Therapy For Cholangiocarcinoma Research Articles

Advances in research on the mechanisms of tamoxifen therapy for cholangiocarcinoma

Advances in research on the mechanisms of tamoxifen therapy for cholangiocarcinoma

Hematoporphyrin derivative‐mediated photodynamic therapy inhibits tumor growth in human cholangiocarcinoma in vitro and in vivo

To investigate the effects of hematoporphyrin derivative-mediated photodynamic therapy (HPD-PDT) on cell growth in human cholangiocarcinoma in vitro and in vivo, as well as the underlying mechanisms of these effects. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to evaluate growth status of human cholangiocarcinoma cell line (QBC939). Hoechst 33258 staining and flow cytometry assays were applied to determine cell apoptosis. Western blotting analysis was performed to detect the release of cytochrome c in QBC939 cells, and caspases enzymatic assay was used to investigate the activation of caspase-3, -8, and -9. Further, tumor growth after subcutaneous implantation of QBC939 cells in nude mice was monitored. HPD-PDT inhibits QBC939 cell growth via cell apoptosis in vitro, and initiates cell mitochondria apoptosis pathway by the release of cytochrome c and the activation of caspase-9 and -3. Moreover, HPD-PDT also inhibits subcutaneous tumor growth of QBC939 cells and reduces tumor cell mitosis in nude mice. HPD-PDT inhibits tumor growth of human cholangiocarcinoma, suggesting that HPD-PDT is useful in cholangiocarcinoma therapy.

Intrahepatic Cholangiocarcinoma Progression: Prognostic Factors and Basic Mechanisms

In this review, we will examine various molecular biomarkers for their potential to serve as independent prognostic factors for predicting survival outcome in postoperative patients with progressive intrahepatic cholangiocarcinoma. Specific rodent models of intrahepatic cholangiocarcinoma that mimic relevant cellular, molecular, and clinical features of the human disease are also described, not only in terms of their usefulness in identifying molecular pathways and mechanisms linked to cholangiocarcinoma development and progression, but also for their potential value as preclinical platforms for suggesting and testing novel molecular strategies for cholangiocarcinoma therapy. Last, recent studies aimed at addressing the role of desmoplastic stroma in promoting intrahepatic cholangiocarcinoma progression are highlighted in an effort to underline the potential value of targeting tumor stromal components together with that of cholangiocarcinoma cells as a novel therapeutic option for this devastating cancer.

Biliary drainage, photodynamic therapy and chemotherapy for unresectable cholangiocarcinoma with jaundice

The combination of photodynamic therapy and biliary stenting seems to be beneficial in the palliative treatment of unresectable cholangiocarcinoma. We aimed to assess the accuracy of photodynamic therapy in a single centre. Fourteen selected patients, with jaundice related to unresectable cholangiocarcinoma, underwent photodynamic therapy and biliary stenting (with or without chemotherapy). Photofrin was injected intravenously (2 mg/kg) 2 days before intraluminal photoactivation. In case of malignant progression, photodynamic therapy was repeated. The outcome parameters were overall survival and quality of life. There were eight men and six women (median age: 67 [42-81]). Unresectability was related to a low Karnofski index (n = 2), peritoneal carcinomatosis (n = 4), vascular involvement (n = 3), invasion of the hepatoduodenal ligament (n = 2) and an under-sized liver remnant (n = 3). Biliary stenting was efficient (> or = 50% total bilirubin) in 78.5% of cases. Eight patients developed cholangitis. The mean number of photodynamic therapy procedures was two (1-4). Six (43%) patients needed > or = 2 procedures. No severe toxicity was noted. Photodynamic therapy improved the Karnofski index in 64% of cases. Six (42.8%) patients received concomitant chemotherapy (gemcitabine). The median survival time was 13.8 [0.7-29.2] months. The 3-, 6- and 12-month survival rates were 85%, 77% and 77%, respectively. These results confirm the beneficial effect of biliary drainage, photodynamic therapy and chemotherapy for unresectable cholangiocarcinoma in selected patients with jaundice.

