MJ, Clain JE, Topazian MD, Harewood GC, et al. EUS-guided FNA of regional lymph nodes in patients with unresectable hilar cholangiocarcinoma. Gastrointest Endosc. 2008;67:438–443. [PubMed]
96. Malhi H, Gores GJ. Review article: the modern diagnosis and therapy of cholangiocarcinoma. Aliment Pharmacol Ther. 2006;23:1287–1296. [PubMed]
97. Petrowsky H, Wildbrett P, Husarik DB, Hany TF, Tam S, Jochum W, et al. Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol. 2006;45:43–50. [PubMed]
98. Fritscher-Ravens A, Bohuslavizki KH, Broering DC, Jenicke L, Schafer H, Buchert R, et al. FDG PET in the diagnosis of hilar cholangiocarcinoma. Nucl Med Commun. 2001;22:1277–1285. [PubMed]
99. Corvera CU, Blumgart LH, Akhurst T, DeMatteo RP, D’Angelica M, Fong Y, et al. 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg. 2008;206:57–65. [PubMed]
100. Dumonceau JM, Macias Gomez C, Casco C, Genevay M, Marcolongo M, Bongiovanni M, et al. Grasp or brush for biliary sampling at endoscopic retrograde cholangiography? A blinded randomized controlled trial. Am J Gastroenterol. 2008;103:333–340. [PubMed]
101. Alvaro D, Macarri G, Mancino MG, Marzioni M, Bragazzi M, Onori P, et al. Serum and biliary insulin-like growth factor I and vascular endothelial growth factor in determining the cause of obstructive cholestasis. Ann Intern Med. 2007;147:451–459. [PubMed]
102. Baron TH, Harewood GC, Rumalla A, Pochron NL, Stadheim LM, Gores GJ, et al. A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol. 2004;2:214–219. [PubMed]
103. Halling KC, Kipp BR. Fluorescence in situ hybridization in diagnostic cytology. Hum Pathol. 2007;38:1137–1144. [PubMed]
104. Burke EC, Jarnagin WR, Hochwald SN, Pisters PW, Fong Y, Blumgart LH. Hilar cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg. 1998;228:385–394. [PMC free article] [PubMed]
105. Pichlmayr R, Weimann A, Klempnauer J, Oldhafer KJ, Maschek H, Tusch G, et al. Surgical treatment in proximal bile duct cancer. A single-center experience. Ann Surg. 1996;224:628–638. [PMC free article] [PubMed]
106. Klempnauer J, Ridder GJ, von Wasielewski R, Werner M, Weimann A, Pichlmayr R. Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol. 1997;15:947–954. [PubMed]
107. Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BJ, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;234:507–517. [discussion: 517-509]. [PMC free article] [PubMed]
108. Casavilla FA, Marsh JW, Iwatsuki S, Todo S, Lee RG, Madariaga JR, et al. Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg. 1997;185:429–436. [PMC free article] [PubMed]
109. Lieser MJ, Barry MK, Rowland C, Ilstrup DM, Nagorney DM. Surgical management of intrahepatic cholangiocarcinoma: a 31-year experience. J Hepatobiliary Pancreat Surg. 1998;5:41–47. [PubMed]
110. Madariaga JR, Iwatsuki S, Todo S, Lee RG, Irish W, Starzl TE. Liver resection for hilar and peripheral cholangiocarcinomas: a study of 62 cases. Ann Surg. 1998;227:70–79. [PMC free article] [PubMed]
111. Ohtsuka M, Ito H, Kimura F, Shimizu H, Togawa A, Yoshidome H, et al. Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival. Br J Surg. 2002;89:1525–1531. [PubMed]
112. Isaji S, Kawarada Y, Taoka H, Tabata M, Suzuki H, Yokoi H. Clinicopathological features and outcome of hepatic resection for intrahepatic cholangiocarcinoma in Japan. J Hepatobiliary Pancreat Surg. 1999;6:108–116. [PubMed]
113. Valverde A, Bonhomme N, Farges O, Sauvanet A, Flejou JF, Belghiti J. Resection of intrahepatic cholangiocarcinoma: a Western experience. J Hepatobiliary Pancreat Surg. 1999;6:122–127. [PubMed]
114. Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463–473. [discussion: 473–465]. [PMC free article] [PubMed]
115. Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg. 2007;11:1488–1496. [discussion: 1496-1487]. [PubMed]
116. Jarnagin WR, Shoup M. Surgical management of cholangiocarcinoma. Semin Liver Dis. 2004;24:189–199. [PubMed]
117. Patel T. Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol. 2006;3:33–42. [PubMed]
