Science.gov

Sample records for advanced intrahepatic cholangiocarcinoma

  1. Is Surgical Resection Justified for Advanced Intrahepatic Cholangiocarcinoma?

    PubMed Central

    Yoh, Tomoaki; Hatano, Etsuro; Yamanaka, Kenya; Nishio, Takahiro; Seo, Satoru; Taura, Kojiro; Yasuchika, Kentaro; Okajima, Hideaki; Kaido, Toshimi; Uemoto, Shinji

    2016-01-01

    Backgrounds Prognosis for patients with advanced intrahepatic cholangiocarcinoma (ICC) with intrahepatic metastasis (IM), vascular invasion (VI), or regional lymph node metastasis (LM) remains poor. The aim of this study was to clarify the indications for surgical resection for advanced ICC. Methods We retrospectively divided 213 ICC patients treated at Kyoto University Hospital between 1993 and 2013 into a resection (n=164) group and a non-resection (n=49) group. Overall survival was assessed after stratification for the presence of IM, VI, or LM. Results Overall median survival times (MSTs) for the resection and non-resection groups were 26.0 and 7.1 months, respectively (p<0.001). After stratification, MSTs in the resection and non-resection groups, respectively, were 18.7 vs. 7.0 months for patients with IM (p<0.001), 23.4 vs. 5.7 months for those with VI (p<0.001), and 12.8 vs. 5.5 months for those with LM (p<0.001). Conclusion When macroscopic curative resection is possible, surgical resection can be justified for some advanced ICC patients with IM, VI, or LM. PMID:27781200

  2. Intrahepatic cholangiocarcinoma: current perspectives

    PubMed Central

    Buettner, Stefan; van Vugt, Jeroen LA; IJzermans, Jan NM; Groot Koerkamp, Bas

    2017-01-01

    Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy arising from the liver. ICC makes up about 10% of all cholangiocarcinomas. It arises from the peripheral bile ducts within the liver parenchyma, proximal to the secondary biliary radicals. Histologically, the majority of ICCs are adenocarcinomas. Only a minority of patients (15%) present with resectable disease, with a median survival of less than 3 years. Multidisciplinary management of ICC is complicated by large differences in disease course for individual patients both across and within tumor stages. Risk models and nomograms have been developed to more accurately predict survival of individual patients based on clinical parameters. Predictive risk factors are necessary to improve patient selection for systemic treatments. Molecular differences between tumors, such as in the epidermal growth factor receptor status, are promising, but their clinical applicability should be validated. For patients with locally advanced disease, several treatment strategies are being evaluated. Both hepatic arterial infusion chemotherapy with floxuridine and yttrium-90 embolization aim to downstage locally advanced ICC. Selected patients have resectable disease after downstaging, and other patients might benefit because of postponing widespread dissemination and biliary obstruction. PMID:28260927

  3. Staging of intrahepatic cholangiocarcinoma

    PubMed Central

    Ronnekleiv-Kelly, Sean M.

    2017-01-01

    Intrahepatic cholangiocarcinoma (ICC) comprises approximately 5−30% of primary liver tumors, however it has been increasing over the last several decades. Up to and including the 6th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) edition staging system, ICC was staged the same as hepatocellular carcinoma. In the 7th edition AJCC/UICC manual, the staging system of ICC was revised such that a distinct classification was proposed. Pathologic features for prognosis included vascular invasion, tumor multiplicity, local extension, periductal infiltration and lymph nodal metastasis. Over the last decade, as the incidence of ICC has increased and surgery for this indication has become more common, more data has been published on the prognostic factors associated with long-term survival. PMID:28261593

  4. Pathology of intrahepatic cholangiocarcinoma

    PubMed Central

    Vijgen, Sandrine; Terris, Benoit

    2017-01-01

    Intrahepatic cholangiocarcinoma (iCC) is a primary carcinoma of the liver with increasing significance and major pathogenic, clinical and therapeutic challenges. Classically, it arises from malignant transformation of cholangiocytes bordering small portal bile duct (BD) to second-order segmental large BDs. It has three major macroscopic growth pattern [mass-forming (MF), periductal infiltrative (PI), and intraductal growth (IG)] and histologically is a desmoplastic stroma-rich adenocarcinoma with cholangiocyte differentiation. Recent data pointed out noteworthy degree of heterogeneity in regards of their epidemiology and risk factors, pathological and molecular features, pathogenesis, clinical behaviors and treatment. Notably, several histological variants are described and can coexist within the same tumor. Several different cells of origin have also been depicted in a fraction of iCCs, amongst which malignant transformation of ductules, of hepatic stem/progenitor cells, of periductal glands or through oncogenic reprogramming of adult hepatocytes. A degree of pathological overlap with hepatocellular carcinoma (HCC) may be observed in a portion of iCC. A series of precursor lesions are today characterized and emphasize the existence of a multistep carcinogenesis process. Overall, these new data have brought up in proposal of new histological or molecular classifications, which could soon replace current anatomic-based classification and could have major impact on establishment of prognosis and on development of novel target treatment approaches. PMID:28261592

  5. [A case of curative resection after downsizing chemotherapy in initially unresectable locally advanced intrahepatic cholangiocarcinoma].

    PubMed

    Aoki, Yu; Suzuki, Takayuki; Kato, Atsushi; Shimizu, Hiroaki; Ohtsuka, Masayuki; Yoshitomi, Hideyuki; Furukawa, Katsunori; Takayashiki, Tsukasa; Kuboki, Satoshi; Takano, Shigetsugu; Okamura, Daiki; Suzuki, Daisuke; Sakai, Nozomu; Kagawa, Shingo; Miyazaki, Masaru

    2014-11-01

    This case report describes an 83-year-old man with intrahepatic cholangiocarcinoma who was referred by a local hospital. Abdominal computed tomography (CT) showed a large tumor in hepatic segments 4, 5, and 8 involving the right hepatic vein and inferior vena cava, which is normally indicative of an unresectable locally advanced tumor. After systemic chemotherapy with gemcitabine and cisplatin, the observed decrease in the level of tumor marker suggested that the cancer was responding to treatment, while radiological findings showed the main tumor shrunk without the presence of distant metastases. Thus, hepatic left trisectionectomy with bile duct resection was performed after portal vein embolization. Pathological examination revealed negative margins (R0). Eighteen months after surgery, the patient is free of disease and shows no signs of recurrence. An initially unresectable, locally advanced biliary tract cancer may be down sized by chemotherapy, which makes radical resection possible, at least in a proportion of patients. This approach provides longer survival and may have a potential for disease eradication as a new multidisciplinary approach for patients with unresectable locally advanced biliary tract cancer.

  6. Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for advanced-stage unresectable intrahepatic cholangiocarcinoma.

    PubMed

    Kim, Young-Il; Park, Joong-Won; Kim, Bo Hyun; Woo, Sang Myung; Kim, Tae Hyun; Koh, Young Hwan; Lee, Woo Jin; Kim, Chang-Min

    2013-12-21

    A standard treatment for unresectable advanced-stage intrahepatic cholangiocarcinoma (IHCC) has not yet been established. Although neoadjuvant concurrent chemoradiotherapy (CCRT) and liver transplantation are associated with long-term survival in select patients, the outcomes of CCRT for advanced-stage unresectable IHCC remain unclear. The aim of our study was to evaluate the outcomes of CCRT in patients with unresectable advanced-stage IHCC. We retrospectively reviewed the records of all patients with unresectable advanced stage (stage IVa or IVb) IHCC who were pathologically diagnosed and treated at National Cancer Center, Korea, from June 2001 to March 2012. Of the total of 92 patients, 25 (27.1%) received capecitabine plus cisplatin (XP) chemotherapy with external radiotherapy (RT) (XP-CCRT group) and 67 (72.8%) received XP chemotherapy alone (XP group). The clinical characteristics and outcomes of the 2 groups were compared. The 92 patients comprised 72 male and 20 female patients, with a median age of 58 years (range 26-78 years). The baseline clinical characteristics of the 2 groups were similar. Patients in the XP-CCRT group received a mean 44.7 Gy of RT and a mean 5.6 cycles of XP chemotherapy, whereas patients in the XP group received a mean 4.0 cycles. The disease control rate was higher in the XP-CCRT group than in the XP group, but the difference was not statistically significant (56.0% vs. 41.5%, p = 0.217). Although neutropenia was significantly more frequent in the XP-CCRT than in the XP group (48% vs. 9%, p < 0.001), the rates of other toxicities and > grade 3 toxicities did not differ. At a median follow-up of 5.3 months, PFS (4.3 vs. 1.9 months, p = 0.001) and OS (9.3 vs. 6.2 months, p = 0.048) were significantly longer in the XP-CCRT than in the XP group. XP-CCRT was well tolerated and was associated with longer PFS and OS than XP chemotherapy alone in patients with unresectable advanced IHCC. Controlled randomized

  7. Genetic Profiling of Intrahepatic Cholangiocarcinoma

    PubMed Central

    Andersen, Jesper B.; Thorgeirsson, Snorri S.

    2014-01-01

    Purpose of review Intrahepatic cholangiocarcinoma (ICC) is a treatment-refractory disease with a dismal outcome. Limited success in the clinical management and a persistent increase in the incidence world-wide have made ICC one of the most lethal and fastest growing malignancies. However, recent advancements in genome-wide technologies combined with the application of integrative multidimensional analytical approaches have begun to provide both detailed insight into the underlying biological traits of ICC and identified new therapeutic opportunities. Recent findings In comparison with other cancers genomic studies of ICC have been limited. We and others have recently procured large cohorts of ICC patients intended for genome-wide analyses. In our study samples from ICC patients were obtained from three cancer centers and subjected to integrated genetic and genomic analyses. We provided new insights into both pathogenesis and optimal treatment options demonstrating the presence of unique subclasses of patients, based partly on KRAS mutations and increased levels of receptor tyrosine kinase signaling. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes regulating inflammation and proteasome activities, suggesting a combination of tyrosine kinase inhibitors and anti-inflammatory drugs as a new therapeutic option for these patients. Summary We have critically examined the progress in genome-wide studies of ICC including genetic profiling, transcriptomics and epigenomics. Current limitations in applying these technologies to archival samples and the insufficient access to fresh-frozen material are partly the cause of the delayed implementation of the omics-based investigations of ICC compared to other hepatobiliary diseases. Thus, selected candidate single gene studies will also be discussed. PMID:22395571

  8. Genetic profiling of intrahepatic cholangiocarcinoma.

    PubMed

    Andersen, Jesper B; Thorgeirsson, Snorri S

    2012-05-01

    Intrahepatic cholangiocarcinoma (ICC) is a treatment-refractory disease with a dismal outcome. Limited success in the clinical management and a persistent increase in the incidence world-wide have made ICC one of the most lethal and fastest growing malignancies. However, recent advancements in genome-wide technologies combined with the application of integrative multidimensional analytical approaches have begun to provide both detailed insight into the underlying biological traits of ICC and identified new therapeutic opportunities. In comparison with other cancers, genomic studies of ICC have been limited. We and others have recently procured large cohorts of ICC patients intended for genome-wide analyses. In our study, samples from ICC patients were obtained from three cancer centers and subjected to integrated genetic and genomic analyses. We provided new insights into both pathogenesis and optimal treatment options demonstrating the presence of unique subclasses of patients, based partly on KRAS mutations and increased levels of receptor tyrosine kinase signaling. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes regulating inflammation and proteasome activities, suggesting a combination of tyrosine kinase inhibitors and anti-inflammatory drugs as a new therapeutic option for these patients. We have critically examined the progress in genome-wide studies of ICC including genetic profiling, transcriptomics, and epigenomics. Current limitations in applying these technologies to archival samples and the insufficient access to fresh-frozen material are partly the cause of the delayed implementation of the omics-based investigations of ICC compared to other hepatobiliary diseases. Thus, selected candidate single-gene studies will also be discussed.

  9. Cholangiocarcinoma

    PubMed Central

    Razumilava, Nataliya; Gores, Gregory J

    2014-01-01

    Cholangiocarcinoma represents a diverse group of epithelial cancers united by late diagnosis and poor outcomes. Specific diagnostic and therapeutic approaches are undertaken for cholangiocarcinomas of different anatomical locations (intrahepatic, perihilar, and distal). Mixed hepatocellular cholangiocarcinomas have emerged as a distinct subtype of primary liver cancer. Clinicians need to be aware of intrahepatic cholangiocarcinomas arising in cirrhosis and properly assess liver masses in this setting for cholangiocarcinoma. Management of biliary obstruction is obligatory in perihilar cholangiocarcinoma, and advanced cytological tests such as fluorescence in-situ hybridisation for aneusomy are helpful in the diagnosis. Liver transplantation is a curative option for selected patients with perihilar but not with intrahepatic or distal cholangiocarcinoma. International efforts of clinicians and scientists are helping to identify the genetic drivers of cholangiocarcinoma progression, which will unveil early diagnostic markers and direct development of individualised therapies. PMID:24581682

  10. Intrahepatic cholangiocarcinoma: current management and emerging therapies.

    PubMed

    Rahnemai-Azar, Amir A; Weisbrod, Allison B; Dillhoff, Mary; Schmidt, Carl; Pawlik, Timothy M

    2017-05-01

    Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with an increasing incidence and a high-case fatality. While surgery offers the best hope at long-term survival, only one-third of tumors are amenable to surgical resection at the time of the diagnosis. Unfortunately, conventional chemotherapy offers limited survival benefit in the management of unresectable or metastatic disease. Recent advances in understanding the molecular pathogenesis of iCCA and the use of next-generation sequencing techniques have provided a chance to identify 'target-able' molecular aberrations. These novel molecular therapies offer the promise to personalize therapy for patients with iCCA and, in turn, improve the outcomes of patients. Area covered: We herein review the current management options for iCCA with a focus on defining both established and emerging therapies. Expert commentary: Surgical resection remains as an only hope for cure in iCCA patients. However, frequently the diagnosis is delayed till advanced stages when surgery cannot be offered; signifying the urge for specific diagnostic tumor biomarkers and targeted therapies. New advances in genomic profiling have contributed to a better understanding of the landscape of molecular alterations in iCCA and offer hope for the development of novel diagnostic biomarkers and targeted therapies.

  11. Transarterial Therapies for the Treatment of Intrahepatic Cholangiocarcinoma

    PubMed Central

    Zechlinski, Joseph J.; Rilling, William S.

    2013-01-01

    Cholangiocarcinoma, whether arising from the intrahepatic or extrahepatic biliary system, is a rare but devastating malignancy. Prognosis is poor, with 5-year overall survival <5% including patients undergoing surgery. Resection is the only curative treatment; however, only ∼30% of patients present at a resectable stage, and intrahepatic recurrence is common even after complete resection. This article discusses the current role of transarterial therapies in the treatment of intrahepatic cholangiocarcinoma. PMID:24436514

  12. Intrahepatic Cholangiocarcinoma Progression: Prognostic Factors and Basic Mechanisms

    PubMed Central

    Sirica, Alphonse E.; Dumur, Catherine I.; Campbell, Deanna J. W.; Almenara, Jorge A.; Ogunwobi, Olorunseun O.; Dewitt, Jennifer L.

    2013-01-01

    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. PMID:19896103

  13. Advanced intrahepatic cholangiocarcinoma in hepatitis C virus-related decompensated cirrhosis: case report and review of the literature.

    PubMed

    Polizos, Asterios; Kelekis, Nikolaos; Sinani, Chrisanthi; Patsiaoura, Kalliopi; Papadamou, Georgia; Dalekos, Georgios N

    2003-03-01

    A 75-year-old man with no known previous liver disease was admitted to our institution because of right pleural effusion, backache, and pain in the upper right quadrant. Physical and laboratory work-up revealed decompensated liver cirrhosis. Spiral computed tomography (CT) showed a 6-cm tumour in the right liver lobe. Serum levels of aminotransferases, prothrombin time, total bilirubin, alphafetoprotein and carcinoembryonic antigen were within normal limits. However, the patient had elevated cholestatic enzymes, diffuse hypergammaglobulinaemia, a six-fold increase in carbohydrate antigen 19-9 (CA 19-9), cryoglobulinaemia, and reactivity against hepatitis C virus (anti-HCV). Although hepatocellular carcinoma is the most common cancer in a cirrhotic patient with chronic viral hepatitis, the investigation revealed the presence of intrahepatic cholangiocarcinoma (ICC). This is a less frequently occurring primary liver tumour, the aetiology and pathogenesis of which remain unclear in the majority of cases. The coexistence of HCV liver disease and ICC might be an incidental finding, but recently some reports have shown a relatively high incidence of this tumour in patients with HCV-related cirrhosis. The current aspects regarding ICC prevalence in HCV patients, the possible aetiopathogenetic links between this tumour and HCV, and the importance for ICC detection and characterization using the enhancement patterns with quadruple-phase spiral CT scan are also discussed.

  14. Recurrence after operative management of intrahepatic cholangiocarcinoma.

    PubMed

    Hyder, Omar; Hatzaras, Ioannis; Sotiropoulos, Georgios C; Paul, Andreas; Alexandrescu, Sorin; Marques, Hugo; Pulitano, Carlo; Barroso, Eduardo; Clary, Bryan M; Aldrighetti, Luca; Ferrone, Cristina R; Zhu, Andrew X; Bauer, Todd W; Walters, Dustin M; Groeschl, Ryan; Gamblin, T Clark; Marsh, J Wallis; Nguyen, Kevin T; Turley, Ryan; Popescu, Irinel; Hubert, Catherine; Meyer, Stephanie; Choti, Michael A; Gigot, Jean-Francois; Mentha, Gilles; Pawlik, Timothy M

    2013-06-01

    Data on recurrence after operation for intrahepatic cholangiocarcinoma (ICC) are limited. We sought to investigate rates and patterns of recurrence in patients after operative intervention for ICC. We identified 301 patients who underwent operation for ICC between 1990 and 2011 from an international, multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed. During the median follow up duration of 31 months (range 1-208), 53.5% developed a recurrence. Median RFS was 20.2 months and 5-year actuarial disease-free survival, 32.1%. The most common site for initial recurrence after operation of ICC was intrahepatic (n = 98; 60.9%), followed by simultaneous intra- and extrahepatic disease (n = 30; 18.6%); 33 (21.0%) patients developed extrahepatic recurrence only as the first site of recurrence. Macrovascular invasion (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.34-3.21; P < .001), nodal metastasis (HR, 1.55; 95% CI, 1.01-2.45; P = .04), unknown nodal status (HR, 1.57; 95% CI, 1.10-2.25; P = .04), and tumor size ≥ 5 cm (HR, 1.84; 95% CI, 1.28-2.65; P < .001) were independently associated with increased risk of recurrence. Patients were assigned a clinical score from 0 to 3 according to the presence of these risk factors. The 5-year RFS for patients with scores of 0, 1, 2, and 3 was 61.8%, 36.2%, 19.5%, and 9.6%, respectively. Recurrence after operative intervention for ICC was common. Disease recurred both at intra- and extrahepatic sites with roughly the same frequency. Factors such as lymph node metastasis, tumor size, and vascular invasion predict highest risk of recurrence. Copyright © 2013 Mosby, Inc. All rights reserved.

  15. Recurrence after operative management of intrahepatic cholangiocarcinoma

    PubMed Central

    Hyder, Omar; Hatzaras, Ioannis; Sotiropoulos, Georgios C.; Paul, Andreas; Alexandrescu, Sorin; Marques, Hugo; Pulitano, Carlo; Barroso, Eduardo; Clary, Bryan M.; Aldrighetti, Luca; Ferrone, Cristina R.; Zhu, Andrew X.; Bauer, Todd W.; Walters, Dustin M.; Groeschl, Ryan; Gamblin, T. Clark; Marsh, J. Wallis; Nguyen, Kevin T.; Turley, Ryan; Popescu, Irinel; Hubert, Catherine; Meyer, Stephanie; Choti, Michael A.; Gigot, Jean-Francois; Mentha, Gilles; Pawlik, Timothy M.

    2014-01-01

    Introduction Data on recurrence after operation for intrahepatic cholangiocarcinoma (ICC) are limited. We sought to investigate rates and patterns of recurrence in patients after operative intervention for ICC. Methods We identified 301 patients who underwent operation for ICC between 1990 and 2011 from an international, multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed. Results During the median follow up duration of 31 months (range 1–208), 53.5% developed a recurrence. Median RFS was 20.2 months and 5-year actuarial disease-free survival, 32.1%. The most common site for initial recurrence after operation of ICC was intrahepatic (n = 98; 60.9%), followed by simultaneous intra- and extrahepatic disease (n = 30; 18.6%); 33 (21.0%) patients developed extra-hepatic recurrence only as the first site of recurrence. Macrovascular invasion (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.34–3.21; P <.001), nodal metastasis (HR, 1.55; 95% CI, 1.01–2.45; P = .04), unknown nodal status (HR, 1.57; 95% CI, 1.10–2.25; P = .04), and tumor size ≥5 cm (HR, 1.84; 95% CI, 1.28–2.65; P <.001) were independently associated with increased risk of recurrence. Patients were assigned a clinical score from 0 to 3 according to the presence of these risk factors. The 5-year RFS for patients with scores of 0, 1, 2, and 3 was 61.8%, 36.2%, 19.5%, and 9.6%, respectively. Conclusion Recurrence after operative intervention for ICC was common. Disease recurred both at intra-and extrahepatic sites with roughly the same frequency. Factors such as lymph node metastasis, tumor size, and vascular invasion predict highest risk of recurrence. PMID:23499016

  16. Radiofrequency Ablation of Intrahepatic Cholangiocarcinoma: Preliminary Experience

    SciTech Connect

    Carrafiello, Gianpaolo Lagana, Domenico; Cotta, Elisa; Mangini, Monica; Fontana, Federico; Bandiera, Francesca; Fugazzola, Carlo

    2010-08-15

    The purpose of this study was to evaluate the safety and efficacy of percutaneous ultrasound (US)-guided radiofrequency ablation (RFA) in patients with intrahepatic cholangiocarcinoma (ICCA) in a small, nonrandomized series. From February 2004 to July 2008, six patients (four men and two women; mean age 69.8 years [range 48 to 83]) with ICCA underwent percutaneous US-guided RFA. Preintervetional transarterial embolization was performed in two cases to decrease heat dispersion during RFA in order to increase the area of ablation. The efficacy of RFA was evaluated using contrast-enhanced dynamic computed tomography (CT) 1 month after treatment and then every 3 months thereafter. Nine RFA sessions were performed for six solid hepatic tumors in six patients. The duration of follow-up ranged from 13 to 21 months (mean 17.5). Posttreatment CT showed total necrosis in four of six tumors after one or two RFA sessions. Residual tumor was observed in two patients with larger tumors (5 and 5.8 cm in diameter). All patients tolerated the procedure, and there with no major complications. Only 1 patient developed post-RFA syndrome (pain, fever, malaise, and leukocytosis), which resolved with oral administration of acetaminophen. Percutaneous RFA is a safe and effective treatment for patients with hepatic tumors: It is ideally suited for those who are not eligible for surgery. Long-term follow-up data regarding local and systemic recurrence and survival are still needed.

  17. Periostin in intrahepatic cholangiocarcinoma: pathobiological insights and clinical implications.

    PubMed

    Sirica, Alphonse E; Almenara, Jorge A; Li, Chao

    2014-12-01

    Periostin is a modular glycoprotein frequently observed to be a major constituent of the extracellular milieu of mass-forming intrahepatic cholangiocarcinoma and other desmoplastic malignant tumors. In intrahepatic cholangiocarcinoma, as well as in desmoplastic pancreatic ductal adenocarcinoma, periostin is overexpressed and hypersecreted in large part, if not exclusively, by cancer-associated fibroblasts within the tumor stroma. Through its interaction with specific components of the extracellular tumor matrix, particularly collagen type I and tenascin-C, and with cell surface receptors, notably integrins leading to activation of the Akt and FAK signaling pathways, this TGF-β family-inducible matricellular protein appears to be functioning as a key extracellular matrix molecule regulating such critically important and diverse malignant tumor behaviors as tumor fibrogenesis and desmoplasia, invasive malignant cell growth, chemoresistance, and metastatic colonization. This review will discuss current evidence and basic molecular mechanisms implicating periostin as a mediator of intrahepatic cholangiocarcinoma invasive growth. In addition, its significance as a potential prognostic biomarker for intrahepatic cholangiocarcinoma patients, as well as future possibilities and challenges as a molecular target for cholangiocarcinoma therapy and/or prevention, will be critically evaluated.

  18. Periostin in Intrahepatic Cholangiocarcinoma: Pathobiological Insights and Clinical Implications

    PubMed Central

    Sirica, Alphonse E.; Almenara, Jorge A.; Li, Chao

    2014-01-01

    Periostin is a modular glycoprotein frequently observed to be a major constituent of the extracellular milieu of mass-forming intrahepatic cholangiocarcinoma and other desmoplastic malignant tumors. In intrahepatic cholangiocarcinoma, as well as in desmoplastic pancreatic ductal adenocarcinoma, periostin is overexpressed and hypersecreted in large part, if not exclusively, by cancer-associated fibroblasts within the tumor stroma. Through its interaction with specific components of the extracellular tumor matrix, particularly collagen type I and tenascin-C, and with cell surface receptors, notably integrins leading to activation of the Akt and FAK signaling pathways, this TGF-β family-inducible matricellular protein appears to be functioning as a key extracellular matrix molecule regulating such critically important and diverse malignant tumor behaviors as tumor fibrogenesis and desmoplasia, invasive malignant cell growth, chemoresistance, and metastatic colonization. This review will discuss current evidence and basic molecular mechanisms implicating periostin as a mediator of intrahepatic cholangiocarcinoma invasive growth. In addition, its significance as a potential prognostic biomarker for intrahepatic cholangiocarcinoma patients, as well as future possibilities and challenges as a molecular target for cholangiocarcinoma therapy and/or prevention, will be critically evaluated. PMID:25446840

  19. New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma

    PubMed Central

    Patel, Tushar

    2013-01-01

    Intrahepatic cholangiocarcinoma is an aggressive malignancy and is one of the most devastating cancers of the gastrointestinal tract. The molecular mechanisms contributing to the pathogenesis of these cancers are not well understood. The recognition and distinction of these cancers from other tumors such as extrahepatic or ductal cholangiocarcinoma and hepatocellular carcinoma have been important in defining the pathogenesis. New insights into molecular mechanisms contributing to disease pathogenesis are emerging from recent epidemiological, genome-wide profiling and laboratory based studies. These have contributed to an improved understanding of risk factors, genetic mutations and pathophysiological mechanisms that are associated with these tumors. The contribution of well-established risk factors such as biliary tract inflammation and key signaling pathways involved in intrahepatic cholangiocarcinoma are being further defined. These new insights have several important implications for both molecular diagnosis and therapy of these cancers. PMID:24145988

  20. Transarterial Chemoembolization (TACE) for Inoperable Intrahepatic Cholangiocarcinoma

    SciTech Connect

    Herber, S. Otto, G.; Schneider, J.; Manzl, N.; Kummer, I.; Kanzler, S.; Schuchmann, A.; Thies, J.; Dueber, C.; Pitton, M.

    2007-11-15

    The aim of this retrospective study was to determine the safety and efficacy of chemoembolization (TACE) as palliative treatment for patients with unresectable intrahepatic cholangiocarcinoma (CCA) and to compare the results with those in the literature. Fifteen patients with histology-proven CCA (5 men, 10 women) had received palliative treatment with TACE over a 6-year period. The treatment protocol comprised repeated TACE at a minimum of 8-week intervals. TACE was performed with a mixture of 10 ml Lipiodol and 10 mg mitomycin C injected into the tumor-supplying vessels. Follow-up investigations after 8-10 weeks comprised contrast-enhanced multislice spiral CT and laboratory control. Statistical evaluation included survival analysis using the Kaplan-Meier method. During the investigation period 58 TACEs (3.9 {+-} 3.8; 1-15) were performed in 15 patients. Mean tumor size was 10.8 {+-} 4.6 cm (range, 2.0-18.0 cm). Unifocal tumor disease was diagnosed in eight patients, and multifocal disease in seven. Mean survival was 21.1 months (95% CI, 9.4-32.5 months). At the end of the investigation period 3 patients are still alive, and 12 patients have died. The 1-, 2-, and 3-year survival rate was 51.3%, 27.5%, and 27.5% respectively. According to RECIST criteria interim best response to therapy was stable disease in 9 of 15 patients, a partial response in 1 of 15 patients, and tumor progression in 4 of 15 patients. No deaths and no acute liver failure occurred under TACE therapy. Major complications were observed in two patients, comprising anaphylactic shock owing to contrast medium administration in one and gastric ulceration due to lipiodol displacement in the second patient. These results demonstrate that TACE is a safe procedure with a moderate number of complications for patients suffering from inoperable CCA. According to recently published data on i.v. chemotherapy we suggest that TACE might be able to prolong survival in selected patients who would succumb under

  1. Multidisciplinary Care of Patients with Intrahepatic Cholangiocarcinoma: Updates in Management

    PubMed Central

    Lafaro, Kelly J.; Cosgrove, David; Geschwind, Jean-Francois H.; Kamel, Ihab; Herman, Joseph M.; Pawlik, Timothy M.

    2015-01-01

    Cholangiocarcinoma is a highly fatal primary cancer of the bile ducts which arises from malignant transformation of bile duct epithelium. While being an uncommon malignancy with an annual incidence in the United States of 5000 new cases, the incidence has been increasing over the past 30 years and comprises 3% of all gastrointestinal cancers. Cholangiocarcinoma can be classified into intrahepatic (ICC) and extrahepatic (including hilar and distal bile duct) according to its anatomic location within the biliary tree with respect to the liver. This paper reviews the management of ICC, focusing on the epidemiology, risk factors, diagnosis, and surgical and nonsurgical management. PMID:26089873

  2. Hepatolithiasis and intrahepatic cholangiocarcinoma: A review

    PubMed Central

    Kim, Hyo Jung; Kim, Jae Seon; Joo, Moon Kyung; Lee, Beom Jae; Kim, Ji Hoon; Yeon, Jong Eun; Park, Jong-Jae; Byun, Kwan Soo; Bak, Young-Tae

    2015-01-01

    Although the incidence of hepatolithiasis is decreasing as the pattern of gallstone disease changes in Asia, the prevalence of hepatolithiasis is persistently high, especially in Far Eastern countries. Hepatolithiasis is an established risk factor for cholangiocarcinoma (CCA), and chronic proliferative inflammation may be involved in biliary carcinogenesis and in inducing the upregulation of cell-proliferating factors. With the use of advanced imaging modalities, there has been much improvement in the management of hepatolithiasis and the diagnosis of hepatolithiasis-associated CCA (HL-CCA). However, there are many problems in managing the strictures in hepatolithiasis and differentiating them from infiltrating types of CCA. Surgical resection is recommended in cases of single lobe hepatolithiasis with atrophy, uncontrolled stricture, symptom duration of more than 10 years, and long history of biliary-enteric anastomosis. Even after resection, patients should be followed with caution for development of HL-CCA, because HL-CCA is an independent prognostic factor for survival. It is not yet clear whether hepatic resection can reduce the occurrence of subsequent HL-CCA. Furthermore, there are no consistent findings regarding prediction of subsequent HL-CCA in patients with hepatolithiasis. In the management of hepatolithiasis, important factors are the reduction of recurrence of cholangitis and suspicion of unrecognized HL-CCA. PMID:26730152

  3. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies

    PubMed Central

    Sia, D; Tovar, V; Moeini, A; Llovet, JM

    2013-01-01

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with very poor prognosis. Genome-wide, high-throughput technologies have made major advances in understanding the molecular basis of this disease, although important mechanisms are still unclear. Recent data have revealed specific genetic mutations (for example, KRAS, IDH1 and IDH2), epigenetic silencing, aberrant signaling pathway activation (for example, interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), tyrosine kinase receptor-related pathways) and molecular subclasses with unique alterations (for example, proliferation and inflammation subclasses). In addition, some ICCs share common genomic traits with hepatocellular carcinoma. All this information provides the basis to explore novel targeted therapies. Currently, surgery at early stage is the only effective therapy. At more advanced stages, chemotherapy regimens are emerging (that is, cisplatin plus gemcitabine), along with molecular targeted agents tested in several ongoing clinical trials. Nonetheless, a first-line conclusive treatment remains an unmet need. Similarly, there are no studies assessing tumor response related with genetic alterations. This review explores the recent advancements in the knowledge of the molecular alterations underlying ICC and the future prospects in terms of therapeutic strategies leading towards a more personalized treatment of this neoplasm. PMID:23318457

  4. Intrahepatic cholangiocarcinoma in a captive meerkat (Suricata suricatta).

    PubMed

    Boonsri, Kittikorn; Sritan, Jiraporn; Vechmanus, Thewarach; O'Sullivan, M Gerard; Pringproa, Kidsadagon

    2013-09-01

    A 9-yr-old male meerkat (Suricata suricatta) living in captivity, with a history of anorexia, lethargy, and weight loss, was examined postmortem. Physical examination revealed poor body condition, dehydration, and icteric mucous membranes. Macroscopically, white to yellowish, multinodulated masses were found protruding from the liver. These multinodular masses were also observed in all lobes of the lungs and the mediastinal lymph nodes. Microscopic examination revealed tumors with well-circumscribed, atypical proliferating cuboidal to columnar bile duct epithelial layers arranged in solid sheets and papillary patterns. The neoplastic masses were separated by dense fibrous connective tissues and invaded the normal parenchyma. Periodic acid-Schiff-positive material was occasionally found within the lumen of tubuloacinar structures. Immunohistochemical labeling revealed that neoplastic cells were intensely positive for pan-cytokeratin, but negative for vimentin. Based on the macroscopic and microscopic findings, intrahepatic cholangiocarcinoma was diagnosed. This is the first report describing cholangiocarcinoma in a meerkat.

  5. Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma

    PubMed Central

    Andrici, Juliana; Goeppert, Benjamin; Sioson, Loretta; Clarkson, Adele; Renner, Marcus; Stenzinger, Albrecht; Tayao, Michael; Watson, Nicole; Farzin, Mahtab; Toon, Christopher W.; Smith, Ross C.; Mittal, Anubhav; Samra, Jaswinder S.; Hugh, Thomas J.; Chou, Angela; Lawlor, Rita T.; Weichert, Wilko; Schirmacher, Peter; Sperandio, Nicola; Ruzzenente, Andrea; Scarpa, Aldo; Gill, Anthony J.

    2016-01-01

    Abstract BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that functions as a tumor suppressor gene. Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation. We performed immunohistochemistry for BAP1 on a well-characterized cohort of 211 ICC patients undergoing surgical resection with curative intent at 3 institutions based in 3 different countries. The median age at diagnosis was 65 years (range, 36.5–86) and 108 (51%) were men. Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in nonneoplastic cells) occurred in 55 ICCs (26%). BAP1 loss predicted a strong trend toward improved median survival of 40.80 months (95% CI, 28.14–53.46) versus 24.87 months (95% CI, 18.73–31.01), P = 0.059). In a multivariate model including age, sex, BAP1 status, tumor stage, tumor grade, lymphovascular invasion, and tumor size, female sex was associated with improved survival (hazard ratio [HR] 0.54; 95% CI, 0.34–0.85), while advanced tumor stage and lymphovascular invasion (HR 1.89; 95% CI, 1.09–3.28) correlated with decreased survival. In a multivariate analysis, high grade tumors were associated with BAP1 loss (odds ratio [OR] 3.32; 95% CI, 1.29–8.55), while lymphatic invasion was inversely associated with BAP1 loss (OR 0.36; 95% CI, 0.13–0.99). In conclusion, we observed a trend toward improved prognosis in ICC associated with absent expression of BAP1 and an association of BAP1 loss with higher histological grade and absent lymphatic invasion. Female sex was associated with improved survival while advanced tumor stage and lymphatic invasion were associated with decreased survival. PMID:26765459

  6. Treatment outcomes and prognostic factors of intrahepatic cholangiocarcinoma

    PubMed Central

    DHANASEKARAN, RENUMATHY; HEMMING, ALAN W.; ZENDEJAS, IVAN; GEORGE, THOMAS; NELSON, DAVID R.; SOLDEVILA-PICO, CONSUELO; FIRPI, ROBERTO J.; MORELLI, GIUSEPPE; CLARK, VIRGINIA; CABRERA, RONIEL

    2013-01-01

    The aim of the present study was to determine the treatment outcome and prognostic factors for survival in patients with peripheral intrahepatic cholangiocarcinoma (ICC). A retrospective chart review was performed for patients diagnosed with ICC between 2000 and 2009 at a single institution. We identified a total of 105 patients with ICC. Among them, 63.8% were older than 60 years of age, 50.5% were male and 88.6% were Caucasian. By preoperative imaging approximately half of the patients (50.5%) were surgical candidates and underwent resection. The other half of the patients (49.5%) were unresectable. The unresectable group received chemoradiotherapy (53%) and transarterial chemoembolization (7.7%) as palliative treatments while 23.0% of the patients (12/52) received best supportive care alone. The median survival rates were 16.1 months (13.1–19.2) for the entire cohort, 27.6 months (17.7–37.6) for curative resection, 12.9 months (6.5–19.2) for palliative chemoradiotherapy and 4.9 months (0.4–9.6) for best supportive care (P<0.001). Independent predictors on multivariate analysis were advanced stage at diagnosis and treatment received. In those patients who underwent resection, advanced AJCC stage and presence of microvascular invasion were also independent predictors of poor survival. We concluded that surgery offers the most beneficial curative option and outcome, emphasizing the importance of resectability as a major prognostic factor. The present study also revealed that use of chemoradiotherapy in the adjuvant setting failed to improve survival but its palliative use in those patients with unresectable ICC offered a modest survival advantage over best supportive care. The overriding factors influencing outcome were stage and the presence of microvascular invasion on pathology. PMID:23426976

  7. Recurrent Cardiac Tamponade: An Unusual Presentation of Intrahepatic Cholangiocarcinoma

    PubMed Central

    Corral, Juan E.; Arosemena, Leopoldo; Garcia-Buitrago, Monica T.; Madrazo, Beatrice; Martin, Paul

    2016-01-01

    A 48-year-old Egyptian woman presented with 8 months of sharp right upper chest pain and weight loss. She was discovered to have an enlarged cardiac silhouette on chest x-ray, and an echocardiogram revealed a large pericardial effusion with diastolic right atrial collapse. Pericardial window was done, and epithelial membrane antigen-positive neoplastic cells were identified in the pericardial fluid. Computed tomography showed a 6-cm hypermetabolic lesion on the liver segment IV, confirmed on biopsy to be a moderately differentiated adenocarcinoma consistent with intrahepatic cholangiocarcinoma. PMID:27144206

  8. Intrahepatic cholangiocarcinoma in a transplant liver--selective internal radiation therapy followed by right hemihepatectomy: report of a case.

    PubMed

    Sperling, Jens; Justinger, Christoph; Schuld, Jochen; Ziemann, Christian; Seidel, Roland; Kollmar, Otto

    2014-07-01

    Intra- or extrahepatic cholangiocarcinomas are the second most common primary liver malignancies behind hepatocellular carcinoma. Whereas the incidence for intrahepatic cholangiocarcinoma is rising, the occurrence of extrahepatic cholangiocarcinoma is trending downwards. The treatment of choice for intrahepatic cholangiocarcinoma remains liver resection. However, a case of liver resection after selective internal radiation therapy in order to treat a recurrent intrahepatic cholangiocarcinoma in a transplant liver is unknown in the literature so far. Herein, we present a case of a patient undergoing liver transplantation for Wilson's disease with an accidental finding of an intrahepatic cholangiocarcinoma within the explanted liver. Due to a recurrent intrahepatic cholangiocarcinoma after liver transplantation, a selective internal radiation therapy with yttrium-90 microspheres was performed followed by right hemihepatectomy. Four years later, the patient is tumor-free and in a healthy condition.

  9. Huge subcapsular hematoma caused by intrahepatic sarcomatoid cholangiocarcinoma.

    PubMed

    Jung, Gum O; Park, Dong Eun; Youn, Gi Jung

    2012-05-01

    Intrahepatic sarcomatoid cholangiocarcinomais is a very rare disease with a poor prognosis due to its biologically aggressive tumor behavior. We report a patient who presented with subcapsular hemorrhage and a rapidly growing liver mass. A 57 year-old man was admitted with severe abdominal pain. CT and MRI images showed the presence of a 10 cm-sized subcapsular hemorrhage connected with a multi-lobulated mass with hemorrhage and necrotic foci in the right liver. The patients underwent right hemihepatectomy with caudate lobectomy and lymphadenectomy. The operation findings revealed metastatic nodules to the diaphragm and omentum. Detailed histopathological analysis through immunohistochemistry confirmed the diagnosis of sarcomatoid cholangiocarcinoma with a poorly undifferentiated sarcomatous component. The patient underwent chemotherapy. To date, the patient is doing well for 8 months after initial diagnosis.

  10. Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma

    PubMed Central

    Guest, Rachel V; Boulter, Luke; Kendall, Timothy J; Minnis-Lyons, Sarah E; Walker, Robert; Wigmore, Stephen J; Sansom, Owen J; Forbes, Stuart J

    2014-01-01

    Intrahepatic cholangiocarcinoma (ICC) is a treatment refractory malignancy with a high mortality and an increasing incidence worldwide. Recent studies have observed that activation of Notch and AKT signalling within mature hepatocytes is able to induce the formation of tumours displaying biliary lineage markers, thereby raising the suggestion that it is hepatocytes, rather than cholangiocytes or hepatic progenitor cells that represent the cell of origin of this tumour. Here we utilise a cholangiocyte-lineage tracing system to target p53 loss to biliary epithelia and observe the appearance of labelled biliary lineage tumours in response to chronic injury. Consequent to this, up-regulation of native functional Notch signalling is observed to occur spontaneously within cholangiocytes and hepatocytes in this model as well as in human ICC. These data prove that in the context of chronic inflammation and p53 loss, frequent occurrences in human disease, biliary epithelia are a target of transformation and an origin of ICC. PMID:24310400

  11. Rapidly aggravated skeletal muscle metastases from an intrahepatic cholangiocarcinoma

    PubMed Central

    Lee, Jiyoung; Lee, Sung Wook; Han, Sang Young; Baek, Yang Hyun; Kim, Su Young; Rhyou, Hyo In

    2015-01-01

    We present a rare case of intrahepatic cholangiocarcinoma (ICC) with multiple skeletal muscle metastases. The patient was a 55-year-old Asian woman presenting with abdominal pain; abdominal and pelvic computed tomography and magnetic resonance cholangiopancreatography revealed an unresectable ICC with hepatic metastasis and metastastatic lymphadenopathy in the porto-caval area. After 3 mo of treatment with palliative radiotherapy and chemotherapy, magnetic resonance imaging of the thoracolumbar spine detected right psoas muscle and paraspinous muscle metastases. We performed an ultrasound-guided percutaneous fine-needle biopsy that confirmed a similar pattern of poorly differentiated adenocarcinoma. The patient treated with palliative chemotherapy and achieved 10 mo of survival. Here we report the first case quickly spread to multiple sites of muscle even though the three-month treatment, compare to the other cases reported muscle metastases at diagnosis. PMID:25684968

  12. Decreased roundabout 1 expression promotes development of intrahepatic cholangiocarcinoma.

    PubMed

    Mano, Yohei; Aishima, Shinichi; Fukuhara, Takasuke; Tanaka, Yuki; Kubo, Yuichiro; Motomura, Takashi; Toshima, Takeo; Iguchi, Tomohiro; Shirabe, Ken; Maehara, Yoshihiko; Oda, Yoshinao

    2013-11-01

    Roundabout 1 (Robo1) is a transmembrane receptor of the immunoglobulin family. Slit2 is one of its ligands. The function of Slit2/Robo1 signaling in the development of intrahepatic cholangiocarcinoma (ICC) remains to be elucidated. We examined the immunohistochemical expression of Robo1 and Slit2 and their clinicopathologic implications in 132 cases of ICC. Also, small interfering RNA of Robo1 was transfected into a high-expression ICC cell line, and a Robo1 vector was transfected into a low-Robo1 expression ICC cell line. The effect of Robo1 suppression and overexpression in cell proliferation and migration of cultured ICC cells with Slit2 stimulation was investigated. Immunohistochemical study of ICC in the low-Robo1 expression group showed larger tumors (P = .015), a higher Ki-67 labeling index (P = .021), and low expression of Slit2 (P = .0005). The low-Slit2 expression group frequently showed perineural invasion (P = .036) and lymph node metastases (P = .013). Low Robo1 expression was associated with a poor prognosis (P = .0207). Robo1 suppression in Huh28 cells tended to promote cell proliferation and migration, whereas Robo1 overexpression in RBE cells significantly suppressed cell proliferation and migration. Low Robo1 expression was associated with cell proliferation and migration in ICC and was one of the adverse prognostic factors in patients with these tumors.

  13. Glass Microspheres 90Y Selective Internal Radiation Therapy and Chemotherapy as First-Line Treatment of Intrahepatic Cholangiocarcinoma.

    PubMed

    Edeline, Julien; Du, Fanny Le; Rayar, Michel; Rolland, Yan; Beuzit, Luc; Boudjema, Karim; Rohou, Tanguy; Latournerie, Marianne; Campillo-Gimenez, Boris; Garin, Etienne; Boucher, Eveline

    2015-11-01

    Intrahepatic cholangiocarcinoma's incidence is increasing. We studied the efficacy of Y selective internal radiation therapy (SIRT) as first-line treatment, with chemotherapy, and compared with the results of chemotherapy alone. We retrospectively studied data from patients treated at our institution with glass microspheres SIRT for intrahepatic cholangiocarcinoma as part of first-line treatment in combination with chemotherapy. We compared results with those of similar patients treated in the ABC-02 study (a study in advanced biliary tract cancer that defined the current standard chemotherapy), assessed as not progressing after the first evaluation. We assessed progression-free survival (PFS) and overall survival (OS). Twenty-four patients were treated with SIRT. Chemotherapy was given concomitantly in 10 (42%), as induction before SIRT in 13 (54%) or after SIRT in 1 (4%). Grade 3 adverse events were reported in 1 (4%). Median PFS after SIRT was 10.3 months. Longer PFS was observed when chemotherapy was given concomitantly than when chemotherapy was given before SIRT, with respective median of 20.0 versus 8.8 months (P = 0.001). Median OS after SIRT was not reached. Eleven patients went to surgery (46%). Thirty-three patients in ABC-02 had locally advanced nonextrahepatic cholangiocarcinoma, not progressing after first evaluation. From the start of any treatment, the median PFS was 16.0 months in our cohort versus 11.3 months in ABC-02 (P = 0.25), whereas the median OS was significantly higher in our cohort, not reached versus 17.9 months, respectively (P = 0.026). Selective internal radiation therapy combined with concomitant chemotherapy seems a promising strategy as first-line treatment for unresectable intrahepatic cholangiocarcinoma.