Photodynamic therapy for cholangiocarcinoma: overview and new developments

Photodynamic therapy (PDT) with hematoporphyrins has emerged as promising treatment for nonresectable cholangiocarcinoma in several prospective observational studies and two randomized studies. This review describes the mechanism of action of PDT, gives an overview of clinical experience in cholangiocarcinoma and summarizes the results published in 2007 and 2008. The mechanism of action of PDT has been further elucidated. PDT induces an apoptotic, antiangiogenic as well as an immunomodulatory response. Interleukin-6, a bile duct epithelium growth factor correlating with tumor burden, decreases after PDT. The efficacy of PDT was confirmed in a comparative study in the United States. Patients with no visible mass on imaging studies, high serum albumin levels and treatment immediately after diagnosis seem to benefit most from PDT. Although it is recommended to perform PDT in bile ducts without stents in place, illumination through metal stents is possible if the light dose is adjusted. Meso-tetrahydroxyphenyl chlorine is a new potent photosensitizer for PDT of cholangiocarcinoma. In advanced nonresectable cholangiocarcinoma, PDT is the only evidence-based treatment that improves survival when compared with stenting. Therefore, PDT should be offered to those who are unsuitable for surgery.

Hilar Cholangiocarcinoma: Current Management

To review the literature with regard to outcome of surgical management for hilar cholangiocarcinoma (Klatskin tumor). Hilar cholangiocarcinoma is a rare tumor with a poor prognosis. Surgical resection provides the only possibility for cure. Advances in hepatobiliary imaging and surgical strategies to treat this disease have resulted in improved postoperative outcomes. We performed a review of the English literature on hilar cholangiocarcinoma from 1990 to 2007. This review included preoperative evaluation, surgical techniques, issues and controversies in management, prognostic variables, and considerations for future directions. Complete resection remains the most effective and only potentially curative therapy for hilar cholangiocarcinoma. Negative resection margins are associated with improved outcomes, and major hepatic resections have enhanced the likelihood of R0 resection. Portal vein embolization may be indicated in selected patients before extensive hepatic resection. Staging laparoscopy should be considered to detect occult metastatic disease. Orthotopic liver transplantation might be applicable for a highly selected subgroup. Surgical resection including major hepatic resection remains the mainstay of treatment of hilar cholangiocarcinoma. Additional evidence is needed to fully define the role of orthotopic liver transplantation. Improvements in adjuvant therapy are essential for improving long-term outcome.

Photodynamic Therapy for Unresectable Cholangiocarcinoma: What Is the Contribution of Single Operator Cholangioscopy for Targeted Treatment?

Photodynamic Therapy for Unresectable Cholangiocarcinoma: What Is the Contribution of Single Operator Cholangioscopy for Targeted Treatment?

Transplantation for Hepatocellular Carcinoma and Cholangiocarcinoma

Hepatocellular carcinoma (HCC) and cholangiocarcinoma represent more than 95% of primary hepatic malignancies in adults. The incidence of both seems to be rising. Any form of cirrhosis and primary sclerosing cholangitis represent independent risk factors for the development of HCC and cholangiocarcinoma, respectively. The surgical treatment of these malignancies has evolved significantly in the past decade, and liver transplantation (LT) has revolutionized the prognosis of these conditions. Provided both malignancies are diagnosed early in their natural history, LT offers a greater than 75% chance of survival at 4 years. This is a remarkable improvement in the treatment of primary hepatic malignancies and compares favorably with any other form of treatment, including partial liver resection. The application of specific pretransplantation staging criteria, along with the addition of neoadjuvant chemoradiation therapy for cholangiocarcinoma, has made these results possible. The development of living donor LT further expands the treatment horizon for both diseases. It also lessens the impact of the scarcity of available deceased donor organs available for transplantation. The future challenge is to better characterize biologic staging/prognostic indicators that could expand the understanding and success in treating both malignancies.

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma.

Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses ⩾12.5 mg kg−1 day−1 (P<0.05), but higher doses (50 mg kg−1 day−1, P<0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg−1 day−1) also significantly (P=0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma.

Molecular Mechanisms of Tamoxifen Therapy for Cholangiocarcinoma: Role of Calmodulin

Cholangiocarcinoma is a fatal tumor with limited therapeutic options. We have reported that calmodulin antagonists tamoxifen and trifluoperazine induced apoptosis in cholangiocarcinoma cells. Here, we determined the effects of tamoxifen on tumorigenesis and the molecular mechanisms of tamoxifen-induced apoptosis. Nude mice xenograft model of cholangiocarcinoma was used and tamoxifen was given i.p. and intratumorally. Cholangiocarcinoma cells were used to characterize molecular mechanisms of tamoxifen-induced apoptosis in vitro. I.p. or intratumoral injection of tamoxifen decreased cholangiocarcinoma tumorigenesis by 40% to 80% in nude mice. In cells isolated from tumor xenografts, tamoxifen inhibited phosphorylation of AKT (pAKT) and cellular FLICE like inhibitory protein (c-FLIP). Immunohistochemical analysis further showed that pAKT was identified in all nontreated tumors but was absent in tamoxifen-treated tumors. In vitro, tamoxifen activated caspase-8 and caspase-10, and their respective inhibitors partially blocked tamoxifen-induced apoptosis. Overexpression of c-FLIP inhibited tamoxifen-induced apoptosis and enhanced tumorigenesis of cholangiocarcinoma cells in nude mice, whereas deletion of the calmodulin-binding domain on c-FLIP restored the sensitivity to tamoxifen and inhibited tumorigenesis. With two additional cholangiocarcinoma cell lines, we confirmed that the expression of FLIP is an important factor in mediating spontaneous and tamoxifen-induced apoptosis. Thus, tamoxifen inhibits cholangiocarcinoma tumorigenesis in nude mice. Tamoxifen-induced apoptosis is partially dependent on caspases, inhibition of pAKT, and FLIP expression. Further, calmodulin-FLIP binding seems to be important in FLIP-mediated resistance to tamoxifen. Therefore, the present studies support the concept that tamoxifen may be used as a therapy for cholangiocarcinoma and possibly other malignancies in which the calmodulin targets AKT and c-FLIP play important roles in the tumor pathogenesis.

Pathobiology of biliary epithelia and cholangiocarcinoma: Proceedings of the Henry M. and Lillian Stratton basic research single-topic conference

In June 2008, the American Association for the Study of Liver Diseases (AASLD) sponsored the Henry M. and Lillian Stratton Basic Research Single-Topic Conference on the Pathobiology of Biliary Epithelia and Cholangiocarcinoma, which was held in Atlanta, GA. Attendees from 12 different countries participated in this conference, making it a truly international scientific event. Both oral and poster presentations were given by multidisciplinary experts, who highlighted important areas of current basic and translational research on biliary epithelial cell biology and pathophysiology, and on the etiology, cellular and molecular pathogenesis, and target-based therapy of cholangiocarcinoma. The specific goals and objectives of the conference were: (1) to advance knowledge of basic and molecular mechanisms underlying developmental and proliferative disorders of the biliary tract; (2) to foster a better and more comprehensive understanding of mechanisms regulating biliary epithelial (cholangiocyte) growth and transport, signaling, cell survival, and abnormalities that result in disease; and (3) to understand basic mechanisms of cholangiocarcinoma development and progression, with the added goal of identifying and exploiting potentially critical molecular pathways that may be targeted therapeutically. A number of interrelated themes emerged from the oral and poster sessions that affected current understandings of the complex organization of transcriptional and signaling mechanisms that regulate bile duct development, hepatic progenitor cell expansion, cholangiocyte secretory functions and proliferation, and mechanisms of cholangiocarcinogenesis and malignant cholangiocyte progression. Most notable were the critical questions raised as to how best to exploit aberrant signaling pathways associated with biliary disease as potential targets for therapy.