118. Nagorney DM, Kendrick ML. Hepatic resection in the treatment of hilar cholangiocarcinoma. Adv Surg. 2006;40:159–171. [PubMed]
119. DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007;245:755–762. [PMC free article] [PubMed]
120. Neuhaus P, Jonas S, Bechstein WO, Lohmann R, Radke C, Kling N, et al. Extended resections for hilar cholangiocarcinoma. Ann Surg. 1999;230:808–818. [discussion: 819]. [PMC free article] [PubMed]
121. Kawarada Y, Das BC, Naganuma T, Tabata M, Taoka H. Surgical treatment of hilar bile duct carcinoma: experience with 25 consecutive hepatectomies. J Gastrointest Surg. 2002;6:617–624. [PubMed]
122. Hemming AW, Reed AI, Fujita S, Foley DP, Howard RJ. Surgical management of hilar cholangiocarcinoma. Ann Surg. 2005;241:693–699. [discussion: 699–702]. [PMC free article] [PubMed]
123. Gazzaniga GM, Filauro M, Bagarolo C, Mori L. Surgery for hilar cholangiocarcinoma: an Italian experience. J Hepatobiliary Pancreat Surg. 2000;7:122–127. [PubMed]
124. Abdalla EK, Barnett CC, Doherty D, Curley SA, Vauthey JN. Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg. 2002;137:675–680. [discussion: 680-671]. [PubMed]
125. Makuuchi M, Thai BL, Takayasu K, Takayama T, Kosuge T, Gunven P, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery. 1990;107:521–527. [PubMed]
126. Nagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg. 2006;243:364–372. [PMC free article] [PubMed]
127. McMasters KM, Tuttle TM, Leach SD, Rich T, Cleary KR, Evans DB, et al. Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg. 1997;174:605–608. [discussion: 608–609]. [PubMed]
128. Wiedmann M, Caca K, Berr F, Schiefke I, Tannapfel A, Wittekind C, et al. Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma: a phase II pilot study. Cancer. 2003;97:2783–2790. [PubMed]
129. Pascher A, Jonas S, Neuhaus P. Intrahepatic cholangiocarcinoma: indication for transplantation. J Hepatobiliary Pancreat Surg. 2003;10:282–287. [PubMed]
130. O’Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg. 1988;207:373–379. [PMC free article] [PubMed]
131. Pichlmayr R, Weimann A, Oldhafer KJ, Schlitt HJ, Klempnauer J, Bornscheuer A, et al. Role of liver transplantation in the treatment of unresectable liver cancer. World J Surg. 1995;19:807–813. [PubMed]
132. Weimann A, Varnholt H, Schlitt HJ, Lang H, Flemming P, Hustedt C, et al. Retrospective analysis of prognostic factors after liver resection and transplantation for cholangiocellular carcinoma. Br J Surg. 2000;87:1182–1187. [PubMed]
133. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation. 2000;69:1633–1637. [PubMed]
134. Iwatsuki S, Todo S, Marsh JW, Madariaga JR, Lee RG, Dvorchik I, et al. Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic resection or transplantation. J Am Coll Surg. 1998;187:358–364. [PMC free article] [PubMed]
135. De Vreede I, Steers JL, Burch PA, Rosen CB, Gunderson LL, Haddock MG, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl. 2000;6:309–316. [PubMed]
136. Sudan D, DeRoover A, Chinnakotla S, Fox I, Shaw B, Jr, McCashland T, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant. 2002;2:774–779. [PubMed]
137. Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005;242:451–458. [discussion: 458–461]. [PMC free article] [PubMed]
138. Heimbach JK, Gores GJ, Haddock MG, Alberts SR, Pedersen R, Kremers W, et al. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation. 2006;82:1703–1707. [PubMed]
139. Heimbach JK, Gores GJ, Haddock MG, Alberts SR, Nyberg SL, Ishitani MB, et al. Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis. 2004;24:201–207. [PubMed]
140. Gores GJ, Nagorney DM, Rosen CB. Cholangiocarcinoma: is transplantation an option? For whom? J Hepatol. 2007;47:455–459. [PubMed]
141. Shepherd HA, Royle G, Ross AP, Diba A, Arthur M, Colin-Jones D. Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial. Br J Surg. 1988;75:1166–1168. [PubMed]
142. Andersen JR, Sorensen SM, Kruse A, Rokkjaer M, Matzen P. Randomised trial of endoscopic endoprosthesis versus operative bypass in malignant obstructive jaundice. Gut. 1989;30:1132–1135. [PMC free article] [PubMed]