  14. Adjuvant therapy for intrahepatic cholangiocarcinoma: the debate continues.

    PubMed

    Zhu, Andrew X; Knox, Jennifer J

    2012-01-01

    lymph nodes were obtained, all of which were negative, consistent with a stage T2, N0, MX intrahepatic cholangiocarcinoma. The tumor was positive for CK7, CK19, and CA19-9 and negative for CK20, CDX2, CA125, ER, PR, GCDFP-15, synaptophysin, and chromogranin (Table 1). The uninvolved liver was unremarkable and a trichrome stain showed no fibrosis. Following an uneventful postoperative recovery, she was referred for consideration of adjuvant therapy.

  15. Predictors of intrahepatic cholangiocarcinoma in cirrhotic patients scanned by gadobenate dimeglumine-enhanced magnetic resonance imaging: diagnostic accuracy and confidence.

    PubMed

    Quaia, Emilio; Angileri, Roberta; Arban, Federica; Gennari, Antonio Giulio; Cova, Maria Assunta

    2015-01-01

    To identify predictors of intrahepatic cholangiocarcinoma in cirrhotic patients scanned by gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance (MR) imaging. Fifty cirrhotic patients with 120 nodules, including 10 mass-forming intrahepatic cholangiocarcinomas and two combined hepatocellular carcinoma-cholangiocarcinomas, were scanned by Gd-BOPTA-enhanced MR imaging. T1 hypointensity [odds ratio (OR), 20.12], peripheral hyperintense rim at hepatic arterial phase (OR, 13.5), and iso-hyperintensity at hepatobiliary phase (OR 21.32) were found to be independent predictors of intrahepatic cholangiocarcinoma. T1 hypointensity, peripheral hyperintense rim at hepatic arterial phase, and iso-hyperintensity at hepatobiliary phase are independent predictors of intrahepatic cholangiocarcinoma diagnosis in patients with liver cirrhosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Stereotactic Radiofrequency Ablation of Unresectable Intrahepatic Cholangiocarcinomas: A Retrospective Study

    SciTech Connect

    Haidu, Marion; Dobrozemsky, Georg; Schullian, Peter Widmann, Gerlig; Klaus, Alexander Weiss, Helmut Margreiter, Raimund; Bale, Reto

    2012-10-15

    Purpose: To evaluate treatment effects, complications, and outcome of percutaneous stereotactic radiofrequency ablation (SRFA) of intrahepatic cholangiocarcinoma (ICC). Patients and Methods: Eleven consecutive patients (nine men and two women) with a total of 36 inoperable ICCs (18 initial lesions, 16 lesions newly detected during follow-up, and two local recurrences) underwent SRFA between December 2004 and June 2010. Two different radiofrequency ablation (RFA) devices with internally cooled electrodes were used. Tumor diameters ranged from 0.5 to 10 cm (median 3.0 cm). A total of 23 SRFA sessions were performed. The efficacy of SRFA was evaluated by contrast-enhanced computed tomography or magnetic resonance imaging 1 month after treatment and then every 3 months. Results: Primary technical effectiveness rate was 92%. Further follow-up every 3 months revealed three local recurrences (8%), two of which were successfully retreated, resulting in a secondary technical effectiveness rate of 98%. After a total of 23 RFA sessions, three major complications occurred (13%) that could be managed interventionally. Mean follow-up time was 35 months (range 12-81 months). One- and 3-year overall survival rates were 91 and 71%, respectively. The median overall survival was 60 months (according to the life table method). Eight (73%) of 11 patients were still alive at the end of follow-up. Conclusion: SRFA is effective in the treatment of unresectable ICC even if the tumor is large and located close to major vessels. SRFA shows a survival benefit compared to other palliative treatment options and may also be considered as the first-line local treatment of ICCs in selected patients.

  17. Coding-noncoding gene expression in intrahepatic cholangiocarcinoma.

    PubMed

    Wang, Jianguo; Xie, Haiyang; Ling, Qi; Lu, Di; Lv, Zhen; Zhuang, Runzhou; Liu, Zhikun; Wei, Xuyong; Zhou, Lin; Xu, Xiao; Zheng, Shusen

    2016-02-01

    Recent studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in human cancers. However, the function of lncRNAs and their downstream mechanisms are largely unknown in the molecular pathogenesis of intrahepatic cholangiocarcinoma (ICC). In the present study, we performed transcriptomic profiling of ICC and paired adjacent noncancerous tissues (N) by using lncRNA and messenger RNA (mRNA) microarrays. Quantitative real-time polymerase chain reaction was used to validate the microarray results. We tested for correlations between the expression levels of lncRNAs and target genes. Clinicopathologic characteristics and overall survival were compared using the t test and the Kaplan-Meier method, respectively. A total of 2773 lncRNAs were significantly upregulated in ICC tissues compared with the noncancerous tissues, whereas 2392 lncRNAs were downregulated. Bioinformatic analysis indicated that most of the genes were involved in carcinogenesis, hepatic system diseases, and signal transductions. Positive correlations were found between 4 lncRNA-mRNA pairs (RNA43085 and SULF1, RNA47504 and KDM8, RNA58630 and PCSK6, and RNA40057 and CYP2D6). When the clinicopathologic characteristics were accounted for, the cumulative overall survival rate was found to be associated with low expression levels of CYP2D6 (P = 0.005) and PCSK6 (P = 0.038). Patients with high expression levels of CYP2D6 and RNA40057 had a better prognosis (P = 0.014). Our results suggested that the lncRNA expression profiling in ICC tissues is profoundly different from that in noncancerous tissues. Thus, lncRNA may be a potential diagnostic and prognostic biomarker for ICC. Furthermore, the combined assessment of lncRNA and mRNA expressions might predict the survival of patients with ICC.

  18. Genome-wide analysis of gene expression in human intrahepatic cholangiocarcinoma.

    PubMed

    Obama, Kazutaka; Ura, Katsuaki; Li, Meihua; Katagiri, Toyomasa; Tsunoda, Tatsuhiko; Nomura, Akinari; Satoh, Seiji; Nakamura, Yusuke; Furukawa, Yoichi

    2005-06-01

    Intrahepatic cholangiocarcinoma is a neoplasm arising in the liver, and its incidence is increasing in Japan as well as in Western countries. Prognosis of patients with this type of tumor remains unsatisfactory because no effective chemotherapeutic drugs are available, we have no sensitive tumor markers to detect this tumor in its early stage, and it is difficult to identify a high-risk group for the disease. To clarify the molecular mechanism of tumorigenesis and identify molecular targets for diagnosis and treatment, we analyzed global gene-expression profiles of 25 intrahepatic cholangiocarcinomas using tumor cell populations purified by laser microbeam microdissection and a cDNA microarray containing 27,648 genes. We identified 52 genes that were commonly upregulated and 421 that were downregulated in intrahepatic cholangiocarcinomas compared with noncancerous biliary epithelial cells. From the 52 upregulated genes, we selected P-cadherin and survivin for further investigation and corroborated enhanced expression of their products in cancer tissues by immunohistochemical staining. Furthermore, comparison between tumors with lymph node metastasis and those without metastasis identified 30 genes that were associated with lymph node involvement. In conclusion, these data should be helpful for a better understanding of the tumorigenesis of intrahepatic cholangiocarcinoma and should contribute to the development of diagnostic and therapeutic strategies for this type of tumor. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

  19. Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma

    PubMed Central

    Liang, Winnie S.; Fonseca, Rafael; Bryce, Alan H.; McCullough, Ann E.; Barrett, Michael T.; Hunt, Katherine; Patel, Maitray D.; Young, Scott W.; Collins, Joseph M.; Silva, Alvin C.; Condjella, Rachel M.; Block, Matthew; McWilliams, Robert R.; Lazaridis, Konstantinos N.; Klee, Eric W.; Bible, Keith C.; Harris, Pamela; Oliver, Gavin R.; Bhavsar, Jaysheel D.; Nair, Asha A.; Middha, Sumit; Asmann, Yan; Kocher, Jean-Pierre; Schahl, Kimberly; Kipp, Benjamin R.; Barr Fritcher, Emily G.; Baker, Angela; Aldrich, Jessica; Kurdoglu, Ahmet; Izatt, Tyler; Christoforides, Alexis; Cherni, Irene; Nasser, Sara; Reiman, Rebecca; Phillips, Lori; McDonald, Jackie; Adkins, Jonathan; Mastrian, Stephen D.; Placek, Pamela; Watanabe, Aprill T.; LoBello, Janine; Han, Haiyong; Von Hoff, Daniel; Craig, David W.; Stewart, A. Keith; Carpten, John D.

    2014-01-01

    Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations. PMID:24550739

  20. First Reported Case of Primary Intrahepatic Cholangiocarcinoma with Pure Squamous Cell Histology: A Case Report

    PubMed Central

    Lubana, Sandeep Singh; Singh, Navdeep; Seligman, Barbara; Tuli, Sandeep S.; Heimann, David M.

    2015-01-01

    Patient: Male, 64 Final Diagnosis: Intrahepatic cholangiocarcinoma with pure squamous cell Symptoms: — Medication: — Clinical Procedure: — Specialty: — Objective: Rare disease Background: In the United States, approximately 2500 cases of cholangiocarcinoma occur each year. The average incidence is 1 case/100 000 persons each year. Surgical resection is the mainstay for the treatment of cholangiocarcinoma. The result of surgery depends on location of the tumor, extent of tumor penetration of the bile duct, tumor-free resection margins, and lymph node and distant metastases. There has been an increase in the incidence of intrahepatic cholangiocarcinoma (IHCC) globally over a period of 30 years from 0.32/100 000 to 0.85/100 000 persons each year. Epidemiologically, the incidence of IHCC has been increasing in the U.S. from year 1973 to 2010. Case Report: We are reporting a first case of primary intrahepatic cholangiocarcinoma of pure squamous cell histology. A 64-year-old man presented with right upper-quadrant pain, jaundice, and weight loss. Imaging studies revealed a large hepatobiliary mass, intrahepatic bile duct dilation, normal common duct, and absence of choledocholithiasis. Delayed-contrast magnetic resonance imaging of the abdomen showed peripheral enhancement of the central lesion, which is typical of cholangiocarcinoma in contrast to hepatocellular carcinoma or metastasis. Cancer antigen 19-9 was markedly elevated. Liver function tests were deranged. Endoscopic retrograde cholangiopancreatography showed high degree of left hepatic duct stricture. Brush cytopathology was positive for atypia. The patient underwent exploratory laparotomy for en-bloc resection of the hepatobiliary mass with colon resection, liver resection, and cholecystectomy. Histology revealed keratinizing squamous cell carcinoma. Based on these findings, a definitive diagnosis of well-differentiated squamous cell carcinoma of the intrahepatic bile duct was made. Conclusions

  1. Arterio-biliary fistula as rare complication of chemoradiation therapy for intrahepatic cholangiocarcinoma.

    PubMed

    Hayano, Koichi; Miura, Fumihiko; Amano, Hodaka; Toyota, Naoyuki; Wada, Keita; Kato, Kenichiro; Takada, Tadahiro; Asano, Takehide

    2010-09-28

    Significant hemobilia due to arterio-biliary fistula is a very rare complication of chemoradiation therapy (CRT) for unresectable intrahepatic cholangiocarcinoma (ICC). Here we report a case of arterio-biliary fistula after CRT for unresectable ICC demonstrated by angiographic examinations. This fistula was successfully treated by endovascular embolization. Hemobilia is a rare complication, but arterio-biliary fistula should be considered after CRT of ICC.

  2. Arterio-biliary fistula as rare complication of chemoradiation therapy for intrahepatic cholangiocarcinoma

    PubMed Central

    Hayano, Koichi; Miura, Fumihiko; Amano, Hodaka; Toyota, Naoyuki; Wada, Keita; Kato, Kenichiro; Takada, Tadahiro; Asano, Takehide

    2010-01-01

    Significant hemobilia due to arterio-biliary fistula is a very rare complication of chemoradiation therapy (CRT) for unresectable intrahepatic cholangiocarcinoma (ICC). Here we report a case of arterio-biliary fistula after CRT for unresectable ICC demonstrated by angiographic examinations. This fistula was successfully treated by endovascular embolization. Hemobilia is a rare complication, but arterio-biliary fistula should be considered after CRT of ICC. PMID:21160700

  3. Genetic profiling of intrahepatic cholangiocarcinoma and its clinical implication in targeted therapy.

    PubMed

    Xie, Diyang; Ren, Zhenggang; Fan, Jia; Gao, Qiang

    2016-01-01

    Intrahepatic cholangiocarcinoma (iCCA) is a treatment-refractory primary liver cancer with an increasing incidence and mortality worldwide in recent years. Lack of a stereotyped genetic signature and limited understanding of genomic landscape make the development of effective targeted therapies challenging. Recent application of advanced technologies such as next-generation sequencing (NGS) has broadened our understanding of genetic heterogeneity in iCCA and many potentially actionable genetic alterations have been identified. This review explores the recent advances in defining genetic alterations in iCCAs, which may present potent therapeutic targets. Chromatin remodeling genes and genes encoding isocitrate dehydrogenase and tyrosine kinase receptors as well as their downstream effectors are among the most frequently altered genes. Clinical trials testing the effect of new targeted agents on iCCA patients, especially those with the above genetic markers are under way. However, the complex interplay of environmental and evolutionary factors contributing to the genetic variability in iCCA calls for a more cautionary use of NGS in tailoring targeted regimen to the patients. Next-generation functional testing may complement NGS to execute precision medicine in future.

  4. Serum liver enzymes serve as prognostic factors in patients with intrahepatic cholangiocarcinoma.

    PubMed

    Zhang, Chenyue; Wang, Haiyong; Ning, Zhouyu; Xu, Litao; Zhuang, Liping; Wang, Peng; Meng, Zhiqiang

    2017-01-01

    Liver functions, reflective of the overall status of the host, have been reported to be important factors affecting the prognosis in many types of cancers. In this study, we explored the influences of liver enzymes albumin (ALB), globulin (GELO), total protein (TP), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), gamma glutamyltranspeptidase (GGT), and lactate dehydrogenase (LDH) on the overall survival (OS) in a number of 173 patients with intrahepatic cholangiocarcinoma (ICC). Between 2011 and 2015, we enrolled patients with pathologically proven locally advanced or metastatic ICC. The impact of ALB, GELO, TP, ALP, ALT, AST, TBIL, DBIL, GGT, and LDH on OS were analyzed using Kaplan-Meier analysis. Next, the associations between these liver enzymes and OS were evaluated by univariate and multivariate analyses. Finally, the role of these enzymes in OS was evaluated in the subgroups. Elevated liver enzymes were linked with OS. We revealed that independent prognostic factors of poor outcome were ALP, TBIL, DBIL, and GGT, whereas ALB is a protective factor in ICC patients. Our results demonstrate that these liver enzymes may serve as valuable predictive markers in ICC patients.

  5. Serum liver enzymes serve as prognostic factors in patients with intrahepatic cholangiocarcinoma

    PubMed Central

    Zhang, Chenyue; Wang, Haiyong; Ning, Zhouyu; Xu, Litao; Zhuang, Liping; Wang, Peng; Meng, Zhiqiang

    2017-01-01

    Objective Liver functions, reflective of the overall status of the host, have been reported to be important factors affecting the prognosis in many types of cancers. In this study, we explored the influences of liver enzymes albumin (ALB), globulin (GELO), total protein (TP), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), gamma glutamyltranspeptidase (GGT), and lactate dehydrogenase (LDH) on the overall survival (OS) in a number of 173 patients with intrahepatic cholangiocarcinoma (ICC). Patients and methods Between 2011 and 2015, we enrolled patients with pathologically proven locally advanced or metastatic ICC. The impact of ALB, GELO, TP, ALP, ALT, AST, TBIL, DBIL, GGT, and LDH on OS were analyzed using Kaplan–Meier analysis. Next, the associations between these liver enzymes and OS were evaluated by univariate and multivariate analyses. Finally, the role of these enzymes in OS was evaluated in the subgroups. Results Elevated liver enzymes were linked with OS. We revealed that independent prognostic factors of poor outcome were ALP, TBIL, DBIL, and GGT, whereas ALB is a protective factor in ICC patients. Conclusion Our results demonstrate that these liver enzymes may serve as valuable predictive markers in ICC patients. PMID:28331337

  6. Histopathology of a benign bile duct lesion in the liver: Morphologic mimicker or precursor of intrahepatic cholangiocarcinoma

    PubMed Central

    Lee, Kyoung-Bun

    2016-01-01

    A bile duct lesion originating from intrahepatic bile ducts is generally regarded as an incidental pathologic finding in liver specimens. However, a recent study on the molecular classification of intrahepatic cholangiocarcinoma has focused on the heterogeneity of this carcinoma and has suggested that the cells of different origins present in the biliary tree may have a major role in the mechanism of oncogenesis. In this review, benign intrahepatic bile duct lesions—regarded in the past as reactive changes or remnant developmental anomalies and now noted to have potential for developing precursor lesions of intrahepatic cholangiocarcinoma—are discussed by focusing on the histopathologic features and its implications in clinical practice. PMID:27729636

  7. Combination of anti-L1 cell adhesion molecule antibody and gemcitabine or cisplatin improves the therapeutic response of intrahepatic cholangiocarcinoma

    PubMed Central

    Cho, Seulki; Lee, Tae Sup; Song, In Ho; Kim, A-Ram; Lee, Yoon-Jin; Kim, Haejung; Hwang, Haein; Jeong, Mun Sik; Kang, Seung Goo; Hong, Hyo Jeong

    2017-01-01

    Cholangiocarcinoma has a poor prognosis and is refractory to conventional chemotherapy and radiation therapy. Improving survival of patients with advanced cholangiocarcinoma urgently requires the development of new effective targeted therapies in combination with chemotherapy. We previously developed a human monoclonal antibody (mAb) Ab417 that binds to both the human and mouse L1 cell adhesion molecule (L1CAM) with high affinities. In the present study, we observed that Ab417 exhibited tumor targeting ability in biodistribution studies and dose-dependent tumor growth inhibition in an intrahepatic cholangiocarcinoma (Choi-CK) xenograft mouse model. Regarding the mechanism of action, Ab417 was internalized into the tumor cells and thereby down-regulated membrane L1CAM, and inhibited tumor growth by reducing tumor cell proliferation in vivo. Gemcitabine inhibited the tumor growth in a dose-dependent manner in the Choi-CK xenograft model. However, cisplatin inhibited the tumor growth moderately and not in a dose-dependent way, suggesting that the tumors may have developed resistance to apoptosis induced by cisplatin. Combined treatment with Ab417 and gemcitabine or cisplatin exerted enhanced tumor growth inhibition compared to treatment with antibody or drug alone. The results suggest that Ab417 in combination with chemotherapy may have potential as a new therapeutic regimen for cholangiocarcinoma. Our study is the first to show an enhanced therapeutic effect of a therapeutic antibody targeting L1CAM in combination with chemotherapy in cholangiocarcinoma models. PMID:28166242

  8. OEM-TACE: a new therapeutic approach in unresectable intrahepatic cholangiocarcinoma.

    PubMed

    Poggi, Guido; Amatu, A; Montagna, B; Quaretti, P; Minoia, C; Sottani, C; Villani, L; Tagliaferri, B; Sottotetti, F; Rossi, O; Pozzi, E; Zappoli, F; Riccardi, A; Bernardo, G

    2009-11-01

    Intrahepatic cholangiocarcinoma (ICC) is a rare life-threatening disease, whose only treatment with potential for cure is surgical resection. However, only 27% of patients at most are suitable for surgery when first diagnosed. For patients with unresectable disease, therapeutic options are chemotherapy or chemoradiation. We evaluated the feasibility and safety of oxaliplatin-eluting microspheres transarterial chemoembolization (OEM-TACE) associated with chemotherapy (ChT) in patients affected by unresectable ICC. Between December 2005 and May 2008 we treated nine patients (six female and three male) with unresectable ICC. All patients had undergone OEM-TACE associated with chemotherapy with oxaliplatin and gemcitabine. A retrospective comparison was carried out with a historical group of 11 patients treated with ChT only, estimating the prevalence of adverse effects and the median survival of the two groups. A total of 30 TACEs were performed during the observational time (ranging from one to seven procedures per patient). OEM-TACEs were followed by few adverse effects (AEs), without G4 AEs, according to CTACAE 3.0. According to RECIST criteria, 44% (4/9) of patients achieved partial responses and 56% (5/9) stabilization of disease. Overall survival analysis in the two groups showed a significantly increased survival in patients treated with ChT and OEM-TACE, with respect to those treated with ChT (30 vs. 12.7 months; p=0.004). In conclusion, in our experience OEM-TACE associated with ChT in the treatment of advanced unresectable ICC is a safe and feasible treatment causing no major adverse events. Although RECIST criteria can underestimate the rate of responses in patients treated with locoregional therapies, we achieved very encouraging results. A randomized multicentric trial is warranted to assess the actual superiority of OEM-TACE associated with ChT compared to conventional chemotherapy.

  9. Peritumoral SPARC expression and patient outcome with resectable intrahepatic cholangiocarcinoma

    PubMed Central

    Cheng, Chi-Tung; Chu, Yin-Yi; Yeh, Chun-Nan; Huang, Shih-Chiang; Chen, Ming Huang; Wang, Shang-Yu; Tsai, Chun-Yi; Chiang, Kun-Chun; Chen, Yen-Yang; Ma, Ming-Chun; Liu, Chien-Ting; Chen, Tsung-Wen; Yeh, Ta-Sen

    2015-01-01

    Background and objectives Cholangiocarcinoma (CCA) affects thousands worldwide with increasing incidence. SPARC (secreted protein acidic and rich in cysteine) plays an important role in cellular matrix interactions, wound repair, and cellular migration, and has been reported to prevent malignancy from growth. SPARC undergoes epigenetic silencing in pancreatic malignancy, but is frequently expressed by stromal fibroblasts adjacent to infiltrating pancreatic adenocarcinomas. CCA is also a desmoplastic tumor, similar to pancreatic adenocarcinoma. SPARC’s clinical influence on clinicopathological characteristics of mass-forming (MF)-CCA still remains unclear. In this study, we evaluate the expression of SPARC in tumor and stromal tissue to clarity its relation with prognosis. Methods Seventy-eight MF-CCA patients who underwent hepatectomy with curative intent were enrolled for an immunohistochemical study of SPARC. The expression of immunostaining of SPARC was characterized for both tumor and stromal tissues. We conducted survival analysis with 16 clinicopathological variables. The overall survival (OS) was analyzed by Kaplan–Meier analysis and Cox proportional hazards regression modeling. Results Thirty-three men and 45 women with MF-CCA were studied. Within total 78 subjects, 12 (15.4%) were classified as tumor negative/stroma negative, 37 (47.4%) as tumor positive/stroma negative, four (5.1%) as tumor negative/stroma positive, and 25 (32.1%) as tumor positive/stroma positive. With a median follow-up of 13.6 months, the 5-year OS was 14.9%. Cox proportional hazard analysis revealed that SPARC tumor positive and stromal negative immunostaining and curative hepatectomy predicted favorable OS in patients with MF-CCA after hepatectomy. Conclusion MF-CCA patients with SPARC tumor positive and stromal negative expression may have favorable OS rates after curative hepatectomy. PMID:26251613

  10. A case of concomitant colitic cancer and intrahepatic cholangiocarcinoma during follow-up for ulcerative colitis.

    PubMed

    Tsuchiya, Kazuyo; Nanashima, Atsushi; Ikeda, Takuto; Minami, Shiro; Nagano, Motoaki; Hamada, Takeomi; Yano, Koichi; Fujii, Yoshiro

    2017-04-01

    Colitis-associated colorectal cancer (CAC) is known to occur in long-standing and extensive ulcerative colitis (UC). Furthermore, UC is known to complicate primary sclerosing cholangitis (PSC), which subsequently results in an increased risk of developing cholangiocarcinoma. We report a case of colitis-associated rectal cancer (CARC) accompanied by intrahepatic cholangiocarcinoma (ICC) based on UC and PSC. A 73-year-old man had suffered from UC for 19 years. During surveillance colonoscopy, a tumor was found in the rectum that was pathologically diagnosed as CARC from the resected specimen. Abdominal computed tomography also revealed a localized dilation of the intrahepatic bile duct, and endoscopic retrograde cholangiography revealed a band-like stricture. This remarkable tumor lesion was not observed in the hepatic duct. Left hepatectomy was performed because of the suspicion of possible ICC at the stenosis of the hepatic duct. The presence of ICC was confirmed at the lesion causing the stricture. The pathological diagnosis from the resected specimen was ICC based on PSC. Adjuvant chemotherapy for ICC was performed for 6 months. Neither cancer has recurred for 2.5 years after hepatectomy. Patients with PSC concomitant with UC should be considered a high-risk group for CAC and ICC.

  11. Intrahepatic cholangiocarcinoma in a worker at an offset color proof-printing company: An autopsy case report.

    PubMed

    Tomimaru, Yoshito; Kobayashi, Shogo; Wada, Hiroshi; Hama, Naoki; Kawamoto, Koichi; Eguchi, Hidetoshi; Kira, Toshihiko; Morii, Eiichi; Doki, Yuichiro; Mori, Masaki; Nagano, Hiroaki

    2015-04-01

    A 40-year-old Japanese man visited our hospital after test results indicated elevated hepatobiliary enzymes. He had worked at a printing plant for 8 years and been exposed to organic solvents, including 1,2-dichloropropane (1,2-DCP) and dichloromethane (DCM). Abdominal computed tomography (CT) showed an intrahepatic tumor with dilation of the intrahepatic bile duct. He was diagnosed with intrahepatic cholangiocarcinoma. He had no known risk factors for cholangiocarcinoma. Extended left hepatectomy with lymph node dissection was performed and the tumor was histologically diagnosed as well-differentiated adenocarcinoma. A histological examination also showed biliary intraepithelial preneoplastic lesions in non-cancerous liver areas. Two years after surgery, the patient developed jaundice, esophageal varices and ascites. A CT examination showed liver cirrhosis without recurrence of the cholangiocarcinoma. Although a liver transplantation was planned as a therapeutic option for his liver cirrhosis, his liver failure progressed rapidly and he died before transplantation could be performed. At autopsy, fibrosis was found in the whole liver, especially in the wall of the bile duct and periductal area suggesting chronic bile duct injury due to exposure to organic solvents. Taken together, the current case may suggest that exposure to organic solvents, including 1,2-DCP and DCM, is a risk factor for cholangiocarcinoma. Identifying risk factors for cholangiocarcinoma will help identify the mechanism and help prevent development of the disease.

  12. Molecular profiling of intrahepatic and extrahepatic cholangiocarcinoma using next generation sequencing

    PubMed Central

    Putra, Juan; de Abreu, Francine B.; Peterson, Jason D.; Pipas, J. Marc; Mody, Kabir; Amos, Christopher I.; Tsongalis, Gregory J.; Suriawinata, Arief A.

    2015-01-01

    Cholangiocarcinoma is a heterogeneous malignant process, which is further classified into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). The poor prognosis of the disease is partly due to the lack of understanding of the disease mechanism. Multiple gene alterations identified by various molecular techniques have been described recently. As a result, multiple targeted therapies for ICC and ECC are being developed. In this study, we identified and compared somatic mutations in ICC and ECC patients using next generation sequencing (NGS) (Ampliseq Cancer Hotspot Panel v2 and Ion Torrent 318v2 chips). Eleven of 16 samples passed internal quality control established for NGS testing. ICC cases (n = 3) showed IDH1 (33.3%) and NRAS (33.3%) mutations. Meanwhile, TP53 (75%), KRAS (50%), and BRAF (12.5%) mutations were identified in ECC cases (n = 8). Our study confirmed the molecular heterogeneity of ICC and ECC using NGS. This information will be important for individual patients as targeted therapies for ICC and ECC become available in the future. PMID:26189129

  13. Molecular profiling of intrahepatic and extrahepatic cholangiocarcinoma using next generation sequencing.

    PubMed

    Putra, Juan; de Abreu, Francine B; Peterson, Jason D; Pipas, J Marc; Mody, Kabir; Amos, Christopher I; Tsongalis, Gregory J; Suriawinata, Arief A

    2015-10-01

    Cholangiocarcinoma is a heterogeneous malignant process, which is further classified into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). The poor prognosis of the disease is partly due to the lack of understanding of the disease mechanism. Multiple gene alterations identified by various molecular techniques have been described recently. As a result, multiple targeted therapies for ICC and ECC are being developed. In this study, we identified and compared somatic mutations in ICC and ECC patients using next generation sequencing (NGS) (Ampliseq Cancer Hotspot Panel v2 and Ion Torrent 318v2 chips). Eleven of 16 samples passed internal quality control established for NGS testing. ICC cases (n=3) showed IDH1 (33.3%) and NRAS (33.3%) mutations. Meanwhile, TP53 (75%), KRAS (50%), and BRAF (12.5%) mutations were identified in ECC cases (n=8). Our study confirmed the molecular heterogeneity of ICC and ECC using NGS. This information will be important for individual patients as targeted therapies for ICC and ECC become available in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Ricolinostat, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients With Unresectable or Metastatic Cholangiocarcinoma

    ClinicalTrials.gov

    2016-08-02

    Non-Resectable Cholangiocarcinoma; Recurrent Cholangiocarcinoma; Stage III Extrahepatic Bile Duct Cancer; Stage III Intrahepatic Cholangiocarcinoma; Stage IIIA Hilar Cholangiocarcinoma; Stage IIIB Hilar Cholangiocarcinoma; Stage IVA Extrahepatic Bile Duct Cancer; Stage IVA Hilar Cholangiocarcinoma; Stage IVA Intrahepatic Cholangiocarcinoma; Stage IVB Extrahepatic Bile Duct Cancer; Stage IVB Hilar Cholangiocarcinoma; Stage IVB Intrahepatic Cholangiocarcinoma; Unresectable Extrahepatic Bile Duct Carcinoma

  15. Cholangiocarcinoma of intrahepatic bile ducts with disseminated metastases in an African lion (Panthera leo).

    PubMed

    Lepri, Elvio; Sforna, Monica; Brachelente, Chiara; Chiara, Brachelente; Vitellozzi, Giovanni; Giovanni, Vitellozzi

    2013-06-01

    A cholangiocarcinoma is reported in an 18-yr-old, female African lion (Panthera leo). The primary tumor consisted of multifocal to coalescing, hepatic, white-yellow masses distributed throughout the liver lobes. Metastases were present in regional lymph nodes, peritoneal surface, and lungs. Histologically, the tumor was characterized by a tubular pattern with alcian- and periodic acid-Schiff-positive secretory material in cystic spaces. The neoplastic cells were positive to broad-spectrum cytokeratins. Histochemical and immunohistochemical stains were consistent with bile duct carcinoma. Biliary tumors arising from the gallbladder have been reported in lions. However, to the authors' knowledge, this is the first case of intrahepatic bile duct carcinoma reported in an African lion.

  16. The effect of wide resection margin in patients with intrahepatic cholangiocarcinoma

    PubMed Central

    Ma, Ka Wing; Cheung, Tan To; She, Wong Hoi; Chok, Kenneth S.H.; Chan, Albert Chi Yan; Ng, Irene Oi Lin; Chan, See Ching; Lo, Chung Mau

    2016-01-01

    Abstract Introduction: Prognosis of intrahepatic cholangiocarcinoma (ICC) remained poor despite the multitude advancement of medical care. Resection margin status is one of the few modifiable factors that a surgeon could possibly manipulate to alter the disease outcome. However, the significance of margin status and margin width is still controversial. This study serves to further elucidate the role of them. Method: This is a retrospective cohort from the Queen Mary Hospital, The University of Hong Kong. Consecutive patients diagnosed to have ICC and with surgical resection performed in curative intent were retrieved, while patients with cholangiohepatocellular carcinoma, Klaskin tumor, tumor of extrahepatic bile duct, and uncertain tumor pathology were excluded. Results: From 1991 to 2013, there were 107 patients underwent hepatectomy for ICC. Gender predilection was not observed with 58 males and 49 females, median age of the patients was 61. The median tumor size was 6 cm and most of them (43%) were moderately differentiated adenocarcinoma. Clear resection margin were achieved in 95 patients (88.8%) and the median margin width was 0.5 cm. The hospital length of stay and operative mortality were 11 days and 3%, respectively. The disease-free survival and overall survival were 17.5 and 25.1 months, respectively. Multivariate analysis showed that margin width was an independent factor associated with disease-free survival (P = 0.015, 95% confidence interval [CI] 0.4–0.9). Subgroup analysis in patients with solitary tumor showed that margin width is an independent factor affecting overall survival (P = 0.048; odds ratio: 0.577; 95% CI: 0.334–0.996). Discriminant analysis showed that the overall survival increased from 36 to 185 months when margin width was >0.9 cm (P = 0.025) in patients with solitary tumor. Conclusion: Aggressive resection to achieve resection margin of at least 1 cm maximizes chance of cure in patients with early ICC. PMID:27428200

  17. Kupffer cells induce Notch-mediated hepatocyte conversion in a common mouse model of intrahepatic cholangiocarcinoma

    PubMed Central

    Terada, Maiko; Horisawa, Kenichi; Miura, Shizuka; Takashima, Yasuo; Ohkawa, Yasuyuki; Sekiya, Sayaka; Matsuda-Ito, Kanae; Suzuki, Atsushi

    2016-01-01

    Intrahepatic cholangiocarcinoma (ICC) is a malignant epithelial neoplasm composed of cells resembling cholangiocytes that line the intrahepatic bile ducts in portal areas of the hepatic lobule. Although ICC has been defined as a tumor arising from cholangiocyte transformation, recent evidence from genetic lineage-tracing experiments has indicated that hepatocytes can be a cellular origin of ICC by directly changing their fate to that of biliary lineage cells. Notch signaling has been identified as an essential factor for hepatocyte conversion into biliary lineage cells at the onset of ICC. However, the mechanisms underlying Notch signal activation in hepatocytes remain unclear. Here, using a mouse model of ICC, we found that hepatic macrophages called Kupffer cells transiently congregate around the central veins in the liver and express the Notch ligand Jagged-1 coincident with Notch activation in pericentral hepatocytes. Depletion of Kupffer cells prevents the Notch-mediated cell-fate conversion of hepatocytes to biliary lineage cells, inducing hepatocyte apoptosis and increasing mortality in mice. These findings will be useful for uncovering the pathogenic mechanism of ICC and developing prevenient and therapeutic strategies for this refractory disease. PMID:27698452

  18. Mutations in Isocitrate Dehydrogenase 1 and 2 Occur Frequently in Intrahepatic Cholangiocarcinomas and Share Hypermethylation Targets with Glioblastomas

    PubMed Central

    Wang, Pu; Dong, Qiongzhu; Zhang, Chong; Kuan, Pei-Fen; Liu, Yufeng; Jeck, William R.; Andersen, Jesper B.; Jiang, Wenqing; Savich, Gleb L.; Tan, Ting-Xu; Auman, J. Todd; Hoskins, Janelle M.; Misher, Anne D.; Moser, Catherine D.; Yourstone, Scott M.; Kim, Jin Woo; Cibulskis, Kristian; Getz, Gad; Hunt, Heike V.; Thorgeirsson, Snorri S.; Roberts, Lewis R.; Ye, Dan; Guan, Kun-Liang; Xiong, Yue; Qin, Lun-Xiu; Chiang, Derek Y.

    2012-01-01

    Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas, and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine (5hmC) and higher 5-methylcytosine (5mC) levels, as well as increased dimethylation of histone H3K79. Mutations in IDH1 or IDH2 were associated with longer overall survival (p = 0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (p = 0.021). IDH1 and IDH2 mutations are significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2,309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors. PMID:22824796

  19. Claudin-7-positive synchronous spontaneous intrahepatic cholangiocarcinoma, adenocarcinoma and adenomas of the gallbladder in a Bearded dragon (Pogona vitticeps).

    PubMed

    Jakab, Csaba; Rusvai, Miklós; Szabó, Zoltán; Gálfi, Péter; Marosán, Miklós; Kulka, Janina; Gál, János

    2011-03-01

    In this study, synchronous spontaneous, independent liver and gallbladder tumours were detected in a Bearded dragon (Pogona vitticeps). The multiple tumours consisted of intrahepatic cholangiocarcinoma as well as in situ adenocarcinoma and two adenomas of the gallbladder. The biliary epithelial cells and the cholangiocarcinoma showed membranous cross-immunoreactivity for claudin-7. The gallbladder epithelial cells, its adenoma and adenocarcinoma showed basolateral cross-reactivity for claudin-7. We think that the humanised anti-claudin-7 antibody is a good marker for the detection of different primary cholangiocellular and gallbladder tumours in Bearded dragons. The cholangiocytes, the cholangiocarcinoma, the endothelial cells of the liver and the epithelial cells and gallbladder tumours all showed claudin-5 cross-reactivity. The humanised anti-cytokeratin AE1-AE3 antibody showed cross-reactivity in the biliary epithelial cells, cholangiocarcinoma cells, epithelial cells and tumour cells of the gallbladder. It seems that this humanised antibody is a useful epithelial marker for the different neoplastic lesions of epithelial cells in reptiles. The humanised anti-α-smooth muscle actin (α-SMA) antibody showed intense cross-reactivity in the smooth muscle cells of the hepatic vessels and in the muscle layer of the gallbladder. The portal myofibroblasts, the endothelial cells of the sinusoids and the stromal cells of the cholangiocarcinoma and gallbladder tumours were positive for α-SMA. The antibovine anti-vimentin and humanised anti-Ki-67 antibodies did not show crossreactivity in the different samples from the Bearded dragon.

  20. Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice.

    PubMed

    Zhang, Shanshan; Song, Xinhua; Cao, Dan; Xu, Zhong; Fan, Biao; Che, Li; Hu, Junjie; Chen, Bin; Dong, Mingjie; Pilo, Maria G; Cigliano, Antonio; Evert, Katja; Ribback, Silvia; Dombrowski, Frank; Pascale, Rosa M; Cossu, Antonio; Vidili, Gianpaolo; Porcu, Alberto; Simile, Maria M; Pes, Giovanni M; Giannelli, Gianluigi; Gordan, John; Wei, Lixin; Evert, Matthias; Cong, Wenming; Calvisi, Diego F; Chen, Xin

    2017-07-19

    Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. We evaluated the therapeutic potential of MLN0128 vs. gemcitabine/oxaliplatin in a novel ICC mouse model. We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their anti-tumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for the characterization and mechanistic study. Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis. Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation. This study suggests that mTOR kinase inhibitors may be beneficial for the treatment of ICC, even in tumors that are resistant to standard of care chemotherapeutics, such as gemcitabine/oxaliplatin-based regimens, especially in the subset of tumors exhibiting activated AKT/mTOR cascade. Lay summary: We established a novel mouse model of intrahepatic cholangiocarcinoma (ICC). Using this

  1. Integrative Molecular Analysis of Intrahepatic Cholangiocarcinoma Reveals 2 Classes That Have Different Outcomes

    PubMed Central

    SIA, DANIELA; HOSHIDA, YUJIN; VILLANUEVA, AUGUSTO; ROAYAIE, SASAN; FERRER, JOANA; TABAK, BARBARA; PEIX, JUDIT; SOLE, MANEL; TOVAR, VICTORIA; ALSINET, CLARA; CORNELLA, HELENA; KLOTZLE, BRANDY; FAN, JIAN–BING; COTSOGLOU, CHRISTIAN; THUNG, SWAN N.; FUSTER, JOSEP; WAXMAN, SAMUEL; GARCIA–VALDECASAS, JUAN CARLOS; BRUIX, JORDI; SCHWARTZ, MYRON E.; BEROUKHIM, RAMEEN; MAZZAFERRO, VINCENZO; LLOVET, JOSEP M.

    2013-01-01

    BACKGROUND & AIMS Cholangiocarcinoma, the second most common liver cancer, can be classified as intra-hepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by GISTIC analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). RESULTS We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation– based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P < .001). CONCLUSIONS We used an integrative genomic analysis to identify 2 classes

  2. Expression of hepatocyte markers in mass-forming peripheral and periductal-infiltrating hilar intrahepatic cholangiocarcinomas

    PubMed Central

    IIDA, HIROYA; HATA, MASAKI; KAKUNO, AYAKO; HIRANO, HIROSHI; YAMANEGI, KOJI; YAMADA, NAOKO; OHYAMA, HIDEKI; TERADA, NOBUYUKI; YASUI, CHIAKI; YAMANAKA, NAOKI; NAKASHO, KEIJI

    2011-01-01

    In this study, the expression of hepatocyte markers, including α-fetoprotein (AFP), HepPar-1 antigen and arginase-1, was examined immunohistochemically in 14 mass-forming peripheral intrahepatic cholangiocarcinomas (ICCs) that arose from the peripheral portion of the biliary tree, and in 14 periductal-infiltrating hilar ICCs that arose from intrahepatic large bile ducts. Only 2 (14.3%) of the 14 hilar ICCs and 2 (14.3%) of the 14 peripheral ICCs expressed AFP or HepPar-1 antigen. Conversely, arginase-1 was expressed in 8 (57.1%) and 11 (78.6%) of the hilar and peripheral ICCs, respectively, and 4 (28.6%) hilar ICCs and 7 (50%) peripheral ICCs expressed arginase-1 in more than 10% of the cancer cells. The expression of arginase-1 did not differ between peripheral ICCs showing major histology of poorly differentiated adenocarcinoma and those showing other major histologies, including well-or moderately differentiated tubular adenocarcinoma or papillary adenocarcinoma. Results of the present study showed that common hepatocyte markers, including AFP and HepPar-1 antigen, are rarely but definitely expressed in hilar and peripheral ICCs, and that a third hepatocyte marker, arginase-1, is expressed at a high rate in both hilar and peripheral ICCs, irrespective of their histology. These results indicate that care should be taken when using arginase-1 as a hepatocyte marker for distinguishing between a poorly differentiated hepatocellular carcinoma and a mass-forming peripheral ICC showing the histology of poorly differentiated adenocarcinoma. PMID:22848265

  3. Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines.

    PubMed

    Ling, Sunbin; Feng, Tingting; Ke, Qinghong; Fan, Ning; Li, Lei; Li, Zhongxing; Dong, Chengyong; Wang, Cong; Xu, Fei; Li, Yan; Wang, Liming

    2014-06-01

    Metformin is an oral anti-hyperglycemic agent of the biguanide family, which is used first-line for type II diabetes with few side-effects. A recent epidemiological study that included 1,828 potential intrahepatic cholangiocarcinoma (ICC) patients showed that metformin use was significantly associated with a 60% reduction in ICC risk in diabetic patients, demonstrating the potential value of metformin in ICC management. In the present study, we firstly showed that metformin exhibited a dose- and time-dependent anti-proliferation effect on ICC cell lines, by mechanisms including apoptosis induction and cell cycle arrest. Metformin targeted the AMPK/mTORC1 pathway in ICC cells. Furthermore, metformin sensitized ICC cells to certain chemotherapeutic agents, such as sorafenib, 5-fluorouracil and As2O3 by targeting the AMPK/mTOR/HIF-1α/MRP1 pathway and ERK. As it is an inexpensive and widely used antidiabetic drug without severe adverse effects, metformin may be a prospective chemotherapeutic agent or a chemosensitizer in future ICC treatment.

  4. Clinicopathologic significance of Sox2, CD44 and CD44v6 expression in intrahepatic cholangiocarcinoma.

    PubMed

    Gu, Mi Jin; Jang, Byung Ik

    2014-07-01

    Embryonic stem cells (ESC) and cancer stem cells (CSC) have a capacity for self-renewal and differentiation into multiple cell lineages. Sox2 plays a critical role in ESC and has been shown to participate in carcinogenesis and tumor progression in many human cancers. CD44 and CD44v6 are putative CSC markers and their association with tumor progression, metastasis, and tumor relapse after treatment has been demonstrated. We evaluated the immunoexpression of Sox2, CD44, and CD44v6 in 85 cases of Intrahepatic cholangiocarcinomas (IHCC) and assessed their prognostic significance. Sox2 expression showed a significant association with lymph node metastasis (p = 0.025), T4 stage (p = 0.046), and worse overall survival (p = 0.047). Greater expression of Sox2 was observed in IHCC with poor differentiation, vascular invasion, and stage IV, without statistical significance (p > 0.05). CD44 expression showed an association with periductal infiltrative type (p = 0.034), poor differentiation (p = 0.012), and vascular invasion (p = 0.009). CD44v6 expression was evident in patients with stage IV (p = 0.019). These results demonstrated that Sox2 expression is associated with aggressive behavior and poor overall survival in IHCC.