Novel endoscopic approaches for assessing biliary tract diseases

Biliary endoscopy offers both diagnostic and therapeutic value in complex clinical situations. This review addresses the latest advances over the past year in endoscopic approaches of biliary tract diseases. Specifically, we focus on the latest findings on endoscopic retrograde cholangiopancreatography for the evaluation of biliary strictures. In addition, key studies have demonstrated the enhanced role of cholangioscopy, photodynamic therapy in cholangiocarcinoma, and biliary stent technology. The following review focuses on the latest advancements in the field of biliary endoscopy. Pivotal studies were selected to highlight some of the current investigations in therapeutic endoscopic retrograde cholangiopancreatography as well as knowledge gaps for future research.

Unresectable Cholangiocarcinoma: Comparison of Survival in Biliary Stenting Alone Versus Stenting With Photodynamic Therapy

Photodynamic therapy (PDT) for unresectable cholangiocarcinoma is associated with improvement in cholestasis, quality of life, and potentially survival. We compared survival in patients with unresectable cholangiocarcinoma undergoing endoscopic retrograde cholangiopancreatography (ERCP) with PDT and stent placement with a group undergoing ERCP with stent placement alone. Forty-eight patients were palliated for unresectable cholangiocarcinoma during a 5-year period. Nineteen were treated with PDT and stents; 29 patients treated with biliary stents alone served as a control group. Multivariate analysis was performed by using Model for End-Stage Liver Disease score, age, treatment by chemotherapy or radiation, and number of ERCP procedures and PDT sessions to detect predictors of survival. Kaplan-Meier analysis demonstrated improved survival in the PDT group compared with the stent only group (16.2 vs 7.4 months, P<.004). Mortality in the PDT group at 3, 6, and 12 months was 0%, 16%, and 56%, respectively. The corresponding mortality in the stent group was 28%, 52%, and 82%, respectively. The difference between the 2 groups was significant at 3 months and 6 months but not at 12 months. Only the number of ERCP procedures and number of PDT sessions were significant on multivariate analysis. Adverse events specific to PDT included 3 patients with skin phototoxicity requiring topical therapy only. ERCP with PDT seems to increase survival in patients with unresectable cholangiocarcinoma when compared with ERCP alone. It remains to be proved whether this effect is attributable to PDT or the number of ERCP sessions. A prospective randomized multicenter study is required to confirm these data.

Diagnosis and management of cholangiocarcinoma

Cholangiocarcinoma (CC) is a rare yet frequently fatal tumor that causes significant morbidity and mortality due to late presentation. Radiology is the mainstay of CC diagnosis; however, advances in understanding the pathogenesis of CC, including the role of oncogenes, inflammation-mediated genomic instability, and interleukin-6/STAT-3 signaling pathways, may allow development of new diagnostic and prognostic markers and targets for CC therapy. Although surgical resection is the standard of care for resectable CC, liver transplantation has shown excellent results in selected patients. The use of chemotherapy and radiotherapy are currently limited by marginal response rates, toxicity, and biliary complications. Locally ablative therapies in the form of transcatheter arterial chemoembolization and radioembolization are under investigation. Molecular therapies (eg, epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor antagonists) and immunotherapy using diabodies are also under investigation for treatment of unresectable CC.

Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma.