143. Smith AC, Dowsett JF, Russell RC, Hatfield AR, Cotton PB. Randomised trial of endoscopic stenting versus surgical bypass in malignant low bileduct obstruction. Lancet. 1994;344:1655–1660. [PubMed]
144. De Palma GD, Galloro G, Siciliano S, Iovino P, Catanzano C. Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: results of a prospective, randomized, and controlled study. Gastrointest Endosc. 2001;53:547–553. [PubMed]
145. Abu-Hamda EM, Baron TH. Endoscopic management of cholangiocarcinoma. Semin Liver Dis. 2004;24:165–175. [PubMed]
146. Kaassis M, Boyer J, Dumas R, Ponchon T, Coumaros D, Delcenserie R, et al. Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc. 2003;57:178–182. [PubMed]
147. Czito BG, Anscher MS, Willett CG. Radiation therapy in the treatment of cholangiocarcinoma. Oncology (Williston Park) 2006;20:873–884. [discussion: 886-878, 893-875]. [PubMed]
148. Foo ML, Gunderson LL, Bender CE, Buskirk SJ. External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys. 1997;39:929–935. [PubMed]
149. Pitt HA, Nakeeb A, Abrams RA, Coleman J, Piantadosi S, Yeo CJ, et al. Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg. 1995;221:788–797. [discussion: 797-788]. [PMC free article] [PubMed]
150. Grove MK, Hermann RE, Vogt DP, Broughan TA. Role of radiation after operative palliation in cancer of the proximal bile ducts. Am J Surg. 1991;161:454–458. [PubMed]
151. Krammer B. Vascular effects of photodynamic therapy. Anticancer Res. 2001;21:4271–4277. [PubMed]
152. Korbelik M, Dougherty GJ. Photodynamic therapy-mediated immune response against subcutaneous mouse tumors. Cancer Res. 1999;59:1941–1946. [PubMed]
153. Abels C. Targeting of the vascular system of solid tumours by photodynamic therapy (PDT) Photochem Photobiol Sci. 2004;3:765–771. [PubMed]
154. Ortner MA, Dorta G. Technology insight: photodynamic therapy for cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol. 2006;3:459–467. [PubMed]
155. Ortner MA, Liebetruth J, Schreiber S, Hanft M, Wruck U, Fusco V, et al. Photodynamic therapy of nonresectable cholangiocarcinoma. Gastroenterology. 1998;114:536–542. [PubMed]
156. Berr F, Wiedmann M, Tannapfel A, Halm U, Kohlhaw KR, Schmidt F, et al. Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival. Hepatology. 2000;31:291–298. [PubMed]
157. Ortner ME, Caca K, Berr F, Liebetruth J, Mansmann U, Huster D, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology. 2003;125:1355–1363. [PubMed]
158. Rumalla A, Baron TH, Wang KK, Gores GJ, Stadheim LM, de Groen PC. Endoscopic application of photodynamic therapy for cholangiocarcinoma. Gastrointest Endosc. 2001;53:500–504. [PubMed]
159. Shim CS, Cheon YK, Cha SW, Bhandari S, Moon JH, Cho YD, et al. Prospective study of the effectiveness of percutaneous transhepatic photodynamic therapy for advanced bile duct cancer and the role of intraductal ultrasonography in response assessment. Endoscopy. 2005;37:425–433. [PubMed]
160. Harewood GC, Baron TH, Rumalla A, Wang KK, Gores GJ, Stadheim LM, et al. Pilot study to assess patient outcomes following endoscopic application of photodynamic therapy for advanced cholangiocarcinoma. J Gastroenterol Hepatol. 2005;20:415–420. [PubMed]
161. Dumoulin FL, Gerhardt T, Fuchs S, Scheurlen C, Neubrand M, Layer G, et al. Phase II study of photodynamic therapy and metal stent as palliative treatment for nonresectable hilar cholangiocarcinoma. Gastrointest Endosc. 2003;57:860–867. [PubMed]
162. Zoepf T, Jakobs R, Arnold JC, Apel D, Riemann JF. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol. 2005;100:2426–2430. [PubMed]
163. Berr F. Photodynamic therapy for cholangiocarcinoma. Semin Liver Dis. 2004;24:177–187. [PubMed]
164. Nanashima A, Yamaguchi H, Shibasaki S, Ide N, Sawai T, Tsuji T, et al. Adjuvant photodynamic therapy for bile duct carcinoma after surgery: a preliminary study. J Gastroenterol. 2004;39:1095–1101. [PubMed]