  5. Risk factors for intrahepatic cholangiocarcinoma: a case-control study in China.

    PubMed

    Zhou, Yan-Ming; Yin, Zheng-Feng; Yang, Jia-Mei; Li, Bin; Shao, Wen-Yu; Xu, Feng; Wang, Yu-Lan; Li, Dian-Qi

    2008-01-28

    To carry out a hospital-based case-control study to investigate risk factors for intrahepatic cholangiocarcinoma (ICC) in China. A total of 312 ICC cases and 438 matched controls were included in the study. The presence of diabetes mellitus, hypertension, hepatolithiasis, primary sclerosing cholangitis, liver fluke infection (Clonorchis sinensis), was investigated through clinical records. Blood from all participants was tested for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression. Compared with controls, ICC patients had a higher prevalence of HBsAg seropositivity (48.4% vs 9.6%, P<0.000), and hepatolithiasis (5.4% vs 1.1%, P=0.001). By multivariate analysis, the significant risk factors for development of ICC were HBsAg seropositivity (adjusted OR, 8.876, 95% CI, 5.973-13.192), and hepatolithiasis (adjusted OR, 5.765, 95% CI, 1.972-16.851). The prevalence of anti-HCV seropositivity, diabetes mellitus, hypertension, cigarette smoking, and alcohol consumption were not significantly different between cases and controls. These findings suggest that HBV infection and hepatolithiasis are strong risk factors for development of ICC in China.

  6. Intrahepatic cholangiocarcinoma: impact of genetic hemochromatosis on outcome and overall survival after surgical resection.

    PubMed

    Sulpice, Laurent; Rayar, Michel; Boucher, Eveline; Pele, Fabienne; Pracht, Marc; Meunier, Bernard; Boudjema, Karim

    2013-03-01

    The influence of genetic hemochromatosis (GH) on outcomes following surgical resections for intrahepatic cholangiocarcinoma (ICC) has not been evaluated. All patients with ICC who underwent a surgical resection between January 1997 and August 2011 were analyzed retrospectively. Risk factors were assessed by univariate and multivariate analyses. Eighty-seven patients were analyzed; 16 of these patients (18.4%) had GH. Among the 71 non-GH patients, 52 (73.2%) and 19 (26.8%) had normal or cirrhotic parenchyma, respectively. There was no significant difference in survival between the GH and non-GH patients. A univariate analysis showed that major hepatectomy (P = 0.012), intraoperative blood transfusion (P = 0.007), tumor size >5 cm (P = 0.006), several nodules (P < 0.001), and microvascular invasion (P = 0.04) were significantly associated with poor survival. A multivariate analysis showed that intraoperative blood infusion (HR 0.37; CI 95% [0.19; 0.71]) and more than one nodule (HR 2.5; CI 95% [1.06; 5.8]) were associated with a lower survival rate. Although the incidence of GH was high in our series, the presence of GH did not affect the outcomes after a liver hepatectomy for ICC. GH does not appear to increase recurrences or worsen the overall and disease-free survival. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Expression of Molecular Differentiation Markers Does Not Correlate with Histological Differentiation Grade in Intrahepatic Cholangiocarcinoma

    PubMed Central

    Demarez, Céline; Hubert, Catherine; Sempoux, Christine; Lemaigre, Frédéric P.

    2016-01-01

    The differentiation status of tumor cells, defined by histomorphological criteria, is a prognostic factor for survival of patients affected with intrahepatic cholangiocarcinoma (ICC). To strengthen the value of morphological differentiation criteria, we wished to correlate histopathological differentiation grade with expression of molecular biliary differentiation markers and of microRNAs previously shown to be dysregulated in ICC. We analysed a series of tumors that were histologically classified as well, moderately or poorly differentiated, and investigated the expression of cytokeratin 7, 19 and 903 (CK7, CK19, CK903), SRY-related HMG box transcription factors 4 and 9 (SOX4, SOX9), osteopontin (OPN), Hepatocyte Nuclear Factor-1 beta (HNF1β), Yes-associated protein (YAP), Epithelial cell adhesion molecule (EPCAM), Mucin 1 (MUC1) and N-cadherin (NCAD) by qRT-PCR and immunostaining, and of miR-31, miR-135b, miR-132, miR-200c, miR-221 and miR-222. Unexpectedly, except for subcellular location of SOX9 and OPN, no correlation was found between the expression levels of these molecular markers and histopathological differentiation grade. Therefore, our data point toward necessary caution when investigating the evolution and prognosis of ICC on the basis of cell differentiation criteria. PMID:27280413

  8. STAT3 overexpression promotes metastasis in intrahepatic cholangiocarcinoma and correlates negatively with surgical outcome.

    PubMed

    Yang, Xin-Wei; Li, Liang; Hou, Guo-Jun; Yan, Xin-Zhou; Xu, Qin-Guo; Chen, Lei; Zhang, Bao-Hua; Shen, Feng

    2017-01-31

    Signal transducer and activator of transcription 3 (STAT3) promotes tumor progression in many types of cancer. In this study, we analyzed the prognostic value of this marker in human intrahepatic cholangiocarcinoma (ICC). Using real-time PCR, western blot and immunohistochemistry assays, we found that STAT3 is overexpressed in ICC patients. STAT3 expression correlated with several clinicopathological features, including tumor size, pathological satellite, vascular invasion, undifferentiated-type histology, lymph node metastasis and TNM stage in two independent cohorts of ICC patients. Patients with high STAT3 levels had a poor prognosis in terms of overall survival (OS) and disease-free survival (DFS). Multivariate survival analysis indicated that STAT3 is an independent prognostic factor for OS and DFS. Furthermore, we observed that STAT3 overexpression promotes the invasion, metastasis and proliferation of ICC cells in vitro and in vivo, and also promotes STAT3 phosphorylation. These findings suggest that STAT3 expression correlated negatively with surgical outcome and inhibition of STAT3 expression may constitute a novel target for the treatment of ICC patients.

  9. Expression of GLP-1R protein and its clinical role in intrahepatic cholangiocarcinoma tissues.

    PubMed

    Chen, Ben-Dong; Zhao, Wen-Chao; Dong, Jian-Da; Sima, Hui

    2014-07-01

    The study investigates the expression and clinical role of GLP-1R in intrahepatic cholangiocarcinoma (ICC) tissues. ICC tissue, tissue around tumour and normal liver tissue samples from 176 ICC patients were investigated for GLP-1R expression by immunohistochemistry and western blots. Expression levels were correlated to clinical variables and to the postoperative outcome. High GLP-1R expression levels were detected in tumor tissue samples. Kaplan-Meier method was used for survival analysis of patients follow-up data. Results showed that median survival time of patients with high GLP-1R positive expression in ICC tissue were 22 months. Median survival time of patients with low GLP-1R positive expression in ICC tissue were 19.8 months. There wasn't statistical difference (p = 0.332) between two groups. Immunohistochemistry semi-quantitative analysis showed that tissue differentiation is not prognostic risk factors. In patients with GLP-1R positive expression in ICC tissue, lymph node metastasis was important prognostic factors (p = 0.001). Although statistical analysis showed that GLP-1R can not be judged as a risk prognostic factors, GLP-1 might become a new target for therapy of ICC.

  10. GNAS1 T393C Polymorphism Is Associated with Clinical Course in Patients with Intrahepatic Cholangiocarcinoma

    PubMed Central

    Schmitz, Klaus J; Lang, Hauke; Frey, Ulrich H; Sotiropoulos, Georgios C; Wohlschlaeger, Jeremias; Reis, Henning; Takeda, Atsushi; Siffert, Winfried; Schmid, Kurt W; Baba, Hideo A

    2007-01-01

    Abstract Background/Aims The GNAS1 locus encodes the Gαs protein, which stimulates the formation of cyclo-adenosinemonophosphate (cAMP). The cAMP pathway mediates pleiotropic effects, including the regulation of apoptosis and proliferation. We have recently shown that TT genotypes of the single-nucleotide polymorphism T393C in the gene GNAS1 predict the clinical outcome of patients with various carcinomas. Methods Eighty-seven patients with intrahepatic cholangiocarcinoma (ICC) were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome. Results ICCs of patients with homozygous TT genotypes revealed a higher proliferation rate and a lower apoptotic rate. Homozygous TT patients were at highest risk for cancer-related deaths (hazard ratio = 2.74; 95% confidence interval = 1.03–7.28) compared with C-allele carriers. Kaplan-Meier curves for disease-specific overall and local recurrence-free survival in a subgroup with R0-resected ICC showed a significant association of T393 homozygosity with outcome, which was confirmed in multivariate Cox regression analysis. Conclusions GNAS1 T393C is a novel independent host factor for disease progression in patients with ICC. Our finding that TT homozygosity (and not CC homozygosity) was associated with unfavorable clinical outcome points to the complex and differing functional effects induced by GNAS1 T393C polymorphism in various human carcinomas. PMID:17356712

  11. GNAS1 T393C polymorphism is associated with clinical course in patients with intrahepatic cholangiocarcinoma.

    PubMed

    Schmitz, Klaus J; Lang, Hauke; Frey, Ulrich H; Sotiropoulos, Georgios C; Wohlschlaeger, Jeremias; Reis, Henning; Takeda, Atsushi; Siffert, Winfried; Schmid, Kurt W; Baba, Hideo A

    2007-02-01

    The GNAS1 locus encodes the Galphas protein, which stimulates the formation of cyclo-adenosinemonophosphate (cAMP). The cAMP pathway mediates pleiotropic effects, including the regulation of apoptosis and proliferation. We have recently shown that TT genotypes of the single-nucleotide polymorphism T393C in the gene GNAS1 predict the clinical outcome of patients with various carcinomas. Eighty-seven patients with intrahepatic cholangiocarcinoma (ICC) were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome. ICCs of patients with homozygous TT genotypes revealed a higher proliferation rate and a lower apoptotic rate. Homozygous TT patients were at highest risk for cancer-related deaths (hazard ratio = 2.74; 95% confidence interval = 1.03-7.28) compared with C-allele carriers. Kaplan-Meier curves for disease-specific overall and local recurrence-free survival in a subgroup with R(0)-resected ICC showed a significant association of T393 homozygosity with outcome, which was confirmed in multivariate Cox regression analysis. GNAS1 T393C is a novel independent host factor for disease progression in patients with ICC. Our finding that TT homozygosity (and not CC homozygosity) was associated with unfavorable clinical outcome points to the complex and differing functional effects induced by GNAS1 T393C polymorphism in various human carcinomas.

  12. MiR-145 functions as a tumor suppressor targeting NUAK1 in human intrahepatic cholangiocarcinoma

    SciTech Connect

    Xiong, Xinkui; Sun, Daoyi; Chai, Hao; Shan, Wengang; Yu, Yue; Pu, Liyong; Cheng, Feng

    2015-09-18

    The dysregulation of micro (mi)RNAs is associated with cancer development. The miRNA miR-145 is downregulated in intrahepatic cholangiocarcinoma (ICC); however, its precise role in tumor progression has not yet been elucidated. Novel (nua) kinase family (NUAK)1 functions as an oncogene in various cancers and is a putative target of miR-145 regulation. In this study, we investigated the regulation of NUAK1 by miR-145 in ICC. We found that miR-145 level was significantly decreased in ICC tissue and cell lines, which corresponded with an increase in NUAK1 expression. NUAK1 was found to be a direct target of miR-145 regulation. The overexpression of miR-145 in ICC cell lines inhibited proliferation, growth, and invasion by suppressing NUAK1 expression, which was associated with a decrease in Akt signaling and matrix metalloproteinase protein expression. Similar results were observed by inhibiting NUAK1 expression. These results demonstrate that miR-145 can prevent ICC progression by targeting NUAK1 and its downstream effectors, and can therefore be useful for clinical diagnosis and targeted therapy of ICC. - Highlights: • MiR-145 suppresses ICC proliferation and invasion abilities. • We demonstrated that miR-145 directly targets NUAK1 in ICC. • MiR-145 expression in ICC was associated with Akt signaling and MMPs expression.

  13. Prognostic nutritional index serves as a predictive marker of survival and associates with systemic inflammatory response in metastatic intrahepatic cholangiocarcinoma

    PubMed Central

    Zhang, Chenyue; Wang, Haiyong; Ning, Zhouyu; Xu, Litao; Zhuang, Liping; Wang, Peng; Meng, Zhiqiang

    2016-01-01

    Objective The significance of the prognostic nutritional index (PNI) has been widely reported and confirmed in many types of cancers. However, few studies are available indicating its prognostic power in patients with intrahepatic cholangiocarcinoma (ICC). Thus, we investigated its relationship with overall survival (OS) to evaluate its role in predicting survival in patients with ICC. Patients and methods Between October 2011 and October 2015, 173 consecutive patients with pathologically confirmed locally advanced or metastatic ICC were enrolled. First, the correlations between PNI and clinical factors were analyzed among these patients. Next, univariate and multivariate analyses were conducted to evaluate the association between PNI and OS among these patients with ICC. In addition, the relationships between PNI and three typical systemic inflammatory response (SIR) markers – the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR), and the lymphocyte/monocyte ratio (LMR) – were also assessed. Results A lower PNI was linked with a shorter OS in patients with ICC, as reflected obviously in the Kaplan–Meier analyses. The patients with ICC were divided into the locally advanced group and the metastatic group. Further analyses revealed that PNI is not associated with OS in the locally advanced group. However, in the subgroup of patients with metastatic ICC, a lower PNI significantly correlated with a worsened OS. The OS for patients with a low PNI is 5 months, whereas the OS is 10.17 months for patients with a high PNI. Multivariate analyses revealed that PNI is independently correlated with OS. We finally proved that PNI is negatively proportional to NLR and PLR and positively proportional to LMR. Conclusion Our results demonstrate that decreased PNI signifies a poor OS and is associated with SIR in patients with metastatic ICC. Therefore, it may serve as a valuable predictive marker in patients with metastatic ICC. PMID:27799789

  14. Management and Outcomes of Patients with Recurrent Intrahepatic Cholangiocarcinoma Following Previous Curative-Intent Surgical Resection.

    PubMed

    Spolverato, Gaya; Kim, Yuhree; Alexandrescu, Sorin; Marques, Hugo P; Lamelas, Jorge; Aldrighetti, Luca; Clark Gamblin, T; Maithel, Shishir K; Pulitano, Carlo; Bauer, Todd W; Shen, Feng; Poultsides, George A; Tran, Thuy B; Wallis Marsh, J; Pawlik, Timothy M

    2016-01-01

    Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma (ICC) following curative-intent surgery are not well documented. We sought to characterize the treatment of patients with recurrent ICC and define therapy-specific outcomes. Patients who underwent surgery for ICC from 1990 to 2013 were identified from an international database. Data on clinicopathological characteristics, operative details, recurrence, and recurrence-related management were recorded and analyzed. A total of 563 patients undergoing curative-intent hepatic resection for ICC who met the inclusion criteria were identified. With a median follow-up of 19 months, 400 (71.0 %) patients developed a recurrence. At initial surgery, treatment was resection only (98.8 %) or resection + ablation (1.2 %). Overall 5-year survival was 23.6 %; 400 (71.0 %) patients recurred with a median disease-free survival of 11.2 months. First recurrence site was intrahepatic only (59.8 %), extrahepatic only (14.5 %), or intra- and extrahepatic (25.7 %). Overall, 210 (52.5 %) patients received best supportive care (BSC), whereas 190 (47.5 %) patients received treatment, such as systemic chemotherapy-only (24.2 %) or repeat liver-directed therapy ± systemic chemotherapy (75.8 %). Repeat liver-directed therapy consisted of repeat hepatic resection ± ablation (28.5 %), ablation alone (18.7 %), and intra-arterial therapy (IAT) (52.8 %). Among patients who recurred, median survival from the time of the recurrence was 11.1 months (BSC 8.0 months, systemic chemotherapy-only 16.8 months, liver-directed therapy 18.0 months). The median survival of patients undergoing resection of recurrent ICC was 26.7 months versus 9.6 months for patients who had IAT (p < 0.001). Recurrence following resection of ICC was common, occurring in up to two-thirds of patients. When there is recurrence, prognosis is poor. Only 9 % of patients underwent repeat liver resection after recurrence, which offered a modest survival

  15. Risk factors for intrahepatic cholangiocarcinoma: a possible role of hepatitis B virus

    PubMed Central

    Tanaka, M; Tanaka, H; Tsukuma, H; Ioka, A; Oshima, A; Nakahara, T

    2010-01-01

    There are several established risk factors for intrahepatic cholangiocarcinoma (ICC), namely primary sclerosing cholangitis, fibropolycystic liver disease, parasitic infection, intrahepatic biliary stones and chemical carcinogen exposure. However, the majority of patients with ICC do not have any of these risk factors. Therefore, identification of other risk factors is warranted for the prevention and early detection of ICC. We evaluated the risk factors for ICC in a large-scale cohort study in the province of Osaka, Japan. This retrospective cohort study included 154,814 apparently healthy individual blood donors, aged 40–64 years at the time of blood donation in the period 1991–1993. The average observation period was 7.6 years, resulting in 1.25 million person-years of observation. Incident ICC cases were identified by linking the blood-donor database to the records in the population-based cancer registry for the province. There were 11 incident ICC cases during follow-up, with an incidence rate of 0.88 per 100 000 person-years. Compared with subjects aged 40–49 years, the subjects aged 50–54 years and 55–59 years had a significantly higher risk for ICC (hazard ratio [HR] = 5.90; 95%CI:1.08–32.31 and 11.07; 95%CI:1.98–61.79, respectively). Compared with those with ALT level of 19 Karmen Units (KU) or less, subjects with ALT level of 40 KU or higher had a significantly higher risk for ICC (HR: 8.30; 95%CI:1.47–46.83). Compared with those who tested negative for both HBsAg and anti-HCV, those who tested HBsAg-positive had a significantly higher risk for ICC (HR: 8.56; 95%CI: 1.33–55.20). Our results suggest that HBV infection and liver inflammation are independently associated with ICC development. These findings need to be verified by further large cohort studies. PMID:20002305

  16. Intra-arterial embolotherapy for intrahepatic cholangiocarcinoma: update and future prospects

    PubMed Central

    Savic, Lynn Jeanette; Chapiro, Julius

    2017-01-01

    Intrahepatic cholangiocarcinoma (ICC) is a rare disease and carries a poor prognosis with surgery remaining the only curative treatment option. However, due to the late presentation of symptoms and close proximity of the tumors to central hepatic structures, only about 30% of patients are classified eligible to resection. As for palliative approaches, ICC constitutes a possible indication for loco-regional therapies (LRT). As such, intra-arterial therapies (IAT) are reported to be feasible, safe and effective in inducing tumor response in unresectable ICC. The paradigm of IAT is premised on the selective delivery of embolic, chemotherapeutic agents to the tumor via its feeding arteries, thus allowing dose escalation within the carcinoma and reduction of systemic toxicity. Conventional transcatheter arterial chemoembolization (cTACE) so far remains the most commonly used IAT modality. However, drug-eluting beads (DEB)-TACE was initiated with the idea of more selective targeting of the tumor owing to the combined embolizing as well as drug-eluting properties of the microspheres used in this setting. Moreover, radioembolization is performed by intra-arterial administration of very small spheres containing β-emitting yttrium-90 (Y90-RE) to the site of the tumor. Clinical evidence exists in support of survival benefits for IAT in the palliative treatment of ICC compared to surgery and systemic chemotherapy. As for combination regimens, cTACE, DEB-TACE and Y90-RE are reported to achieve conversion of patients to surgery in a sequential treatment planning and simultaneous IAT combinations may provide a therapeutic option for treatment escalation. Regarding the current status of literature, controlled randomized prospective trials to compare different IAT techniques and combination therapies as well as treatment recommendations for different IAT modalities are needed. PMID:28261591

  17. Chemoembolization (TACE) of Unresectable Intrahepatic Cholangiocarcinoma with Slow-Release Doxorubicin-Eluting Beads: Preliminary Results

    SciTech Connect

    Aliberti, Camillo; Benea, Giorgio Tilli, Massimo; Fiorentini, Giammaria

    2008-09-15

    The purpose of this study was to evaluate the safety and efficacy of TACE with microspheres preloaded with doxorubicin in unresectable intrahepatic cholangiocarcinoma (UCH). Twenty patients with UCH were observed; 9 refused, preferring other palliative care or chemotherapy, and 11 agreed to be treated with one or more cycles of DC beads loaded with doxorubicin (100-150 mg) in a TACE procedure between February 2006 and September 2007. A total of 29 individual TACE procedures were performed. Follow-up imaging was performed on all patients before, immediately after, and 4 weeks after each TACE procedure to evaluate the response and need for further treatment. Each patient received i.v hydration, antibiotics, and medications against nausea and pain before TACE. Survival rate was calculated using Kaplan-Meier survival curve. A response rate of 100% followed RECIST criteria was observed. Eight of eleven patients are alive, with a median survival of 13 months. TACE was well tolerated by all patients. One patient developed hepatic abscess requiring antibiotic therapy. No evidence of marrow toxicity has been reported. Only one of nine patients treated with chemotherapy or palliative care is alive (with a median survival of 7 months in this group of patients). In conclusion, we suggest that doxorubicin-eluting beads TACE is a feasible and effective treatment in patients with UCH. Survival seems to be clearly prolonged in the treated group with respect to the palliative group. We consider that doxorubicin-eluting beads TACE of 100-150 mg may be an appropriate palliative therapy for these patients. Further studies are warranted to confirm these interesting preliminary data.

  18. CUL4A overexpression as an independent adverse prognosticator in intrahepatic cholangiocarcinoma.

    PubMed

    Huang, Gong -Kai; Liu, Ting-Ting; Weng, Shao-Wen; You, Huey-Ling; Wei, Yu-Ching; Chen, Chang-Han; Eng, Hock-Liew; Huang, Wan-Ting

    2017-06-02

    CUL4A has been known for its oncogenic properties in various human cancers. However, its role in intrahepatic cholangiocarcinoma (iCCA) has not been explored. We retrospectively investigated 105 iCCA cases from a single medical institution. Tissue microarrays were used for immunohistochemical analysis of CUL4A expression. CUL4A expression vectors were introduced in cell lines. Cell migration and invasion assays were used to compare the mobility potential of iCCA cells under basal conditions and after manipulation. Then we evaluated the effects of CUL4A on the cell growth by proliferation assay, and further checked the susceptibility to cisplatin in iCCA cells with or without CUL4A overexpression. CUL4A overexpression was detected in 34 cases (32.4%). Patients with CUL4A-overexpressing tumors exhibited shortened disease-free survival (mean, 27.7 versus 90.4 months; P = 0.011). In the multivariate analysis model, CUL4A overexpression was shown to be an independent unfavorable predictor for disease-free survival (P = 0.045). Moreover, stably transfected CUL4A-overexpressing iCCA cell lines displayed an increased mobility potential and enhanced cell growth without impact on susceptibility to cisplatin. Our data demonstrate that overexpression of CUL4A plays an oncogenic role in iCCA and adversely affects disease-free survival. Thus, it may prove to be a powerful prognostic factor and a potential therapeutic target.

  19. Actual over 10-year survival after liver resection for patients with intrahepatic cholangiocarcinoma.

    PubMed

    Si, Anfeng; Li, Jun; Xiang, Hongjun; Zhang, Shichao; Bai, Shilei; Yang, Pinghua; Zhang, Xiaofeng; Xia, Yong; Wang, Kui; Yan, Zhenlin; Lau, Wan Yee; Shi, Lehua; Shen, Feng

    2017-07-04

    Partial hepatectomy is a potentially curative therapy for intrahepatic cholangiocarcinoma (ICC). Unfortunately, the overall surgical prognosis remains dismal and the actual 10-year survival has not been reported. This study aimed to document 10-year actual survival rates, identify the prognostic factors associated with 10-year survival rate, and analyze the characteristics of patients who survived ≥ 10 years. Among 251 patients who underwent curative liver resection for ICC between 2003 and 2006 at the Eastern Hepatobiliary Surgery Hospital, 21 patients (8.4%) survived ≥ 10 years. The 5-, 7-, and 10-year overall survival rates were 32.3%, 22.3% and 8.4%, respectively. The 10-year cumulative incidence of ICC-related death and recurrence were 80.9% and 85.7%, respectively. Multivariate analysis based on competing risk survival analysis identified that tumor > 5 cm was independently associated with ICC-related death and recurrence (hazard ratios: 1.369 and 1.445, respectively), in addition to carcinoembryonic antigen (CEA) >10 U/mL, carbohydrate antigen 19-9 (CA19-9) >39 U/mL, multiple nodules, vascular invasion, nodal metastasis and local extrahepatic invasion. Patients who survived ≥ 10 years had a longer time to first recurrence, lower levels of CEA, CA19-9 and alkaline phosphatase, less perioperative blood loss, solitary tumor, smaller tumor size, and absence of nodal metastasis or local extrahepatic invasion. In conclusion, a 10-year survival after liver resection for ICC is possible and can be expected in approximately 8.4% of patients.

  20. Transarterial Hepatic Yttrium-90 Radioembolization in Patients with Unresectable Intrahepatic Cholangiocarcinoma: Factors Associated with Prolonged Survival

    SciTech Connect

    Hoffmann, Ralf-T. Paprottka, Philipp M.; Schoen, Agnes; Bamberg, Fabian; Haug, Alexander; Duerr, Eva-Maria; Rauch, Barbara; Trumm, Christoph T.; Jakobs, Tobias F.; Helmberger, Thomas K.; Reiser, Maximilian F.; Kolligs, Frank T.

    2012-02-15

    Introduction: In unresectable intrahepatic cholangiocarcinoma (ICC), systemic chemotherapy often is viewed as the only option, although efficacy is limited. Radioembolization (RE) using yttrium-90 ({sup 90}Y) microspheres is an accepted therapy for patients with hepatocellular-carcinoma or metastatic liver tumors. However, there are limited data on the value of RE in patients with ICC and few data on factors influencing prognosis. The purpose of our retrospective analysis was to establish which factors influenced time-to-progression (TTP) and overall survival (OS). Methods: Patients with unresectable ICC were treated with {sup 90}Y resin-microspheres and assessed at 3-monthly intervals. Radiologic response was evaluated by using Response Criteria in Solid Tumors (RECIST). Baseline characteristics, biochemical/clinical toxicities, and response were examined for impact on TTP and OS. Results: Thirty-four treatments were administered to 33 patients without major complications. By RECIST, 12 patients had a partial response, 17 had stable disease, and 5 had progressive disease after 3 months. The median OS was 22 months posttreatment and 43.7 months postdiagnosis. Median TTP was 9.8 months. Survival and TTP were significantly prolonged in patients with ECOG 0 (vs. ECOG 1 or 2; median OS: 29.4, 10, and 5.1 months; TTP: 17.5, 6.9, and 2.4 months), tumor burden {<=}25% (OS: 26.7 vs. 6 months; TTP: 17.5 vs. 2.3 months), or tumor response (PR or SD vs. PD; OS: 35.5, 17.7 vs. 5.7 months; TTP: 31.9, 9.8 vs. 2.5 months), respectively (P < 0.001). Conclusions: Radioembolization is an effective and safe option for patients with unresectable ICC. Predictors for prolonged survival are performance status, tumor burden, and RECIST response.

  1. Knockdown of Sall4 inhibits intrahepatic cholangiocarcinoma cell migration and invasion in ICC-9810 cells

    PubMed Central

    Zhu, Lei; Huang, Feizhou; Deng, Gang; Nie, Wanpin; Huang, Wei; Xu, Hongbo; Zheng, Shaopeng; Yi, Zhongjie; Wan, Tao

    2016-01-01

    In spite of improvements in surgical technology, the resectability and curability of intrahepatic cholangiocarcinoma (ICC) are still low. Our previous study showed that the strong Sal-like protein 4 (Sall4)-positive cases had shorter overall survival compared to Sall4-negative cases, indicating an oncogenic role of Sall4 in ICC. In this study, we aimed to explore the precise mechanism of Sall4 on ICC cell invasion and metastasis. We evaluated the expression of Sall4, PTEN, and Bmi-1 in 28 cases of adjacent tissues and 175 cases of ICC tissues by using immunohistochemical staining. We found that the expression of Sall4 and Bmi-1 was significantly increased in ICC tissues compared with the adjacent tissues, while PTEN expression was reduced in ICC tissues compared with the adjacent tissues, and there was a reverse relationship between Sall4 and PTEN in ICC, whereas there was a positive correlation in Sall4 and Bmi-1 expression in ICC. In addition, overall survival analysis showed that ICC patients with low PTEN exhibited a worse prognosis than ICC patients with high PTEN, and lower Bmi-1 expression showed a better prognosis than ICC patients with high Bmi-1. By a battery of experiments in vitro, we demonstrated that Sall4 promotes ICC cell proliferation, and progression of ICC might be through PTEN/PI3K/Akt and Bmi-1/Wnt/β-catenin signaling and enhancing epithelial–mesenchymal transition process. Thus, Sall4 may be a potential target for the treatment of ICC metastasis. PMID:27601921

  2. Intrahepatic peripheral cholangiocarcinoma (IPCC): comparison between perfusion ultrasound and CT imaging.

    PubMed

    D'Onofrio, M; Vecchiato, F; Cantisani, V; Barbi, E; Passamonti, M; Ricci, P; Malagò, R; Faccioli, N; Zamboni, G; Pozzi Mucelli, R

    2008-02-01

    This study was done to compare the perfusion patterns of intrahepatic peripheral cholangiocarcinoma (IPCC) on contrast-enhanced ultrasound (CEUS) and dynamic computed tomography (CT). We retrospectively reviewed 23 histologically proven cases of IPCC. All lesions were studied by CEUS with sulfur hexafluoride-filled microbubbles coated with a phospholipid capsule, and by dynamic CT. Contrast-enhancement patterns were evaluated in the arterial phase (CEUS 10-20 s after the injection; CT 25-30 s after the injection) and in the delayed phase (CEUS 120 s after the injection; CT>2-3 min after the injection). Lesions were single in 18/23 cases (78%), single with nearby satellite lesions in 1/23 (4%) cases and multifocal with distant secondary lesions in 4/23 (17%) cases. Lesion diameter was 2-5 cm in 7/23 cases (30%), 5-7 cm in 13/23 cases (57%) and >7 cm in 3/23 (13%) cases. On CEUS, lesions were hypervascular in 16/23 cases (70%). On delayed-phase CEUS, 22/23 lesions (96%) were markedly hypoechoic. CT showed that the lesions were hypovascular in the arterial phase in 15/23 cases (66%) and hypervascular in 7/23 (30%) cases; one lesion (1/23; 4%) was isovascular. On delayed-phase CT, lesions were hyperdense in 17/23 cases (74%), hypodense in 5/23 (22%) cases and isodense in 1/23 (43%) cases. Enhancement discrepancy between delayed-phase CEUS (hypoechogenicity) and CT (hyperdensity) is common semiological findings in the study of IPCC.

  3. Mutation inactivation of Nijmegen breakage syndrome gene (NBS1) in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

    PubMed

    Wang, Yan; Hong, Yu; Li, Man; Long, Jiang; Zhao, Yan-Ping; Zhang, Jun-Xia; Li, Qian; You, Hong; Tong, Wei-Min; Jia, Ji-Dong; Huang, Jian

    2013-01-01

    Nijmegen breakage syndrome (NBS) with NBS1 germ-line mutation is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition. The NBS1 gene codes for a protein, Nbs1(p95/Nibrin), involved in the processing/repair of DNA double-strand breaks. Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. Recent studies have shown that heterozygous NBS1 mice exhibited a higher incidence of HCC than did wild-type mice. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of human primary liver cancer, including HBV-associated HCC and intrahepatic cholangiocarcinoma (ICC). Eight missense NBS1 mutations were identified in six of 64 (9.4%) HCCs and two of 18 (11.1%) ICCs, whereas only one synonymous mutation was found in 89 control cases of cirrhosis and chronic hepatitis B. Analysis of the functional consequences of the identified NBS1 mutations in Mre11-binding domain showed loss of nuclear localization of Nbs1 partner Mre11, one of the hallmarks for Nbs1 deficiency, in one HCC and two ICCs with NBS1 mutations. Moreover, seven of the eight tumors with NBS1 mutations had at least one genetic alteration in the TP53 pathway, including TP53 mutation, MDM2 amplification, p14ARF homozygous deletion and promoter methylation, implying a synergistic effect of Nbs1 disruption and p53 inactivation. Our findings provide novel insight on the molecular pathogenesis of primary liver cancer characterized by mutation inactivation of NBS1, a DNA repair associated gene.

  4. Effect of transforming growth factor-β1 on human intrahepatic cholangiocarcinoma cell growth

    PubMed Central

    Shimizu, Tetsuya; Yokomuro, Shigeki; Mizuguchi, Yoshiaki; Kawahigashi, Yutaka; Arima, Yasuo; Taniai, Nobuhiko; Mamada, Yasuhiro; Yoshida, Hiroshi; Akimaru, Koho; Tajiri, Takashi

    2006-01-01

    AIM: To elucidate the biological effects of transforming growth factor-β1 (TGF-β1) on intrahepatic cholan-giocarcinoma (ICC). METHODS: We investigated the effects of TGF-β1 on human ICC cell lines (HuCCT1, MEC, and HuH-28) by monitoring the influence of TGF-β1 on tumor growth and interleukin-6 (IL-6) expression in ICC cells. RESULTS: All three human ICC cell lines produced TGF-β1 and demonstrated accelerated growth in the presence of TGF-β1 with no apoptotic effect. Studies on HuCCT1 revealed a TGF-β1-induced stimulation of the expression of TGF-β1, as well as a decrease in TGF-β1 mRNA expression induced by neutralizing anti-TGF-β1 antibody. These results indicate that TGF-β1 stimulates the production and function of TGF-β1 in an autocrine fashion. Further, IL-6 secretion was observed in all three cell lines and exhibited an inhibitory response to neutralizing anti-TGF-β1 antibody. Experiments using HuCCT1 revealed a TGF-β1-induced acceleration of IL-6 protein expression and mRNA levels. These findings demonstrate a functional interaction between TGF-β1 and IL-6. All three cell lines proliferated in the presence of IL-6. In contrast, TGF-β1 induced no growth effect in HuCCT1 in the presence of small interfering RNA against a specific cell surface receptor of IL-6 and signal transducer and activator of transcription-3. CONCLUSION: ICC cells produce TGF-β1 and confer a TGF-β1-induced growth effect in an autocrine fashion. TGF-β1 activates IL-6 production, and the functional interaction between TGF-β1 and IL-6 contributes to ICC cell growth by TGF-β1. PMID:17072955

  5. Impact Factors for Microinvasion in Intrahepatic Cholangiocarcinoma: A Possible System for Defining Clinical Target Volume

    SciTech Connect

    Bi Aihong; Zeng Zhaochong; Ji Yuan; Zeng Haiying; Xu Chen; Tang Zhaoyou; Fan Jia; Zhou Jian; Zeng Mengsu; Tan Yunshan

    2010-12-01

    Purpose: To quantify microscopic invasion of intrahepatic cholangiocarcinoma (IHC) into nontumor tissue and define the gross tumor volume (GTV)-to-clinical target volume (CTV) expansion necessary for radiotherapy. Methods and Materials: One-hundred IHC patients undergoing radical resection from January 2004 to July 2008 were enrolled in this study. Pathologic and clinical data including maximum tumor diameter, tumor boundary type, TNM stage, histologic grade, tumor markers, and liver enzymes were reviewed. The distance of microinvasion from the tumor boundary was measured by microscopy. The contraction coefficient for tumor measurements in radiographs and slide-mounted tissue was calculated. SPSS15.0 was used for statistical analysis. Results: Sixty-five patients (65%) exhibited tumor microinvasions. Microinvasions ranged from 0.4-8 mm, with 96% of patients having a microinvasion distance {<=}6 mm measured on slide. The radiograph-to-slide contraction coefficient was 82.1%. The degree of microinvasion was correlated with tumor boundary type, TNM stage, histologic grade, and serum levels of carbohydrate antigen 19-9, alanine aminotransferase, aspartate aminotransferase, {gamma}-glutamyltransferase and alkaline phosphatase. To define CTV accurately, we devised a scoring system based on combination of these factors. According to this system, a score {<=}1.5 is associated with 96.1% sensitivity in detecting patients with a microextension {<=}4.9 mm in radiographs, whereas a score {>=}2 has a 95.1% sensitivity in detecting microextension {<=}7.9 mm measured on radiograph. Conclusions: Patients with a score {<=}1.5 and {>=}2 require a radiographic GTV-to-CTV expansions of 4.9 and 7.9 mm, respectively, to encompass >95% of microinvasions.

  6. The associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma

    PubMed Central

    Romani, Antonello A; Soliani, Paolo; Desenzani, Silvia; Borghetti, Angelo F; Crafa, Pellegrino

    2006-01-01

    Background Maspin, a member of the serpin family, is a suppressor of tumor growth, an inhibitor of angiogenesis and an inducer of apoptosis. Maspin induces apoptosis by increasing Bax, a member of the Bcl-2 family of apoptosis-regulating proteins. In this exploratory study, we investigated the associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma (IHCCA). Methods Twenty-two paraffin-embedded samples were analyzed by immunohistochemical methods using Maspin, Bax and CD34 antibodies. Maspin was scored semiquantitatively (HSCORE). Apoptosis was assessed using an antibody against cleaved caspase-3. Results The strong relationship observed between the expression of Maspin and Bax, indicates that Bax is likely to be the key effector of Maspin-mediated induction of apoptosis as indicated by the activation of cleaved caspase-3. We categorized Maspin HSCORE by calculating the optimal cutpoint. A Maspin HSCORE above the cutpoint was inversely related with tumor dimension, depth of tumor and vascular invasion. Uni/multivariate analysis suggests that a Maspin HSCORE below the cutpoint significantly worsens the patients' prognosis. Tumors with Maspin HSCORE below the cutpoint had a shorter survival (11+/-5 months) than did patients with Maspin HSCORE above the cutpoint (27+/-4 months), whereas Kaplan-Meier analysis and logrank test showed no significant difference in overall survival between the patients. Conclusion The associated expression of Maspin and Bax might delay tumor progression in IHCCA. Maspin above the cutpoint might counteract tumor development by increasing cell apoptosis, and by decreasing tumor mass and cell invasion. The combined expression of Maspin and Bax appears to influence the susceptibility of tumor cholangiocytes to apoptosis and thus may be involved in delaying IHCCA progression. PMID:17067385

  7. Yttrium-90 Radioembolization for Unresectable Standard-chemorefractory Intrahepatic Cholangiocarcinoma: Survival, Efficacy, and Safety Study

    SciTech Connect

    Rafi, Shoaib; Piduru, Sarat M.; El-Rayes, Bassel; Kauh, John S.; Kooby, David A.; Sarmiento, Juan M.; Kim, Hyun S.

    2013-04-15

    To assess the overall survival, efficacy, and safety of radioembolization with yttrium-90 (Y90) for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma (ICC). Patients with unresectable standard-chemorefractory ICC treated with Y90 were studied. Survival was calculated from the date of first Y90 procedure. Tumor response was assessed with the Response Evaluation Criteria in Solid Tumors criteria on follow-up computed tomography or magnetic resonance imaging scans. National Cancer Institute Common Terminology Criteria (NCI CTCAE), version 3, were used for complications. Statistical analysis was performed by the Kaplan-Meier estimator by the log rank test. Nineteen patients underwent a total of 24 resin-based Y90 treatments. Median survival from the time of diagnosis and first Y90 procedure was 752 {+-} 193 [95 % confidence interval (CI) 374-1130] and 345 {+-} 128 (95 % CI 95-595) days, respectively. Median survival with Eastern Cooperative Oncology Group (ECOG) performance status 1 (n = 15) and ECOG performance status 2 (n = 4) was 450 {+-} 190 (95 % CI 78-822) and 345 {+-} 227 (95 % CI 0-790) days, respectively (p = .214). Patients with extrahepatic metastasis (n = 11) had a median survival of 404 {+-} 309 (95 % CI 0-1010) days versus 345 {+-} 117 (95 % CI 115-575) days for patients without metastasis (n = 8) (p = .491). No mortality was reported within 30 days from first Y90 radioembolization. One patient developed grade 3 thrombocytopenia as assessed by NCI CTCAE. Fatigue and transient abdominal pain were observed in 4 (21 %) and 6 (32 %) patients, respectively. Y90 radioembolization is effective for unresectable standard-chemorefractory ICC.

  8. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment.

    PubMed

    de Jong, Mechteld C; Nathan, Hari; Sotiropoulos, Georgios C; Paul, Andreas; Alexandrescu, Sorin; Marques, Hugo; Pulitano, Carlo; Barroso, Eduardo; Clary, Bryan M; Aldrighetti, Luca; Ferrone, Cristina R; Zhu, Andrew X; Bauer, Todd W; Walters, Dustin M; Gamblin, T Clark; Nguyen, Kevin T; Turley, Ryan; Popescu, Irinel; Hubert, Catherine; Meyer, Stephanie; Schulick, Richard D; Choti, Michael A; Gigot, Jean-Francois; Mentha, Gilles; Pawlik, Timothy M

    2011-08-10

    To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival. From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34). Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.

  9. NSAID Use and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: The Liver Cancer Pooling Project.

    PubMed

    Petrick, Jessica L; Sahasrabuddhe, Vikrant V; Chan, Andrew T; Alavanja, Michael C; Beane-Freeman, Laura E; Buring, Julie E; Chen, Jie; Chong, Dawn Q; Freedman, Neal D; Fuchs, Charles S; Gaziano, John Michael; Giovannucci, Edward; Graubard, Barry I; Hollenbeck, Albert R; Hou, Lifang; Jacobs, Eric J; King, Lindsay Y; Koshiol, Jill; Lee, I-Min; Linet, Martha S; Palmer, Julie R; Purdue, Mark P; Rosenberg, Lynn; Schairer, Catherine; Sesso, Howard D; Sigurdson, Alice J; Wactawski-Wende, Jean; Zeleniuch-Jacquotte, Anne; Campbell, Peter T; McGlynn, Katherine A

    2015-12-01

    Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC = 679, ICC = 225) from 10 U.S.-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted HRs and 95% confidence intervals (CI). Current aspirin use, versus nonuse, was inversely associated with HCC (HR, 0.68; 95% CI, 0.57-0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5- and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR, 0.64; 95% CI, 0.42-0.98) but not women (HR, 1.34; 95% CI, 0.89-2.01; P(interaction) = 0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC.

  10. NSAID use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project

    PubMed Central

    Petrick, Jessica L.; Sahasrabuddhe, Vikrant V.; Chan, Andrew T.; Alavanja, Michael C.; Beane-Freeman, Laura E.; Buring, Julie E.; Chen, Jie; Chong, Dawn Q.; Freedman, Neal D.; Fuchs, Charles S.; Gaziano, John Michael; Giovannucci, Edward; Graubard, Barry I.; Hollenbeck, Albert R.; Hou, Lifang; Jacobs, Eric J.; King, Lindsay Y.; Koshiol, Jill; Lee, I-Min; Linet, Martha S.; Palmer, Julie R.; Purdue, Mark P.; Rosenberg, Lynn; Schairer, Catherine; Sesso, Howard D.; Sigurdson, Alice J.; Wactawski-Wende, Jean; Zeleniuch-Jacquotte, Anne; Campbell, Peter T.; McGlynn, Katherine A.

    2015-01-01

    Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC=679, ICC=225) from ten US-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Current aspirin use, versus nonuse, was inversely associated with HCC (HR=0.68, 95% CI=0.57-0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5 and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR=0.64, 95% CI=0.42-0.98) but not women (HR=1.34, 95% CI=0.89-2.01, pinteraction=0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggest the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC. PMID:26391917

  11. Integrative Analysis of Transcriptional Regulatory Network and Copy Number Variation in Intrahepatic Cholangiocarcinoma

    PubMed Central

    Li, Ling; Lian, Baofeng; Li, Chao; Li, Wei; Li, Jing; Zhang, Yuannv; He, Xianghuo; Li, Yixue; Xie, Lu

    2014-01-01

    Background Transcriptional regulatory network (TRN) is used to study conditional regulatory relationships between transcriptional factors and genes. However few studies have tried to integrate genomic variation information such as copy number variation (CNV) with TRN to find causal disturbances in a network. Intrahepatic cholangiocarcinoma (ICC) is the second most common hepatic carcinoma with high malignancy and poor prognosis. Research about ICC is relatively limited comparing to hepatocellular carcinoma, and there are no approved gene therapeutic targets yet. Method We first constructed TRN of ICC (ICC-TRN) using forward-and-reverse combined engineering method, and then integrated copy number variation information with ICC-TRN to select CNV-related modules and constructed CNV-ICC-TRN. We also integrated CNV-ICC-TRN with KEGG signaling pathways to investigate how CNV genes disturb signaling pathways. At last, unsupervised clustering method was applied to classify samples into distinct classes. Result We obtained CNV-ICC-TRN containing 33 modules which were enriched in ICC-related signaling pathways. Integrated analysis of the regulatory network and signaling pathways illustrated that CNV might interrupt signaling through locating on either genomic sites of nodes or regulators of nodes in a signaling pathway. In the end, expression profiles of nodes in CNV-ICC-TRN were used to cluster the ICC patients into two robust groups with distinct biological function features. Conclusion Our work represents a primary effort to construct TRN in ICC, also a primary effort to try to identify key transcriptional modules based on their involvement of genetic variations shown by gene copy number variations (CNV). This kind of approach may bring the traditional studies of TRN based only on expression data one step further to genetic disturbance. Such kind of approach can easily be extended to other disease samples with appropriate data. PMID:24897108

  12. Prognostic significance of the combined expression of neutral endopeptidase and dipeptidyl peptidase IV in intrahepatic cholangiocarcinoma patients after surgery resection

    PubMed Central

    Zhu, Jianyong; Guo, XiaoDong; Qiu, Baoan; Li, Zhiyan; Xia, Nianxin; Yang, Yingxiang; Liu, Peng

    2014-01-01

    Aim The aim of this study was to investigate the relationship between the expression of neutral endopeptidase (NEP) and dipeptidyl peptidase IV (DPP IV) proteins, and the clinical significance of the two proteins in patients with intrahepatic cholangiocarcinomas (IHCC). Methods Expression patterns and subcellular localizations of NEP and DPP IV proteins in 186 primary IHCC and 60 noncancerous liver tissue specimens were detected by immunohistochemistry. Results Both the expression of NEP and DPP IV proteins in IHCC tissues were significantly higher than those in noncancerous liver tissues (both P<0.001). Of 186 patients with IHCC, 128 (68.82%) highly expressed both NEP and DPP IV proteins. In addition, the coexpression of NEP and DPP IV proteins was significantly associated with advanced tumor stage (P=0.009), positive lymph node metastasis (P=0.016) and distant metastasis (P=0.013), and the presence of recurrence (P=0.027). Moreover, Kaplan–Meier analysis showed that IHCC patients with high NEP expression, high DPP IV expression, and combined overexpression of NEP and DPP IV proteins all had poorer overall survival and early recurrence after surgery. Furthermore, Cox analysis suggested that NEP expression, DPP IV expression, and combined expression of NEP and DPP IV proteins were all independent prognostic markers for overall survival and recurrence-free survival in patients with IHCC. Conclusion Our data suggest, for the first time, that both the expression of NEP and DPP IV proteins may be upregulated in human IHCC tissues and the combined expression of NEP and DPP IV proteins may play important roles in progression and prognosis of patients with IHCC. PMID:24570591

  13. Unresectable intrahepatic cholangiocarcinoma: Systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone.

    PubMed

    Konstantinidis, Ioannis T; Groot Koerkamp, Bas; Do, Richard K G; Gönen, Mithat; Fong, Yuman; Allen, Peter J; D'Angelica, Michael I; Kingham, T Peter; DeMatteo, Ronald P; Klimstra, David S; Kemeny, Nancy E; Jarnagin, William R

    2016-03-01

    Intrahepatic cholangiocarcinoma (ICC) is associated with poor survival. This study compared the outcomes of patients with unresectable ICC treated with hepatic arterial infusion (HAI) plus systemic chemotherapy (SYS) with the outcomes of patients treated with SYS alone. Consecutive patients with ICC were retrospectively reviewed. Clinicopathologic data were reviewed. Survival rates were compared by Kaplan-Meier analysis and log-rank testing. Between January 2000 and August 2012, 525 patients with ICC were evaluated at Memorial Sloan Kettering Cancer Center, and 236 patients with unresectable tumors (locally advanced or metastatic) were analyzed. Disease was confined to the liver in 104 patients, who underwent treatment with combined HAI and SYS (n = 78 or 75%) or SYS alone (n = 26 or 25%). The response rate in the combined group was better than the rate in the group receiving SYS alone, although this did not reach statistical significance (59% vs 39%, P = .11). Overall survival for the combined group was longer than overall survival for the patients who received SYS alone (30.8 vs 18.4 months, P < .001), and this difference was maintained when patients with portal lymph node disease were included in the survival analysis (29.6 months with HAI and SYS [n = 93] vs 15.9 months with SYS [n = 74], P < .001). Eight patients who initially presented with unresectable tumors responded enough to undergo complete resection and had a median overall survival of 37 months (range, 10.4-92.3 months). In patients with unresectable ICC confined to the liver or with limited regional nodal disease, a combination of SYS and HAI chemotherapy is associated with greater survival than SYS alone. Cancer 2016;122:758-765. © 2015 American Cancer Society. © 2015 American Cancer Society.