Aberrant expression and signaling of epidermal growth factor receptor (ErbB) family receptor tyrosine kinases, most notably that of ErbB2 and ErbB1, have been implicated in the molecular pathogenesis of intrahepatic cholangiocarcinoma. Constitutive overexpression of ErbB2 and/or ErbB1 in malignant cholangiocytes has raised interest in the possibility that agents which selectively target these receptors could potentially be effective in cholangiocarcinoma therapy. However, current experience with such ErbB-directed therapies have at best produced only modest responses in patients with biliary tract cancers. This review provides a comprehensive and critical analysis of both preclinical and clinical studies aimed at assessing the role of altered ErbB2 and/or ErbB1 expression, genetic modifications, and dysregulated signaling on cholangiocarcinoma development and progression. Specific limitations in experimental approaches that have been used to assess human cholangiocarcinoma specimens for ErbB2 and/or ErbB1 overexpression and gene amplification are discussed. In addition, current rodent models of intrahepatic cholangiocarcinogenesis associated with constitutive ErbB2 overexpression are reviewed. Select interactive relationships between ErbB2 or ErbB1 with other relevant molecular signaling pathways associated with intrahepatic cholangiocarcinoma development and progression are also detailed, including those linking ErbB receptors to bile acid, cyclooxygenase-2, interleukin-6/gp130, transmembrane mucins, hepatocyte growth factor/Met, and vascular endothelial growth factor signaling. Lastly, various factors that can limit therapeutic efficacy of ErbB-targeted agents against cholangiocarcinoma are considered.

Development and controversy of surgical therapy for hilar cholangiocarcinoma

Development and controversy of surgical therapy for hilar cholangiocarcinoma

C-Met targeted therapy of cholangiocarcinoma

Cholangiocarcinoma continues to be a challenging disease to treat. Systemic therapy is used in unresectable disease, disease progression after surgery, and in the palliative setting. Unfortunately, results of multiple phase II trials have rarely yielded positive results. As data on the molecular carcinogenesis of cholangiocarcinoma is developing, we are more able to understand the disease process and can use this understanding to create unique targeted therapies. We reviewed the role of c-Met/hepatocyte growth factor (HGF) in the development of cholangiocarcinoma. Furthermore, we explored the use of the c-Met guided cascade as a target to treat cholangiocarcinoma. We reviewed the current use and options for future development of c-Met agents to treat this disease.

Effect of mutant p27kip1 gene on human cholangiocarcinoma cell line, QBC939

To investigate the effects of exogenously mutated p27(kipl) (p27) on proliferation and apoptosis of human cholangiocarcinoma cell line, QBC(939)in vivo. Adenviral vectors were used to transfect mutated p27 cDNA into human QBC(939)cell line. Expression of p27 was detected by RT-PCR. Western blot. Cell growth, morphological change, cell cycle, apoptosis and cloning formation were determined by MTT assay and flow cytometry. The expression of p27 protein and mRNA was increased significantly in QBC(939) cell line transfected with Ad-p27mt. The transfer of Ad-p27mt could significantly inhibit the growth of QBC(939) cells, decrease the cloning formation rate and induce apoptosis. p27 over expression caused cell cycle arrest at G(0)/G(1)phase 72 h after infection with Ad-p27mt. p27 may cause cell cycle arrest at G(0)/G(1)phase and subsequently lead to apoptosis. Recombinant adenovirus expressing mutant p27 may be potentially useful in gene therapy for cholangiocarcinoma.

Progress in imaging diagnosis and interventional therapy of cholangiocarcinoma associated with obstructive jaundice

Progress in imaging diagnosis and interventional therapy of cholangiocarcinoma associated with obstructive jaundice

Radical surgery for hilar cholangiocarcinoma

In the therapy of hilar cholangiocarcinoma, the most favorable survival rates over the long-term are achieved by a surgical concept involving a no-touch-technique, en-bloc-resection and wide tumor-free margins. Currently, these goals can be best achieved by our strategy to combine extended right hepatic resections and principle portal vein resection. In spite of extending resectability to patients with locally advanced tumors, formally curative resections could be performed in 80% of the patients. The 5-year survival rate in these patients is 61%. Liver transplantation had been abandoned by most centers in the 1980s due to poor overall results. Recently, a neoadjuvant strategy involving radiochemotherapy has been reported to result in excellent survival figures at least in a subset of patients suffering from cholangiocellular carcinoma arising in a primary sclerosing cholangitis (PSC). This protocol has been mainly proposed by the Mayo Clinic group and reached 5-year survival rates of 80% in those patients in whom it had been applicable. A substantial drop out rate from this neoadjuvant regimen due to tumor progression or treatment related complications is still a problem.