165. Alberts SR, Gores GJ, Kim GP, Roberts LR, Kendrick ML, Rosen CB, et al. Treatment options for hepatobiliary and pancreatic cancer. Mayo Clin Proc. 2007;82:628–637. [PubMed]
166. Falkson G, MacIntyre JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer. 1984;54:965–969. [PubMed]
167. Takada T, Kato H, Matsushiro T, Nimura Y, Nagakawa T, Nakayama T. Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas. Oncology. 1994;51:396–400. [PubMed]
168. Choi CW, Choi IK, Seo JH, Kim BS, Kim JS, Kim CD, et al. Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas. Am J Clin Oncol. 2000;23:425–428. [PubMed]
169. Patt YZ, Jones DV, Jr, Hoque A, Lozano R, Markowitz A, Raijman I, et al. Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer. J Clin Oncol. 1996;14:2311–2315. [PubMed]
170. Patt YZ, Hassan MM, Lozano RD, Waugh KA, Hoque AM, Frome AI, et al. Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and 5-fluorouracil for biliary tract cancer. Clin Cancer Res. 2001;7:3375–3380. [PubMed]
171. Ducreux M, Rougier P, Fandi A, Clavero-Fabri MC, Villing AL, Fassone F, et al. Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin. Ann Oncol. 1998;9:653–656. [PubMed]
172. Lee MA, Woo IS, Kang JH, Hong YS, Lee KS. Epirubicin, cisplatin, and protracted infusion of 5-FU (ECF) in advanced intrahepatic cholangiocarcinoma. J Cancer Res Clin Oncol. 2004;130:346–350. [PubMed]
173. Taieb J, Mitry E, Boige V, Artru P, Ezenfis J, Lecomte T, et al. Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Ann Oncol. 2002;13:1192–1196. [PubMed]
174. Raderer M, Hejna MH, Valencak JB, Kornek GV, Weinlander GS, Bareck E, et al. Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer. Oncology. 1999;56:177–180. [PubMed]
175. Jones DV, Jr, Lozano R, Hoque A, Markowitz A, Patt YZ. Phase II study of paclitaxel therapy for unresectable biliary tree carcinomas. J Clin Oncol. 1996;14:2306–2310. [PubMed]
176. Kiba T, Nishimura T, Matsumoto S, Hatano E, Mori A, Yasumi S, et al. Single-agent gemcitabine for biliary tract cancers. Study outcomes and systematic review of the literature. Oncology. 2006;70:358–365. [PubMed]
177. Scheithauer W. Review of gemcitabine in biliary tract carcinoma. Semin Oncol. 2002;29:40–45. [PubMed]
178. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–134. [PubMed]
179. Yu C, Bruzek LM, Meng XW, Gores GJ, Carter CA, Kaufmann SH, et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene. 2005;24:6861–6869. [PubMed]
180. Mott JL, Kobayashi S, Bronk SF, Gores GJ. mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene. 2007;26:6133–6140. [PMC free article] [PubMed]
181. Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007;104:19512–19517. [PMC free article] [PubMed]
182. Ishimura N, Bronk SF, Gores GJ. Inducible nitric oxide synthase upregulates Notch-1 in mouse cholangiocytes: implications for carcinogenesis. Gastroenterology. 2005;128:1354–1368. [PubMed]
183. Jimeno A, Rubio-Viqueira B, Amador ML, Oppenheimer D, Bouraoud N, Kulesza P, et al. Epidermal growth factor receptor dynamics influences response to epidermal growth factor receptor targeted agents. Cancer Res. 2005;65:3003–3010. [PubMed]
184. Wiedmann M, Feisthammel J, Bluthner T, Tannapfel A, Kamenz T, Kluge A, et al. Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib. Anticancer Drugs. 2006;17:783–795. [PubMed]
185. Zhang Z, Lai GH, Sirica AE. Celecoxib-induced apoptosis in rat cholangiocarcinoma cells mediated by Akt inactivation and Bax translocation. Hepatology. 2004;39:1028–1037. [PubMed]
186. Wu T, Leng J, Han C, Demetris AJ. The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells. Mol Cancer Ther. 2004;3:299–307. [PubMed]
187. Date K, Matsumoto K, Kuba K, Shimura H, Tanaka M, Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene. 1998;17:3045–3054. [PubMed]
188. Sirica AE, Lai GH, Endo K, Zhang Z, Yoon BI. Cyclooxygenase-2 and ERBB-2 in cholangiocarcinoma: potential therapeutic targets. Semin Liver Dis. 2002;22:303–313. [PubMed]
189. Katayose Y, Kudo T, Suzuki M, Shinoda M, Saijyo S, Sakurai N, et al. MUC1-specific targeting immunotherapy with bispecific antibodies: inhibition of xenografted human bile duct carcinoma growth. Cancer Res. 1996;56:4205–4212. [PubMed]