  14. Modulatory role of garlicin in migration and invasion of intrahepatic cholangiocarcinoma via PI3K/AKT pathway.

    PubMed

    Xie, Kun; Nian, Jianze; Zhu, Xingyang; Geng, Xiaoping; Liu, Fubao

    2015-01-01

    Increasing evidences have indicated the role of garlicin in inhibiting the progression of various tumors including glioma, pulmonary carcinoma and pancreatic carcinoma, via mediating cell apoptosis or cell cycle. The regulatory effect and related molecular mechanism of garlicin in intrahepatic cholangiocarcinoma, however, remained unknown. This study thus aimed to investigate this scientific issue. HCCC-9810 cell line was treated with serially diluted garlicin, followed by cell proliferation assay using MTT approach. Transwell migration and invasion assays were further employed the regulatory effect of garlicin. The expression level of p-AKT and AKT proteins in tumor cells was quantified by Western blot. The growth of tumor cells was significantly inhibited by high concentration of garlicin (> 1.5 μM). Lower concentration of garlicin showed dose-dependent inhibition of tumor cell invasion and migration. After using specific agonist IGF-1 (50 ng/mL) of PI3K/AKT signaling pathway, such facilitating effects of garlicin were depressed (P < 0.05). Western blotting showed significantly decreased phosphorylation level of AKT after treated with gradient concentrations of garlicin, while leaving the total AKT protein level unchanged. Garlicin may inhibit the invasion and migration of intrahepatic cholangiocarcinoma cells via inhibiting PI3K/AKT signaling pathway.

  15. Modulatory role of garlicin in migration and invasion of intrahepatic cholangiocarcinoma via PI3K/AKT pathway

    PubMed Central

    Xie, Kun; Nian, Jianze; Zhu, Xingyang; Geng, Xiaoping; Liu, Fubao

    2015-01-01

    Increasing evidences have indicated the role of garlicin in inhibiting the progression of various tumors including glioma, pulmonary carcinoma and pancreatic carcinoma, via mediating cell apoptosis or cell cycle. The regulatory effect and related molecular mechanism of garlicin in intrahepatic cholangiocarcinoma, however, remained unknown. This study thus aimed to investigate this scientific issue. HCCC-9810 cell line was treated with serially diluted garlicin, followed by cell proliferation assay using MTT approach. Transwell migration and invasion assays were further employed the regulatory effect of garlicin. The expression level of p-AKT and AKT proteins in tumor cells was quantified by Western blot. The growth of tumor cells was significantly inhibited by high concentration of garlicin (> 1.5 μM). Lower concentration of garlicin showed dose-dependent inhibition of tumor cell invasion and migration. After using specific agonist IGF-1 (50 ng/mL) of PI3K/AKT signaling pathway, such facilitating effects of garlicin were depressed (P < 0.05). Western blotting showed significantly decreased phosphorylation level of AKT after treated with gradient concentrations of garlicin, while leaving the total AKT protein level unchanged. Garlicin may inhibit the invasion and migration of intrahepatic cholangiocarcinoma cells via inhibiting PI3K/AKT signaling pathway. PMID:26823715

  16. Neddylation pathway is up-regulated in human intrahepatic cholangiocarcinoma and serves as a potential therapeutic target.

    PubMed

    Gao, Qiang; Yu, Guang-Yang; Shi, Jie-Yi; Li, Li-Hui; Zhang, Wen-Juan; Wang, Zhi-Chao; Yang, Liu-Xiao; Duan, Meng; Zhao, Hu; Wang, Xiao-Ying; Zhou, Jian; Qiu, Shuang-Jian; Jeong, Lak Shin; Jia, Li-Jun; Fan, Jia

    2014-09-15

    Therapeutic intervention in neddylation pathway is an emerging area for cancer treatment. Herein, we evaluated the clinical relevance and therapeutic potential of targeting this pathway in intrahepatic cholangiocarcinoma (ICC). Immunohistochemistry of neddylation pathway components in a cohort of 322 cases showed that E1 (NAE1 and UBA3) and E2 (UBC12) enzymes, as well as global NEDD8 conjugation, were upregulated in over 2/3 of human ICC. Notably, NAE1 was identified as an independent prognosticator for postoperative recurrence (P=0.009) and a combination of NEDD8 and NAE1 provided a better power for predicting patient clinical outcomes. In vitro treatment with MLN4924, a small-molecule NEDD8-activating enzyme inhibitor, led to a dose-dependent decrease of viability in both established and primary cholangiocarcinoma cell lines. Additionally, MLN4924 exhibited at least additive effect when combined with cisplatin. By blocking cullins neddylation, MLN4924 inactivated Cullin-Ring ligase (CRL) and caused the accumulation of CRL substrates that triggered cell cycle arrest, senescence or apoptosis. Meanwhile, MLN4924 was well-tolerated and significantly inhibited tumor growth in xenograft model of cholangiocarcinoma. Taken together, our findings indicated that upregulated neddylation pathway was involved in ICC progression and interference in this pathway could be a promising target for ICC therapy.

  17. Computed tomography-guided interstitial HDR brachytherapy (CT-HDRBT) of the liver in patients with irresectable intrahepatic cholangiocarcinoma.

    PubMed

    Schnapauff, Dirk; Denecke, Timm; Grieser, Christian; Collettini, Federico; Colletini, Federico; Seehofer, Daniel; Sinn, Marianne; Banzer, Jan; Lopez-Hänninen, Enrique; Hamm, Bernd; Wust, Peter; Gebauer, Bernhard

    2012-06-01

    This study was designed to investigate the clinical outcome of patients with irresectable, intrahepatic cholangiocarcinoma (IHC) treated with computed tomography (CT)-guided HDR-brachytherapy (CT-HDRBT) for local tumor ablation. Fifteen consecutive patients with histologically proven cholangiocarcinoma were selected for this retrospective study. Patients were treated by high-dose-rate internal brachytherapy (HDRBT) using an Iridium-192 source in afterloading technique through CT-guided percutaneous placed catheters. A total of 27 brachytherapy treatments were performed in these patients between 2006 and 2009. Median tumor enclosing target dose was 20 Gy, and mean target volume of the radiated tumors was 131 (±90) ml (range, 10-257 ml). Follow-up consisted of clinical visits and magnetic resonance imaging of the liver every third month. Statistical evaluation included survival analysis using the Kaplan-Meier method. After a median follow-up of 18 (range, 1-27) months after local ablation, 6 of the 15 patients are still alive; 4 of them did not get further chemotherapy and are regarded as disease-free. The reached median local tumor control was 10 months; median local tumor control, including repetitive local ablation, was 11 months. Median survival after local ablation was 14 months and after primary diagnosis 21 months. In view of current clinical data on the clinical outcome of cholangiocarcinoma, locally ablative treatment with CT-HDRBT represents a promising and safe technique for patients who are not eligible for tumor resection.

  18. Intrahepatic cholestasis of pregnancy: Recent advances.

    PubMed

    Ovadia, Caroline; Williamson, Catherine

    2016-01-01

    Intrahepatic cholestasis of pregnancy, also known as obstetric cholestasis, is a pruritic condition of pregnancy characterized by an underlying elevation in circulating bile acids and liver derangement, and associated with adverse fetal outcomes, such as preterm labor and stillbirth. Limited understanding of the underlying pathophysiology and mechanisms involved in adverse outcomes has previously restricted treatment options and pregnancy management. Recent advances in these research fields provide tantalizing targets to improve the care of pregnant women affected by this condition. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. The expression of HSP27 is associated with poor clinical outcome in intrahepatic cholangiocarcinoma

    PubMed Central

    Romani, Antonello A; Crafa, Pellegrino; Desenzani, Silvia; Graiani, Gallia; Lagrasta, Costanza; Sianesi, Mario; Soliani, Paolo; Borghetti, Angelo F

    2007-01-01

    Background The heat shock proteins (HSPs) 27-kDa (HSP27) and 72-kDa (HSP72), are ubiquitous chaperone molecules inducible in cells exposed to different stress conditions. Increased level of HSPs are reported in several human cancers, and found to be associated with the resistance to some anticancer treatments and poor prognosis. However, there is no study of the relationship between HSPs expression and patient's prognosis in intrahepatic cholangiocarcinoma (IHCCA). In this exploratory retrospective study, we investigated the expressions of HSP27 and HSP72 as potential prognostic factors in IHCCA. Methods Thirty-one paraffin-embedded samples were analyzed by immunohistochemical methods using HSP27 and HSP72 monoclonal antibodies. Proliferation rate was assessed in the same specimens by using monoclonal antibody against phosphorylated histone H3 (pHH3). Fisher's exact test was used to assess the hypothesis of independence between categorical variables in 2 × 2 tables. The ANOVA procedure was used to evaluate the association between ordinal and categorical variables. Estimates of the survival probability were calculated using the Kaplan-Meier method, and the log rank test was employed to test the null hypothesis of equality in overall survival among groups. The hazard ratio associated with HSP27 and HSP72 expression was estimated by Cox hazard-proportional regression. Results The expression of HSP27 was related to mitotic index, tumor greatest dimension, capsular and vascular invasion while the expression of HSP72 was only related to the presence of necrosis and the lymphoid infiltration. Kaplan-Maier analysis suggested that the expression of HSP27 significantly worsened the patients' median overall survival (11 ± 3.18 vs 55 ± 4.1 months, P-value = 0.0003). Moreover HSP27-positive patients exhibited the worst mean survival (7.0 ± 3.2 months) in the absence of concomitant HSP72 expression. Conclusion The expression of HSP27, likely increasing cell proliferation

  20. Radiation Therapy Is Associated With Improved Survival in the Adjuvant and Definitive Treatment of Intrahepatic Cholangiocarcinoma

    SciTech Connect

    Shinohara, Eric T. Mitra, Nandita; Guo Mengye; Metz, James M.

    2008-12-01

    Purpose: Intrahepatic cholangiocarcinomas (IHC) are rare tumors for which large randomized studies regarding the use of radiation are not available. The purpose of this study was to examine the role of adjuvant and definitive radiation therapy in the treatment of IHC in a large group of patients. Methods and Materials: This is a retrospective analysis of 3,839 patients with IHC collected from the Surveillance, Epidemiology, and End Results (SEER) database. The primary endpoint was overall survival (OS). Results: Patients received either surgery alone (25%), radiation therapy alone (10%), surgery and adjuvant radiation therapy (7%) or no treatment (58%). The median age of the patient population was 73 years (range, 22-102 years); 52% of patients were male and 81% were Caucasian. Median OS was 11 (95% confidence interval [CI], 9-13), 6 (95% CI, 5-6), 7 (95% CI, 6-8), and 3 months for surgery and adjuvant radiation therapy, sugery alone, radiation therapy alone, and no treatment, respectively. The OS was significantly different between surgery alone and surgery and adjuvant radiation therapy (p = 0.014) and radiation therapy alone and no treatment (p < 0.0001). Use of surgery and adjuvant radiation therapy conferred the greatest benefit on OS (HR = 0.40; 95% CI, 0.34-0.47), followed by surgery alone (hazard ratio [HR], 0.49; 95% CI, 0.44-0.54) and radiation therapy alone (HR, 0.68; 95% CI, 0.59-0.77) compared with no treatment, on multivariate analysis. Propensity score adjusted hazard ratios (controlling for age, race/ethnicity, stage, and year of diagnosis) were also significant (surgery and adjuvant radiation therapy vs. surgery alone (HR, 0.82; 95% CI, 0.70-0.96); radiation therapy alone vs. no treatment (HR, 0.67; 95% CI, 0.58-0.76)). Conclusions: The study results suggest that adjuvant and definitive radiation treatment prolong survival, although cure rates remain low. Future studies should evaluate the addition of chemotherapy and biologics to the treatment of

  1. A significant cancer burden and high mortality of intrahepatic cholangiocarcinoma in Thailand: a nationwide database study.

    PubMed

    Treeprasertsuk, Sombat; Poovorawan, Kittiyod; Soonthornworasiri, Ngamphol; Chaiteerakij, Roongruedee; Thanapirom, Kessarin; Mairiang, Pisaln; Sawadpanich, Kookwan; Sonsiri, Kanokwan; Mahachai, Varocha; Phaosawasdi, Kamthorn

    2017-01-05

    We aimed to examine the burden of intrahepatic cholangiocarcinoma (ICC) in Thailand and identify the prognostic factors for all-causes of death. We conducted a population-based study of ICC patients admitted during 2009-2013 using the Nationwide Hospital Admission Database, the National Health Security Office (NHSO). There was an average of 1,051,146 patients/year with diagnosis of gastrointestinal diseases (GI). All patients with a diagnosis of ICC (ICD10- C221) were included from a total of 72,479 admissions from 858 hospitals. The surgical resection procedures such as the radical pancreaticoduodenectomy, subtotal and partial hepatectomy were analyzed. Data for all patients were censored 1 year post-study or death, whichever came first. A total of 34,325 patients with ICC during a 5-year study period (on average, 6865 patients/year, with the incidence rate of 14.6 per 100,000 population, per year. The ICC patients had a mean age of 63.8+/-11.6 years and 63% were males. The mean length of hospital stay was 6.4+/-7.3 days with a mean+/-SD cost of hospitalization of $595+/-$1160 USD per admission. There were 659 patients (1.9%) underwent surgical resection. The overall survival of ICC patients with surgery was significantly better than those patients without surgery. Hazard ratio of death for patients without surgery was 2.5 (95% CI of 2.3-2.7). Approximately 14% of the ICC patients died during hospitalization. The median overall survival of all patients after the first admission was 53 +/-0.6 days. From the multivariate analysis, factors related to all-causes of death were: patients' age >60 years (OR = 1.2, 95% CI; 1.1-1.3), length of hospital stay of >7 days (OR = 1.1, 95% CI; 1.02-1.2), male (OR = 1.3, 95% CI; 1.2-1.4), living in the northern part of Thailand (OR = 1.5, 95% CI; 1.3-1.8) and presence of complications during admission (OR = 1.3, 95% CI; 1.1-1.5). The disease burden of patients with ICC in Thailand is significant with the

  2. Delayed-Phase Cone-Beam CT Improves Detectability of Intrahepatic Cholangiocarcinoma During Conventional Transarterial Chemoembolization

    SciTech Connect

    Schernthaner, Ruediger Egbert; Lin, MingDe; Duran, Rafael; Chapiro, Julius; Wang, Zhijun; Geschwind, Jean-François

    2015-08-15

    PurposeTo evaluate the detectability of intrahepatic cholangiocarcinoma (ICC) on dual-phase cone-beam CT (DPCBCT) during conventional transarterial chemoembolization (cTACE) compared to that of digital subtraction angiography (DSA) with respect to pre-procedure contrast-enhanced magnetic resonance imaging (CE-MRI) of the liver.MethodsThis retrospective study included 17 consecutive patients (10 male, mean age 64) with ICC who underwent pre-procedure CE-MRI of the liver, and DSA and DPCBCT (early-arterial phase (EAP) and delayed-arterial phase (DAP)) just before cTACE. The visibility of each ICC lesion was graded by two radiologists on a three-rank scale (complete, partial, and none) on DPCBCT and DSA images, and then compared to pre-procedure CE-MRI.ResultsOf 61 ICC lesions, only 45.9 % were depicted by DSA, whereas EAP- and DAP-CBCT yielded a significantly higher detectability rate of 73.8 % and 93.4 %, respectively (p < 0.01). Out of the 33 lesions missed on DSA, 18 (54.5 %) and 30 (90.9 %) were revealed on EAP- and DAP-CBCT images, respectively. DSA depicted only one lesion that was missed by DPCBCT due to streak artifacts caused by a prosthetic mitral valve. DAP-CBCT identified significantly more lesions than EAP-CBCT (p < 0.01). Conversely, EAP-CBCT did not detect lesions missed by DAP-CBCT. For complete lesion visibility, DAP-CBCT yielded significantly higher detectability (78.7 %) compared to EAP (31.1 %) and DSA (21.3 %) (p < 0.01).ConclusionDPCBCT, and especially the DAP-CBCT, significantly improved the detectability of ICC lesions during cTACE compared to DSA. We recommend the routine use of DAP-CBCT in patients with ICC for per-procedure detectability and treatment planning in the setting of TACE.

  3. Change in total lesion glycolysis and clinical outcome after (90)Y radioembolization in intrahepatic cholangiocarcinoma.

    PubMed

    Filippi, Luca; Pelle, Giuseppe; Cianni, Roberto; Scopinaro, Francesco; Bagni, Oreste

    2015-01-01

    Our aim was to assess the prognostic value of post-treatment decrease in total lesion glycolysis (ΔTLG) assessed by 2-[(18)F]-fluorodeoxyglucose ([(18)F] FDG) PET-CT performed 6weeks after (90)Y radioembolization ((90)Y RE) in patients affected by intrahepatic cholangiocarcinoma (ICC). A total of 18 patients were accepted into our department for (90)Y RE. Before the procedure, all patients underwent [(18)F] FDG PET-CT, and total lesion glycolysis was calculated. Six weeks after (90)Y administration, PET scan was performed, and ΔTLG was determined. Patients underwent follow up by imaging and laboratory at quarterly intervals until death or for at least 24 months from (90)Y RE. Furthermore, subjects were divided in 2 groups (group 1: 6 weeks ΔTLG>50%, group 2: ΔTLG<50%). Kaplan-Meier method was used to achieve time to progression (TTP) and overall survival (OS) curves for each group. TTP and OS curves were compared to demonstrate eventual relevant differences between the 2 groups. Seventeen patients underwent (90)Y RE, and one subject was considered ineligible. According to PET Response Criteria in Solid Tumors, partial response was found in 14 patients (82.4%), stable disease in 3 (17.6%). No patient showed complete metabolic response. The mean OS for all patients was 64.5±5.0 weeks. Subjects with a ΔTLG>50% and ΔTLG<50% had a mean OS of 79.6±3.6 and 43.1±2.0 weeks, respectively (p<0.001). TTP resulted of 28.9±3.8 weeks for the whole cohort. Patients with ΔTLG>50% had a significantly longer TTP (mean 36.9±3.6 weeks) than those with ΔTLG<50% (mean 13.7±1.7 weeks, p=0.001). Our results indicate that (90)Y RE can be an effective and safe therapy for ICC. ΔTLG calculated on post-treatment [(18)F] FDG PET-CT agrees with patients' final outcome. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Intrahepatic clear cell cholangiocarcinoma - An uncommon histologic subtype: case report and literature review.

    PubMed

    Fernandes, Samuel Raimundo; Baldaia, Cilénia; Pinto Marques, Hugo; Tortosa, Francisco; Ramalho, Fernando

    2017-02-03

    Clear-cell cholangiocarcinoma is a very uncommon variant of cholangiocarcinoma with a largely unknown natural history and prognosis. We report a case of a 51-year-old previously healthy woman presenting with a large liver nodule found on routine imaging. Needle biopsy of the lesion suggested a non-hepatocellular carcinoma. After extensive workup for other primary neoplasms, the patient underwent a partial hepatectomy. Histopathology was compatible with a moderately differentiated clear-cell cholangiocarcinoma. There was no evidence of liver disease in the remaining tissue. The patient underwent chemotherapy and remains in clinical remission after two years.

  5. Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma

    PubMed Central

    Yeh, Chun-Nan; Hsieh, Feng-Jen; Chiang, Kun-Chun; Chen, Jen-Shi; Yeh, Ta-Sen; Jan, Yi-Yin; Chen, Miin-Fu

    2015-01-01

    Background Several unfavorable prognostic factors have been proposed for peripheral cholangiocarcinoma (PCC) in patients undergoing hepatectomy, including gross type of tumor, vascular invasion, lymph node metastasis, a high carbohydrate antigen 19-9 level, and a positive resection margin. However, the clinical effect of a positive surgical margin on the survival of patients with PCC after hepatectomy still needs to be clarified due to conflicting results. Methods A total of 224 PCC patients who underwent hepatic resection with curative intent between 1977 and 2007 were retrospectively reviewed. Eighty-nine patients had a positive resection margin, with 62 having a microscopically positive margin and 27 a grossly positive margin (R2). The clinicopathological features, outcomes, and recurrence pattern were compared with patients with curative hepatectomy. Results PCC patients with hepatolithiasis, periductal infiltrative or periductal infiltrative mixed with mass-forming growth, higher T stage, and more advanced stage tended to have higher positive resection margin rates after hepatectomy. PCC patients who underwent curative hepatectomy had a significantly higher survival rate than did those with a positive surgical margin. When PCC patients underwent hepatectomy with a positive resection margin, the histological grade of the tumor, nodal positivity, and chemotherapy significantly affected overall survival. Locoregional recurrence was the most common pattern of recurrence. Conclusion A positive resection margin had an unfavorable effect on overall survival in PCC patients undergoing hepatectomy. In these patients, the prognosis was determined by the biology of the tumor, including differentiation and nodal positivity, and chemotherapy increased overall survival. PMID:25552905

  6. Integrin β3 and LKB1 are independently involved in the inhibition of proliferation by lovastatin in human intrahepatic cholangiocarcinoma

    PubMed Central

    Yang, Sheng-Huei; Lin, Hung-Yun; Changou, Chun A; Chen, Chun-Han; Liu, Yun-Ru; Wang, Jinghan; Jiang, Xiaoqing; Luh, Frank; Yen, Yun

    2016-01-01

    Human intrahepatic cholangiocarcinomas are one of the most difficult cancers to treat. In our study, Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme-CoA (HMG-CoA) reductase inhibitor, demonstrated anticancer properties by inhibiting cancer cell proliferation, cell migration and cell adhesion. Lovastatin inhibited the expressions of transforming growth factor (TGF)-β1, cyclooxygenase (COX)-2, and intercellular adhesion molecule (ICAM)-1. Furthermore, lovastatin inhibited the expressions of integrin β1 and integrin β3 but not integrin αv or integrin β5. While Lovastatin's inhibitory effects on TGFβ1, COX2, and ICAM-1 expression were independently controlled by the tumor suppressor LKB1, integrin β3 expression was not affected. Lovastatin's inhibitory effect on cell adhesion was associated with the decreased expression of integrin β3 and cell surface heterodimer integrin αvβ3. Quantitative real time PCR, fluorescent microscopy, and cell migration assays all confirmed that Lovastatin inhibits integrin αvβ3 downstream signaling including FAK activation, and β-catenin, vimentin, ZO-1, and β-actin. Overall, Lovastatin reduced tumor cell proliferation and migration by modifying the expression of genes involved in cell adhesion and other critical cellular processes. Our study highlights novel anti-cancer properties of Lovastatin and supports further exploration of statins in the context of cholangiocarcinoma therapy. PMID:26517522

  7. Integrin β3 and LKB1 are independently involved in the inhibition of proliferation by lovastatin in human intrahepatic cholangiocarcinoma.

    PubMed

    Yang, Sheng-Huei; Lin, Hung-Yun; Changou, Chun A; Chen, Chun-Han; Liu, Yun-Ru; Wang, Jinghan; Jiang, Xiaoqing; Luh, Frank; Yen, Yun

    2016-01-05

    Human intrahepatic cholangiocarcinomas are one of the most difficult cancers to treat. In our study, Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme-CoA (HMG-CoA) reductase inhibitor, demonstrated anticancer properties by inhibiting cancer cell proliferation, cell migration and cell adhesion. Lovastatin inhibited the expressions of transforming growth factor (TGF)-β1, cyclooxygenase (COX)-2, and intercellular adhesion molecule (ICAM)-1. Furthermore, lovastatin inhibited the expressions of integrin β1 and integrin β3 but not integrin αv or integrin β5. While Lovastatin's inhibitory effects on TGFβ1, COX2, and ICAM-1 expression were independently controlled by the tumor suppressor LKB1, integrin β3 expression was not affected. Lovastatin's inhibitory effect on cell adhesion was associated with the decreased expression of integrin β3 and cell surface heterodimer integrin αvβ3. Quantitative real time PCR, fluorescent microscopy, and cell migration assays all confirmed that Lovastatin inhibits integrin αvβ3 downstream signaling including FAK activation, and β-catenin, vimentin, ZO-1, and β-actin. Overall, Lovastatin reduced tumor cell proliferation and migration by modifying the expression of genes involved in cell adhesion and other critical cellular processes. Our study highlights novel anti-cancer properties of Lovastatin and supports further exploration of statins in the context of cholangiocarcinoma therapy.

  8. MicroRNA profiling of human intrahepatic cholangiocarcinoma cell lines reveals biliary epithelial cell-specific microRNAs.

    PubMed

    Kawahigashi, Yutaka; Mishima, Takuya; Mizuguchi, Yoshiaki; Arima, Yasuo; Yokomuro, Shigeki; Kanda, Tomohiro; Ishibashi, Osamu; Yoshida, Hiroshi; Tajiri, Takashi; Takizawa, Toshihiro

    2009-08-01

    Intrahepatic cholangiocarcinoma (ICC), which arises in the small bile ducts of the liver, is the second most common liver malignancy. Although modulation of microRNA (miRNA) expression has been shown to be a potent sign of malignant tumors, miRNA profiles of ICC remains unclear. We performed sequencing analysis of the small RNA libraries of 2 ICC cell lines (HuCCT1 and MEC) and one normal intrahepatic biliary epithelial cell line (HIBEpiC) to produce the miRNA profiles of ICC in vitro. Furthermore, by means of the real-time polymerase chain reaction (PCR) we validated the differential expression of miRNAs cloned exclusively or predominantly from each of the cell lines. A total of 35,759 small RNA clones were obtained from the 3 cell lines. We identified 27 miRNAs that were expressed exclusively or predominantly in each cell line. Subsequent validation with the real-time PCR confirmed that the miRNAs hsa-miR-22, -125a, -127, -199a, -199a*, -214, -376a, and -424 were expressed specifically in HIBEpiC but were downregulated in the ICC cell lines. Our study provides important information for facilitating studies of the functional role(s) of miRNAs in carcinogenesis of the hepatobiliary system. The biliary epithelial cell-specific miRNAs identified in this study may serve as potential biomarkers for ICC.

  9. Novel Preoperative Nomogram for Prediction of Futile Resection in Patients Undergoing Exploration for Potentially Resectable Intrahepatic Cholangiocarcinoma

    PubMed Central

    Nam, Kwangwoo; Hwang, Dae Wook; Shim, Ju Hyun; Song, Tae Jun; Lee, Sang Soo; Seo, Dong-Wan; Lee, Sung Koo; Kim, Myung-Hwan; Kim, Ki-Hun; Hwang, Shin; Park, Kwang-Min; Lee, Young-Joo; Han, Minkyu; Park, Do Hyun

    2017-01-01

    Surgical resection is the treatment of choice for intrahepatic cholangiocarcinoma (IHCC). However, discrepancies between preoperative workup and intraoperative findings can occur, resulting in unexpected and unfavorable surgical outcomes. The aim of this study was to develop a feasible preoperative nomogram to predict futile resection of IHCC. A total of 718 patients who underwent curative-intent surgery for IHCC between January 2005 and December 2014 were included. The patients were divided into a training cohort (2005–2010, n = 377) and validation cohort (2011–2014, n = 341). The predictive accuracy and discriminative ability of the nomogram were determined by the concordance index and calibration curves. In multivariate analysis of the training cohort, tumor number, lymph node enlargement, presence of intrahepatic duct stones, and elevated neutrophil-to-lymphocyte ratio (NLR) (≥2.7) were independently correlated with the risk of futile resection. The predictive nomogram was established based on these factors. The concordance index of the nomogram for the training and the validation cohorts was 0.847 and 0.740, respectively. In this nomogram, the negative predictive value (128 points, probability of futile resection of 36%) in the validation cohort was 93.3%. In conclusion, our novel preoperatively applicable nomogram is a feasible method to predict futile resection of IHCC in curative-intent surgery. PMID:28211504

  10. Comparison of Choi criteria and Response Evaluation Criteria in Solid Tumors (RECIST) for intrahepatic cholangiocarcinoma treated with glass-microspheres Yttrium-90 selective internal radiation therapy (SIRT).

    PubMed

    Beuzit, Luc; Edeline, Julien; Brun, Vanessa; Ronot, Maxime; Guillygomarc'h, Anne; Boudjema, Karim; Gandon, Yves; Garin, Etienne; Rolland, Yan

    2016-08-01

    To compare Choi criteria with Response Evaluation Criteria in Solid Tumors (RECIST) for the prediction of overall survival (OS) in patients treated with glass-microspheres, Yttrium-90 selective internal radiation therapy (SIRT) for intrahepatic cholangiocarcinoma (ICC). Between 2010 and 2014, 45 adult patients with locally advanced ICC treated with SIRT were retrospectively analyzed. Computed tomography scans performed before and after treatment were analyzed using both RECIST 1.1 and Choi criteria. Response was correlated with survival. Patients who achieved an objective response according to Choi had a longer OS than non-responders (median OS 19.9 months [95% CI, 1.1-38.7 months] vs. 7.5 months if stable disease [uncountable CI] and 3 months if progressive disease [95% CI, 0-6.2 months], log-rank test: p=0.003) whereas there was no significant survival difference according to the RECIST response (p=0.339). Among the 39 RECIST non-responding patients, those identified as responders by Choi (n=31) had significantly better OS than Choi non-responders (median OS 19.9 months (95% CI, 5.1-34.7 months) and 5.4 months (95% CI, 0-11.6 months), p=0.005). Choi criteria appear more appropriate than RECIST to identify responders with long survival among patients who received SIRT for ICC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Protein tyrosine phosphatase PTP4A1 promotes proliferation and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma via the PI3K/AKT pathway

    PubMed Central

    Ma, Li-Jie; Wang, Zhi-Chao; Liu, Xin-Yang; Duan, Meng; Yang, Liu-Xiao; Shi, Jie-Yi; Zhou, Jian; Fan, Jia; Gao, Qiang; Wang, Xiao-Ying

    2016-01-01

    The protein tyrosine phosphatase PTP4A1 is a key molecule that activates tyrosine phosphorylation, which is important for cancer progression and metastasis. However, the clinical implications and biological function of PTP4A1 in intrahepatic cholangiocarcinoma (ICC) remains unknown. Here, we showed that PTP4A1 was frequently overexpressed in ICC versus adjacent non-tumor tissues. This overexpression significantly correlated with aggressive tumor characteristics like the presence of lymph node metastasis and advanced tumor stages. Survival analysis further indicated that high PTP4A1 expression was significantly and independently associated with worse survival and increased recurrence in ICC patients. Moreover, through forced overexpression and knock-down of PTPT4A1, we demonstrated that PTP4A1 could significantly promote ICC cells proliferation, colony formation, migration, and invasion in vitro, and markedly enhance tumor progression in vivo. Mechanistically, PTP4A1 was involved in PI3K/AKT signaling and its downstream molecules, such as phosphorylation level of GSK3β and up-regulation of CyclinD1, in ICC cells to promote proliferation. Importantly, PTP4A1 induced ICC cells invasion was through activating PI3K/AKT signaling controlled epithelial-mesenchymal transition (EMT) process by up-regulating Zeb1 and Snail. Thus, PTP4A1 may serve as a potential oncogene that was a valuable prognostic biomarker and therapeutic target for ICC. PMID:27655691

  12. Identification of biomarkers of intrahepatic cholangiocarcinoma via integrated analysis of mRNA and miRNA microarray data

    PubMed Central

    Chen, Yaqing; Liu, Dan; Liu, Pengfei; Chen, Yajing; Yu, Huiling; Zhang, Quan

    2017-01-01

    The present study aimed to identify potential therapeutic targets of intrahepatic cholangiocarcinoma (ICC) via integrated analysis of gene (transcript version) and microRNA (miRNA/miR) expression. The miRNA microarray dataset GSE32957 contained miRNA expression data from 16 ICC, 7 mixed type of combined hepatocellular-cholangiocarcinoma (CHC), 2 hepatic adenoma, 3 focal nodular hyperplasia (FNH) and 5 healthy liver tissue samples, and 2 cholangiocarcinoma cell lines. In addition, the mRNA microarray dataset GSE32879 contained mRNA expression data from 16 ICC, 7 CHC, 2 hepatic adenoma, 5 FNH and 7 healthy liver tissue samples. The datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and miRNAs (DEMs) in ICC samples compared with healthy liver tissues were identified via the limma package, following data preprocessing. Genes that exhibited alternative splicing (AS) in ICC samples were identified via AltAnalyze software. Functional enrichment analysis of DEGs was performed using the Database for Annotation, Visualization and Integrated Analysis. Target genes of DEMs were identified using the TargetScan database. The regulatory association between DEMs and any overlaps among DEGs, alternative splicing genes (ASGs) and target genes of DEMs were retrieved, and a network was visualized using the Cytoscape software. A total of 2,327 DEGs, 70 DEMs and 623 ASGs were obtained. Functional enrichment analysis indicated that DEGs were primarily enriched in biological processes and pathways associated with cell activity or the immune system. A total of 63 overlaps were obtained among DEGs, ASGs and target genes of DEMs, and a regulation network that contained 243 miRNA-gene regulation pairs was constructed between these overlaps and DEMs. The overlapped genes, including sprouty-related EVH1 domain containing 1, protein phosphate 1 regulatory subunit 12A, chromosome 20 open reading frame 194, and DEMs, including hsa-miR-96, hsa

  13. Integrated mRNA and lncRNA expression profiling for exploring metastatic biomarkers of human intrahepatic cholangiocarcinoma

    PubMed Central

    Lv, Lisheng; Wei, Miaoyan; Lin, Peiyi; Chen, Zhisheng; Gong, Peng; Quan, Zhiwei; Tang, Zhaohui

    2017-01-01

    Long noncoding RNAs (lncRNAs) is crucial for various human cancers, but the function and mechanism of lncRNAs is largely unknown in human intrahepatic cholangiocarcinoma (ICC), the second most common liver cancer. In this study, we performed transcriptomic profiling of ICC and normal tissues, and found 2148 lncRNAs and 474 mRNAs were significantly upregulated, whereas 568 lncRNAs and 409 mRNAs were downregulated in ICC tissues. Enrichment analysis suggests these differentially expressed genes mainly focus on response to stimulus, development, and cell proliferation. Further, potential lncRNAs involved in five signaling pathways (ERBB, JAK/STAT, MAPK, VEGF and WNT) were constructed by highly co-expressed with mRNAs in these signaling pathways. The differentially expressed lncRNA-mRNA co-regulated signaling pathways in ICC were further confirmed by lncRNA target prediction. Finally, the differentially expressed lncRNAs were confirmed by quantitative real-time PCR in 32 paired ICC and adjacent tissues. The correlation analysis between the expression levels of lncRNAs and clinicopathologic characteristics showed that EMP1-008, ATF3-008, and RCOR3-013 were observed significantly downregulated in ICC with tumor metastasis. These findings suggested that lncRNA expression profiling in ICC is profoundly different from that in noncancerous tissues, and lncRNA may be used as a potential diagnostic and prognostic biomarker for ICC metastasis.

  14. A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion

    PubMed Central

    Ikenoue, Tsuneo; Terakado, Yumi; Nakagawa, Hayato; Hikiba, Yohko; Fujii, Tomoaki; Matsubara, Daisuke; Noguchi, Rei; Zhu, Chi; Yamamoto, Keisuke; Kudo, Yotaro; Asaoka, Yoshinari; Yamaguchi, Kiyoshi; Ijichi, Hideaki; Tateishi, Keisuke; Fukushima, Noriyoshi; Maeda, Shin; Koike, Kazuhiko; Furukawa, Yoichi

    2016-01-01

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis and its incidence is increasing worldwide. Recently, several types of cells have been considered as the origin of ICC, namely cholangiocytes, liver progenitor cells, and hepatocytes. Here, we have established a novel mouse model of ICC by liver-specific Kras activation and Pten deletion. An activating mutation of Kras in combination with deletion of Pten was introduced in embryonic hepatic bipotential progenitor cells (so-called hepatoblasts) and mature hepatocytes using the Cre-loxP system. As a result, liver-specific Kras activation and homozygous Pten deletion cooperated to induce ICCs exclusively. In contrast, Kras activation in combination with heterozygous Pten deletion induced both ICCs and HCCs, whereas Kras activation alone resulted in HCCs but not ICCs. Furthermore, a cell-lineage visualization system using tamoxifen-inducible Cre-loxP demonstrated that the ICCs did not originate from hepatocytes but from cholangiocytes. Our data suggest that mice carrying liver-specific Kras activation in combination with homozygous Pten deletion should be useful for the investigation of therapeutic strategies for human ICC. PMID:27032374

  15. The Prognostic Impact of Controlling Nutritional Status (CONUT) in Intrahepatic Cholangiocarcinoma Following Curative Hepatectomy: A Retrospective Single Institution Study.

    PubMed

    Miyata, Tatsunori; Yamashita, Yo-Ichi; Higashi, Takaaki; Taki, Katsunobu; Izumi, Daisuke; Kosumi, Keisuke; Tokunaga, Ryuma; Nakagawa, Shigeki; Okabe, Hirohisa; Imai, Katsunori; Hashimoto, Daisuke; Chikamoto, Akira; Baba, Hideo

    2017-09-08

    Several studies have examined controlling nutritional status (CONUT), which is one of the useful biomarkers for predicting patients' prognosis following cancer treatment. The aim of this study was to evaluate the value of CONUT as a postoperative prognostic marker in patients with intrahepatic cholangiocarcinoma (ICC) following curative hepatectomy. We retrospectively analyzed 71 patients who underwent curative hepatectomy for ICC between May 2002 and November 2016. Patients were divided into two groups according to their preoperative CONUT score (i.e., CONUT ≧ 2 or CONUT < 2). The number of patients assigned to the normal, mild, moderate, or severe malnutrition groups was 40, 28, two, and one, respectively. The high CONUT group (CONUT ≧ 2) consisted of 31 patients (43.7%) and had a poor prognosis with regard to overall survival (OS) (p = 0.0149). A high CONUT score is also identified as one of the independent predictors of poor prognosis in OS (hazard ratio 3.02; 95% confidence interval 1.4-6.8; p = 0.007). However, in the current study, a high CONUT score was not associated with postoperative complications (Clavien-Dindo classification ≧ III or more). CONUT may be useful for the preoperative assessment of prognosis in patients with ICC who have undergone curative hepatectomy.

  16. Identification of Cellular Targets in Human Intrahepatic Cholangiocarcinoma Using Laser Microdissection and Accurate Mass and Time Tag Proteomics*

    PubMed Central

    Dos Santos, Alexandre; Court, Magali; Thiers, Valérie; Sar, Sokhavuth; Guettier, Catherine; Samuel, Didier; Bréchot, Christian; Garin, Jérôme; Demaugre, France; Masselon, Christophe D.

    2010-01-01

    Obtaining accurate protein profiles from homogeneous cell populations in heterogeneous tissues can enhance the capability to discover protein biomarkers. In this context, methodologies to access specific cellular populations and analyze their proteome with exquisite sensitivity have to be selected. We report here the results of an investigation using a combination of laser microdissection and accurate mass and time tag proteomics. The study was aimed at the precise determination of proteome alterations in intrahepatic cholangiocarcinoma ICC, a markedly heterogeneous tumor. This cancer, which is difficult to diagnose and carries a very poor prognosis, has shown an unexplained increase in incidence over the last few years. Among a pool of 574 identified proteins, we were able to report on altered abundance patterns affecting 39 proteins conforming to a variety of potential tumorigenic pathways. The reliability of the proteomics results was confirmed by Western blot and immunohistochemistry on matched samples. Most of the proteins displaying perturbed abundances had not yet been described in the setting of ICC. These include proteins involved in cell mobility and actin cytoskeleton remodeling, which may participate in the epithelial to mesenchymal transition, a process invoked in migration and invasion of cancer cells. The biological relevance of these findings was explored using a tissue microarray. An increased abundance of vimentin was thus detected in 70% of ICC and none of the controls. These results suggest that vimentin could play a role in the aggressiveness of ICC and provide a basis for the serious outcome of this cancer. PMID:20513801

  17. Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma

    PubMed Central

    Mao, Yize; Wang, Jun; Shuang, Zeyu; Chen, Jianlin; Li, Shengping

    2016-01-01

    We investigated whether elevated neutrophil-to-lymphocyte ratio (NLR) was associated with poor anti-tumor immunity and prognosis in patients with intrahepatic cholangiocarcinoma (ICC). Clinicopathologic data of 102 patients with ICC who underwent hepatectomy was retrospectively analyzed. The Kaplan-Meier method and Cox regression model were used to analyze the survival and prognosis. The percentage of overall lymphocytes, T cells and CD8+ T cells in the high NLR group was lower than that in the low NLR group. The percentage of PD-1+CD4+ and PD-1+CD8+ T cells was higher and the percentage of IFN-γ+CD4+ and IFN-γ+CD8+ T cells was lower in the high NLR group than that in the low NLR group (p = 0.045, p = 0.008; p = 0.012, p = 0.006). Density of tumor-infiltrating CD3+ T cells in the high NLR group was lower than that in the low NLR group (p < 0.001). Elevated NLR was an independent predictor for poor overall survival (OS; p = 0.035) and recurrence-free survival (RFS; p = 0.008). These results indicate that elevated NLR is associated with poor anti-tumor immunity and could be a poor biomarker for prognosis in patients with ICC. PMID:26918355

  18. Comparison of the prognostic accuracy of the sixth and seventh editions of the TNM classification for intrahepatic cholangiocarcinoma

    PubMed Central

    Ribero, Dario; Nuzzo, Gennaro; Amisano, Marco; Tomatis, Mariano; Guglielmi, Alfredo; Giulini, Stefano Maria; Aldrighetti, Luca; Calise, Fulvio; Gerunda, Giorgio Enrico; Pinna, Antonio Daniele; Capussotti, Lorenzo

    2011-01-01

    Background The seventh TNM edition introduced a new, specific staging structure for intrahepatic cholangiocarcinoma (IHC). Objective To compare the accuracy of the sixth and the new seventh edition to predict survival after hepatectomy for IHC. Methods In all, 434 consecutive patients who underwent hepatectomy at 16 tertiary-care centres (1990–2008) were identified. End points were overall (OS) and recurrence-free survival (RFS) for both T cohorts and stage strata. Results After a median follow-up of 32.4 months, 3- and 5-year OS and RFS estimates were 47.1% and 32.9%, and 26.5% and 19.1%, respectively. Overall, both the editions were statistically significant discriminators of OS and RFS (P < 0.05). However, the survival curves of the new T2a and T2b cohorts appear superimposed. Conversely, the old T2 and T3 cohorts accurately stratify patients into distinct prognostic groups (P < 0.01). The seventh edition does not show monotonicity of gradients (the T4 category demonstrates significantly better OS and RFS compared with T2 patients). The seventh edition stage I and II are significantly different whereas the old stage I and II were not. Conclusions The new seventh edition of the AJCC/UICC Staging System proved to be adequate although further studies are need to confirm its superiority compared with the previous edition. PMID:21309938

  19. Comparison of the prognostic accuracy of the sixth and seventh editions of the TNM classification for intrahepatic cholangiocarcinoma.

    PubMed

    Ribero, Dario; Nuzzo, Gennaro; Amisano, Marco; Tomatis, Mariano; Guglielmi, Alfredo; Giulini, Stefano Maria; Aldrighetti, Luca; Calise, Fulvio; Gerunda, Giorgio Enrico; Pinna, Antonio Daniele; Capussotti, Lorenzo

    2011-03-01

    The seventh TNM edition introduced a new, specific staging structure for intrahepatic cholangiocarcinoma (IHC). To compare the accuracy of the sixth and the new seventh edition to predict survival after hepatectomy for IHC. In all, 434 consecutive patients who underwent hepatectomy at 16 tertiary-care centres (1990-2008) were identified. End points were overall (OS) and recurrence-free survival (RFS) for both T cohorts and stage strata. After a median follow-up of 32.4 months, 3- and 5-year OS and RFS estimates were 47.1% and 32.9%, and 26.5% and 19.1%, respectively. Overall, both the editions were statistically significant discriminators of OS and RFS (P < 0.05). However, the survival curves of the new T2a and T2b cohorts appear superimposed. Conversely, the old T2 and T3 cohorts accurately stratify patients into distinct prognostic groups (P < 0.01). The seventh edition does not show monotonicity of gradients (the T4 category demonstrates significantly better OS and RFS compared with T2 patients). The seventh edition stage I and II are significantly different whereas the old stage I and II were not. The new seventh edition of the AJCC/UICC Staging System proved to be adequate although further studies are need to confirm its superiority compared with the previous edition. © 2011 International Hepato-Pancreato-Biliary Association.

  20. Members of the Cyr61/CTGF/NOV Protein Family: Emerging Players in Hepatic Progenitor Cell Activation and Intrahepatic Cholangiocarcinoma

    PubMed Central

    Jorgensen, Marda; Song, Joanna; Zhou, Junmei; Liu, Chen

    2016-01-01

    Hepatic stem/progenitor cells (HPC) reside quiescently in normal biliary trees and are activated in the form of ductular reactions during severe liver damage when the replicative ability of hepatocytes is inhibited. HPC niches are full of profibrotic stimuli favoring scarring and hepatocarcinogenesis. The Cyr61/CTGF/NOV (CCN) protein family consists of six members, CCN1/CYR61, CCN2/CTGF, CCN3/NOV, CCN4/WISP1, CCN5/WISP2, and CCN6/WISP3, which function as extracellular signaling modulators to mediate cell-matrix interaction during angiogenesis, wound healing, fibrosis, and tumorigenesis. This study investigated expression patterns of CCN proteins in HPC and cholangiocarcinoma (CCA). Mouse HPC were induced by the biliary toxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Differential expression patterns of CCN proteins were found in HPC from DDC damaged mice and in human CCA tumors. In addition, we utilized reporter mice that carried Ccn2/Ctgf promoter driven GFP and detected strong Ccn2/Ctgf expression in epithelial cell adhesion molecule (EpCAM)+ HPC under normal conditions and in DDC-induced liver damage. Abundant CCN2/CTGF protein was also found in cytokeratin 19 (CK19)+ human HPC that were surrounded by α-smooth muscle actin (α-SMA)+ myofibroblast cells in intrahepatic CCA tumors. These results suggest that CCN proteins, particularly CCN2/CTGF, function in HPC activation and CCA development. PMID:27829832

  1. MicroRNA-212 targets FOXA1 and suppresses the proliferation and invasion of intrahepatic cholangiocarcinoma cells

    PubMed Central

    Zhu, Lei; Huang, Feizhou; Deng, Gang; Nie, Wanpin; Huang, Wei; Xu, Hongbo; Zheng, Shaopeng; Yi, Zhongjie; Wan, Tao

    2016-01-01

    MicroRNAs (miRNAs), which are a class of small RNAs, have been shown to negatively regulate the expression of their target genes by directly binding to the 3′-untranslated region (3′-UTR) of mRNA. miRNA dysregulation has been associated with the pathogenesis of numerous types of human cancer. However, the role of miRNAs in intrahepatic cholangiocarcinoma (ICC) has yet to be fully elucidated. The present study aimed to investigate the role of miR-212 in the growth and metastasis of ICC in vitro, as well as the underlying mechanism. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to examine mRNA and protein expression. An MTT assay and transwell assay were conducted to determine cell proliferation and invasion rates. The results of the RT-qPCR demonstrated that miR-212 was downregulated in the majority of investigated ICC tissues, as compared with their matched adjacent non-tumor tissues. In addition, miR-212 expression was shown to be markedly downregulated in three ICC cell lines, as compared with human intrahepatic biliary epithelial cells. Furthermore, restoration of miR-212 expression significantly suppressed the proliferation and invasion of ICC QBC939 cells. Forkhead box protein A1 (FOXA1) was predicted to be a putative target of miR-212 by bioinformatics analysis with TargetScan. Therefore, a luciferase reporter assay was conducted to confirm that miR-212 was able to directly bind to the 3′-UTR of FOXA1 mRNA. In addition, using western blot analysis, the protein expression of FOXA1 was shown to be negatively regulated by miR-212 in ICC QBC939 cells. In conclusion, it was demonstrated that FOXA1 was frequently upregulated in various ICC tissues and cell lines. The results of the present study suggested that miR-212 inhibits the proliferation and invasion of ICC cells by directly targeting FOXA1, and thus may be considered a potential candidate for the treatment of ICC. PMID:28105112

  2. Improving patient selection for selective internal radiation therapy of intra-hepatic cholangiocarcinoma: A meta-regression study.

    PubMed

    Cucchetti, Alessandro; Cappelli, Alberta; Mosconi, Cristina; Zhong, Jian-Hong; Cescon, Matteo; Pinna, Antonio D; Golfieri, Rita

    2017-07-01

    Selective internal radiation therapy (SIRT) is emerging as a potential therapy for unresectable intra-hepatic cholangiocarcinoma (iCCA) able to prolong life-expectancy. Aim of this study was to collect available literature meta-analyse data and results and investigate sources of heterogeneity through a meta-regression approach before suggesting SIRT as a valuable option. A systematic review of studies published until 1 September 2016 in PubMed and Scopus databases was performed. Patient survival was the primary outcome measure. Meta-analysis was performed using a random-effects model. Meta-regression was applied to investigate relationships existing between clinical and tumour features and the primary outcome. Nine observational studies were included in the analysis involving 224 patients. The 1-, 2- and 3-year pooled survival estimates were 55.7%, 33.1% and 20.2%. Clinical and tumour characteristics showed medium-to-considerable heterogeneity (I(2) >50%). Meta-regression analysis showed that determinants of best survivals were the presence of mass-forming iCCA type (median survival=19.9 months vs 8.1 months for the infiltrative type; P=.002) that also accounted for most of the heterogeneity between included studies (residual I(2) =0); SIRT as first-line therapy (median survival=24 months vs 11.5 months for non-naïve patients; P=.048) and the adoption of concomitant chemotherapy (median survival 19.5 months vs 5.5 months in patients not receiving chemotherapy; P=.042). There is considerable heterogeneity between studies highlighting that indications for SIRT are extremely varied. To ameliorate SIRT results naïve patients with mass-forming iCCA should be selected as the best candidates with the possibility of adding concomitant standard chemotherapy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Determining the role of external beam radiotherapy in unresectable intrahepatic cholangiocarcinoma: a retrospective analysis of 84 patients

    PubMed Central

    2010-01-01

    Background Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary liver cancer. Only few studies have focused on palliative radiotherapy used for patients who weren't suitable for resection by surgery. This study was conducted to investigate the effect of external beam radiotherapy (EBRT) for patients with unresectable ICC. Methods We identified 84 patients with ICC from December 1998 through December 2008 for retrospective analysis. Thirty-five of 84 patients received EBRT therapy five times a week (median dose, 50 Gy; dose range, 30-60 Gy, in fractions of 1.8-2.0 Gy daily; EBRT group); the remaining 49 patients comprised the non-EBRT group. Tumor response, jaundice relief, and survival rates were compared by Kaplan-Meier analysis. Patient records were reviewed and compared using Cox proportional hazard analysis to determine factors that affect survival time in ICC. Results After EBRT, complete response (CR) and partial response (PR) of primary tumors were observed in 8.6% and 28.5% of patients, respectively, and CR and PR of lymph node metastases were observed in 20% and 40% of patients. In 19 patients with jaundice, complete and partial relief was observed in 36.8% and 31.6% of patients, respectively. Median survival times were 5.1 months for the non-EBRT group and 9.5 months for the EBRT group (P = 0.003). One-and two-year survival rates for EBRT versus non-EBRT group were 38.5% versus 16.4%, and 9.6% versus 4.9%, respectively. Multivariate analysis revealed that clinical symptoms, larger tumor size, no EBRT, multiple nodules and synchronous lymph node metastases were associated with poorer prognosis. Conclusions EBRT as palliative care appears to improve prognosis and relieve the symptom of jaundice in patients with unresectable ICC. PMID:20840777

  4. Coffee Consumption and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma by Sex: The Liver Cancer Pooling Project.

    PubMed

    Petrick, Jessica L; Freedman, Neal D; Graubard, Barry I; Sahasrabuddhe, Vikrant V; Lai, Gabriel Y; Alavanja, Michael C; Beane-Freeman, Laura E; Boggs, Deborah A; Buring, Julie E; Chan, Andrew T; Chong, Dawn Q; Fuchs, Charles S; Gapstur, Susan M; Gaziano, John Michael; Giovannucci, Edward L; Hollenbeck, Albert R; King, Lindsay Y; Koshiol, Jill; Lee, I-Min; Linet, Martha S; Palmer, Julie R; Poynter, Jenny N; Purdue, Mark P; Robien, Kim; Schairer, Catherine; Sesso, Howard D; Sigurdson, Alice J; Zeleniuch-Jacquotte, Anne; Wactawski-Wende, Jean; Campbell, Peter T; McGlynn, Katherine A

    2015-09-01

    Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee-HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53-0.99; Ptrend cups/day = <0.0001). More notable reduced risk was seen among women than men (Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26-0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63-1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50-1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55-1.54). There was no association between coffee consumption and ICC. These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC. Further research into specific coffee compounds and mechanisms that may account for these associations is needed. ©2015 American Association for Cancer Research.

  5. Coffee consumption and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma by sex: The Liver Cancer Pooling Project

    PubMed Central

    Petrick, Jessica L.; Freedman, Neal D.; Graubard, Barry I.; Sahasrabuddhe, Vikrant V.; Lai, Gabriel Y.; Alavanja, Michael C.; Beane-Freeman, Laura E.; Boggs, Deborah A.; Buring, Julie E.; Chan, Andrew T.; Chong, Dawn Q.; Fuchs, Charles S.; Gapstur, Susan M.; Gaziano, John Michael; Giovannucci, Edward L.; Hollenbeck, Albert R.; King, Lindsay Y.; Koshiol, Jill; Lee, I-Min; Linet, Martha S.; Palmer, Julie R.; Poynter, Jenny N.; Purdue, Mark P.; Robien, Kim; Schairer, Catherine; Sesso, Howard D.; Sigurdson, Alice J.; Zeleniuch-Jacquotte, Anne; Wactawski-Wende, Jean; Campbell, Peter T.; McGlynn, Katherine A.

    2015-01-01

    Background Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee-HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Methods In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC n=860, ICC n=260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Results Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53-0.99; ptrend cups/day=<0.0001). More notable reduced risk was seen among women than men (pinteraction=0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26-0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63-1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71, 95% CI, 0.50-1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55-1.54). There was no relationship between coffee consumption and ICC. Conclusions These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC. Impact Further research into specific coffee compounds and mechanisms that may account for these associations is needed. PMID:26126626

  6. Taurolithocholic acid promotes intrahepatic cholangiocarcinoma cell growth via muscarinic acetylcholine receptor and EGFR/ERK1/2 signaling pathway

    PubMed Central

    AMONYINGCHAROEN, SUMET; SURIYO, TAWIT; THIANTANAWAT, APINYA; WATCHARASIT, PIYAJIT; SATAYAVIVAD, JUTAMAAD

    2015-01-01

    Cholangiocarcinoma (CCA) is a malignant cancer of the biliary tract and its occurrence is associated with chronic cholestasis which causes an elevation of bile acids in the liver and bile duct. The present study aimed to investigate the role and mechanistic effect of bile acids on the CCA cell growth. Intrahepatic CCA cell lines, RMCCA-1 and HuCCA-1, were treated with bile acids and their metabolites to determine the growth promoting effect. Cell viability, cell cycle analysis, EdU incorporation assays were conducted. Intracellular signaling proteins were detected by western immunoblotting. Among eleven forms of bile acids and their metabolites, only taurolithocholic acid (TLCA) concentration dependently (1–40 μM) increased the cell viability of RMCCA-1, but not HuCCA-1 cells. The cell cycle analysis showed induction of cells in the S phase and the EdU incorporation assay revealed induction of DNA synthesis in the TLCA-treated RMCCA-1 cells. Moreover, TLCA increased the phosphorylation of EGFR, ERK 1/2 and also increased the expression of cyclin D1 in RMCCA-1 cells. Furthermore, TLCA-induced RMCCA-1 cell growth could be inhibited by atropine, a non-selective muscarinic acetylcholine receptor (mAChR) antagonist, AG 1478, a specific EGFR inhibitor, or U 0126, a specific MEK 1/2 inhibitor. These results suggest that TLCA induces CCA cell growth via mAChR and EGFR/EKR1/2 signaling pathway. Moreover, the functional presence of cholinergic system plays a certain role in TLCA-induced CCA cell growth. PMID:25815516

  7. PD-L1 and HLA Class I Antigen Expression and Clinical Course of the Disease in Intrahepatic Cholangiocarcinoma.

    PubMed

    Sabbatino, Francesco; Villani, Vincenzo; Yearley, Jennifer H; Deshpande, Vikram; Cai, Lei; Konstantinidis, Ioannis T; Moon, Christina; Nota, Sjoerd; Wang, Yangyang; Al-Sukaini, Ahmad; Zhu, Andrew X; Goyal, Lipika; Ting, David T; Bardeesy, Nabeel; Hong, Theodore S; Fernandez-del Castillo, Carlos; Tanabe, Kenneth K; Lillemoe, Keith D; Ferrone, Soldano; Ferrone, Cristina R

    2016-01-15

    More effective therapy is needed for intrahepatic cholangiocarcinoma (ICC). The encouraging clinical results obtained with checkpoint molecule-specific monoclonal antibodies (mAb) have prompted us to investigate whether this type of immunotherapy may be applicable to ICC. The aims of this study were to determine whether (i) patients mount a T-cell immune response to their ICC, (ii) checkpoint molecules are expressed on both T cells and tumor cells, and (iii) tumor cells are susceptible to recognition by cognate T cells. Twenty-seven ICC tumors were analyzed for (i) lymphocyte infiltrate, (ii) HLA class I and HLA class II expression, and (iii) PD-1 and PD-L1 expression by T cells and ICC cells, respectively. The results of this analysis were correlated with the clinicopathologic characteristics of the patients investigated. Lymphocyte infiltrates were identified in all tumors. PD-L1 expression and HLA class I antigen expression by ICC cells was observed in 8 and 11, respectively, of the 27 tumors analyzed. HLA class I antigen expression correlated with CD8(+) T-cell infiltrate. Furthermore, positive HLA class I antigen expression in combination with negative/rare PD-L1 expression was associated with favorable clinical course of the disease. ICC patients are likely to mount a T-cell immune response against their own tumors. Defects in HLA class I antigen expression in combination with PD-L1 expression by ICC cells provide them with an immune escape mechanism. This mechanism justifies the implementation of immunotherapy with checkpoint molecule-specific mAbs in patients bearing ICC tumors without defects in HLA class I antigen expression. ©2015 American Association for Cancer Research.

  8. Ablative Radiotherapy Doses Lead to a Substantial Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective Dose Response Analysis

    PubMed Central

    Tao, Randa; Krishnan, Sunil; Bhosale, Priya R.; Javle, Milind M.; Aloia, Thomas A.; Shroff, Rachna T.; Kaseb, Ahmed O.; Bishop, Andrew J.; Swanick, Cameron W.; Koay, Eugene J.; Thames, Howard D.; Hong, Theodore S.; Das, Prajnan

    2016-01-01

    Purpose Standard therapies for localized inoperable intrahepatic cholangiocarcinoma (IHCC) are ineffective. Advances in radiotherapy (RT) techniques and image guidance have enabled ablative doses to be delivered to large liver tumors. This study evaluated the effects of RT dose escalation in the treatment of IHCC. Patients and Methods Seventy-nine consecutive patients with inoperable IHCC were identified and treated with definitive RT from 2002 to 2014. At diagnosis, the median tumor size was 7.9 cm (range, 2.2 to 17 cm). Seventy patients (89%) received systemic chemotherapy before RT. RT doses were 35 to 100 Gy (median, 58.05 Gy) in three to 30 fractions for a median biologic equivalent dose (BED) of 80.5 Gy (range, 43.75 to 180 Gy). Results Median follow-up time for patients alive at time of analysis was 33 months (range, 11 to 93 months). Median overall survival (OS) time after diagnosis was 30 months; 3-year OS rate was 44%. Radiation dose was the single most important prognostic factor; higher doses correlated with an improved local control (LC) rate and OS. The 3-year OS rate for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses (P = .017); 3-year LC rate was significantly higher (78%) after a BED greater than 80.5 Gy than after lower doses (45%, P = .04). BED as a continuous variable significantly affected LC (P = .009) and OS (P = .004). There were no significant treatment-related toxicities. Conclusion Delivery of higher doses of RT improves LC and OS in inoperable IHCC. A BED greater than 80.5 Gy seems to be an ablative dose of RT for large IHCCs, with long-term survival rates that compare favorably with resection. PMID:26503201

  9. Primary or metastatic hepatic carcinoma? A breast cancer patient after adjuvant chemotherapy and radiotherapy postoperatively with intrahepatic cholangiocarcinoma and review of the literature.

    PubMed

    Liu, Zhao-Yun; Sun, Ju-Jie; He, Ke-Wen; Zhuo, Pei-Ying; Yu, Zhi-Yong

    2016-07-15

    The liver is a common site of metastases, followed by the bone and lung in breast cancer. The symptoms of hepatic metastases are similar to intrahepatic cholangiocarcinoma (ICC). ICC is rare, with an overall incidence rate of 0.95 cases per 100,000 adults. The incidence of ICC for patients with breast cancer is very uncommon. Breast cancer patient with ICC is easily misdiagnosed as hepatic metastases. We report a breast cancer patient postoperatively who was hospitalized because of having continuous irregular fever for 1 month. Antibiotics were given for 1 week without any significant effect. Her admission bloods revealed elevated levels of carcino-embryonic antigen. Magnetic resonance imaging diagnosis showed multiple liver metastases. We believed that the woman had hepatic metastases until biopsy guided by computed tomography. The liver biopsy pathology analysis considered the possibility of primary intrahepatic cholangiocarcinoma. Breast cancer patient with space-occupying lesions in the liver is easily considered to be progressed hepatic metastases. Image-guided biopsy is the best diagnostic method for breast cancer with liver mass to avoid misdiagnosis and classify the molecular subtypes to make appropriate treatment.

  10. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990-2009

    PubMed Central

    Aljiffry, Murad; Walsh, Mark J; Molinari, Michele

    2009-01-01

    Several advances in diagnosis, treatment and palliation of cholangiocarcinoma (CC) have occurred in the last decades. A multidisciplinary approach to this disease is therefore recommended. CC is a relatively rare tumor and the main risk factors are: chronic inflammation, genetic predisposition and congenital abnormalities of the biliary tree. While the incidence of intra-hepatic CC is increasing, the incidence of extra-hepatic CC is trending down. The only curative treatment for CC is surgical resection with negative margins. Liver transplantation has been proposed only for selected patients with hilar CC that cannot be resected who have no metastatic disease after a period of neoadjuvant chemo-radiation therapy. Magnetic resonance imaging/magnetic resonance cholangiopancreatography, positron emission tomography scan, endoscopic ultrasound and computed tomography scans are the most frequently used modalities for diagnosis and tumor staging. Adjuvant therapy, palliative chemotherapy and radiotherapy have been relatively ineffective for inoperable CC. For most of these patients biliary stenting provides effective palliation. Photodynamic therapy is an emerging palliative treatment that seems to provide pain relief, improve biliary patency and increase survival. The clinical utility of other emerging therapies such as transarterial chemoembolization, hepatic arterial chemoinfusion and high intensity intraductal ultrasound needs further study. PMID:19750567

  11. Outcomes of Hepatic Resection in Intrahepatic Cholangiocarcinoma Patients with Diabetes, Hypertension, and Dyslipidemia: Significance of Routine Follow-Up

    PubMed Central

    Nishioka, Takayoshi; Kubo, Shoji; Tanaka, Shogo; Wakasa, Kenichi; Takemura, Shigekazu; Kinoshita, Masahiko; Hamano, Genya; Kuwae, Yuko; Shibata, Toshihiko; Suehiro, Shigefumi

    2016-01-01

    Background The outcomes of hepatic resection in intrahepatic cholangiocarcinoma (ICC) patients with diabetes mellitus (DM), hypertension (HT), and dyslipidemia (DL) (metabolic components) remain unclear. Methods The outcomes of 43 ICC patients without known risk factors for ICC who underwent hepatic resection were retrospectively reviewed. These patients were divided into three groups: those followed-up for metabolic components at least every 6 months (follow-up group, n=16), those not followed-up for metabolic components (no follow-up group, n=14), and those without metabolic components (control group, n=13). Results In the follow-up group, 13 (81%) patients were further examined for ICC during follow-up because of abnormal screening results, such as elevated serum gamma-glutamyl transpeptidase and carbohydrate antigen 19-9 (CA19-9) concentrations or detection of hepatic tumor on ultrasonography and/or computed tomography, whereas most patients in the other two groups exhibited ICC-related symptoms. No patient in the follow-up group exhibited lymph node metastasis, whereas 43% of those in the no follow-up group and 46% in the control group had lymph node metastasis (p=0.005 and 0.004 vs. the follow-up group, respectively). All 16 patients in the follow-up group were diagnosed as International Union Against Cancer pathologic stage I or II (early stage). There were no significant differences in the incidence of postoperative recurrence between the three groups; however, the incidence of extrahepatic recurrence was lower in the follow-up group than in the no follow-up group and the control group (13% vs. 78% vs. 63%, p=0.0232). The 1-, 3-, and 5-year overall survivalrates in the follow-up group were better than those in the no follow-up and control groups (93/93/66% vs. 77/34/34% and 85/24/0%, p=0.034 and 0.001, respectively). Conclusions Routine measurement of serum gamma-glutamyl transpeptidase and/or CA19-9 levels and imaging examinations every 12 months (or 6

  12. Andrographis paniculata extracts and major constituent diterpenoids inhibit growth of intrahepatic cholangiocarcinoma cells by inducing cell cycle arrest and apoptosis.

    PubMed

    Suriyo, Tawit; Pholphana, Nanthanit; Rangkadilok, Nuchanart; Thiantanawat, Apinya; Watcharasit, Piyajit; Satayavivad, Jutamaad

    2014-05-01

    -ribose) polymerase was also found in the ethanolic extract of A. paniculata in the first true leaf stage treatment. This study suggests that A. paniculata could be a promising herbal plant for the alternative treatment of intrahepatic cholangiocarcinoma.

  13. Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations

    ClinicalTrials.gov

    2017-09-12

    Advanced Malignant Solid Neoplasm; Glioblastoma; Grade II Glioma; IDH1 Gene Mutation; IDH2 Gene Mutation; Recurrent Cholangiocarcinoma; Recurrent Glioma; Recurrent Malignant Solid Neoplasm; WHO Grade III Glioma

  14. Chemotherapy for cholangiocarcinoma: An update.

    PubMed

    Ramírez-Merino, Natalia; Aix, Santiago Ponce; Cortés-Funes, Hernán

    2013-07-15

    Cholangiocarcinomas (bile duct cancers) are a heterogeneous group of malignancies arising from the epithelial cells of the intrahepatic, perihilar and extrahepatic bile ducts. Patients diagnosed with cholangiocarcinoma must be evaluated by a multidisciplinary team and be treated with individualized management. First of all, it is very important to define the potential resectability of the tumor because surgery is the main therapeutic option for these patients. Overall, cholangiocarcinomas have a very poor prognosis. The 5-year survival rate is 5%-10%. In cases with a potentially curative surgery, 5-year survival rates of 25%-30% are reported. Therefore, it is necessary to increase the cure rate from surgery, exploring the survival benefit of any adjuvant strategy. It is difficult to clarify the role of adjuvant treatment in localized and locally advanced cholangiocarcinomas. There are limited data and the role of adjuvant chemotherapy/chemoradiation in patients with resected biliary tract cancer is poorly defined. The most relevant studies in the adjuvant setting are one from Japan, the well known ESPAC-3 and BILCAP from the United Kingdom and a meta-analysis. We show the results of these trials. According to medical oncology guidelines, postoperative adjuvant therapy is widely recommended for all patients with intrahepatic or extrahepatic cholangiocarcinoma who have microscopically positive resection margins, as well as for those with a complete resection but node-positive disease. Clinical trials are ongoing. The locally advanced cholangiocarcinoma setting includes a heterogeneous mix of patients: (1) patients who have had surgery but with macroscopic residual disease; (2) patients with locally recurrent disease after potentially curative treatment; and (3) patients with locally unresectable disease at presentation. In these patients, surgery is not an option and chemoradiation therapy can prolong overall survival and provide control of symptoms due to local

  15. Chemotherapy for cholangiocarcinoma: An update

    PubMed Central

    Ramírez-Merino, Natalia; Aix, Santiago Ponce; Cortés-Funes, Hernán

    2013-01-01

    Cholangiocarcinomas (bile duct cancers) are a heterogeneous group of malignancies arising from the epithelial cells of the intrahepatic, perihilar and extrahepatic bile ducts. Patients diagnosed with cholangiocarcinoma must be evaluated by a multidisciplinary team and be treated with individualized management. First of all, it is very important to define the potential resectability of the tumor because surgery is the main therapeutic option for these patients. Overall, cholangiocarcinomas have a very poor prognosis. The 5-year survival rate is 5%-10%. In cases with a potentially curative surgery, 5-year survival rates of 25%-30% are reported. Therefore, it is necessary to increase the cure rate from surgery, exploring the survival benefit of any adjuvant strategy. It is difficult to clarify the role of adjuvant treatment in localized and locally advanced cholangiocarcinomas. There are limited data and the role of adjuvant chemotherapy/chemoradiation in patients with resected biliary tract cancer is poorly defined. The most relevant studies in the adjuvant setting are one from Japan, the well known ESPAC-3 and BILCAP from the United Kingdom and a meta-analysis. We show the results of these trials. According to medical oncology guidelines, postoperative adjuvant therapy is widely recommended for all patients with intrahepatic or extrahepatic cholangiocarcinoma who have microscopically positive resection margins, as well as for those with a complete resection but node-positive disease. Clinical trials are ongoing. The locally advanced cholangiocarcinoma setting includes a heterogeneous mix of patients: (1) patients who have had surgery but with macroscopic residual disease; (2) patients with locally recurrent disease after potentially curative treatment; and (3) patients with locally unresectable disease at presentation. In these patients, surgery is not an option and chemoradiation therapy can prolong overall survival and provide control of symptoms due to local

  16. Resin-based Yttrium-90 microspheres for unresectable and failed first-line chemotherapy intrahepatic cholangiocarcinoma: preliminary results.

    PubMed

    Jia, Zhongzhi; Paz-Fumagalli, Ricardo; Frey, Gregory; Sella, David M; McKinney, J Mark; Wang, Weiping

    2017-03-01

    To evaluate the value of resin-based yttrium-90 ((90)Y) radioembolization for unresectable and failed first-line chemotherapy (cisplatin plus gemcitabine) intrahepatic cholangiocarcinoma (ICC). From February 2006 to September 2015, a retrospective study was conducted of all patients who underwent resin-based (90)Y therapy for unresectable and failed first-line chemotherapy ICC. Tumor response was assessed using modified RECIST criteria; side effects were assessed using Common Terminology Criteria for Adverse Events version 4.03; survivals were calculated from the date of diagnosis of ICC, beginning of first-line chemotherapy and first (90)Y procedure, respectively; effects of factors on survival were analyzed by Cox regression model. Twenty-four patients (eight male and 16 female) were included in this study. Mean 5.6 ± 1.6 cycles of first-line chemotherapy were performed prior to (90)Y treatment. The mean delivered activity of (90)Y was 1.6 ± 0.4 GBq with a total of 27 treatments. Disease control rate was 81.8% at 3 months after (90)Y therapy, with partial response (n = 8, 36.4%), stable disease (n = 10, 45.5%) and progressive disease (n = 6, 18.2%). CA199 changes pre- and 1 month post-treatment were complete (n = 2), partial (n = 2), none (n = 5) and progression (n = 2), respectively. Side effects included fatigue (n = 21, 87.5%), anorexia (n = 19, 79.2%), nausea (n = 15, 62.5%), abdominal pain (n = 10, 58.3%), vomiting (n = 4, 16.7%) and fever (n = 3, 12.5%). Radiation-induced gastrointestinal ulcer was identified in one patient. The mean follow-up was 11.3 ± 6.6 months, and the median survivals from the time of diagnosis of ICC, beginning of first-line chemotherapy and first (90)Y procedure were 24.0, 16.0 and 9.0 months, respectively, and the 6-, 12-, 18-, 24- and 30-month survival after (90)Y therapy were 69.9, 32.6, 27.2, 20.4 and 20.4%, respectively. ECOG performance status (P = 0.002) and lymph node metastases (P

  17. Cholangiocarcinoma and malignant bile duct obstruction: A review of last decades advances in therapeutic endoscopy

    PubMed Central

    Bertani, Helga; Frazzoni, Marzio; Mangiafico, Santi; Caruso, Angelo; Manno, Mauro; Mirante, Vincenzo Giorgio; Pigò, Flavia; Barbera, Carmelo; Manta, Raffaele; Conigliaro, Rita

    2015-01-01

    In the last decades many advances have been achieved in endoscopy, in the diagnosis and therapy of cholangiocarcinoma, however blood test, magnetic resonance imaging, computed tomography scan may fail to detect neoplastic disease at early stage, thus the diagnosis of cholangiocarcinoma is achieved usually at unresectable stage. In the last decades the role of endoscopy has moved from a diagnostic role to an invaluable therapeutic tool for patients affected by malignant bile duct obstruction. One of the major issues for cholangiocarcinoma is bile ducts occlusion, leading to jaundice, cholangitis and hepatic failure. Currently, endoscopy has a key role in the work up of cholangiocarcinoma, both in patients amenable to surgical intervention as well as in those unfit for surgery or not amenable to immediate surgical curative resection owing to locally advanced or advanced disease, with palliative intention. Endoscopy allows successful biliary drainage and stenting in more than 90% of patients with malignant bile duct obstruction, and allows rapid reduction of jaundice decreasing the risk of biliary sepsis. When biliary drainage and stenting cannot be achieved with endoscopy alone, endoscopic ultrasound-guided biliary drainage represents an effective alternative method affording successful biliary drainage in more than 80% of cases. The purpose of this review is to focus on the currently available endoscopic management options in patients with cholangiocarcinoma. PMID:26078827

  18. Circulating Plasma Levels of MicroRNA-21 and MicroRNA-221 Are Potential Diagnostic Markers for Primary Intrahepatic Cholangiocarcinoma

    PubMed Central

    Kemeny, Nancy; Kingham, T. Peter; Allen, Peter J.; D’Angelica, Michael I.; DeMatteo, Ronald P.; Betel, Doron; Klimstra, David; Jarnagin, William R.; Ventura, Andrea

    2016-01-01

    Background MicroRNAs (miRNAs) are potential biomarkers in various malignancies. We aim to characterize miRNA expression in intrahepatic cholangiocarcinoma (ICC) and identify circulating plasma miRNAs with potential diagnostic and prognostic utility. Methods Using deep-sequencing techniques, miRNA expression between tumor samples and non-neoplastic liver parenchyma were compared. Overexpressed miRNAs were measured in plasma from an independent cohort of patients with cholangiocarcinoma using RT-qPCR and compared with that healthy volunteers. The discriminatory ability of the evaluated plasma miRNAs between patients and controls was evaluated with receiving operating characteristic (ROC) curves. Results Small RNAs from 12 ICC and 11 tumor-free liver samples were evaluated. Unsupervised hierarchical clustering using the miRNA expression data showed clear grouping of ICC vs. non-neoplastic liver parenchyma. We identified 134 down-regulated and 128 upregulated miRNAs. Based on overexpression and high fold-change, miR21, miR200b, miR221, and miR34c were measured in plasma from an independent cohort of patients with ICC (n = 25) and healthy controls (n = 7). Significant overexpression of miR-21 and miR-221 was found in plasma from ICC patients. Furthermore, circulating miR-21 demonstrated a high discriminatory ability between patients with ICC and healthy controls (AUC: 0.94). Conclusion Among the differentially expressed miRNAs in ICC, miR-21 and miR-221 are overexpressed and detectable in the circulation. Plasma expression levels of these miRNAs, particularly miR-21, accurately differentiates patients with ICC from healthy controls and could potentially serve as adjuncts in diagnosis. Prospective validation and comparison with other hepatobiliary malignancies is required to establish their potential role as diagnostic and prognostic biomarkers. PMID:27685844

  19. [Cholangiocarcinoma among printing workers].

    PubMed

    Kumagai, Shinji

    2014-02-01

    By June 2013, seventeen workers had suffered from intrahepatic or extrahepatic bile duct cancer (cholangiocarcinoma) in an offset proof-printing company in Osaka and nine of the workers had died. Ages at diagnosis were 25 to 45 years old. Known risk factors for cholangiocarcinoma were not found in the patients. All of the patients were exposed to 1,2-dichloropropane at high level for long-term and were diagnosed with cholangiocarcinoma 7 to 20 years after the first exposure. Twelve of the patients were also exposed to dichloromethane. The Japan Ministry of Health, Labour and Welfare recognized the cancer to be an occupational disease.

  20. Downregulation of ROS-FIG inhibits cell proliferation, colony‑formation, cell cycle progression, migration and invasion, while inducing apoptosis in intrahepatic cholangiocarcinoma cells.

    PubMed

    Deng, Gang; Hu, Chenghuan; Zhu, Lei; Huang, Feizhou; Huang, Wei; Xu, Hongbo; Nie, Wanpin

    2014-09-01

    Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer with poor responsiveness to existing drug therapies. Therefore, novel treatment strategies against ICC are required to improve survival. The aim of this study was to demonstrate the role of fused-in-glioblastoma-c-ros-oncogene1 (FIG-ROS) fusion gene in ICC. ROS was positively expressed in ICC tissues and HUCCT1 cells. Plasmids expressing ROS- and FIG-specific shRNAs were constructed and transfected into HUCCT1 cells. The results showed that single transfection of ROS- or FIG-specific shRNA inhibited HUCCT1 cell proliferation, colony formation, cell cycle progression, migration and invasion, while inducing apoptosis. Moreover, the co-inhibition of ROS- and FIG-specific shRNA exhibited stronger effects on HUCCT1 cell proliferation, apoptosis, colony formation, cell cycle progression, migration and invasion, when compared to single inhibition of ROS and FIG. Furthermore, findings of this study suggested that the AKT signaling pathway was involved in the ROS-FIG-mediated biological processes of HUCCT1 cells. In summary, the results suggest that FIG-ROS plays an oncogenic role in ICC. Additionally, ROS1-6290 and FIG-363 segments may become effective therapeutic targets for ICC harboring ROS-FIG fusion protein.

  1. Downregulation of ROS-FIG inhibits cell proliferation, colony-formation, cell cycle progression, migration and invasion, while inducing apoptosis in intrahepatic cholangiocarcinoma cells

    PubMed Central

    DENG, GANG; HU, CHENGHUAN; ZHU, LEI; HUANG, FEIZHOU; HUANG, WEI; XU, HONGBO; NIE, WANPIN

    2014-01-01

    Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer with poor responsiveness to existing drug therapies. Therefore, novel treatment strategies against ICC are required to improve survival. The aim of this study was to demonstrate the role of fused-in-glioblastoma-c-ros-oncogene1 (FIG-ROS) fusion gene in ICC. ROS was positively expressed in ICC tissues and HUCCT1 cells. Plasmids expressing ROS- and FIG-specific shRNAs were constructed and transfected into HUCCT1 cells. The results showed that single transfection of ROS- or FIG-specific shRNA inhibited HUCCT1 cell proliferation, colony formation, cell cycle progression, migration and invasion, while inducing apoptosis. Moreover, the co-inhibition of ROS- and FIG-specific shRNA exhibited stronger effects on HUCCT1 cell proliferation, apoptosis, colony formation, cell cycle progression, migration and invasion, when compared to single inhibition of ROS and FIG. Furthermore, findings of this study suggested that the AKT signaling pathway was involved in the ROS-FIG-mediated biological processes of HUCCT1 cells. In summary, the results suggest that FIG-ROS plays an oncogenic role in ICC. Additionally, ROS1-6290 and FIG-363 segments may become effective therapeutic targets for ICC harboring ROS-FIG fusion protein. PMID:24968753

  2. MRI of small intrahepatic mass-forming cholangiocarcinoma and atypical small hepatocellular carcinoma (≤3 cm) with cirrhosis and chronic viral hepatitis: a comparative study.

    PubMed

    Sheng, Ruo-Fan; Zeng, Meng-Su; Rao, Sheng-Xiang; Ji, Yuan; Chen, Ling-Li

    2014-01-01

    The objective was to identify the decision-making magnetic resonance (MR) features in differentiating small intrahepatic mass-forming cholangiocarcinoma (sIMCC) from atypical small hepatocellular carcinoma (sHCC) (≤3 cm) in patients with cirrhosis and chronic viral hepatitis. Signal features and relative contrast of sHCCs and sIMCCs in T2-weighted and dynamic enhanced imaging were analyzed. A subgroup comparison between the cirrhosis and noncirrhosis chronic viral hepatitis group was also made. Univariate analysis revealed that tumor contours (P<.001), signals in T2-weighted (P<.001) and each phase of contrast-enhanced scanning (P<.001), enhancement patterns (P<.001), as well as accompanying findings of tumor capsule (P<.001), hepatic capsule retraction (P<.001), bile duct dilation (P=.031), and transient hepatic intensity difference (P=.002) were different between sIMCC and atypical sHCC. Multivariate analysis indicated that dynamic enhancement patterns (P<.001) and signals in T2-weighted images (P=.024) were independent predictors for differentiation. Confusing MR features were more often observed in the cirrhosis group compared with those in the noncirrhosis chronic viral hepatitis group. Dynamic enhancement patterns and signals in T2-weighted images were the most important MR features to differentiate sIMCC from atypical sHCC with cirrhosis and chronic viral hepatitis. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Gene and microRNA modulation upon trabectedin treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line

    PubMed Central

    Peraldo Neia, Caterina; Cavalloni, Giuliana; Chiorino, Giovanna; Ostano, Paola; Aglietta, Massimo; Leone, Francesco

    2016-01-01

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy with limited therapeutic options. Trabectedin has a high antitumor activity in preclinical models of biliary tract carcinoma (BTC), being a promising alternative treatment. Here, we studied the effect of trabectedin at transcriptomic level on an ICC patient derived xenograft (PDX) and on the derived cell line, MT-CHC01. Further, putative targets of trabectedin were explored in the in vitro model. In vitro, trabectedin inhibited genes involved in protein modification, neurogenesis, migration, and motility; it induced the expression of genes involved in keratinization, tissues development, and apoptotic processes. In the PDX model, trabectedin affected ECM-receptor interaction, focal adhesion, complement and coagulation cascades, Hedgehog, MAPK, EGFR signaling via PIP3 pathway, and apoptosis. Among down-regulated genes, we selected SYK and LGALS1; their silencing caused a significantly reduction of migration, but did not affect proliferation in in vitro models. In MT-CHC01 cells, 24 microRNAs were deregulated upon drug treatment, while only 5 microRNAs were perturbed by trabectedin in PDX. The target prediction analysis showed that SYK and LGALS1 are putative targets of up-regulated microRNAs. In conclusion, we described that trabectedin affected genes and microRNAs involved in tumor progression and metastatic processes, reflecting data previously obtained at macroscopically level; in particular, we identified SYK and LGALS1 as new putative targets of trabectedin. PMID:27902465

  4. MiR-21 promotes intrahepatic cholangiocarcinoma proliferation and growth in vitro and in vivo by targeting PTPN14 and PTEN

    PubMed Central

    Wang, Li-Juan; He, Chen-Chen; Sui, Xin; Cai, Meng-Jiao; Zhou, Cong-Ya; Ma, Jin-Lu; Wu, Lei; Wang, Hao; Han, Su-Xia; Zhu, Qing

    2015-01-01

    Intrahepatic cholangiocarcinoma (ICC) constitutes the second-most common primary hepatic malignancy. MicroRNAs (miRNAs) play important roles in the pathogenesis of ICC. However, the clinical significance of miR-21 levels in ICC remains unclear. Here, we investigated the role of miR-21 in ICC and found that its expression was significantly upregulated in serum of ICC patients. Serum miR-21 levels robustly distinguished ICC patients from control subjects. Further experiments showed that inhibition of miR-21 suppressed ICC cell proliferation in vitro and tumor growth in vivo. Specifically, inhibition of miR-21 induced cell cycle arrest and apoptosis. Moreover, PTPN14 and PTEN were identified as direct and functional targets of miR-21. Finally, we showed high expression levels of miR-21 were closely related to adverse clinical features, diminished survival, and poor prognosis in ICC patients. This study revealed functional and mechanistic links between miR-21 and tumor suppressor genes, PTPN14 and PTEN, in the pathogenesis of ICC. MiR-21 not only plays important roles in the regulation of cell proliferation and tumor growth in ICC, but is also a diagnostic and prognostic marker, and a potential therapeutic target for ICC. PMID:25803229

  5. MiR-376c down-regulation accelerates EGF-dependent migration by targeting GRB2 in the HuCCT1 human intrahepatic cholangiocarcinoma cell line.

    PubMed

    Iwaki, Jun; Kikuchi, Kunio; Mizuguchi, Yoshiaki; Kawahigashi, Yutaka; Yoshida, Hiroshi; Uchida, Eiji; Takizawa, Toshihiro

    2013-01-01

    MicroRNA miR-376c was expressed in normal intrahepatic biliary epithelial cells (HIBEpiC), but was significantly suppressed in the HuCCT1 intrahepatic cholangiocarcinoma (ICC) cell line. The biological significance of the down-regulation of miR-376c in HuCCT1 cells is unknown. We hypothesized that miR-376c could function as a tumor suppressor in these cells. To test this hypothesis, we sought the targets of miR-376c, and characterized the effect of its down-regulation on HuCCT1 cells. We performed proteomic analysis of miR-376c-overexpressing HuCCT1 cells to identify candidate targets of miR-376c, and validated these targets by 3'-UTR reporter assay. Transwell migration assays were performed to study the migratory response of HuCCT1 cells to miR-376c overexpression. Furthermore, microarrays were used to identify the signaling that were potentially involved in the miR-376c-modulated migration of HuCCT1. Finally, we assessed epigenetic changes within the potential promoter region of the miR-376c gene in these cells. Proteomic analysis and subsequent validation assays showed that growth factor receptor-bound protein 2 (GRB2) was a direct target of miR-376c. The transwell migration assay revealed that miR-376c significantly reduced epidermal growth factor (EGF)-dependent cell migration in HuCCT1 cells. DNA microarray and subsequent pathway analysis showed that interleukin 1 beta and matrix metallopeptidase 9 were possible participants in EGF-dependent migration of HuCCT1 cells. Bisulfite sequencing showed higher methylation levels of CpG sites upstream of the miR-376c gene in HuCCT1 relative to HIBEpiC cells. Combined treatment with the DNA-demethylating agent 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor trichostatin A significantly upregulated the expression of miR-376c in HuCCT1 cells. We revealed that epigenetic repression of miR-376c accelerated EGF-dependent cell migration through its target GRB2 in HuCCT1 cells. These findings suggest that miR-376

  6. MiR-376c Down-Regulation Accelerates EGF-Dependent Migration by Targeting GRB2 in the HuCCT1 Human Intrahepatic Cholangiocarcinoma Cell Line

    PubMed Central

    Mizuguchi, Yoshiaki; Kawahigashi, Yutaka; Yoshida, Hiroshi; Uchida, Eiji; Takizawa, Toshihiro

    2013-01-01

    MicroRNA miR-376c was expressed in normal intrahepatic biliary epithelial cells (HIBEpiC), but was significantly suppressed in the HuCCT1 intrahepatic cholangiocarcinoma (ICC) cell line. The biological significance of the down-regulation of miR-376c in HuCCT1 cells is unknown. We hypothesized that miR-376c could function as a tumor suppressor in these cells. To test this hypothesis, we sought the targets of miR-376c, and characterized the effect of its down-regulation on HuCCT1 cells. We performed proteomic analysis of miR-376c-overexpressing HuCCT1 cells to identify candidate targets of miR-376c, and validated these targets by 3′-UTR reporter assay. Transwell migration assays were performed to study the migratory response of HuCCT1 cells to miR-376c overexpression. Furthermore, microarrays were used to identify the signaling that were potentially involved in the miR-376c-modulated migration of HuCCT1. Finally, we assessed epigenetic changes within the potential promoter region of the miR-376c gene in these cells. Proteomic analysis and subsequent validation assays showed that growth factor receptor-bound protein 2 (GRB2) was a direct target of miR-376c. The transwell migration assay revealed that miR-376c significantly reduced epidermal growth factor (EGF)-dependent cell migration in HuCCT1 cells. DNA microarray and subsequent pathway analysis showed that interleukin 1 beta and matrix metallopeptidase 9 were possible participants in EGF-dependent migration of HuCCT1 cells. Bisulfite sequencing showed higher methylation levels of CpG sites upstream of the miR-376c gene in HuCCT1 relative to HIBEpiC cells. Combined treatment with the DNA-demethylating agent 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor trichostatin A significantly upregulated the expression of miR-376c in HuCCT1 cells. We revealed that epigenetic repression of miR-376c accelerated EGF-dependent cell migration through its target GRB2 in HuCCT1 cells. These findings suggest that mi

  7. Metabolic characteristics distinguishing intrahepatic cholangiocarcinoma: a negative pilot study of 18F-fluorocholine PET/CT clarified by transcriptomic analysis

    PubMed Central

    Kwee, Sandi A; Okimoto, Gordon S; Chan, Owen TM; Tiirikainen, Maarit; Wong, Linda L

    2016-01-01

    PET using fluorine-18 fluorocholine (18F-fluorocholine) may detect malignancies that involve altered choline metabolism. While 18F-fluorocholine PET/CT has shown greater sensitivity for detecting hepatocellular carcinoma (HCC) than 18F-fluoro-D-deoxyglucose (FDG) PET/CT, it is not known whether it can also detect intrahepatic cholangiocarcinoma (ICC), a less common form of primary liver cancer. Clinical, radiographic, and histopathologic data from 5 patients with ICC and 23 patients with HCC from a diagnostic trial of liver 18F-fluorocholine PET/CT imaging were analyzed to preliminarily evaluate 18F-fluorocholine PET/CT for ICC. Imaging was correlated with whole-genome expression profiling to identify molecular pathways associated with tumor phenotypes. On PET/CT, all ICC tumors demonstrated low 18F-fluorocholine uptake with a significantly lower tumor to mean background uptake ratio than HCC tumors (0.69 vs. 1.64, p < 0.0001), but no corresponding significant difference in liver parenchyma uptake of 18F-fluorocholine between ICC and HCC patients (8.0 vs. 7.7, p = 0.74). Two ICC patients demonstrated increased tumor metabolism on FDG PET/CT, while immunohistochemical analysis of ICC tumors revealed overexpression of glucose transporter 1 (GLUT-1) and hexokinase indicating a hyper-glycolytic phenotype. Gene expression analysis revealed down-regulation of farnesoid-X-receptor and other lipid pathways in ICC relative to HCC, and up-regulation of glycolytic pathways and GLUT-1 by HIF1α. These results imply limited utility of 18F-fluorocholine in ICC, however, significant metabolic differences between ICC, HCC, and parenchymal liver tissue may still provide clues about the underlying liver pathology. Gene and protein expression analysis support hyperglycolysis as a more dominant metabolic trait of ICC. PMID:27069767

  8. Multi-modality treatment of primary nonresectable intrahepatic cholangiocarcinoma with /sup 131/I anti-CEA--a Radiation Therapy Oncology Group Study

    SciTech Connect

    Stillwagon, G.B.; Order, S.E.; Klein, J.L.; Leichner, P.K.; Leibel, S.A.; Siegelman, S.S.; Fishman, E.K.; Ettinger, D.S.; Haulk, T.; Kopher, K.