190. Ahn EY, Pan G, Vickers SM, McDonald JM. IFN-gammaupregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma. Int J Cancer. 2002;100:445–451. [PubMed]
191. Tanaka S, Sugimachi K, Shirabe K, Shimada M, Wands JR. Expression and antitumor effects of TRAIL in human cholangiocarcinoma. Hepatology. 2000;32:523–527. [PubMed]
192. Thamavit W, Pairojkul C, Tiwawech D, Itoh M, Shirai T, Ito N. Promotion of cholangiocarcinogenesis in the hamster liver by bile duct ligation after dimethylnitrosamine initiation. Carcinogenesis. 1993;14:2415–2417. [PubMed]
193. Imray CH, Newbold KM, Davis A, Lavelle-Jones M, Neoptolemos JP. Induction of cholangiocarcinoma in the Golden Syrian hamster using methylazoxymethyl acetate. Eur J Surg Oncol. 1992;18:373–378. [PubMed]
194. Radaeva S, Ferreira-Gonzalez A, Sirica AE. Overexpression of C-NEU and C-MET during rat liver cholangiocarcinogenesis: A link between biliary intestinal metaplasia and mucin-producing cholangiocarcinoma. Hepatology. 1999;29:1453–1462. [PubMed]
195. Xu X, Kobayashi S, Qiao W, Li C, Xiao C, Radaeva S, et al. Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. J Clin Invest. 2006;116:1843–1852. [PMC free article] [PubMed]
196. Fava G, Marucci L, Glaser S, Francis H, De Morrow S, Benedetti A, et al. gamma-Aminobutyric acid inhibits cholangiocarcinoma growth by cyclic AMP-dependent regulation of the protein kinase A/extracellular signal-regulated kinase 1/2 pathway. Cancer Res. 2005;65:11437–11446. [PubMed]
197. Marienfeld C, Tadlock L, Yamagiwa Y, Patel T. Inhibition of cholangiocarcinoma growth by tannic acid. Hepatology. 2003;37:1097–1104. [PubMed]
198. Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM, Schepartz S, et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer. 2001;84:1424–1431. [PMC free article] [PubMed]
199. Voskoglou-Nomikos T, Pater JL, Seymour L. Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. Clin Cancer Res. 2003;9:4227–4239. [PubMed]
200. Sausville EA, Burger AM. Contributions of human tumor xenografts to anticancer drug development. Cancer Res. 2006;66:3351–3354. [discussion: 3354]. [PubMed]
201. Bibby MC. Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages. Eur J Cancer. 2004;40:852–857. [PubMed]
202. Maronpot RR, Giles HD, Dykes DJ, Irwin RD. Furan-induced hepatic cholangiocarcinomas in Fischer 344 rats. Toxicol Pathol. 1991;19:561–570. [PubMed]
203. Jan YY, Yeh TS, Yeh JN, Yang HR, Chen MF. Expression of epidermal growth factor receptor, apomucins, matrix metalloproteinases, and p53 in rat and human cholangiocarcinoma: appraisal of an animal model of cholangiocarcinoma. Ann Surg. 2004;240:89–94. [PMC free article] [PubMed]
204. Yeh CN, Maitra A, Lee KF, Jan YY, Chen MF. Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. Carcinogenesis. 2004;25:631–636. [PubMed]
205. Farazi PA, Zeisberg M, Glickman J, Zhang Y, Kalluri R, DePinho RA. Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice. Cancer Res. 2006;66:6622–6627. [PubMed]
206. Sirica AE, Zhang Z, Lai GH, Asano T, Shen XN, Ward DJ, et al. A novel “patient-like” model of cholangiocarcinoma progression based on bile duct inoculation of tumorigenic rat cholangiocyte cell lines. Hepatology. 2008;47:1178–1190. [PubMed]
207. Nakajima T, Takayama T, Miyanishi K, Nobuoka A, Hayashi T, Abe T, et al. Reversal of multiple drug resistance in cholangiocarcinoma by the glutathione S-transferase-pi-specific inhibitor O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-D-phenylglycine ethylester. J Pharmacol Exp Ther. 2003;306:861–869. [PubMed]
208. ClinicalTrials.gov. List results for search of “cholangiocarcinoma”. 2008. [Accessed January, 2008]. Available at: http://clinicaltrials.gov/ct2/results?term=cholangiocarcinoma.
209. Ricci MS, Kim SH, Ogi K, Plastaras JP, Ling J, Wang W, et al. Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. Cancer Cell. 2007;12:66–80. [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...