    1987-05-01

    Thirty-seven patients with primary nonresectable intrahepatic cholangiocarcinoma (57% with prior treatment and/or metastasis) were prospectively treated with external radiation, chemotherapy, and /sup 131/I labelled anti-CEA. Therapy began in all trials with whole liver irradiation (21.0 Gy, 3.0 Gy/Fx, 4 days/week, 10 MV photons) with alternate treatment day chemotherapy (Adriamycin, 15 mg + 5-FU, 500 mg). One month after external beam therapy, chemotherapy was given (Adriamycin, 15 mg + 5-FU, 500 mg) followed the next day by the first administration of /sup 131/I anti-CEA. The treatment schedule used was 20 mCi day 0; 10 mCi day 5 as an outpatient. This schedule was derived from tumor dose estimates which indicated that 20 mCi (8-10 mCi/mg IgG) was sufficient to achieve tumor saturation with a tumor effective half-life of 3 to 5 days, depending upon the species of animal from which the antibody was obtained. The median tumor dose for the 20 mCi + 10 mCi regimen was 6.2 Gy. Antibody therapy was delivered in 2-month cycles using antibody generated in different species of animals; rabbit, pig, monkey, and bovine. Toxicity was limited to hematologic toxicity and was manifested as thrombocytopenia and leukocytopenia (3.2% Grade IV for each according to RTOG toxicity criteria). Tumor remission evaluated by CT scan digitized tumor volume analysis indicated a 26.6% partial response (PR). Tumor remission by physical examination indicated a 33.3% remission rate (25.9% PR and 7.4% complete remission (CR). The median survival for patients who responded was 15.2 months. The actuarial median survival for the entire group of patients (metastases and previous treatment) was 6.5 months. The longest partial remission is presently more than 4 years.

  9. Classification, Diagnosis, and Management of Cholangiocarcinoma

    PubMed Central

    Razumilava, Nataliya; Gores, Gregory J.

    2013-01-01

    Cholangiocarcinomas (CCAs) are tumors that develop along the biliary tract. Depending on their site of origin, they have different features and require specific treatments. Classification of CCAs into intrahepatic, perihilar, and distal subgroups has helped standardize the registration, treatment, and study of this lethal malignancy. Physicians should remain aware that cirrhosis and viral hepatitis B and C are predisposing conditions for intrahepatic CCA. Treatment options under development include locoregional therapies and a chemotherapy regimen of gemcitabine and cisplatin. It is a challenge to diagnose perihilar CCA, but an advanced cytologic technique of fluorescence in situ hybridization for polysomy can aid in diagnosis. It is important to increase our understanding of the use of biliary stents and liver transplantation in the management of perihilar CCA, as well as to distinguish distal CCAs from pancreatic cancer, because of different outcomes from surgery. We review advances in the classification, diagnosis, and staging of CCA, along with treatment options. PMID:22982100

  10. Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

    PubMed Central

    Wo, Jennifer Y.; Yeap, Beow Y.; Ben-Josef, Edgar; McDonnell, Erin I.; Blaszkowsky, Lawrence S.; Kwak, Eunice L.; Allen, Jill N.; Clark, Jeffrey W.; Goyal, Lipika; Murphy, Janet E.; Javle, Milind M.; Wolfgang, John A.; Drapek, Lorraine C.; Arellano, Ronald S.; Mamon, Harvey J.; Mullen, John T.; Yoon, Sam S.; Tanabe, Kenneth K.; Ferrone, Cristina R.; Ryan, David P.; DeLaney, Thomas F.; Crane, Christopher H.; Zhu, Andrew X.

    2016-01-01

    Purpose To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Materials and Methods In this single-arm, phase II, multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate > 80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC. Results Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC. Conclusion High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC. PMID:26668346

  11. Differentiation of small intrahepatic mass-forming cholangiocarcinoma from small liver abscess by dual source dual-energy CT quantitative parameters.

    PubMed

    Kim, Ji Eun; Kim, Hyun Ok; Bae, Kyungsoo; Cho, Jae Min; Choi, Ho Cheol; Choi, Dae Seob

    2017-07-01

    To investigate the use of dual source dual-energy CT (DECT) quantitative parameters compared with the use of conventional CT for differentiating small (≤3cm) intrahepatic mass-forming cholangiocarcinoma (IMCC) from small liver abscess (LA) during the portal venous phase (PVP). In this institutional review board-approved, retrospective study, 64 patients with IMCCs and 52 patients with LAs who were imaged in PVP using dual-energy mode were included retrospectively. A radiologist drew circular regions of interest in the lesion on the virtual monochromatic images (VMI), color-coded iodine overlay images, and linear blending images with a linear blending ratio of 0.3 to obtain CT value, its standard deviation, slope (k) of spectral curve and normalized iodine concentration (NIC). Two radiologists assessed lesion type on the basis of qualitative CT imaging features. CT values on VMI at 50-130keV (20keV-interval), k, and NIC values were significantly higher in IMCCs than in LAs (p<0.0001). The best single parameter for differentiating IMCC from LA was CT value at 90keV, with sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 89.1%, 86.5%, 87.9%, 89.1%, and 86.5%, respectively. The best combination of parameters was CT value at 90keV, k, and NIC, with values of 87.5%, 84.6%, 83.6%, 87.5%, and 84.6%, respectively. Compared with CT value at linear blending images, CT value at 90keV showed greater sensitivity (89.1% vs 60.9%, p<0.0001) and similar specificity (86.5% vs 84.6%, p=1.0000), and combined CT value at 90keV, k, and NIC showed greater sensitivity (87.5% vs 60.9%, p<0.0001) and similar specificity (84.6% vs 84.6%, p=1.0000). Compared with qualitative analysis, CT value at 90keV showed greater sensitivity (89.1% vs 65.6%, p=0.0059) and specificity (86.5% vs 69.2%, p=0.0352), and combined CT value at 90keV, k, and NIC showed greater sensitivity (87.5% vs 65.6%, p=0.0094) and similar specificity (84.6% vs 69.2%, p >0

  12. Leptin Enhances Cholangiocarcinoma Cell Growth

    PubMed Central

    Fava, Giammarco; Alpini, Gianfranco; Rychlicki, Chiara; Saccomanno, Stefania; DeMorrow, Sharon; Trozzi, Luciano; Candelaresi, Cinzia; Venter, Julie; Di Sario, Antonio; Marzioni, Marco; Bearzi, Italo; Glaser, Shannon; Alvaro, Domenico; Marucci, Luca; Francis, Heather; Svegliati-Baroni, Gianluca; Benedetti, Antonio

    2008-01-01

    Cholangiocarcinoma is a strongly aggressive malignancy with a very poor prognosis. Effective therapeutic strategies are lacking because molecular mechanisms regulating cholangiocarcinoma cell growth are unknown. Furthermore, experimental in vivo animal models useful to study the pathophysiologic mechanisms of malignant cholangiocytes are lacking. Leptin, the hormone regulating caloric homeostasis, which is increased in obese patients, stimulates the growth of several cancers, such as hepatocellular carcinoma. The aim of this study was to define if leptin stimulates cholangiocarcinoma growth. We determined the expression of leptin receptors in normal and malignant human cholangiocytes. Effects on intrahepatic cholangiocarcinoma (HuH-28) cell proliferation, migration, and apoptosis of the in vitro exposure to leptin, together with the intracellular pathways, were then studied. Moreover, cholangiocarcinoma was experimentally induced in obese fa/fa Zucker rats, a genetically established animal species with faulty leptin receptors, and in their littermates by chronic feeding with thioacetamide, a potent carcinogen. After 24 weeks, the effect of leptin on cholangiocarcinoma development and growth was assessed. Normal and malignant human cholangiocytes express leptin receptors. Leptin increased the proliferation and the metastatic potential of cholangiocarcinoma cells in vitro through a signal transducers and activators of transcription 3–dependent activation of extracellular signal-regulated kinase 1/2. Leptin increased the growth and migration, and was antiapoptotic for cholangiocarcinoma cells. Moreover, the loss of leptin function reduced the development and the growth of cholangiocarcinoma. The experimental carcinogenesis model induced by thioacetamide administration is a valid and reproducible method to study cholangiocarcinoma pathobiology. Modulation of the leptin-mediated signal could be considered a valid tool for the prevention and treatment of

  13. The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma.

    PubMed

    Shroff, Rachna T; Yarchoan, Mark; O'Connor, Ashley; Gallagher, Denise; Zahurak, Marianna L; Rosner, Gary; Ohaji, Chimela; Sartorius-Mergenthaler, Susan; Subbiah, Vivek; Zinner, Ralph; Azad, Nilofer S

    2017-05-23

    Cholangiocarcinoma is an aggressive malignancy with limited therapeutic options. MEK inhibition and antiangiogenic therapies have individually shown modest activity in advanced cholangiocarcinoma, whereas dual inhibition of these pathways has not been previously evaluated. We evaluated the safety and efficacy of combination therapy with the oral VEGF receptor tyrosine kinase inhibitor pazopanib plus the MEK inhibitor trametinib in patients with advanced cholangiocarcinoma. In this open-label, multicentre, single-arm trial, adults with advanced unresectable cholangiocarcinoma received pazopanib 800 mg daily and trametinib 2 mg daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) with secondary end points including overall survival (OS), response rate, and disease control rate (DCR). A total of 25 patients were enrolled and had received a median of 2 prior systemic therapies (range 1-7). Median PFS was 3.6 months (95% CI: 2.7-5.1) and the 4-month PFS was 40% (95% CI: 24.7-64.6%). There was a trend towards increased 4-month PFS as compared with the prespecified null hypothesised 4-month PFS of 25%, but this difference did not reach statistical significance (P=0.063). The median survival was 6.4 months (95% CI: 4.3-10.2). The objective response rate was 5% (95% CI: 0.13-24.9%) and the DCR was 75% (95% CI: 51%, 91%). Grade 3/4 adverse events attributable to study drugs were observed in 14 (56%) and included thrombocytopenia, abnormal liver enzymes, rash, and hypertension. Although the combination of pazopanib plus trametinib had acceptable toxicity with evidence of clinical activity, it did not achieve a statistically significant improvement in 4-month PFS over the prespecified null hypothesised 4-month PFS.

  14. Surgical treatment of mucin-producing cholangiocarcinoma arising from intraductal papillary neoplasm of the intrahepatic bile duct: a report of 2 cases

    PubMed Central

    Baterdene, Namsrai; Lee, Jong-Wook; Jung, Min-Jae; Shin, Heeji; Seo, Hye Kyoung; Kim, Myeong-Hwan; Lee, Sung-Koo

    2016-01-01

    Intraductal papillary neoplasms of the bile duct (IPNB) leads to malignant transformation and mucin production. Herein, we presented two cases of mucin-producing IPNB with obstructive jaundice who underwent resection of the intrahepatic lesions and bypass hepaticojejunostomy. The first case was a 69 year-old male patient with 5-year follow up for gallstone disease. Imaging studies showed mucin-secreting IPNB mainly in the hepatic segment III bile duct (B3) and multiple intrahepatic duct stones for which, segment III resection, intrahepatic stone removal, end-to-side choledochojejunostomy and B3 hepaticojejunostomy were conducted. The second case was a 74 year-old female patient with 11-year follow up for gallstone disease. Imaging studies showed mucin-producing IPNB with dilatation of the segment IV duct (B4) and mural nodules for which, segment IV resection, partial resection of the diaphragm and central hepaticojejunostomy were conducted. Both patients recovered uneventfully from surgery. These cases highlight that in patients with IPNB, abundant production of highly viscous mucin inducing obstructive jaundice may be associated with malignant transformation. PMID:27621752

  15. Obesity and cholangiocarcinoma

    PubMed Central

    Parsi, Mansour A

    2013-01-01

    It is estimated that about half of the population in developed countries are either overweight or obese. In some developing nations obesity rates have increased to surpass those seen in Western countries. This rate increase in obesity has many implications as obesity has been associated with numerous negative health effects including increased risks of hypertension, diabetes, cardiovascular disease, stroke, liver disease, apnea, and some cancer types. Obesity is now considered to be one of the major public health concerns facing the society. Cholangiocarcinomas (bile duct cancers) are malignant tumors arising from cholangiocytes inside or outside of the liver. Although cholangiocarcinomas are relatively rare, they are highly lethal. The low survival rate associated with cholangiocarcinoma is due to the advanced stage of the disease at the time of diagnosis. Prevention is therefore especially important in this cancer type. Some data suggest that the incidence of cholangiocarcinoma in the western world is on the rise. Increasing rate of obesity may be one of the factors responsible for this increase. Determining whether obesity is a risk factor for cholangiocarcinoma has significant clinical and societal implications as obesity is both prevalent and modifiable. This paper seeks to provide a summary of the current knowledge linking obesity and cholangiocarcinoma, and encourage further research on this topic. PMID:23382624

  16. Living Donor Liver Transplantation for Combined Hepatocellular Carcinoma and Cholangiocarcinoma: Experience of a Single Center.

    PubMed

    Chang, Cheng-Chih; Chen, Ying-Ju; Huang, Tzu-Hao; Chen, Chun-Han; Kuo, Fang-Ying; Eng, Hock-Liew; Yong, Chee-Chien; Liu, Yueh-Wei; Lin, Ting-Lung; Li, Wei-Feng; Lin, Yu-Hung; Lin, Chih-Che; Wang, Chih-Chi; Chen, Chao-Long

    2017-02-28

    BACKGROUND Because the outcome of liver transplantation for cholangiocarcinoma is often poor, cholangiocarcinoma is a contraindication for liver transplantation in most centers. Combined hepatocellular carcinoma and cholangiocarcinoma is a rare type of primary hepatic malignancy containing features of hepatocellular carcinoma and cholangiocarcinoma. Diagnosing combined hepatocellular carcinoma and cholangiocarcinoma pre-operatively is difficult. Because of sparse research presentations worldwide, we report our experience with living donor liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma. MATERIAL AND METHODS A total of 710 patients underwent living donor liver transplantation at our institution from April 2006 to June 2014; 377 of them received transplantation because of hepatocellular carcinoma with University of California San Francisco (UCSF) staging criteria fulfilled pre-operatively. Eleven patients (2.92%) were diagnosed with combined hepatocellular carcinoma and cholangiocarcinoma confirmed pathologically from explant livers; we reviewed these cases retrospectively. Long-term survival was compared between patients diagnosed with combined hepatocellular carcinoma and cholangiocarcinoma and patients diagnosed with hepatocellular carcinoma. RESULTS The mean age of the patients in our series was 60.2 years, and the median follow-up period was 23.9 months. Four patients were diagnosed with a recurrence during the follow-up period, including one intra-hepatic and three extra-hepatic recurrences. Four patients died due to tumor recurrence. Except for patients with advanced-stage cancer, disease-free survival of patients with combined hepatocellular carcinoma and cholangiocarcinoma compared with that of patients with hepatocellular carcinoma was 80% versus 97.2% in 1 year, and 46.7% versus 92.5% in 3 years (p<0.001), and overall survival was 90% versus 97.2% in 1 year, and 61.7% versus 95.1% in 3 years (p<0.001). CONCLUSIONS

  17. Molecular Pathogenesis of Cholangiocarcinoma

    PubMed Central

    Rizvi, Sumera; Gores, Gregory J.

    2014-01-01

    It has become increasingly apparent of late that inflammation plays an integral role in a spectrum of malignancies including cholangiocarcinoma. Primary sclerosing cholangitis with chronic inflammation is the most common risk factor for cholangiocarcinoma in the Western World. Recent work has highlighted that inflammatory pathways are essential in carcinogenesis and tissue invasion and migration. Inflammation advances carcinogenesis by induction of DNA damage, evasion of apoptosis, promotion of cell proliferation, and neoangiogenesis. Cholangiocarcinoma is characterized by the presence of a desmoplastic stroma consisting of cancer associated fibroblasts, tumor associated macrophages, and tumor infiltrating lymphocytes. This rich inflammatory milieu is vital to the cancer ecosystem, and targeting its components represents an attractive therapeutic option. PMID:25034289

  18. Involvement of PSMD10, CDK4, and Tumor Suppressors in Development of Intrahepatic Cholangiocarcinoma of Syrian Golden Hamsters Induced by Clonorchis sinensis and N-Nitrosodimethylamine.

    PubMed

    Uddin, Md Hafiz; Choi, Min-Ho; Kim, Woo Ho; Jang, Ja-June; Hong, Sung-Tae

    2015-01-01

    Clonorchis sinensis is a group-I bio-carcinogen for cholangiocarcinoma (CCA). Although the epidemiological evidence links clonorchiasis and CCA, the underlying molecular mechanism involved in this process is poorly understood. In the present study, we investigated expression of oncogenes and tumor suppressors, including PSMD10, CDK4, p53 and RB in C. sinensis induced hamster CCA model. Different histochemical/immunohistochemical techniques were performed to detect CCA in 4 groups of hamsters: uninfected control (Ctrl.), infected with C. sinensis (Cs), ingested N-nitrosodimethylamine (NDMA), and both Cs infected and NDMA introduced (Cs+NDMA). The liver tissues from all groups were analyzed for gene/protein expressions by quantitative PCR (qPCR) and western blotting. CCA was observed in all hamsters of Cs+NDMA group with well, moderate, and poorly differentiated types measured in 21.8% ± 1.5%, 13.3% ± 1.3%, and 10.8% ± 1.3% of total tissue section areas respectively. All CCA differentiations progressed in a time dependent manner, starting from the 8th week of infection. CCA stroma was characterized with increased collagen type I, mucin, and proliferative cell nuclear antigen (PCNA). The qPCR analysis showed PSMD10, CDK4 and p16INK4 were over-expressed, whereas p53 was under-expressed in the Cs+NDMA group. We observed no change in RB1 at mRNA level but found significant down-regulation of RB protein. The apoptosis related genes, BAX and caspase 9 were found downregulated in the CCA tissue. Gene/protein expressions were matched well with the pathological changes of different groups except the NDMA group. Though the hamsters in the NDMA group showed no marked pathological lesions, we observed over-expression of Akt/PKB and p53 genes proposing molecular interplay in this group which might be related to the CCA initiation in this animal model. The present findings suggest that oncogenes, PSMD10 and CDK4, and tumor suppressors, p53 and RB, are involved in the

  19. Angiotensin II enhances epithelial-to-mesenchymal transition through the interaction between activated hepatic stellate cells and the stromal cell-derived factor-1/CXCR4 axis in intrahepatic cholangiocarcinoma.

    PubMed

    Okamoto, Koichi; Tajima, Hidehiro; Nakanuma, Shinichi; Sakai, Seisho; Makino, Isamu; Kinoshita, Jun; Hayashi, Hironori; Nakamura, Keishi; Oyama, Katsunobu; Nakagawara, Hisatoshi; Fujita, Hideto; Takamura, Hiroyuki; Ninomiya, Itasu; Kitagawa, Hirohisa; Fushida, Sachio; Fujimura, Takashi; Harada, Shinichi; Wakayama, Tomohiko; Iseki, Shoichi; Ohta, Tetsuo

    2012-08-01

    We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facilitate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1α was released into the supernatant of LI-90 cells to which AngII had been added. SDF-1α increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1α and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of β-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1α, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1α-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and meta-stasis of tumor cells expressing AT-1 and CXCR4.

  20. Imaging spectrum of cholangiocarcinoma: role in diagnosis, staging, and posttreatment evaluation.

    PubMed

    Mar, Winnie A; Shon, Andrew M; Lu, Yang; Yu, Jonathan H; Berggruen, Senta M; Guzman, Grace; Ray, Charles E; Miller, Frank

    2016-03-01

    Cholangiocarcinoma, a tumor of biliary epithelium, is increasing in incidence. The imaging appearance, behavior, and treatment of cholangiocarcinoma differ according to its location and morphology. Cholangiocarcinoma is usually classified as intrahepatic, perihilar, or distal. The three morphologies are mass-forming, periductal sclerosing, and intraductal growing. As surgical resection is the only cure, prompt diagnosis and accurate staging is crucial. In staging, vascular involvement, longitudinal spread, and lymphadenopathy are important to assess. The role of liver transplantation for unresectable peripheral cholangiocarcinoma will be discussed. Locoregional therapy can extend survival for those with unresectable intrahepatic tumors. The main risk factors predisposing to cholangiocarcinoma are parasitic infections, primary sclerosing cholangitis, choledochal cysts, and viral hepatitis. Several inflammatory conditions can mimic cholangiocarcinoma, including IgG4 disease, sclerosing cholangitis, Mirizzi's syndrome, and recurrent pyogenic cholangitis. The role of PET in diagnosis and staging will also be discussed. Radiologists play a crucial role in diagnosis, staging, and treatment of this disease.

  1. Bile Duct Cancer (Cholangiocarcinoma)

    MedlinePlus

    ... Types of Cancer > Bile Duct Cancer (Cholangiocarcinoma) Bile Duct Cancer (Cholangiocarcinoma) This is Cancer.Net’s Guide to Bile Duct Cancer (Cholangiocarcinoma). Use the menu below to choose ...

  2. Positron emission tomography (PET) for cholangiocarcinoma

    PubMed Central

    Breitenstein, S.; Apestegui, C.

    2008-01-01

    The combination of positron emission tomography (PET) with computed tomography (PET-CT) provides simultaneous metabolic and anatomic information on tumors in the same imaging session. Sensitivity of PET/PET-CT is higher for intrahepatic (>90%) than for extrahepatic cholangiocarcinoma (CCA) (about 60%). The detection rate of distant metastasis is 100%. PET, and particularly PET-CT, improves the results and impacts on the oncological management in CCA compared with other imaging modalities. Therefore, PET-CT is recommended in the preoperative staging of intrahepatic (strength of recommendation: moderate) and extrahepatic (strength of recommendation: low) CCA. PMID:18773069

  3. Elevated plasma IL-6 associates with increased risk of advanced fibrosis and cholangiocarcinoma in individuals infected by Opisthorchis viverrini.

    PubMed

    Sripa, Banchob; Thinkhamrop, Bandit; Mairiang, Eimorn; Laha, Thewarach; Kaewkes, Sasithorn; Sithithaworn, Paiboon; Periago, Maria Victoria; Bhudhisawasdi, Vajarabhongsa; Yonglitthipagon, Ponlapat; Mulvenna, Jason; Brindley, Paul J; Loukas, Alex; Bethony, Jeffrey M

    2012-01-01

    Opisthorchis viverrini is considered among the most important of the food-borne trematodes due to its strong association with advanced periductal fibrosis and bile duct cancer (cholangiocarcinoma). We investigated the relationship between plasma levels of Interleukin (IL)-6 and the risk of developing advanced fibrosis and bile duct cancer from chronic Opisthorchis infection. We show that IL-6 circulates in plasma at concentrations 58 times higher in individuals with advanced fibrosis than age, sex, and nearest-neighbor matched controls and 221 times higher in individuals with bile duct cancer than controls. We also observed a dose-response relationship between increasing levels of plasma IL-6 and increasing risk of advanced fibrosis and bile duct cancer; for example, in age and sex adjusted analyses, individuals with the highest quartiles of plasma IL-6 had a 19 times greater risk of developing advanced periductal fibrosis and a 150 times greater risk of developing of bile duct cancer than individuals with no detectable level of plasma IL-6. Finally, we show that a single plasma IL-6 measurement has excellent positive predictive value for the detection of both advanced bile duct fibrosis and bile duct cancer in regions with high O. viverrini transmission. These data support our hypothesis that common mechanisms drive bile duct fibrosis and bile duct tumorogenesis from chronic O. viverrini infection. Our study also adds a unique aspect to the literature on circulating levels of IL-6 as an immune marker of hepatobiliary pathology by showing that high levels of circulating IL-6 in plasma are not related to infection with O. viverrini, but to the development of the advanced and often lethal pathologies resulting from chronic O. viverrini infection.

  4. Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma

    PubMed Central

    Rizvi, Sumera; Gores, Gregory J.

    2013-01-01

    Cholangiocarcinomas (CCAs) are hepatobiliary cancers with features of cholangiocyte differentiation; they can be classified anatomically as intrahepatic (iCCA), perihilar (pCCA), or distal CCA (dCCA). These subtypes differ not only in their anatomic location but in epidemiology, origin, etiology, pathogenesis, and treatment. The incidence and mortality of iCCA has been increasing over the past 3 decades, and only a low percentage of patients survive until 5 y after diagnosis. Geographic variations in the incidence of CCA are related to variations in risk factors. Changes in oncogene and inflammatory signaling pathways, as well as genetic and epigenetic alterations and chromosome aberrations, have been shown to contribute to development of CCA. Furthermore, CCAs are surrounded by a dense stroma that contains many cancer-associated fibroblasts, which promotes their progression. We have gained a better understanding of the imaging characteristics of iCCAs and have developed advanced cytologic techniques to detect pCCAs. Patients with iCCAs are usually treated surgically, whereas liver transplantation following neoadjuvant chemoradiation is an option for a subset of patients with pCCAs. We review recent developments in our understanding of the epidemiology, pathogenesis, of CCA, along with advances in classification, diagnosis and treatment. PMID:24140396

  5. Long-term outcome of photodynamic therapy with systemic chemotherapy compared to photodynamic therapy alone in patients with advanced hilar cholangiocarcinoma.

    PubMed

    Hong, Mi Jin; Cheon, Young Koog; Lee, Eung Jun; Lee, Tae Yoon; Shim, Chan Sup

    2014-05-01

    Patients with cholangiocarcinoma usually present at an advanced stage, and more than 50% of cases are not resectable at the time of diagnosis. Recently, photodynamic therapy (PDT) has been proposed as a palliative and neoadjuvant modality. We evaluated whether combination of PDT and chemotherapy is more effective than PDT alone. In total, 161 patients with cholangiocarcinoma diagnosed between February 1999 and September 2009 were evaluated. Sixteen patients were treated with PDT and chemotherapy (group A), and 58 were treated with PDT (group B). The median survival was 538 days (95% confidence interval [CI], 475.3 to 600.7) in group A and 334 days (95% CI, 252.5 to 415.5) in group B (p=0.05). Lymph node metastasis status, serum bilirubin of pretreatment, tumor node metastasis stage, treatment method (PDT with chemotherapy vs PDT alone), time to PDT and the number of PDT sessions were prognostic factors with statistical significance in the univariate analysis. A multivariate analysis showed that PDT with chemotherapy and more than two sessions of PDT were significant independent predictors of longer survival in advanced cholangiocarcinoma (hazard ratio [HR], 2.23; 95% CI, 1.18 to 4.20; p=0.013 vs HR, 1.79; 95% CI, 1.044 to 3.083; p=0.034). PDT with chemotherapy results in longer survival than PDT alone.

  6. Sorafenib Tosylate and Erlotinib Hydrochloride in Treating Patients With Locally Advanced, Unresectable, or Metastatic Gallbladder Cancer or Cholangiocarcinoma

    ClinicalTrials.gov

    2015-06-03

    Extrahepatic Bile Duct Adenocarcinoma; Gallbladder Adenocarcinoma; Gallbladder Adenocarcinoma With Squamous Metaplasia; Hilar Cholangiocarcinoma; Recurrent Extrahepatic Bile Duct Carcinoma; Recurrent Gallbladder Carcinoma; Undifferentiated Gallbladder Carcinoma; Unresectable Extrahepatic Bile Duct Carcinoma; Unresectable Gallbladder Carcinoma

  7. Prognostic value of CA 19-9 kinetics during gemcitabine-based chemotherapy in patients with advanced cholangiocarcinoma.

    PubMed

    Lee, Ban Seok; Lee, Sang Hyub; Son, Jun Hyuk; Jang, Dong Kee; Chung, Kwang Hyun; Paik, Woo Hyun; Ryu, Ji Kon; Kim, Yong-Tae

    2016-02-01

    Little is known of the prognostic value of CEA/CA 19-9 kinetics during chemotherapy in patients with advanced cholangiocarcinoma (CCA). A total of 236 patients with pathologically confirmed advanced CCA received gemcitabine-based chemotherapy were reviewed, and 179 were eligible for analysis. Baseline, pre-, and post-treatment (after two cycles of chemotherapy) CEA and CA 19-9 values were checked, and survival was compared according to various cutting points of baseline measurement or extent of change of tumor marker level. Patients with a ≥ 50% decline in CA 19-9 level had better survival than the others (16.0 vs 9.0 months). However, CEA decline did not predict survival gain. Significant favorable prognostic factors of survival in multivariable analysis included initial treatment response (HR 0.61), distal location of tumor (HR 0.46), baseline CA 19-9 level ≤ 1000 U/mL (HR 0.58), and ≥ 50% decline in CA 19-9 level (HR 0.50). Subgroup analysis was conducted in 114 patients with pre-treatment CA 19-9 > 37 U/mL and bilirubin ≤ 2 mg/dL. Decline ≥ 50% in CA 19-9 level still showed an independent prognostic significance (HR 0.45). CA 19-9 but not CEA kinetics serves as a predictor of better survival in patients with advanced CCA on gemcitabine-based chemotherapy. A ≥ 50% decline in CA 19-9 level after two cycles of chemotherapy may have clinical utility as an early indicator of better response to gemcitabine-based chemotherapy. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  8. Update on the Diagnosis and Treatment of Cholangiocarcinoma.

    PubMed

    Doherty, Bryan; Nambudiri, Vinod E; Palmer, William C

    2017-01-01

    Cholangiocarcinoma is a rare biliary adenocarcinoma associated with poor outcomes. Cholangiocarcinoma is subdivided into extrahepatic and intrahepatic variants. Intrahepatic cholangiocarcinoma is then further differentiated into (1) peripheral mass-forming tumors and (2) central periductal infiltrating tumors. We aimed to review the currently known risk factors, diagnostic tools, and treatment options, as well as highlight the need for further clinical trials and research to improve overall survival rates. Cholangiocarcinoma has seen significant increase in incidence rates over the last several decades. Most patients do not carry the documented risk factors, which include infections and inflammatory conditions, but cholangiocarcinoma typically forms in the setting of cholestasis and chronic inflammation. Management strategies include multispecialty treatments, with consideration of surgical resection, systemic chemotherapy, and targeted radiation therapy. Surgically resectable disease is the only curable treatment option, which may involve liver transplantation in certain selected cases. Referrals to centers of excellence, along with enrollment in novel clinical trials are recommended for patients with unresectable or recurrent disease. This article provides an overview of cholangiocarcinoma and discusses the current diagnosis and treatment options. While incidence is increasing and more risk factors are being discovered, much more work remains to improve outcomes of this ominous disease.

  9. The PD-1/PD-L1 axis may be aberrantly activated in occupational cholangiocarcinoma.

    PubMed

    Sato, Yasunori; Kinoshita, Masahiko; Takemura, Shigekazu; Tanaka, Shogo; Hamano, Genya; Nakamori, Shoji; Fujikawa, Masahiro; Sugawara, Yasuhiko; Yamamoto, Takatsugu; Arimoto, Akira; Yamamura, Minako; Sasaki, Motoko; Harada, Kenichi; Nakanuma, Yasuni; Kubo, Shoji

    2017-03-01

    An outbreak of cholangiocarcinoma in a printing company was reported in Japan, and these cases were regarded as an occupational disease (occupational cholangiocarcinoma). This study examined the expression status of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in occupational cholangiocarcinoma. Immunostaining of PD-1, PD-L1, CD3, CD8, and CD163 was performed using tissue sections of occupational cholangiocarcinoma (n = 10), and the results were compared with those of control cases consisting of intrahepatic (n = 23) and extrahepatic (n = 45) cholangiocarcinoma. Carcinoma cells expressed PD-L1 in all cases of occupational cholangiocarcinoma, whereas the detection of PD-L1 expression in cholangiocarcinoma cells was limited to a low number of cases (less than 10%) in the control subjects. In cases of occupational cholangiocarcinoma, occasional PD-L1 expression was also noted in precancerous/preinvasive lesions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. Additionally, tumor-associated macrophages and tumor-infiltrating T cells expressed PD-L1 and PD-1, respectively. The number of PD-L1-positive mononuclear cells, PD-1-positive lymphocytes, and CD8-positive lymphocytes infiltrating within the tumor was significantly higher in occupational cholangiocarcinoma compared with that in control cases. These results indicate that immune escape via the PD-1/PD-L1 axis may be occurring in occupational cholangiocarcinoma.

  10. [Research advances in diagnosis and treatment of post-transjugular intrahepatic portosystemic shunt hepatic encephalopathy].

    PubMed

    Yang, J F; Zhang, B Q

    2016-07-20

    Transjugular intrahepatic portosystemic shunt (TIPS) has become an important minimally invasive interventional technique for the treatment of complications of cirrhotic portal hypertension, and currently, it is often used in cirrhotic patients with esophagogastric variceal bleeding (EVB), intractable ascites, hepatic hydrothorax, and Budd-Chiari syndrome. On one hand, TIPS can effectively reduce portal vein pressure and the risk of EVB and intractable ascites; on the other hand, it may reduce the blood flow in liver perfusion, aggravate liver impairment, and cause porto-systemic encephalopathy. Related influencing factors should be evaluated comprehensively in order to prevent the development of post-TIPS hepatic encephalopathy. The diagnosis and treatment of post-TIPS hepatic encephalopathy is still a great challenge in current clinical practice. This article reviews the diagnosis and treatment of post-TIPS hepatic encephalopathy to enhance people's knowledge of this disease.

  11. Computed tomography of primary intrahepatic biliary malignancy

    SciTech Connect

    Itai, Y.; Araki, T.; Furui, S.; Yashiro, N.; Ohtomo, K.; Iio, M.

    1983-05-01

    Fifteen patients with primary intrahepatic biliary malignancy (cholangiocarcinoma in 13, biliary cystadenocarcinoma in two) were examined by computed tomography (CT). The CT features were classified into three types: (A) a well-defined round cystic mass with internal papillary projections, (B) a localized intrahepatic biliary dilatation without a definite mass lesion, and (C) miscellaneous low-density masses. Intraphepatic biliary dilatation was noted in all cases of Types A and B and half of those of Type C; dilatation of extrahepatic bile ducts occurred in 4/4, 1/3, and 0/8, respectively. CT patterns, such as a well-defined round cystic mass with papillary projections or dilatation of intra- and extrahepatic ducts, give important clues leading to a correct diagnosis of primary intrahepatic biliary malignancy.

  12. Locoregional Therapies of Cholangiocarcinoma.

    PubMed

    Sommer, Christof M; Kauczor, Hans U; Pereira, Philippe L

    2016-12-01

    Cholangiocarcinoma (CC) is the second most primary liver malignancy with increasing incidence in Western countries. Currently, surgical R0 resection is regarded as the only potentially curative treatment. The results of systemic chemotherapy and best supportive care (BSC) in patients with metastatic disease are often disappointing in regard to toxicity, oncologic efficacy, and overall survival. In current practice, the use of different locoregional therapies is increasingly more accepted. A review of the literature on locoregional therapies for intrahepatic cholangiocarcinoma (ICC) was undertaken. There are no prospective randomized controlled trials. For localized ICC, either primary or recurrent, radiofrequency ablation (RFA) is by far the most commonly used thermal ablation modality. Thereby, a systematic review and meta-analysis reports major complication in 3.8% as well as 1-, 3-, and 5-year overall survival rates of 82, 47, and 24%, respectively. In selected patients (e.g. with a tumor diameter of ≤3 cm), oncologic efficacy and survival after RFA are comparable with surgical resection. For diffuse ICC, different transarterial therapies, either chemotherapy-based (hepatic artery infusion (HAI), transarterial chemoembolization (TACE)) or radiotherapy-based (transarterial radioembolization (TARE)), show extremely promising results. With regard to controlled trials (transarterial therapy versus systemic chemotherapy, BSC or no treatment), tumor control is virtually always better for transarterial therapies and very often accompanied by a dramatic survival benefit and improvement of quality of life. Of note, the latter is the case not only for patients without extrahepatic metastatic disease but also for those with liver-dominant extrahepatic metastatic disease. There are other locoregional therapies such as microwave ablation, irreversible electroporation, and chemosaturation; however, the current data support their use only in controlled trials or as last

  13. An Autopsy Case of Lepidic Pulmonary Metastasis from Cholangiocarcinoma

    PubMed Central

    Nagayoshi, Yohsuke; Yamamoto, Kazuko; Hashimoto, Satoru; Hisatomi, Keiko; Doi, Seiji; Nagashima, Seiji; Kurohama, Hirokazu; Ito, Masahiro; Takazono, Takahiro; Nakamura, Shigeki; Miyazaki, Taiga; Kohno, Shigeru

    2016-01-01

    We herein report the first case of pulmonary metastasis with lepidic growth that originated from cholangiocarcinoma. A 77-year-old man was admitted to our hospital due to exertional dyspnea and liver dysfunction. Computed tomography showed widespread infiltration and a ground-glass opacity in the lung and dilation of the intrahepatic bile duct. The pulmonary lesion progressed rapidly, and the patient died of respiratory failure. Cholangiocarcinoma and lepidic pulmonary metastasis were pathologically diagnosed by an autopsy. Lepidic pulmonary growth is an atypical pattern of metastasis, and immunopathological staining is useful to distinguish pulmonary metastasis from extrapulmonary cancer and primary pulmonary adenocarcinoma. PMID:27725547

  14. New insights on cholangiocarcinoma

    PubMed Central

    Gatto, Manuela; Alvaro, Domenico

    2010-01-01

    Cholangiocarcinoma (CCA) is a devastating cancer arising from the neoplastic transformation of the biliary epithelium. It is characterized by a progressive increase in incidence and prevalence. The only curative therapy is radical surgery or liver transplantation but, unfortunately, the majority of patients present with advanced stage disease, which is not amenable to surgical therapies. Recently, proposed serum and bile biomarkers could help in the screening and surveillance of categories at risk and in diagnosing CCA at an early stage. The molecular mechanisms triggering neoplastic transformation and growth of biliary epithelium are still undefined, but significant progress has been achieved in the last few years. This review deals with the most recent advances on epidemiology, biology, and clinical management of CCA. PMID:21160821

  15. Cholangiocarcinoma: increasing burden of classifications

    PubMed Central

    Cardinale, Vincenzo; Bragazzi, Maria Consiglia; Carpino, Guido; Torrice, Alessia; Fraveto, Alice; Gentile, Raffaele; Pasqualino, Vincenzo; Melandro, Fabio; Aliberti, Camilla; Bastianelli, Carlo; Brunelli, Roberto; Berloco, Pasquale Bartolomeo; Gaudio, Eugenio

    2013-01-01

    Cholangiocarcinoma (CCA) is a very heterogeneous cancer from any point of view, including epidemiology, risk factors, morphology, pathology, molecular pathology, modalities of growth and clinical features. Given this heterogeneity, a uniform classification respecting the epidemiologic, pathologic and clinical needs is currently lacking. In this manuscript we discussed the different proposed classifications of CCA in relation with recent advances in pathophysiology and biology of this cancer. PMID:24570958

  16. Bile Duct Cancer (Cholangiocarcinoma) Treatment (PDQ®)—Health Professional Version

    Cancer.gov

    Bile duct cancer (also called cholangiocarcinoma) can occur in the bile ducts in the liver (intrahepatic) or outside the liver (perihilar or distal extrahepatic). Learn about the types of bile duct cancer, risk factors, clinical features, staging, and treatment for bile duct cancer in this expert-reviewed summary.

  17. Congenital Intrahepatic Bile Duct Dilatation is a Potentially Curable Disease

    PubMed Central

    Mabrut, Jean-Yves; Partensky, Christian; Jaeck, Daniel; Oussoultzoglou, Elie; Baulieux, Jacques; Boillot, Olivier; Lerut, Jan; de Ville de Goyet, Jean; Hubert, Catherine; Otte, Jean-Bernard; Audet, Maxime; Ducerf, Christian; Gigot, Jean-François

    2007-01-01

    Objective: To report clinical presentation, perioperative outcome, and long-term results of surgical management of congenital intrahepatic bile duct (IHBD) dilatations (including Caroli disease) in a multi-institutional setting. Summary Background Data: Congenital IHBD dilatations are a rare congenital disorder predisposing to intrahepatic stones, cholangitis, and cholangiocarcinoma. The management remains difficult and controversial for bilobar forms of the disease or when concurrent congenital hepatic fibrosis is associated. Methods: From 1976 to 2004, 33 patients (range 11 to 79 years) were retrospectively enrolled. Disease extent into the liver was unilobar in 26 patients and bilobar in 7 patients (21%). Cholangiocarcinoma, congenital hepatic fibrosis, and intrahepatic stones were present in 2, 10, and 20 patients, respectively. Transplantations or liver resections were performed in 5 and 27 patients, respectively, whereas 1 asymptomatic patient was managed conservatively. Results: Postoperative mortality was nil. Postoperative complications occurred in 16 of 32 operated patients (50%) and additional procedures for residual stones were required in 5 patients. During a median follow-up of 80 months (1 patient being lost for follow-up) no patient developed metachronous carcinoma. Six patients (30%) developed recurrent intrahepatic stones but satisfactory late outcome was achieved in 27 patients (87%). Conclusions: Partial or total liver resection achieves satisfactory late outcome in congenital IHBD dilatations, when the affection is treated at an early stage and when the extent of liver resection is tailored to intrahepatic disease extent and takes into consideration the presence and severity of underlying chronic liver and renal diseases. PMID:17667502

  18. Risk factors and classifications of hilar cholangiocarcinoma.

    PubMed

    Suarez-Munoz, Miguel Angel; Fernandez-Aguilar, Jose Luis; Sanchez-Perez, Belinda; Perez-Daga, Jose Antonio; Garcia-Albiach, Beatriz; Pulido-Roa, Ysabel; Marin-Camero, Naiara; Santoyo-Santoyo, Julio

    2013-07-15

    Cholangiocarcinoma is the second most common primary malignant tumor of the liver. Perihilar cholangiocarcinoma or Klatskin tumor represents more than 50% of all biliary tract cholangiocarcinomas. A wide range of risk factors have been identified among patients with Perihilar cholangiocarcinoma including advanced age, male gender, primary sclerosing cholangitis, choledochal cysts, cholelithiasis, cholecystitis, parasitic infection (Opisthorchis viverrini and Clonorchis sinensis), inflammatory bowel disease, alcoholic cirrhosis, nonalcoholic cirrhosis, chronic pancreatitis and metabolic syndrome. Various classifications have been used to describe the pathologic and radiologic appearance of cholangiocarcinoma. The three systems most commonly used to evaluate Perihilar cholangiocarcinoma are the Bismuth-Corlette (BC) system, the Memorial Sloan-Kettering Cancer Center and the TNM classification. The BC classification provides preoperative assessment of local spread. The Memorial Sloan-Kettering cancer center proposes a staging system according to three factors related to local tumor extent: the location and extent of bile duct involvement, the presence or absence of portal venous invasion, and the presence or absence of hepatic lobar atrophy. The TNM classification, besides the usual descriptors, tumor, node and metastases, provides additional information concerning the possibility for the residual tumor (R) and the histological grade (G). Recently, in 2011, a new consensus classification for the Perihilar cholangiocarcinoma had been published. The consensus was organised by the European Hepato-Pancreato-Biliary Association which identified the need for a new staging system for this type of tumors. The classification includes information concerning biliary or vascular (portal or arterial) involvement, lymph node status or metastases, but also other essential aspects related to the surgical risk, such as remnant hepatic volume or the possibility of underlying disease.

  19. Intrahepatic ovulation

    PubMed Central

    Wozniak, Artur L.; Visscher, Kari L.; Bhaduri, Mousumi

    2015-01-01

    Ectopic ovaries are a rare finding in the literature, with fewer than 50 published cases to date. This phenomenon has been found in the omentum, bladder, mesentery, and uterus; attached to the colon; inside the left labia majora; and in the kidney. Various etiologies have been proposed, including postsurgical or postinflammatory transplantation, malignant origins, and abnormal embryologic development. We report the ultrasonographic, computed tomographic (CT), and magnetic resonance (MR) imaging of, what is to the best of our knowledge, the first case of an intrahepatic ectopic ovary. PMID:27186252

  20. Clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification.

    PubMed

    Akiba, Jun; Nakashima, Osamu; Hattori, Satoshi; Tanikawa, Ken; Takenaka, Miki; Nakayama, Masamich; Kondo, Reiichiro; Nomura, Yoriko; Koura, Keiko; Ueda, Kousuke; Sanada, Sakiko; Naito, Yoshiki; Yamaguchi, Rin; Yano, Hirohisa

    2013-04-01

    Combined hepatocellular-cholangiocarcinoma comprises <1% of all liver carcinomas. The histogenesis of combined hepatocellular-cholangiocarcinoma has remained unclear for many years. However, recent advances in hepatic progenitor cell (HPC) investigations have provided new insights. The concept that combined hepatocellular-cholangiocarcinoma originates from HPCs is adopted in the chapter "combined hepatocellular-cholangiocarcinoma" of the latest World Health Organization (WHO) classification. In this study, we conducted clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification. Fifty-four cases were included in this study. Pathologic diagnosis was made according to the WHO classification. When a tumor contained plural histologic patterns, predominant histologic pattern (≥50%) was defined. Minor histologic patterns were also appended. Immunohistochemical staining with biliary markers (CK7, CK19, and EMA), hepatocyte paraffin (HepPar)-1, HPC markers (CD56, c-kit, CD133, and EpCAM), and vimentin was performed. Forty-five and 50 patients were analyzed for progression-free survival and overall survival, respectively. Ten, 1, 32, and 11 cases were diagnosed as: combined hepatocellular-cholangiocarcinoma, classical type; combined hepatocellular-cholangiocarcinoma, stem cell features, typical subtype; combined hepatocellular-cholangiocarcinoma, stem cell features, intermediate cell subtype; and combined hepatocellular-cholangiocarcinoma, stem cell features, cholangiolocellular type, respectively. Combined hepatocellular-cholangiocarcinomas usually have high expression of biliary markers. CD56, c-kit, and EpCAM were expressed to various degrees in all combined hepatocellular-cholangiocarcinomas apart from the hepatocellular carcinoma component of combined hepatocellular-cholangiocarcinoma, classical type. The expression of CD133 and vimentin was observed only in combined hepatocellular-cholangiocarcinoma, stem cell

  1. Liver transplantation for cholangiocarcinoma: Current status and new insights

    PubMed Central

    Sapisochín, Gonzalo; Fernández de Sevilla, Elena; Echeverri, Juan; Charco, Ramón

    2015-01-01

    Cholangiocarcinoma is a malignant tumor of the biliary system that can be classified into intrahepatic (iCCA), perihiliar (phCCA) and distal. Initial experiences with orthotopic liver transplantation (OLT) for patients with iCCA and phCCA had very poor results and this treatment strategy was abandoned. In the last decade, thanks to a strict selection process and a neoadjuvant chemoradiation protocol, the results of OLT for patients with non-resectable phCCA have been shown to be excellent and this strategy has been extended worldwide in selected transplant centers. Intrahepatic cholangiocarcinoma is a growing disease in most countries and can be diagnosed both in cirrhotic and in non-cirrhotic livers. Even though OLT is contraindicated in most centers, recent investigations analyzing patients that were transplanted with a misdiagnosis of HCC and were found to have an iCCA have shown encouraging results. There is some information suggesting that patients with early stages of the disease could benefit from OLT. In this review we analyze the current state-of-the-art of OLT for cholangiocarcinoma as well as the new insights and future perspectives. PMID:26464755

  2. Cholangiocarcinomas can originate from hepatocytes in mice

    PubMed Central

    Fan, Biao; Malato, Yann; Calvisi, Diego F.; Naqvi, Syed; Razumilava, Nataliya; Ribback, Silvia; Gores, Gregory J.; Dombrowski, Frank; Evert, Matthias; Chen, Xin; Willenbring, Holger

    2012-01-01

    Intrahepatic cholangiocarcinomas (ICCs) are primary liver tumors with a poor prognosis. The development of effective therapies has been hampered by a limited understanding of the biology of ICCs. Although ICCs exhibit heterogeneity in location, histology, and marker expression, they are currently thought to derive invariably from the cells lining the bile ducts, biliary epithelial cells (BECs), or liver progenitor cells (LPCs). Despite lack of experimental evidence establishing BECs or LPCs as the origin of ICCs, other liver cell types have not been considered. Here we show that ICCs can originate from fully differentiated hepatocytes. Using a mouse model of hepatocyte fate tracing, we found that activated NOTCH and AKT signaling cooperate to convert normal hepatocytes into biliary cells that act as precursors of rapidly progressing, lethal ICCs. Our findings suggest a previously overlooked mechanism of human ICC formation that may be targetable for anti-ICC therapy. PMID:22797301

  3. Current Status on Cholangiocarcinoma and Gallbladder Cancer

    PubMed Central

    Ebata, Tomoki; Ercolani, Giorgio; Alvaro, Domenico; Ribero, Dario; Di Tommaso, Luca; Valle, Juan W.

    2016-01-01

    Background Cholangiocarcinomas (CC) as well as gallbladder cancers are relatively rare and intractable diseases. Clinical, pathological, and epidemiological studies on these tumors have been under investigation. The current status and/or topics on biliary tract cancers have been reported in the East West Association of Liver Tumor (EWALT), held in Milano, Italy in 2015. Summary All the authors, herein, specifcally reported the current status and leading-edge findings on biliary tract cancers as the following sequence: epidemiology of CC, surgical therapy for intrahepatic CC, surgical therapy for perihilar CC, surgical therapy for gallblad der cancer, chemotherapy for biliary tract cancers, and new histological features in CC. Key Message The present review article will update the knowledge on biliary tract cancers, en hancing the quality of daily clinical practice. However, many features about these cancers remain unknown; further studies are required to establish disease-specific optimal treatment strategies. PMID:27995089

  4. Estrogens and Insulin-Like Growth Factor 1 Modulate Neoplastic Cell Growth in Human Cholangiocarcinoma

    PubMed Central

    Alvaro, Domenico; Barbaro, Barbara; Franchitto, Antonio; Onori, Paolo; Glaser, Shannon S.; Alpini, Gianfranco; Francis, Heather; Marucci, Luca; Sterpetti, Paola; Ginanni-Corradini, Stefano; Onetti Muda, Andrea; Dostal, David E.; De Santis, Adriano; Attili, Adolfo F.; Benedetti, Antonio; Gaudio, Eugenio

    2006-01-01

    We investigated the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF-1), and IGF-1R (receptor) in human cholangiocarcinoma and cholangiocarcinoma cell lines (HuH-28, TFK-1, Mz-ChA-1), evaluating the role of estrogens and IGF-1 in the modulation of neoplastic cell growth. ER-α, ER-β, IGF-1, and IGF-1R were expressed (immunohistochemistry) in all biopsies (18 of 18) of intrahepatic cholangiocarcinoma. ER-α was expressed (Western blot) only by the HuH-28 cell line (intrahepatic cholangiocarcinoma), whereas ER-β, IGF-1, and IGF-1R were expressed in the three cell lines examined. In serum-deprived HuH-28 cells, serum readmission induced stimulation of cell proliferation that was inhibited by ER and IGF-1R antagonists. 17β-Estradiol and IGF-1 stimulated proliferation of HuH-28 cells to a similar extent to that of MCF7 (breast cancer) but greater than that of TFK-1 and Mz-ChA-1, inhibiting apoptosis and exerting additive effects. These effects of 17β-estradiol and IGF-1 were associated with enhanced protein expression of ER-α, phosphorylated (p)-ERK1/2 and pAKT but with decreased expression of ER-β. Finally, transfection of IGF-1R anti-sense oligonucleotides in HuH-28 cells markedly decreased cell proliferation. In conclusion, human intrahepatic cholangiocarcinomas express receptors for estrogens and IGF-1, which cooperate in the modulation of cell growth and apoptosis. Modulation of ER and IGF-1R could represent a strategy for the management of cholangiocarcinoma. PMID:16936263

  5. Palliation: Hilar cholangiocarcinoma

    PubMed Central

    Goenka, Mahesh Kr; Goenka, Usha

    2014-01-01

    Hilar cholangiocarcinomas are common tumors of the bile duct that are often unresectable at presentation. Palliation, therefore, remains the goal in the majority of these patients. Palliative treatment is particularly indicated in the presence of cholangitis and pruritus but is often also offered for high-grade jaundice and abdominal pain. Endoscopic drainage by placing stents at endoscopic retrograde cholangio-pancreatography (ERCP) is usually the preferred modality of palliation. However, for advanced disease, percutaneous stenting has been shown to be superior to endoscopic stenting. Endosonography-guided biliary drainage is emerging as an alternative technique, particularly when ERCP is not possible or fails. Metal stents are usually preferred over plastic stents, both for ERCP and for percutaneous biliary drainage. There is no consensus as to whether it is necessary to place multiple stents within advanced hilar blocks or whether unilateral stenting would suffice. However, recent data have suggested that, contrary to previous belief, it is useful to drain more than 50% of the liver volume for favorable long-term results. In the presence of cholangitis, it is beneficial to drain all of the obstructed biliary segments. Surgical bypass plays a limited role in palliation and is offered primarily as a segment III bypass if, during a laparotomy for resection, the tumor is found to be unresectable. Photodynamic therapy and, more recently, radiofrequency ablation have been used as adjuvant therapies to improve the results of biliary stenting. The exact technique to be used for palliation is guided by the extent of the biliary involvement (Bismuth class) and the availability of local expertise. PMID:25232449

  6. Atypical Ormond's disease associated with bile duct stricture mimicking cholangiocarcinoma.

    PubMed

    Quante, Michael; Appenrodt, Beate; Randerath, Simone; Wolff, Martin; Fischer, Hans-Peter; Sauerbruch, Tilman

    2009-01-01

    A 55-year-old woman with suspected hilar cholangiocarcinoma presented with jaundice and dilated intrahepatic bile ducts owing to high-grade hepatic duct confluence stenosis. The suspected tumour and the entire extrahepatic bile duct system were resected and Roux-en-Y hepaticojejunostomy was performed. Histological investigations showed perihepatic fibrosis but no signs of malignancy. One year later the patient developed bilateral hydronephrosis caused by ureteral obstruction. Since the patient had a gynaecological history of widespread inflammation, she was referred for transabdominal operative ureterolysis combined with hysterectomy and adnexectomy. Histological investigations as well as fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) findings were compatible with retroperitoneal fibrosis (Ormond's disease). Treatment with tamoxifen was initiated. To the best of our knowledge, only a few cases of intraperitoneal fibroses mimicking cholangiocarcinoma followed by the typical symptoms of retroperitoneal Ormond's disease have been reported.

  7. Pathological aspects of so called "hilar cholangiocarcinoma"

    PubMed Central

    Castellano-Megías, Víctor M; Ibarrola-de Andrés, Carolina; Colina-Ruizdelgado, Francisco

    2013-01-01

    Cholangiocarcinoma (CC) arising from the large intrahepatic bile ducts and extrahepatic hilar bile ducts share clinicopathological features and have been called hilar and perihilar CC as a group. However, “hilar and perihilar CC” are also used to refer exclusively to the intrahepatic hilar type CC or, more commonly, the extrahepatic hilar CC. Grossly, a major distinction can be made between papillary and non-papillary tumors. Histologically, most hilar CCs are well to moderately differentiated conventional type (biliary) carcinomas. Immunohistochemically, CK7, CK20, CEA and MUC1 are normally expressed, being MUC2 positive in less than 50% of cases. Two main premalignant lesions are known: biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the biliary tract (IPNB). IPNB includes the lesions previously named biliary papillomatosis and papillary carcinoma. A series of 29 resected hilar CC from our archives is reviewed. Most (82.8%) were conventional type adenocarcinomas, mostly well to moderately differentiated, although with a broad morphological spectrum; three cases exhibited a poorly differentiated cell component resembling signet ring cells. IPNB was observed in 5 (17.2%), four of them with an associated invasive carcinoma. A clear cell type carcinoma, an adenosquamous carcinoma and two gastric foveolar type carcinomas were observed. PMID:23919110

  8. Cholangiocarcinoma presenting as hemobilia and recurrent iron-deficiency anemia: a case report

    PubMed Central

    2010-01-01

    Introduction Iron-deficiency anemia is a relatively common presenting feature of several gastrointestinal malignancies. However, cholangiocarcinoma has rarely been reported as an underlying cause. The association of cholangiocarcinoma with the rare clinical finding of hemobilia is also highly unusual. To our knowledge, this is the first case report of cholangiocarcinoma presenting with acute hemobilia and chronic iron-deficiency anemia. Case presentation We report the case of a Caucasian, 84-year-old woman presenting with recurrent, severe iron-deficiency anemia who was eventually diagnosed with intra-hepatic cholangiocarcinoma, following an acute episode of hemobilia. A right hepatectomy was subsequently performed with curative intent, and our patient has now fully recovered. Conclusion This is a rare example of hemobilia and chronic iron-deficiency anemia in association with cholangiocarcinoma. We suggest that a diagnosis of cholangiocarcinoma should be considered in patients who present with iron-deficiency anemia of unknown cause, particularly in the presence of abnormal liver function. PMID:20459809

  9. The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets

    PubMed Central

    Chong, Dawn Q.; Zhu, Andrew X.

    2016-01-01

    Cholangiocarcinoma (CCA) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) represents the second most common primary liver cancer, after hepatocellular cancer. Two-thirds of the patients with ICC present with locally advanced or metastatic disease. Despite standard treatment with gemcitabine and cisplatin, prognosis remains dismal with a median survival of less than one year. Several biological plausibilities can account for its poor clinical outcomes. First, despite the advent of next generation and whole exome sequencing, no oncogenic addiction loops have been validated as clinically actionable targets. Second, the anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials. Last, most of the studies were not biomarker-driven, which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature. Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). In this review, we will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions (e.g. FGFR2 and ROS1) and somatic mutations (e.g. IDH1/2), which are promising actionable molecular targets. PMID:27102149

  10. Cholangiocarcinoma in Italy: A national survey on clinical characteristics, diagnostic modalities and treatment. Results from the "Cholangiocarcinoma" committee of the Italian Association for the Study of Liver disease.

    PubMed

    Alvaro, Domenico; Bragazzi, Maria Consiglia; Benedetti, Antonio; Fabris, Luca; Fava, Giammarco; Invernizzi, Pietro; Marzioni, Marco; Nuzzo, Gennaro; Strazzabosco, Mario; Stroffolini, Tommaso

    2011-01-01

    Very few studies assessed cholangiocarcinoma clinical characteristics. To evaluate the clinical characteristics of intra-hepatic (IH) and extra-hepatic (EH)-CCA. We performed a national survey based on a questionnaire. 218 cholangiocarcinomas were observed (47% EH-CCA, 53% IH-CCA) with an age at the diagnosis higher for EH-CCA. Coexistence of cirrhosis or viral cirrhosis was more frequent in IH-CCA than EH-CCA. An incidental asymptomatic presentation occurred in 28% of IH-CCA vs 4% EH-CCA whilst, 74% EH-CCA vs 28% IH-CCA presented with jaundice. 91% of IH-CCA presented as a single intra-hepatic mass, whilst 50% of EH-CCA was peri-hilar. In the diagnostic work-up, 70% of all cholangiocarcinoma cases received at least 3 different imaging procedures. Tissue-proven diagnosis was obtained in 80% cholangiocarcinoma. Open surgery with curative intent was performed in 45% of IH-CCA and 29% EH-CCA. 18% IH-CCA vs 4% EH-CCA did not received treatment. In Italy IH-CCA is managed as frequently as EH-CCA. In comparison to EH-CCA, IH-CCA occurs at younger age and is more frequently associated with cirrhosis and with an incidental asymptomatic presentation. In contrast, most EH-CCAs are jaundiced at the diagnosis. Cholangiocarcinoma diagnostic management is cost- and time-consuming with curative surgical treatment applicable more frequently in IH-CCA. Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  11. Comparison of transjugular intrahepatic portosystemic shunt (TIPS) alone versus TIPS combined with embolotherapy in advanced cirrhosis: a retrospective study.

    PubMed

    Xiao, Tianli; Chen, Lei; Chen, Wensheng; Xu, Baoyan; Long, Qingling; Li, Rongjun; Li, Linming; Peng, Zhihong; Fang, Dianchun; Wang, Rongquan

    2011-08-01

    This study was designed to determine whether a transjugular intrahepatic portosystemic shunt (TIPS) combined with embolotherapy was superior to TIPS alone. Seventy-nine patients were included in the study (43 in the TIPS and embolotherapy group and 36 in the TIPS alone group). Embolotherapy was performed after TIPS using coils and a tissue adhesive agent. The portosystemic pressure gradient (PPG) after TIPS was lower than 12 mm Hg in all patients. Multivariate analyses were performed using a Cox regression model, and the probabilities of survival and rebleeding were estimated with the Kaplan-Meier method. Baseline patient survey data showed similar distributions in both groups. The mean follow-up time was 45.6 months (range: 1 to 85.6 mo). There were no significant differences in the incidences of rebleeding (P=0.889), stent revision (P=0.728), encephalopathy (P=0.728), the cumulative survival rate (P=0.552), or the probability of being free of rebleeding (P=0.806) between the 2 groups. Of 9 patients with rebleeding after TIPS plus embolotherapy, 7 had a history of esophageal variceal bleeding and 2 had gastric variceal bleeding. Of 8 patients with rebleeding after TIPS alone, 4 had a history of esophageal variceal bleeding and 4 had gastric variceal bleeding (P=0.247). Multivariate analysis showed that PPG after TIPS was an independent predictor of rebleeding (P=0.036). Age and Model of End-stage Liver Disease score were independent predictors of survival (P=0.048 and 0.037). The results suggest that TIPS with embolotherapy cannot reduce the risk of rebleeding if PPG is less than 12 mm Hg after TIPS. PPG after TIPS is an independent predictor of rebleeding.

  12. Current update on combined hepatocellular-cholangiocarcinoma

    PubMed Central

    Maximin, Suresh; Ganeshan, Dhakshina Moorthy; Shanbhogue, Alampady K.; Dighe, Manjiri K.; Yeh, Matthew M.; Kolokythas, Orpheus; Bhargava, Puneet; Lalwani, Neeraj

    2014-01-01

    Combined hepatocellular-cholangiocarcinoma is a rare but unique primary hepatic tumor with characteristic histology and tumor biology. Recent development in genetics and molecular biology support the fact that combined hepatocellular-cholangiocarcinoma is closely linked with cholangiocarcinoma, rather than hepatocellular carcinoma. Combined hepatocellular cholangiocarcinoma tends to present with an more aggressive behavior and a poorer prognosis than either hepatocellular carcinoma or cholangiocarcinoma. An accurate preoperative diagnosis and aggressive treatment planning can play crucial roles in appropriate patient management. PMID:26937426

  13. CXCL7 promotes proliferation and invasion of cholangiocarcinoma cells.

    PubMed

    Guo, Qian; Jian, Zhixiang; Jia, Baoqing; Chang, Liang

    2017-02-01

    CXCL7 is an important chemoattractant cytokine, which signals through binding to its receptor CXCR2. Recent studies have demonstrated that the CXCL7/CXCR2 signaling plays a promoting role in several common malignancies, including lung, renal, colon, and breast cancer. However, the regulatory role of CXCL7, in cholangiocarcinoma, as well as the underlying mechanism, has not been previously reported. Herein, we found more positive expression of CXCL7 in cholangiocarcinoma tissues compared to adjacent non-tumor tissues. High CXCL7 expression was significantly correlated with poor differentiation, lymph node metastasis, vascular invasion and advanced clinical stage, but was not associated with age, gender, or tumor size. Besides, the expression of CXCL7 was significantly associated with the Ki67 expression, but not associated with CA199, AFP, or P53 expression in cholangiocarcinoma. Moreover, the overall survival of cholangiocarcinoma patients with high CXCL7 expression was significantly shorter than those with low CXCL7 expression. In vitro study indicated that CXCL7 and CXCR2 were also positively expressed in several common cholangiocarcinoma cell lines, including HuCCT1, HuH28, QBC939, EGI-1, OZ and WITT. SiRNA-induced inhibition of CXCL7 significantly reduced the proliferation and invasion of QBC939 cells. On the contrary, overexpression of CXCL7 markedly promoted these malignant phenotypes of QBC939 cells. Of note, the conditioned medium of CXCL7-overexpresing human hepatic stellate cells could also promote the proliferation and invasion of QBC939 cells, suggesting that CXCL7 may also play an oncogenic role in cholangiocarcinoma in a paracrine-dependent manner, not only in an autocrine-dependent manner. Molecular assay data suggested that the AKT signaling pathway was involved in the CXCL7-mediated malignant phenotypes of QBC939 cells. In summary, our study suggests that CXCL7 plays a promoting role in regulating the growth and metastasis of cholangiocarcinoma.

  14. Intrahepatic cholestasis of pregnancy.

    PubMed

    Williamson, Catherine; Geenes, Victoria

    2014-07-01

    Intrahepatic cholestasis of pregnancy is the most common pregnancy-specific liver disease that typically presents in the third trimester. The clinical features are maternal pruritus in the absence of a rash and deranged liver function tests, including raised serum bile acids. Intrahepatic cholestasis of pregnancy is associated with an increased risk of adverse perinatal outcomes, including spontaneous preterm delivery, meconium staining of the amniotic fluid, and stillbirth. It is commonly treated with ursodeoxycholic acid. There is accumulating evidence to suggest that intrahepatic cholestasis of pregnancy has a lasting influence on both maternal and fetal health. We review the etiology, diagnosis, and management of this intriguing condition.

  15. Resection of Perihilar Cholangiocarcinoma.

    PubMed

    Hartog, Hermien; Ijzermans, Jan N M; van Gulik, Thomas M; Groot Koerkamp, Bas

    2016-04-01

    Perihilar cholangiocarcinoma presents at the biliary and vascular junction of the hepatic hilum with a tendency to extend longitudinally into segmental bile ducts. Most patients show metastatic or unresectable disease at time of presentation or surgical exploration. In patients eligible for surgical resection, challenges are to achieve negative bile duct margins, adequate liver remnant function, and adequate portal and arterial inflow to the liver remnant. Surgical treatment is characterized by high rates of postoperative morbidity and mortality. This article reviews the various strategies and techniques, the role of staging laparoscopy, intraoperative frozen section, caudate lobectomy, and vascular reconstruction.

  16. Case series of 17 patients with cholangiocarcinoma among young adult workers of a printing company in Japan.

    PubMed

    Kubo, Shoji; Nakanuma, Yasuni; Takemura, Shigekazu; Sakata, Chikaharu; Urata, Yorihisa; Nozawa, Akinori; Nishioka, Takayoshi; Kinoshita, Masahiko; Hamano, Genya; Terajima, Hiroaki; Tachiyama, Gorou; Matsumura, Yuji; Yamada, Terumasa; Tanaka, Hiromu; Nakamori, Shoji; Arimoto, Akira; Kawada, Norifumi; Fujikawa, Masahiro; Fujishima, Hiromitsu; Sugawara, Yasuhiko; Tanaka, Shogo; Toyokawa, Hideyoshi; Kuwae, Yuko; Ohsawa, Masahiko; Uehara, Shinichiro; Sato, Kyoko Kogawa; Hayashi, Tomoshige; Endo, Ginji

    2014-07-01

    An outbreak of cholangiocarcinoma occurred among workers in the offset color proof-printing department at a printing company in Japan. The aim of this study was to clarify the characteristics of the patients with cholangiocarcinoma. This was a retrospective study conducted in 13 Japanese hospitals between 1996 to 2013. The clinicopathological findings of cholangiocarcinoma developed in 17 of 111 former or current workers in the department were investigated. Most workers were relatively young. The cholangiocarcinoma was diagnosed at 25-45 years old. They were exposed to chemicals, including dichloromethane and 1,2-dichloropropane. The serum γ-glutamyl transpeptidase activity was elevated in all patients. Dilated intrahepatic bile ducts without tumor-induced obstruction were observed in five patients. The cholangiocarcinomas arose from the large bile ducts. The precancerous or early cancerous lesions, such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile ducts, as well as non-specific bile duct injuries, such as fibrosis, were observed in various sites of the bile ducts in all eight patients for whom operative specimens were available. The present results showed that cholangiocarcinomas occurred at a high incidence in relatively young workers of a printing company, who were exposed to chemicals including chlorinated organic solvents. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  17. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.

    PubMed

    Arai, Yasuhito; Totoki, Yasushi; Hosoda, Fumie; Shirota, Tomoki; Hama, Natsuko; Nakamura, Hiromi; Ojima, Hidenori; Furuta, Koh; Shimada, Kazuaki; Okusaka, Takuji; Kosuge, Tomoo; Shibata, Tatsuhiro

    2014-04-01

    Cholangiocarcinoma is an intractable cancer, with limited therapeutic options, in which the molecular mechanisms underlying tumor development remain poorly understood. Identification of a novel driver oncogene and applying it to targeted therapies for molecularly defined cancers might lead to improvements in the outcome of patients. We performed massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients without KRAS/BRAF/ROS1 alterations and identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In reverse-transcriptase polymerase chain reaction (RT-PCR) screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%), rarely in colorectal (1/149) and hepatocellular carcinoma (1/96), and none in gastric cancer (0/212). The rearrangements were mutually exclusive with KRAS/BRAF mutations. Expression of the fusion kinases in NIH3T3 cells activated MAPK and conferred anchorage-independent growth and in vivo tumorigenesis of subcutaneous transplanted cells in immune-compromised mice. This transforming ability was attributable to its kinase activity. Treatment with the fibroblast growth factor receptor (FGFR) kinase inhibitors BGJ398 and PD173074 effectively suppressed transformation. FGFR2 fusions occur in 13.6% of intrahepatic cholangiocarcinoma. The expression pattern of these fusions in association with sensitivity to FGFR inhibitors warrant a new molecular classification of cholangiocarcinoma and suggest a new therapeutic approach to the disease. © 2014 by the American Association for the Study of Liver Diseases.

  18. In-vivo monitoring of development of cholangiocarcinoma induced with C. sinensis and N-nitrosodimethylamine in Syrian golen hamsters using ultrasonography and magnetic resonance imaging: a preliminary study.

    PubMed

    Woo, Hyunsik; Han, Joon Koo; Kim, Jung Hoon; Hong, Sung-Tae; Uddin, Md Hafiz; Jang, Ja-June

    2017-04-01

    The purpose of this study is to evaluate high-resolution ultrasound and magnetic resonance imaging (MRI) in monitoring of cholangiocarcinoma in the hamsters with C. sinensis infection and N-nitrosodimethylamine (NDMA). Twenty-four male Syrian golden hamsters of were divided into four groups composed of five hamsters as control, five hamsters receiving 30 metacercariae of C. sinensis per each hamster, five hamsters receiving NDMA in drinking water, and nine hamsters receiving both metacercariae and NDMA. Ultrasound was performed every other week from baseline to the 12th week of infection. MRI and histopathologic examination was done from the 4th week to 12th week. Cholangiocarcinomas appeared as early as the 6th week of infection. There were 12 cholangiocarcinomas, nine and ten of which were demonstrated by ultrasound and MRI, respectively. Ultrasound and MRI findings of cholangiocarcinomas in the hamsters were similar to those of the mass-forming intrahepatic cholangiocarcinomas in humans. Ultrasound and MRI also showed other findings of disease progression such as periductal increased echogenicity or signal intensity, ductal dilatation, complicated cysts, and sludges in the gallbladder. High-resolution ultrasound and MRI can monitor and detect the occurrence of cholangiocarcinoma in the hamsters non-invasively. • High-resolution ultrasound and MRI can monitor occurrence of cholangiocarcinoma in the hamsters. • Cholangiocarcinomas were detected as early as the 6th week after C. sinensis infection. • Axial T2-weighted MRI demonstrated cholangiocarcinomas and various inflammatory findings in the hamsters.

  19. Radiation therapy for intrahepatic malignancies.

    PubMed

    Quick, Allison M; Lo, Simon S; Mayr, Nina A; Kim, Edward Y

    2009-10-01

    Historically, radiation was not used in the management of hepatocellular carcinoma and liver metastasis because of the low tolerance of the liver to radiation. More recently, improvements in radiation delivery using advanced techniques, such as 3D conformal radiation therapy, intensity-modulated radiation therapy, image-guided radiation therapy, stereotactic body radiation therapy, proton-beam therapy and internal radiation therapy, have enabled partial and selective irradiation of the liver with promising response rates and toxicity profiles. This review will discuss the different techniques of radiation that can now be used to treat intrahepatic malignancies and the important clinical studies in the medical literature.

  20. Cholangiocarcinoma: Biology, Clinical Management, and Pharmacological Perspectives

    PubMed Central

    Macias, Rocio I. R.

    2014-01-01

    Cholangiocarcinoma (CCA), or tumor of the biliary tree, is a rare and heterogeneous group of malignancies associated with a very poor prognosis. Depending on their localization along the biliary tree, CCAs are classified as intrahepatic, perihilar, and distal, and these subtypes are now considered different entities that differ in tumor biology, the staging system, management, and prognosis. When diagnosed, an evaluation by a multidisciplinary team is essential; the team must decide on the best therapeutic option. Surgical resection of tumors with negative margins is the best option for all subtypes of CCA, although this is only achieved in less than 50% of cases. Five-year survival rates have increased in the recent past owing to improvements in imaging techniques, which permits resectability to be predicted more accurately, and in surgery. Chemotherapy and radiotherapy are relatively ineffective in treating nonoperable tumors and the resistance of CCA to these therapies is a major problem. Although the combination of gemcitabine plus platinum derivatives is the pharmacological treatment most widely used, to date there is no standard chemotherapy, and new combinations with targeted drugs are currently being tested in ongoing clinical trials. This review summarizes the biology, clinical management, and pharmacological perspectives of these complex tumors. PMID:27335842

  1. Chemoresistance and chemosensitization in cholangiocarcinoma.

    PubMed

    Marin, Jose J G; Lozano, Elisa; Herraez, Elisa; Asensio, Maitane; Di Giacomo, Silvia; Romero, Marta R; Briz, Oscar; Serrano, Maria A; Efferth, Thomas; Macias, Rocio I R

    2017-07-07

    One of the main difficulties in the management of patients with advanced cholangiocarcinoma (CCA) is their poor response to available chemotherapy. This is the result of powerful mechanisms of chemoresistance (MOC) of quite diverse nature that usually act synergistically. The problem is often worsened by altered MOC gene expression in response to pharmacological treatment. Since CCA includes a heterogeneous group of cancers their genetic signature coding for MOC genes is also diverse; however, several shared traits have been defined. Some of these characteristics are shared with other types of liver cancer, namely hepatocellular carcinoma and hepatoblastoma. An important goal in modern oncologic pharmacology is to develop novel strategies to overcome CCA chemoresistance either by increasing drug specificity, such as in targeted therapies aimed to inhibit receptors with tyrosine kinase activity, or to increase the amounts of active agents inside CCA cells by enhancing drug uptake or reducing efflux through export pumps. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Pathological aspects of cholangiocarcinoma

    PubMed Central

    Esposito*, I.

    2008-01-01

    Cholangiocarcinoma (CC) arises from the biliary epithelium and in most cases represents adenocarcinoma. Pathomorphological evaluation is of decisive impact for the prognosis and management of CC. Morphological subtyping (histotype; hilar vs peripheral type), TNM classification, lymphatic spread, and resection margin status are of prognostic relevance. Distinction from hepatic metastases may be aided by immunohistology and clinico-pathological correlation. There is convincing evidence of the development of CC via premalignant lesions, especially biliary intraepithelial neoplasia, although further knowledge about the biology and diagnostic definition of these lesions has to be accumulated. Currently, there are no established molecular markers of prognosis or therapeutic target structures to be evaluated at the tissue level. Future progress is needed and expected in novel differential diagnostic and predictive markers, in uniform definition of resection margin status and further understanding of molecular and morphological changes in the development of CC. PMID:18773061

  3. The impact of changed strategies for patients with cholangiocarcinoma in this millenium.

    PubMed

    Lindnér, Per; Rizell, Magnus; Hafström, Lo

    2015-01-01

    Background. Cholangiocarcinoma is a cancer with a poor prognosis. In this millennium there are new diagnostic and therapeutic strategies for these patients. Aim. The aim of this study was to find if these changes influenced survival of individuals with proximal cholangiocarcinoma. Material. 627 individuals with a diagnosis of cholangiocarcinoma (not including distal common duct cancer) during the period from 2000 to 2011 were registered in Sweden's Western Region. The material was divided into three consecutive time periods. Results. The overall survival curves for individuals with cholangiocarcinoma improved over the three time periods (n = 627) (P = 0.0013). Median survival increased from 2.6 months in the first period (2000-2003) to 3.6 months in the final four years (2008-2011). Patients with perihilar cholangiocarcinoma (PHC) had longer median survival than those with intrahepatic cholangiocarcinoma (IHC): 6.8 versus 3.2 months (P = 0.0003). An improvement in the survival curves over time was seen for those with IHC (P = 0.034) but not for patients with PHC (P = 0.38). Nine percent of the patients with IHC had potential curative surgical therapy. The three-year survival rate after liver resection for patients with IHC was 35% and 60% after liver transplantation. Among patients with PHC, 15.3% had potential curative bile duct resection with a concomitant liver resection and 6.1% bile duct resection alone. The three-year survival rate for these two groups was 32% and 20%, respectively. Conclusion. Overall survival for individuals with PHC was better than for those with IHC. Over time survival in IHC patients improved but not in those with PHC.

  4. Spontaneous external biliary fistula: a rare complication of cholangiocarcinoma.

    PubMed

    Song, In Do; Oh, Hyoung-Chul; Do, Jae Hyuk; Jeong, Lae Ik; Kim, Beom Jin; Kim, Jeong Wook; Kim, Jae Gyu; Chi, Kyong Choun; Kim, Mi Kyung

    2011-01-01

    A 68-year-old woman presented with yellowish discharge oozing from a fistula opening in the upper epigastric area that had persisted for one month prior to her visit. The patient had undergone a left lateral segmentectomy of the liver ten years prior for treatment of intrahepatic duct (IHD) stones. An abdominal computed tomography (CT) scan showed focal stricture and proximal dilatation of remnant IHD and a 1 cm-sized rim-enhancing lesion located under the surgical bed of the abdominal wall surrounding the dilated remnant IHD. Despite conservative management including nasobiliary drainage, no further improvement was anticipated. Partial hepatectomy and fistulectomy were performed for pathologic diagnosis and treatment of the enhancing lesion. Histopathology revealed adenocarcinoma. In this case, cholangiocarcinoma might have arisen in association with IHD stones and then developed a choledocho-cutaneous fistula as a clinical manifestation.

  5. [A Case of Cholangiocarcinoma with Intestinal Malrotation Treated with Pancreaticoduodenectomy].

    PubMed

    Saito, Yurina; Miyamoto, Atsushi; Maeda, Sakae; Hama, Naoki; Haraguchi, Naotsugu; Yamamoto, Kazuyoshi; Miyake, Masakazu; Nishikawa, Kazuhiro; Miyazaki, Michihiko; Ikeda, Masataka; Hirao, Motohiro; Sekimoto, Mitsugu; Nakamori, Shoji

    2015-11-01

    We report a case of cholangiocarcinoma with intestinal malrotation that was treated with pancreaticoduodenectomy. The patient was a 74-year-old man, who underwent laboratory screening and was subsequently found to have elevated γglutamyl transpeptidase levels. Preoperative ultrasonography revealed intrahepatic bile duct dilatation. Endoscopic retrograde cholangiopancreatography demonstrated a filling defect in the common bile duct and cytology of the bile demonstrated the presence of an adenocarcinoma. On preoperative computed tomography (CT), the SMV was located on the left side of the SMA, which showed the SMV rotation sign. Additionally, the small intestine and the colon were deviated to the right and left side of abdominal cavity, respectively. We diagnosed the patient with cholangiocarcinoma with intestinal malrotation and preduodenal portal vein involvement using the CT scan, and performed pancreaticoduodenectomy. Since the ligament of Treitz was absent during surgery, we diagnosed this as a case of the nonrotation type of malrotation. The postoperative course was uneventful and the patient was discharged from the hospital 42 days after the surgery. Anomalies of the portal venous system are so rare that recognition of its variation is important in order to avoid accidental injuries during the operation.

  6. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.

    PubMed

    Farshidfar, Farshad; Zheng, Siyuan; Gingras, Marie-Claude; Newton, Yulia; Shih, Juliann; Robertson, A Gordon; Hinoue, Toshinori; Hoadley, Katherine A; Gibb, Ewan A; Roszik, Jason; Covington, Kyle R; Wu, Chia-Chin; Shinbrot, Eve; Stransky, Nicolas; Hegde, Apurva; Yang, Ju Dong; Reznik, Ed; Sadeghi, Sara; Pedamallu, Chandra Sekhar; Ojesina, Akinyemi I; Hess, Julian M; Auman, J Todd; Rhie, Suhn K; Bowlby, Reanne; Borad, Mitesh J; Zhu, Andrew X; Stuart, Josh M; Sander, Chris; Akbani, Rehan; Cherniack, Andrew D; Deshpande, Vikram; Mounajjed, Taofic; Foo, Wai Chin; Torbenson, Michael S; Kleiner, David E; Laird, Peter W; Wheeler, David A; McRee, Autumn J; Bathe, Oliver F; Andersen, Jesper B; Bardeesy, Nabeel; Roberts, Lewis R; Kwong, Lawrence N

    2017-03-14

    Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups

    PubMed Central

    Mafficini, Andrea; Wood, Laura D.; Corbo, Vincenzo; Melisi, Davide; Malleo, Giuseppe; Vicentini, Caterina; Malpeli, Giorgio; Antonello, Davide; Sperandio, Nicola; Capelli, Paola; Tomezzoli, Anna; Iacono, Calogero; Lawlor, Rita T.; Bassi, Claudio; Hruban, Ralph H.; Guglielmi, Alfredo; Tortora, Giampaolo; de Braud, Filippo; Scarpa, Aldo

    2014-01-01

    One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing. Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry. At least one mutated gene was observed in 118/153 (77%) cancers. The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%). IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC. Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival. Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases. Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases. Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials. PMID:24867389

  8. Targeting PDGFR-β in Cholangiocarcinoma

    PubMed Central

    Fingas, Christian D; Mertens, Joachim C; Razumilava, Nataliya; Bronk, Steven F; Sirica, Alphonse E; Gores, Gregory J

    2011-01-01

    Background Cholangiocarcinomas (CCAs) are highly desmoplastic neoplasms with a tumor microenvironment plentiful in myofibroblasts (MFBs). MFB-derived PDGF-BB survival signaling is a mediator of CCA cell resistance to apoptotic stimuli. This raises the concept that targeting PDGFR-β, a cognate receptor of PDGF-BB, represents a potential strategy for the treatment of human CCA. Aims Herein, we examine a role for inhibiting PDGFR-β in restoring CCA cell sensitivity to apoptotic stimuli in vitro and in vivo. Methods We employed human CCA samples from 41 patients (19 intrahepatic and 22 extrahepatic CCA samples), the human CCA cell lines KMCH-1 and HUCCT-1 as well as shPDGFR-β-KMCH-1 and human myofibroblastic LX-2 cells for these studies. In vivo-experiments were conducted using a syngeneic rat orthotopic CCA model. Results Of several MFB-derived growth factors profiled, PDGF-BB and CTGF were most abundantly expressed; however, only PDGF-BB attenuated TRAIL cytotoxicity. Co-culturing CCA cells with PDGF-BB-secreting MFBs significantly decreased TRAIL-induced CCA cell apoptosis as compared to monoculture conditions; this cytoprotective effect was abrogated in the presence of the tyrosine kinase inhibitors imatinib mesylate or linifanib, which inhibit PDGFR-β. Consistent with these findings, MFB-imparted cytoprotection also was abolished when PDGFR-β was knocked down as demonstrated in shPDGFR-β-KMCH-1 cells. Finally, administration of imatinib mesylate increased CCA cell apoptosis and reduced tumor growth in a rodent in vivo-CCA model that mimics the human disease. Conclusions Targeting PDGFR-β sensitizes CCA cells to apoptotic stimuli and appears to be therapeutic in vivo. PMID:22133064

  9. The significance of genetics for cholangiocarcinoma development

    PubMed Central

    Maroni, Luca; Pierantonelli, Irene; Banales, Jesus M.; Benedetti, Antonio

    2013-01-01

    Cholangiocarcinoma (CCA) is a rare malignancy of the liver, arising from bile ducts. The incidence is increasing worldwide, but the prognosis has remained dismal and virtually unchanged in the past 30 years. Although several risk factors have been associated with the development of this cancer, none of them are normally identified in most patients. Diagnosis in advanced stages of the disease and limited therapeutic options contribute to poor survival rates. The recent analysis of genetic and epigenetic alterations occurring in CCA has shed new light in the understanding of the molecular mechanisms leading to the malignant transformation of biliary cells. Further studies in this direction may foster new diagnostic, prognostic and therapeutic approaches. This review provides a global overview of recent advances in CCA and describes the most important genetic mutations and epigenetic alterations so far reported in CCA. PMID:25332972

  10. The significance of genetics for cholangiocarcinoma development.

    PubMed

    Maroni, Luca; Pierantonelli, Irene; Banales, Jesus M; Benedetti, Antonio; Marzioni, Marco

    2013-10-01

    Cholangiocarcinoma (CCA) is a rare malignancy of the liver, arising from bile ducts. The incidence is increasing worldwide, but the prognosis has remained dismal and virtually unchanged in the past 30 years. Although several risk factors have been associated with the development of this cancer, none of them are normally identified in most patients. Diagnosis in advanced stages of the disease and limited therapeutic options contribute to poor survival rates. The recent analysis of genetic and epigenetic alterations occurring in CCA has shed new light in the understanding of the molecular mechanisms leading to the malignant transformation of biliary cells. Further studies in this direction may foster new diagnostic, prognostic and therapeutic approaches. This review provides a global overview of recent advances in CCA and describes the most important genetic mutations and epigenetic alterations so far reported in CCA.

  11. Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein.

    PubMed

    Wang, Yu; Ding, Xiwei; Wang, Shaoqing; Moser, Catherine D; Shaleh, Hassan M; Mohamed, Essa A; Chaiteerakij, Roongruedee; Allotey, Loretta K; Chen, Gang; Miyabe, Katsuyuki; McNulty, Melissa S; Ndzengue, Albert; Barr Fritcher, Emily G; Knudson, Ryan A; Greipp, Patricia T; Clark, Karl J; Torbenson, Michael S; Kipp, Benjamin R; Zhou, Jie; Barrett, Michael T; Gustafson, Michael P; Alberts, Steven R; Borad, Mitesh J; Roberts, Lewis R

    2016-09-28

    Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions.

  12. Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein

    PubMed Central

    Wang, Yu; Ding, Xiwei; Wang, Shaoqing; Moser, Catherine D.; Shaleh, Hassan M.; Mohamed, Essa A.; Chaiteerakij, Roongruedee; Allotey, Loretta K.; Chen, Gang; Miyabe, Katsuyuki; McNulty, Melissa S.; Ndzengue, Albert; Knudson, Ryan A.; Greipp, Patricia T.; Clark, Karl J.; Torbenson, Michael S.; Kipp, Benjamin R.; Zhou, Jie; Barrett, Michael T.; Gustafson, Michael P.; Alberts, Steven R.; Borad, Mitesh J.; Roberts, Lewis R.

    2016-01-01

    Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions. PMID:27216979

  13. Comparison of Intrahepatic and Pancreatic Perfusion on Fusion Images Using a Combined SPECT/CT System and Assessment of Efficacy of Combined Continuous Arterial Infusion and Systemic Chemotherapy in Advanced Pancreatic Carcinoma

    SciTech Connect

    Ikeda, Osama Tamura, Yoshitaka; Nakasone, Yutaka; Shiraishi, Shinya; Kawanaka, Kouichi; Tomiguchi, Seiji; Yamashita, Yasuyuki; Takamori, Hiroshi; Kanemitsu, Keiichiro; Baba, Hideo

    2007-09-15

    Purpose. The purpose of this study was to compare intrahepatic and pancreatic perfusion on fusion images using a combined single-photon emission computed tomography (SPECT)/CT system and to evaluate the efficacy of combined continuous transcatheter arterial infusion (CTAI) and systemic chemotherapy in the treatment of advanced pancreatic carcinoma. Materials and Methods. CTAI was performed in 33 patients (22 men, 11 women; age range, 35-77 years; mean age, 60 years) with stage IV pancreatic cancer with liver metastasis. The reservoir was transcutaneously implanted with the help of angiography. The systemic administration of gemcitabine was combined with the infusion of 5-fluorouracil via the reservoir. In all patients we obtained fusion images using a combined SPECT/CT system. Pancreatic perfusion on fusion images was classified as perfusion presence or as perfusion absent in the pancreatic cancer. Using WHO criteria we recorded the tumor response after 3 months on multislice helical CT scans. Treatment effects were evaluated based on the pancreatic cancer, liver metastasis, and factors such as intrahepatic and pancreatic perfusion on fusion images. For statistical analysis we used the chi-square test; survival was evaluated by the Kaplan Meier method (log-rank test). Results. On fusion images, pancreatic and intrahepatic perfusion was recorded as hot spot and as homogeneous distribution, respectively, in 18 patients (55%) and as cold spot and heterogeneous distribution, respectively, in 15 (45%). Patients with hot spot in the pancreatic tumor and homogeneous distribution in the liver manifested better treatment results (p < 0.05 and p < 0.01, respectively). Patients with hot spot both in the pancreatic cancer and in the liver survived longer than those with cold spot in the pancreatic cancer and heterogeneous distribution in the liver (median {+-} SD, 16.0 {+-} 3.7 vs. 8.0 {+-} 1.4 months; p < 0.05). Conclusions. We conclude that in patients with advanced

  14. Intrahepatic cholestasis of pregnancy

    PubMed Central

    Pusl, Thomas; Beuers, Ulrich

    2007-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by (i) pruritus with onset in the second or third trimester of pregnancy, (ii) elevated serum aminotransferases and bile acid levels, and (iii) spontaneous relief of signs and symptoms within two to three weeks after delivery. ICP is observed in 0.4–1% of pregnancies in most areas of Central and Western Europe and North America, while in Chile and Bolivia as well as Scandinavia and the Baltic states roughly 5–15% and 1–2%, respectively, of pregnancies are associated with ICP. Genetic and hormonal factors, but also environmental factors may contribute to the pathogenesis of ICP. Intrahepatic cholestasis of pregnancy increases the risk of preterm delivery (19–60%), meconium staining of amniotic fluid (27%), fetal bradycardia (14%), fetal distress (22–41%), and fetal loss (0.4–4.1%), particularly when associated with fasting serum bile acid levels > 40 μmol/L. The hydrophilic bile acid ursodeoxycholic acid (10–20 mg/kg/d) is today regarded as the first line treatment for intrahepatic cholestasis of pregnancy. Delivery has been recommended in the 38th week when lung maturity has been established. PMID:17535422

  15. Cholangiocarcinoma: Current Knowledge and New Developments

    PubMed Central

    Blechacz, Boris

    2017-01-01

    Cholangiocarcinoma (CCA) is the second most common primary malignancy. Although it is more common in Asia, its incidence in Europe and North America has significantly increased in recent decades. The prognosis of CCA is dismal. Surgery is the only potentially curative treatment, but the majority of patients present with advanced stage disease, and recurrence after resection is common. Over the last two decades, our understanding of the molecular biology of this malignancy has increased tremendously, diagnostic techniques have evolved, and novel therapeutic approaches have been established. This review discusses the changing epidemiologic trends and provides an overview of newly identified etiologic risk factors for CCA. Furthermore, the molecular pathogenesis is discussed as well as the influence of etiology and biliary location on the mutational landscape of CCA. This review provides an overview of the diagnostic evaluation of CCA and its staging systems. Finally, new therapeutic options are critically reviewed, and future therapeutic strategies discussed. PMID:27928095

  16. Cholangiocarcinoma: Molecular Pathways and Therapeutic Opportunities

    PubMed Central

    Rizvi, Sumera; Borad, Mitesh J.; Patel, Tushar; Gores, Gregory J.

    2015-01-01

    Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. Currently, there are no curative medical therapies for CCA. Recent advances have enhanced our understanding of the genetic basis of this disease, and elucidated therapeutically relevant targets. Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks. A highly desmoplastic, hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion. Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma. As the mutational landscape of CCA is being illuminated, molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed, personalized treatment options. PMID:25369307

  17. Cholangiocarcinoma: Current Knowledge and New Developments.

    PubMed

    Blechacz, Boris

    2017-01-15

    Cholangiocarcinoma (CCA) is the second most common primary malignancy. Although it is more common in Asia, its incidence in Europe and North America has significantly increased in recent decades. The prognosis of CCA is dismal. Surgery is the only potentially curative treatment, but the majority of patients present with advanced stage disease, and recurrence after resection is common. Over the last two decades, our understanding of the molecular biology of this malignancy has increased tremendously, diagnostic techniques have evolved, and novel therapeutic approaches have been established. This review discusses the changing epidemiologic trends and provides an overview of newly identified etiologic risk factors for CCA. Furthermore, the molecular pathogenesis is discussed as well as the influence of etiology and biliary location on the mutational landscape of CCA. This review provides an overview of the diagnostic evaluation of CCA and its staging systems. Finally, new therapeutic options are critically reviewed, and future therapeutic strategies discussed.

  18. Radiotherapy in the Treatment of Patients With Unresectable Extrahepatic Cholangiocarcinoma

    SciTech Connect

    Ghafoori, A. Paiman; Nelson, John W.; Willett, Christopher G.; Chino, Junzo; Tyler, Douglas S.; Hurwitz, Herbert I.; Uronis, Hope E.; Morse, Michael A.; Clough, Robert W.; Czito, Brian G.

    2011-11-01

    Purpose: Extrahepatic cholangiocarcinoma is an uncommon but lethal malignancy. We analyzed the role of definitive chemoradiotherapy for patients with nonmetastatic, locally advanced extrahepatic cholangiocarcinoma treated at a single institution. Methods and Materials: This retrospective analysis included 37 patients who underwent external beam radiation therapy (EBRT) with concurrent chemotherapy and/or brachytherapy (BT) for locally advanced extrahepatic cholangiocarcinoma. Local control (LC) and overall survival (OS) were assessed, and univariate regression analysis was used to evaluate the effects of patient- and treatment-related factors on clinical outcomes. Results: Twenty-three patients received EBRT alone, 8 patients received EBRT plus BT, and 6 patients received BT alone (median follow-up of 14 months). Two patients were alive without evidence of recurrence at the time of analysis. Actuarial OS and LC rates at 1 year were 59% and 90%, respectively, and 22% and 71%, respectively, at 2 years. Two patients lived beyond 5 years without evidence of recurrence. On univariate analysis, EBRT with or without BT improved LC compared to BT alone (97% vs. 56% at 1 year; 75% vs. 56% at 2 years; p = 0.096). Patients who received EBRT alone vs. BT alone also had improved LC (96% vs. 56% at 1 year; 80% vs. 56% at 2 years; p = 0.113). Age, gender, tumor location (proximal vs. distal), histologic differentiation, EBRT dose ({<=} or >50 Gy), EBRT planning method (two-dimensional vs. three-dimensional), and chemotherapy were not associated with patient outcomes. Conclusions: Patients with locally advanced extrahepatic cholangiocarcinoma have poor survival. Long-term survival is rare. The majority of patients treated with EBRT had local control at the time of death, suggesting that symptoms due to the local tumor effect might be effectively controlled with radiation therapy, and EBRT is an important element of treatment. Novel treatment approaches are indicated in the therapy

  19. RADIOTHERAPY IN THE TREATMENT OF PATIENTS WITH UNRESECTABLE EXTRAHEPATIC CHOLANGIOCARCINOMA

    PubMed Central

    Ghafoori, A. Paiman; Nelson, John W.; Willett, Christopher G.; Chino, Junzo; Tyler, Douglas S.; Hurwitz, Herbert I.; Uronis, Hope E.; Morse, Michael A.; Clough, Robert W.; Czito, Brian G.

    2014-01-01

    Purpose Extrahepatic cholangiocarcinoma is an uncommon but lethal malignancy. We analyzed the role of definitive chemoradiotherapy for patients with nonmetastatic, locally advanced extrahepatic cholangiocarcinoma treated at a single institution. Methods and Materials This retrospective analysis included 37 patients who underwent external beam radiation therapy (EBRT) with concurrent chemotherapy and/or brachytherapy (BT) for locally advanced extrahepatic cholangiocarcinoma. Local control (LC) and overall survival (OS) were assessed, and univariate regression analysis was used to evaluate the effects of patient- and treatment-related factors on clinical outcomes. Results Twenty-three patients received EBRT alone, 8 patients received EBRT plus BT, and 6 patients received BT alone (median follow-up of 14 months). Two patients were alive without evidence of recurrence at the time of analysis. Actuarial OS and LC rates at 1 year were 59% and 90%, respectively, and 22% and 71%, respectively, at 2 years. Two patients lived beyond 5 years without evidence of recurrence. On univariate analysis, EBRT with or without BT improved LC compared to BT alone (97% vs. 56% at 1 year; 75% vs. 56% at 2 years; p = 0.096). Patients who received EBRT alone vs. BT alone also had improved LC (96% vs. 56% at 1 year; 80% vs. 56% at 2 years; p = 0.113). Age, gender, tumor location (proximal vs. distal), histologic differentiation, EBRT dose (≤ or >50 Gy), EBRT planning method (two-dimensional vs. three-dimensional), and chemotherapy were not associated with patient outcomes. Conclusions Patients with locally advanced extrahepatic cholangiocarcinoma have poor survival. Long-term survival is rare. The majority of patients treated with EBRT had local control at the time of death, suggesting that symptoms due to the local tumor effect might be effectively controlled with radiation therapy, and EBRT is an important element of treatment. Novel treatment approaches are indicated in the therapy for

  20. Preliminary experience with CT-guided high-dose rate brachytherapy as an alternative treatment for hepatic recurrence of cholangiocarcinoma

    PubMed Central

    Kamphues, Carsten; Seehofer, Daniel; Collettini, Federico; Bahra, Marcus; Neuhaus, Peter; Wust, Peter; Denecke, Timm; Gebauer, Bernhard; Schnapauff, Dirk

    2012-01-01

    Background Intrahepatic recurrence after resection of intrahepatic or hilar cholangiocarcinoma represents a main reason for the poor prognosis of bile duct cancer. As no standard treatment has been established so far, the aim of this study was to analyse the safety and efficacy of computed tomography-guided high-dose rate brachytherapy (CT-HDRBT) as an alternative treatment in those patients. Methods The outcomes of 10 patients, who had been treated at least once for recurrent cholangiocarcinoma by CT-HDRBT, were retrospectively analysed. Results The median survival of all patients after primary liver resection was 85 months [95% confidence interval (CI) 68.129-101.871] with overall 1- and 5-year survival rates of 100% and 78.7%, respectively. After the occurrence of intrahepatic tumour recurrence, a total of 15 CT-HDRBT procedures were performed, alone or combined with other recurrence treatments, without any major complications according to the Society of Interventional Radiology classification. The 1-year and 5-year survival rates after recurrence treatment were 77.1% and 51.4%, respectively. Conclusions CT-HDRBT represents a safe treatment option for patients with recurrent bile duct cancer. As a part of a multimodal concept, CT-HDRBT might lead to a prolongation of survival in selected patients but further studies are urgently needed to prove this concept. PMID:23134179

  1. Cholangiocarcinoma Presenting as Uterine Metastasis

    PubMed Central

    Dendas, W.; Cappelle, L.; Verguts, J.; Orye, G.

    2014-01-01

    Metastases to the female genital tract are rare, with metastatic disease restricted to the uterus being even less frequent. The primary tumor is most often intragenital rather than extragenital. The diagnosis is usually made after occurrence of gynecological symptoms. We describe the case of a 26-year-old female, in whom a curettage for menorrhagia revealed a uterine malignancy, at first thought to be a carcinosarcoma. Biochemistry only showed iron deficiency anemia. Imaging showed discrepant results with liver lesions, suspect of neoplastic or inflammatory disease. She underwent an abdominal hysterectomy and, peroperatively, a frozen section of a mass in the liver hilus demonstrated a cholangiocarcinoma. The diagnosis of a uterine metastasized cholangiocarcinoma was made. We emphasize the fact that uterine metastases have to be excluded in every woman with abnormal uterine bleeding and a personal history of malignancy. However, our case also indicates that gynecological metastatic disease may be the first presentation of an extragenital primary neoplasm. PMID:25610676

  2. Right Hemihepatectomy by Suprahilar Intrahepatic Transection of the Right Hemipedicle using a Vascular Stapler

    PubMed Central

    Königsrainer, Ingmar; Nadalin, Silvio; Königsrainer, Alfred

    2010-01-01

    Successful hepatic resection requires profound anatomical knowledge and delicate surgical technique. Hemihepatectomies are mostly performed after preparing the extrahepatic hilar structures within the hepatoduodenal ligament, even in benign tumours or liver metastasis.1-5. Regional extrahepatic lymphadenectomy is an oncological standard in hilar cholangiocarcinoma, intrahepatic cholangio-cellular carcinoma and hepatocellular carcinoma, whereas lymph node metastases in the hepatic hilus in patients with liver metastasis are rarely occult. Major disadvantages of these procedures are the complex preparation of the hilus with the risk of injuring contralateral structures and the possibility of bleeding from portal vein side-branches or impaired perfusion of bile ducts. We developed a technique of right hemihepatectomy or resection of the left lateral segments with intrahepatic transection of the pedicle that leaves the hepatoduodenal ligament completely untouched. 6 However, if intraoperative visualization or palpation of the ligament is suspicious for tumor infiltration or lymph node metastasis, the hilus should be explored and a lymphadenectomy performed. PMID:20101200

  3. TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT

    PubMed Central

    Patidar, Kavish R.; Sydnor, Malcolm; Sanyal, Arun J.

    2014-01-01

    Transjugular intrahepatic portosystemic shunt (TIPS) is an established procedure for the complications of portal hypertension. The largest body of evidence for its use has been supported for recurrent or refractory variceal bleeding and refractory ascites. Its use has also been advocated for acute variceal bleed, hepatic hydrothorax, and hepatorenal syndrome. With the replacement of bare metal stents with polytetrafluoroethylen (PTFE) covered stents, shunt patency has improved dramatically thus improving outcomes. Therefore, reassessment of its utility, management of its complications, and understanding of various TIPS techniques is important. PMID:25438287

  4. Intrahepatic cholestasis of pregnancy

    PubMed Central

    Geenes, Victoria; Williamson, Catherine

    2009-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by maternal pruritus in the third trimester, raised serum bile acids and increased rates of adverse fetal outcomes. The etiology of ICP is complex and not fully understood, but it is likely to result from the cholestatic effects of reproductive hormones and their metabolites in genetically susceptible women. Equally unclear are the mechanisms by which the fetal complications occur. This article reviews the epidemiology, clinical features, diagnosis, etiology and management of ICP. PMID:19418576

  5. Intrahepatic cholestasis of pregnancy.

    PubMed

    Phillips, Cathi; Boyd, Margaret

    2015-01-01

    Itching is commonly reported by pregnant women and may be due to physiologic changes of pregnancy or could indicate a more serious health concern. Intrahepatic cholestasis of pregnancy, while classified as a pregnancy dermatosis, is actually a liver disease of pregnancy associated with significant fetal mortality and morbidity, as well as lifelong health risks for the offspring. In these challenging cases, nurses must understand the differential diagnoses and be prepared to provide comprehensive care, education and support to women with this condition. A case example is included. © 2015 AWHONN.

  6. Unusual Paraneoplastic Presentation of Cholangiocarcinoma

    PubMed Central

    Opneja, Aman; Mahajan, Sonia; Kapoor, Sargam; Marur, Shanthi; Yang, Steve Hoseong; Manno, Rebecca

    2015-01-01

    Introduction. Cutaneous paraneoplastic syndromes are a heterogeneous group of skin manifestations that occur in relation to many known malignancies. Paraneoplastic occurrence of SCLE has been noted but is not commonly reported. SCLE association with cholangiocarcinoma is rare. Case Presentation. A 72-year-old man with a history of extrahepatic stage IV cholangiocarcinoma presented with a pruritic rash. Cholangiocarcinoma had been diagnosed three years earlier and was treated. Five months after interruption of his chemotherapy due to a semiurgent surgery, he presented with explosive onset of a new pruritic rash, arthralgias, and lower extremity edema. Physical exam revealed a scaly erythematous rash on his arms, hands, face, neck, legs, and trunk. It was thick and scaly on sun exposed areas. Skin biopsy revealed vacuolar interface dermatitis. Immunofluorescence revealed IgM positive cytoid bodies scattered along the epidermal basement membrane zone. PET-CT scanning revealed metabolically active recurrent disease in peripancreatic and periportal region with hypermetabolic lymph nodes. Oral steroids and new regimen of chemotherapy were started. Rash improved and steroids were tapered off. Discussion. Paraneoplastic syndromes demonstrate the complex interaction between the immune system and cancer. Treatment resistant SCLE should raise a suspicion for paraneoplastic etiology. PMID:26495003

  7. Progressive familial intrahepatic cholestasis.

    PubMed

    Cavestro, Giulia Martina; Frulloni, Luca; Cerati, Elena; Ribeiro, Luciana Andrea; Corrente, Vincenzo; Sianesi, Mario; Franzè, Angelo; Di Mario, Francesco

    2002-01-01

    Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive childhood cholestasis of hepatocellular origin. PFIC 1, also known as Byler disease, was first described in Amish kindred. It is characterized by cholestasis often arising in the neonatal period and it leads to death due to liver failure. PFIC 1, like Benign Recurrent Intrahepatic Cholestasis (BRIC) which is the benign form of the same disease, recognizes mutations in the ATP8B1 gene. PFIC 2 disease is clinically similar to PFIC 1 but it has a different gene mutation causing a defect in the Bile Salt Export Pump (BSEP), exclusively expressed in the liver and involved in the canalicular secretion of bile acids. PFIC 3 usually appears later in life and it has a higher risk of portal hypertension, gastrointestinal bleeding and liver failure. This particular form of disease (the only one with high serum values of g-glutamil transpeptidase), is associated to a genetic defect in the class III multidrug resistance protein (MDR). External biliary diversion and ursodeoxycholic acid therapy, should be considered as the initial therapy in these patients, even if liver transplantation still seems to be the only solution for most patients.

  8. Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma

    SciTech Connect

    Xu, Yun-Fei; Yang, Xiao-Qing; Lu, Xiao-Fei; Guo, Sen; Liu, Yi; Iqbal, Mohammad; Ning, Shang-Lei; Yang, Hui; Suo, Ning; Chen, Yu-Xin

    2014-03-28

    Highlights: • FGFR4 is significantly related with N stage in IHCC, with T stage and TNM stage in PHCC. • FGFR4 is an independent prognostic factor in IHCC and PHCC. • FGFR4 promotes proliferation, invasion and EMT in cholangiocarinoma cell lines. • Inhibitor AP24354 can decrease proliferation, invasion and induce apoptosis of CCA. - Abstract: Fibroblast growth factor receptor 4 (FGFR4) is related to poor prognosis of several cancers, but the correlation between FGFR4 expression and cholangiocarcinoma (CCA) has not been well elucidated. We investigated the expression of FGFR4 in 83 intrahepatic cholangiocarcinomas (IHCCs), 75 perihilar cholangiocarcinomas (PHCCs) and 41 distal cholangiocarcinomas (DCCs) by immunohistochemistry (IHC), and subsequently evaluated association of FGFR4 with clinicopathologic parameters and survival rate. The rate of FGFR4 higher expression was 61.4% (51/83) in IHCCs, 53.3% (40/75) in PHCCs and 56.1% (23/41) in DCCs. FGFR4 expression was significantly related to poor prognosis of IHCC (P = 0.002) and PHCC (P = 0.019) with univariate analysis, and also identified as an independent prognostic factor in IHCC (P = 0.045) and PHCC (P = 0.049) with multivariate analysis. Additionally, with functional assays in vitro, we found FGFR4 can induce proliferation, invasion and epithelial–mesenchymal transition (EMT) of CCA cell lines with FGF19 stimulation. Moreover, FGFR4 inhibitor AP24354 can suppress proliferation, invasion and induce apoptosis of CCA cells. In conclusion, FGFR4 expression can be identified as a significant independent prognostic biomarker of IHCC and PHCC. FGFR4 played a pivotal role in proliferation, invasion and EMT of CCA. FGFR4 inhibitor can suppress proliferation, invasion and induce apoptosis of CCA, indicating that FGFR4 may act as a potential therapeutic target.

  9. TTF-1 and Napsin-A are expressed in a subset of cholangiocarcinomas arising from the gallbladder and hepatic ducts: continued caveats for utilization of immunohistochemistry panels.

    PubMed

    Surrey, Lea F; Frank, Renee; Zhang, Paul J; Furth, Emma E

    2014-02-01

    Thyroid transcription factor-1 (TTF-1) and Napsin-A (NapA) are frequently used to classify a tumor of unknown origin as lung or thyroid primary. Although recent studies have shown that nuclear TTF-1 positivity occasionally occurs in adenocarcinoma of nonpulmonary or thyroid origin dependent upon the antibody clone, TTF-1 has been reported as negative or infrequently positive in tumors of biliary origin. On the basis of an index case of cholangiocarcinoma expressing TTF-1, we were prompted to study TTF-1 and NapA positivity in cholangiocarcinoma. Archived paraffin-embedded tissue blocks from liver, gallbladder, and pancreato-biliary resections were chosen for cholangiocarcinoma (n=33) and non-neoplastic intrahepatic and extrahepatic biliary epithelium control tissue (n=26). Immunohistochemical analysis for TTF-1 and NapA was performed and graded for intensity and quantity. TTF-1 was negative in control biliary tissue but positive in 27.2% of cholangiocarcinomas. All TTF-1-positive cases (n=9) were extrahepatic (P=0.01), and most arose from the upper biliary tract (gallbladder and hepatic ducts). TTF-1 positivity was associated with age 60 years and above (P=0.01) but not with sex. Three TTF-1-positive cases were also NapA positive. NapA staining showed apical granular staining of the adjacent non-neoplastic epithelium in 6 cases (18.1%). In summary, 47.4% of extrahepatic cholangiocarcinoma expressed TTF-1, 33.3% of which coexpressed NapA. Cholangiocarcinoma should be considered in the differential when evaluating a TTF-1-positive tumor of unknown primary. As TTF-1 and NapA are not known for biliary system development or detected in non-neoplastic biliary epithelium, the significance of this "pulmonary" phenotype in a subset of extrahepatic cholangiocarcinoma is unknown and needs further investigation.

  10. Transjugular intrahepatic portosystemic shunt (TIPS)

    MedlinePlus

    ... Transjugular intrahepatic portosystemic shunt. In: Mauro MA, Murphy KPJ, Thomson KR, Venbrux AC, Morgan RA, eds. Image- ... of Georgia, Austell, GA. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, ...

  11. Progressive familial intrahepatic cholestasis.

    PubMed

    Srivastava, Anshu

    2014-03-01

    Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types-PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options.

  12. Progressive Familial Intrahepatic Cholestasis

    PubMed Central

    Srivastava, Anshu

    2013-01-01

    Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types—PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options. PMID:25755532

  13. Extended Resections for Hilar Cholangiocarcinoma

    PubMed Central

    Neuhaus, Peter; Jonas, Sven; Bechstein, Wolf O.; Lohmann, Rüdiger; Radke, Cornelia; Kling, Norbert; Wex, Cora; Lobeck, Hartmut; Hintze, Rainer

    1999-01-01

    Objective To evaluate different strategies for extended resections of hilar cholangiocarcinomas on radicality and survival. Summary Background Data Surgical resection of hilar cholangiocarcinoma is the only potentially curative treatment. Resection of central bile duct carcinomas, however, cannot always comply with the general principles of surgical oncology to achieve wide tumor-free margins with no-touch techniques. Methods From 1988 to 1998, 95 patients underwent resection of hilar cholangiocarcinoma. Eighty patients had hilar and hepatic resections and 15 had liver transplantation and partial pancreatoduodenectomy (LTPP;i.e., eradication of the entire biliary tract using a no-touch technique). Results The 60-day death rate was 8%. The overall 1- and 5-year survival rates were 67% and 22%, respectively. Five-year survival rates after R0, R1, and R2 resections were 37%, 9%, and 0%. In a multivariate analysis, surgical radicality was the strongest determinant of survival (p < 0.001). The rate of formally curative resection (R0 resection) was significantly lower in hilar resections (29%) than in liver resections (left hemihepatectomy 59%, right hemihepatectomy 55%, right trisegmentectomy 65%; p < 0.05). The highest rate of R0 resection was observed after LTPP (93%; p < 0.05). Right trisegmentectomies achieved the highest rate of 5-year survival after R0 resection (57%). In a multivariate analysis of patient survival after R0 resection, additional portal vein resection was the only significant factor. The 5-year survival rate after formally curative liver resection with portal vein resection was 65%versus 28% without. Conclusion Extended resections, especially right trisegmentectomies and LTPP, resulted in the highest rate of R0 resection. Right trisegmentectomy together with portal vein resection best represents the principles of surgical oncology and may be regarded as the surgical procedure of choice. Immunosuppression limits the applicability of LTPP. PMID

  14. Guadecitabine and Durvalumab in Treating Patients With Advanced Liver, Pancreatic, Bile Duct, or Gallbladder Cancer

    ClinicalTrials.gov

    2017-08-19

    Extrahepatic Bile Duct Adenocarcinoma, Biliary Type; Gallbladder Adenocarcinoma, Biliary Type; Metastatic Pancreatic Adenocarcinoma; Recurrent Cholangiocarcinoma; Recurrent Gallbladder Carcinoma; Recurrent Hepatocellular Carcinoma; Recurrent Intrahepatic Cholangiocarcinoma; Recurrent Pancreatic Carcinoma; Stage III Gallbladder Cancer AJCC V7; Stage III Hepatocellular Carcinoma AJCC v7; Stage III Intrahepatic Cholangiocarcinoma AJCC v7; Stage III Pancreatic Cancer AJCC v6 and v7; Stage IIIA Gallbladder Cancer AJCC v7; Stage IIIA Hepatocellular Carcinoma AJCC v7; Stage IIIB Gallbladder Cancer AJCC v7; Stage IIIB Hepatocellular Carcinoma AJCC v7; Stage IIIC Hepatocellular Carcinoma AJCC v7; Stage IV Gallbladder Cancer AJCC v7; Stage IV Hepatocellular Carcinoma AJCC v7; Stage IV Pancreatic Cancer AJCC v6 and v7; Stage IVA Gallbladder Cancer AJCC v7; Stage IVA Hepatocellular Carcinoma AJCC v7; Stage IVA Intrahepatic Cholangiocarcinoma AJCC v7; Stage IVB Gallbladder Cancer AJCC v7; Stage IVB Hepatocellular Carcinoma AJCC v7; Stage IVB Intrahepatic Cholangiocarcinoma AJCC v7; Unresectable Gallbladder Carcinoma; Unresectable Pancreatic Carcinoma

  15. Clinical analysis of cholangiocarcinoma patients receiving adjuvant radiotherapy

    PubMed Central

    Nantajit, Danupon; Trirussapanich, Pornwaree; Rojwatkarnjana, Sunanta; Soonklang, Kamonwan; Pattaranutraporn, Poompis; Laebua, Kanyanee; Chamchod, Sasikarn

    2016-01-01

    Cholangiocarcinoma (CCA) or bile duct cancer is a rare cancer type in developed countries, while its prevalence is increased in southeast Asia, affecting ~33.4 men and ~12.3 women per 100,000 individuals. CCA is one of the most lethal types of cancer. Neo-adjuvant and adjuvant therapies have been shown to have limited efficacy in improving the overall prognosis of patients. Radiotherapy has been reported to prolong the survival times of patients with certain characteristics. The present study retrospectively evaluated the medical records and follow-up data from 27 CCA patients who received radiotherapy at Chulabhorn Hospital (Bangkok, Thailand) between 2008 and 2014. A total of 14 patients underwent surgery followed by adjuvant chemoradiotherapy. Of the 27 CCA patients, 14 had intrahepatic CCA, 2 had extrahepatic CCA and 11 had hilar CCA. The 2-year survival rate was 40.7%. Tumor resectability, clinical symptoms and the Eastern Cooperative Oncology Group performance status score were found to be indicative of patient prognosis. In addition, the planning target volume and biologically effective radiotherapy dose were of prognostic value; however, initial treatment response was ambiguous in predicting survival time. The findings of the present study suggested that the currently used radiotherapy protocols for CCA may require modification to improve their efficacy. PMID:28105359

  16. Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma—2 case reports and a brief review

    PubMed Central

    Lavingia, Viraj

    2016-01-01

    Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced stage and is associated with a poor oncological outcome. The median survival for metastatic ICC is less than 1 year with standard chemotherapy. ICC is associated with distinct oncogenic drivers including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B), which may benefit from matching targeted therapies. Hereby we report 2 cases of BRAF V600E refractory ICC treated with dual BRAF and MEK inhibitors (dabrafenib and trametinib) with excellent clinical and radiological response to therapy and with protracted duration of disease control. Our first patient achieved CR (complete remission) at 6 months of treatment with ultimate disease progression at 9 months. The second patient achieved a PR (partial response) at 2 months from starting treatment and remains progression free at 5 months. Our results confirm the activity of dual BRAF and MEK targeting in BRAF mutated ICC, adding further support to 3 additional case-reports in the literature. Dual targeting appears superior to other case reports with BRAF inhibition alone and appear favorable to historic data with cytotoxic chemotherapy. Given the poor outlook and refractoriness of BRAF mutant ICC, future studies should focus on early integration of BRAF/MEK inhibition. PMID:28078132

  17. Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice.

    PubMed

    Martínez, Allyson K; Jensen, Kendal; Hall, Chad; O'Brien, April; Ehrlich, Laurent; White, Tori; Meng, Fanyin; Zhou, Tianhao; Greene, John; Bernuzzi, Francesca; Invernizzi, Pietro; Dostal, David E; Lairmore, Terry; Alpini, Gianfranco; Glaser, Shannon S

    2017-05-01

    Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR-dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  18. Progressive familial intrahepatic cholestasis.

    PubMed

    Jacquemin, E

    1999-06-01

    Progressive familial intrahepatic cholestasis (PFIC), also known as Byler disease, is an inherited disorder of childhood in which cholestasis of hepatocellular origin often presents in the neonatal period and leads to death from liver failure before adolescence. The pattern of appearance of affected children within families is consistent with autosomal recessive inheritance. Several studies have provided support for the heterogeneity of this clinical entity suggesting the existence of different types due to different disorders affecting the hepatocyte and related to defects of bile acid secretion or bile acid metabolism. Recent molecular and genetic studies have identified genes responsible for three types of PFIC and have shown that PFIC was related to mutations in hepatocellular transport system genes involved in bile formation. These findings now provide specific diagnostic tools for the investigation of children with PFIC and should allow prenatal diagnosis in the future. Genotype-phenotype correlations performed in patients treated with ursodeoxycholic acid or biliary diversion should allow those PFIC patients who could benefit from these therapies to be precisely identified. In the future, other therapies, such as cell and gene therapies, might be considered and could also represent an alternative to liver transplantation.

  19. Intrahepatic Transposition of Bile Ducts

    PubMed Central

    Delić, Jasmin; Savković, Admedina; Isaković, Eldar; Marković, Sergije; Bajtarevic, Alma; Denjalić, Amir

    2012-01-01

    Objective. To describe the intrahepatic bile duct transposition (anatomical variation occurring in intrahepatic ducts) and to determine the frequency of this variation. Material and Methods. The researches were performed randomly on 100 livers of adults, both sexes. Main research methods were anatomical macrodissection. As a criterion for determination of variations in some parts of bile tree, we used the classification of Segmentatio hepatis according to Couinaud (1957) according to Terminologia Anatomica, Thieme Stuugart: Federative Committee on Anatomical Terminology, 1988. Results. Intrahepatic transposition of bile ducts was found in two cases (2%), out of total examined cases (100): right-left transposition (right segmental bile duct, originating from the segment VIII, joins the left liver duct-ductus hepaticus sinister) and left-right intrahepatic transposition (left segmental bile duct originating from the segment IV ends in right liver duct-ductus hepaticus dexter). Conclusion. Safety and success in liver transplantation to great extent depends on knowledge of anatomy and some common embryological anomalies in bile tree. Variations in bile tree were found in 24–43% of cases, out of which 1–22% are the variations of intrahepatic bile ducts. Therefore, good knowledge on ductal anatomy enables good planning, safe performance of therapeutic and operative procedures, and decreases the risk of intraoperative and postoperative complications. PMID:22550601

  20. Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy.

    PubMed

    van der Woerd, Wendy L; van Mil, Saskia W C; Stapelbroek, Janneke M; Klomp, Leo W J; van de Graaf, Stan F J; Houwen, Roderick H J

    2010-10-01

    Progressive familial intrahepatic cholestasis (PFIC) type 1, 2 and 3 are due to mutations in ATP8B1, ABCB11 and ABCB4, respectively. Each of these genes encodes a hepatocanalicular transporter, which is essential for the proper formation of bile. Mutations in ABCB4 can result in progressive cholestatic disease, while mutations in ATP8B1 and ABCB11 can result both in episodic cholestasis, referred to as benign recurrent intrahepatic cholestasis (BRIC) type 1 and 2, as well as in progressive cholestatic disease. This suggests a clinical continuum and these diseases are therefore preferably referred to as ATP8B1 deficiency and ABCB11 deficiency. Similarly PFIC type 3 is designated as ABCB4 deficiency. Heterozygous mutations in each of these transporters can also be associated with intrahepatic cholestasis of pregnancy. This review summarizes the pathophysiology, clinical features and current as well as future therapeutic options for progressive familial- and benign recurrent intrahepatic cholestasis as well as intrahepatic cholestasis of pregnancy.

  1. A perspective on molecular therapy in cholangiocarcinoma: present status and future directions

    PubMed Central

    Andersen, Jesper B; Thorgeirsson, Snorri S

    2014-01-01

    SUMMARY Cholangiocarcinoma (CCA) is an orphan cancer with limited understanding of its genetic and genomic pathogenesis. Typically, it is highly treatment-refractory and patient outcome is dismal. Currently, there are no approved therapeutics for CCA and surgical resection remains the only option with curative intent. Clinical trials are currently being performed in a mixed cohort of biliary tract cancers that includes intrahepatic CCA, extrahepatic/perihilar CCA, distal extrahepatic CCA, gallbladder carcinoma and, in rare cases, even pancreatic cancers. Today, clinical trials fail primarily because they are underpowered mixed cohorts and designed without intent to enrich for markers to optimize success for targeted therapy. This review aims to emphasize current clinical attempts for targeted therapy of CCA, as well as highlight promising new candidate pathways revealed by translational genomics. PMID:24772266

  2. Intrahepatic peribiliary perivascular epithelioid cell tumor (PEComa) associated with heterotopic pancreas: A case report.

    PubMed

    Kiriyama, Yuka; Tsukamoto, Tetsuya; Mizoguchi, Yoshikazu; Ishihara, Shin; Horiguchi, Akihiko; Tokoro, Takamasa; Kato, Yutaro; Sugioka, Atsushi; Kuroda, Makoto

    2016-08-20

    Perivascular epithelioid-cell tumor (PEComa) is a group of rare mesenchymal neoplasms that express myomelanocytic-cell markers and exhibit a wide variety of histopathological features. Although heterotopic pancreas has been reported to occur in the gastrointestinal tract, intrahepatic heterotopic pancreas has been reported only rarely. We present a case of intrahepatic PEComa that showed a strong regional correlation with the presence of heterotopic pancreas. An intrahepatic tumor and biliary dilatation was incidentally discovered during a diagnostic evaluation to investigate low-back pain in a 47-year-old Japanese male. Cholangiocarcinoma was suspected and a left hemihepatectomy performed. Histological examination revealed a 3 × 3.8-mm tumor in the neighboring B2 bile duct. Histological and immunohistochemical investigations revealed the presence of a PEComa and pancreatic acini within the tumor mass. PEComa in the hepatobiliary and pancreatic regions are extremely rare. The presence of heterotopic pancreas is also relatively uncommon. The strong regional association of these 2 lesions raises the possibility of a PEComa originating from heterotopic pancreas or from an irritable response caused by heterotopic pancreas.

  3. Current Diagnostic and Management Options in Perihilar Cholangiocarcinoma

    PubMed Central

    Rizvi, Sumera; Gores, Gregory J.

    2014-01-01

    Cholangiocarcinomas (CCA) are heterogeneous biliary tract tumors with dismal prognosis. Perihilar cholangiocarcinoma (pCCA) involves the large bile ducts of the hepatic hilum, and is the most common type of CCA. Primary sclerosing cholangitis (PSC) is an established risk factor for pCCA. Although the diagnosis of pCCA is challenging, recent advances have been made including cytologic techniques such as fluorescence in situ hybridization. Endoscopic ultrasound with sampling of regional lymph nodes is emerging as a valuable diagnostic modality in the diagnosis and staging of pCCA. Curative treatment options are limited to early stage disease, and include surgical resection and liver transplantation after neoadjuvant therapy. This underscores the importance of early detection, and the need for development of innovative diagnostic tools such as biomarkers. A dense desmoplastic tumor stroma plays an integral role in pCCA progression. The tumor stroma represents an additional target for development of new therapies. Herein, we discuss these advances in the diagnosis and treatment of pCCA. PMID:24860985

  4. Cholangiocarcinoma

    MedlinePlus

    Bile duct cancer ... Bile duct cancers are slow-growing. They don't spread (metastasize) quickly. The exact cause of CCA isn't ... found. CCA may start anywhere along the bile ducts. These tumors block off the bile ducts. Both ...

  5. Concurrent Chemoradiotherapy in Resected Extrahepatic Cholangiocarcinoma

    SciTech Connect

    Nelson, John W.; Ghafoori, A. Paiman; Willett, Christopher G.; Tyler, Douglas S.; Pappas, Theodore N.; Clary, Bryan M.; Hurwitz, Herbert I.; Bendell, Johanna C.; Morse, Michael A.; Clough, Robert W.; Czito, Brian G.

    2009-01-01

    Purpose: Extrahepatic cholangiocarcinoma is a rare malignancy. Despite radical resection, survival remains poor, with high rates of local and distant failure. To clarify the role of radiotherapy with chemotherapy, we performed a retrospective analysis of resected patients who had undergone chemoradiotherapy. Methods and Materials: A total of 45 patients (13 with proximal and 32 with distal disease) underwent resection plus radiotherapy (median dose, 50.4 Gy). All but 1 patient received concurrent fluoropyrimidine-based chemotherapy. The median follow-up was 30 months for all patients and 40 months for survivors. Results: Of the 45 patients, 33 underwent adjuvant radiotherapy, and 12 were treated neoadjuvantly. The 5-year actuarial overall survival, disease-free survival, metastasis-free survival, and locoregional control rates were 33%, 37%, 42%, and 78%, respectively. The median survival was 34 months. No patient died perioperatively. Patient age {<=}60 years and perineural involvement adversely affected survival on univariate analysis. Patients undergoing R0 resection had a significantly improved rate of local control but no survival advantage. Despite having more advanced disease at presentation, patients treated neoadjuvantly had a longer survival (5-year survival 53% vs. 23%, p = 0.16) and similar rates of Grade 2-3 surgical morbidity (16% vs. 33%, p = 0.24) compared with those treated in the postoperative setting. Conclusion: These study results suggest a possible local control benefit from chemoradiotherapy combined with surgery in patients with advanced, resected biliary cancer. Furthermore, our results suggest that a treatment strategy that includes preoperative chemoradiotherapy might result in improved tumor resectability with similar surgical morbidity compared with patients treated postoperatively, as well as potentially improved survival outcomes. Distant failure remains a significant failure pattern, suggesting the need for more effective systemic

  6. CONCURRENT CHEMORADIOTHERAPY IN RESECTED EXTRAHEPATIC CHOLANGIOCARCINOMA

    PubMed Central

    Nelson, John W.; Ghafoori, A. Paiman; Willett, Christopher G.; Tyler, Douglas S.; Pappas, Theodore N.; Clary, Bryan M.; Hurwitz, Herbert I.; Bendell, Johanna C.; Morse, Michael A.; Clough, Robert W.; Czito, Brian G.

    2014-01-01

    Purpose Extrahepatic cholangiocarcinoma is a rare malignancy. Despite radical resection, survival remains poor, with high rates of local and distant failure. To clarify the role of radiotherapy with chemotherapy, we performed a retrospective analysis of resected patients who had undergone chemoradiotherapy. Methods and Materials A total of 45 patients (13 with proximal and 32 with distal disease) underwent resection plus radiotherapy (median dose, 50.4 Gy). All but 1 patient received concurrent fluoropyrimidine-based chemotherapy. The median follow-up was 30 months for all patients and 40 months for survivors. Results Of the 45 patients, 33 underwent adjuvant radiotherapy, and 12 were treated neoadjuvantly. The 5-year actuarial overall survival, disease-free survival, metastasis-free survival, and locoregional control rates were 33%, 37%, 42%, and 78%, respectively. The median survival was 34 months. No patient died perioperatively. Patient age ≤60 years and perineural involvement adversely affected survival on univariate analysis. Patients undergoing R0 resection had a significantly improved rate of local control but no survival advantage. Despite having more advanced disease at presentation, patients treated neoadjuvantly had a longer survival (5-year survival 53% vs. 23%, p = 0.16) and similar rates of Grade 2–3 surgical morbidity (16% vs. 33%, p = 0.24) compared with those treated in the postoperative setting. Conclusion These study results suggest a possible local control benefit from chemoradiotherapy combined with surgery in patients with advanced, resected biliary cancer. Furthermore, our results suggest that a treatment strategy that includes preoperative chemoradiotherapy might result in improved tumor resectability with similar surgical morbidity compared with patients treated postoperatively, as well as potentially improved survival outcomes. Distant failure remains a significant failure pattern, suggesting the need for more effective systemic

  7. Schisandrin B inhibits cell proliferation and induces apoptosis in human cholangiocarcinoma cells.

    PubMed

    Yang, Xiaohui; Wang, Shuai; Mu, Yunchuan; Zheng, Yixiong

    2016-10-01

    Cholangiocarcinoma (CCA) is the second most common hepatic cancer with high resistance to current chemotherapies and extremely poor prognosis. The present study aimed to examine the effects of schisandrin B (Sch B) on CCA cells both in vitro and in vivo and to examine its underlying mechanism. We found that Sch B inhibited the viability and proliferation of CCA cells in a dose- and time-dependent manner as assessed by MTT and colony formation assays. The flow cytometric assay revealed G0/G1 phase arrest in the Sch B-treated HCCC-9810 and RBE cells. In addition, Sch B induced intrahepatic cholangiocarcinoma apoptosis as shown by the results of Annexin V/PI double staining. Rhodamine 123 staining revealed that Sch B decreased the mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Mechanistically, western blot analysis indicated that Sch B induced apoptosis by upregulating Bax, cleaved caspase-3, cleaved caspase-9 and cleaved PARP, and by downregulating cyclin D1, Bcl-2 and CDK-4. Moreover, Sch B significantly inhibited HCCC-9810 xenograft growth in athymic nude mice. In summary, these findings suggest that Sch B exhibited potent antitumor activities via the induction of CCA apoptosis and that Sch B may be a promising drug for the treatment of CCA.

  8. Schisandrin B inhibits cell proliferation and induces apoptosis in human cholangiocarcinoma cells

    PubMed Central

    Yang, Xiaohui; Wang, Shuai; Mu, Yunchuan; Zheng, Yixiong

    2016-01-01

    Cholangiocarcinoma (CCA) is the second most common hepatic cancer with high resistance to current chemotherapies and extremely poor prognosis. The present study aimed to examine the effects of schisandrin B (Sch B) on CCA cells both in vitro and in vivo and to examine its underlying mechanism. We found that Sch B inhibited the viability and proliferation of CCA cells in a dose- and time-dependent manner as assessed by MTT and colony formation assays. The flow cytometric assay revealed G0/G1 phase arrest in the Sch B-treated HCCC-9810 and RBE cells. In addition, Sch B induced intrahepatic cholangiocarcinoma apoptosis as shown by the results of Annexin V/PI double staining. Rhodamine 123 staining revealed that Sch B decreased the mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Mechanistically, western blot analysis indicated that Sch B induced apoptosis by upregulating Bax, cleaved caspase-3, cleaved caspase-9 and cleaved PARP, and by downregulating cyclin D1, Bcl-2 and CDK-4. Moreover, Sch B significantly inhibited HCCC-9810 xenograft growth in athymic nude mice. In summary, these findings suggest that Sch B exhibited potent antitumor activities via the induction of CCA apoptosis and that Sch B may be a promising drug for the treatment of CCA. PMID:27499090

  9. Intrahepatic accessory spleen: imaging features.

    PubMed

    Izzo, Luciano; Caputo, Maria; Galati, Gaspare

    2004-06-01

    The authors present a case report of a 60-year-old man with a hepatic unknown mass. For diagnosis, they used ECO, CT (with and without contrast), MR (with and without contrast) and an ultrasound-assisted percutaneous lesion biopsy. Thus the mass-lesion in the liver appeared to be an intrahepatic accessory spleen in a patient afflicted with chronic hepatitis.

  10. Progressive familial intrahepatic cholestasis.

    PubMed

    Jacquemin, Emmanuel

    2012-09-01

    Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal-recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and associated with mutations in hepatocellular transport-system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may arise later in infancy, in childhood or even during young adulthood. The main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and in ABCB11 encoding bile salt export pump (BSEP) protein, respectively. Defects in ABCB4, encoding multidrug resistance 3 protein (MDR3), impair biliary phospholipid secretion, resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests to exclude other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates for whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis may be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 and PFIC2 patients, biliary diversion may also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of liver tumors

  11. Progressive familial intrahepatic cholestasis.

    PubMed

    Davit-Spraul, Anne; Gonzales, Emmanuel; Baussan, Christiane; Jacquemin, Emmanuel

    2009-01-08

    Progressive familial intrahepatic cholestasis (PFIC) refers to heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may also occur later in infancy, in childhood or even during young adulthood. Main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due respectively to defects in ATP8B1 encoding the FIC1 protein, and in ABCB11 encoding the bile salt export pump protein (BSEP). Defects in ABCB4, encoding the multi-drug resistant 3 protein (MDR3), impair biliary phospholipid secretion resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests for excluding other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates in whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis can be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 or PFIC2 patients, biliary diversion can also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of

  12. Pancreatic cancer risk variant ABO rs505922 in patients with cholangiocarcinoma

    PubMed Central

    Krawczyk, Marcin; Mihalache, Florentina; Höblinger, Aksana; Acalovschi, Monica; Lammert, Frank; Zimmer, Vincent

    2011-01-01

    The aim of this study was to investigate an association between the development of cholangiocarcinoma (CCA) and the ABO variant rs505922 (known to increase pancreatic cancer risk) in a large cohort of European individuals with CCA. In total, 180 individuals with CCA and 350 CCA-free controls were included. The ABO variant rs505922 was genotyped using a polymerase chain reaction-based assay. Association between this single nucleotide polymorphism (SNP) and CCA was tested in contingency tables. Neither allele distributions nor association tests and regression analysis provided evidence for an increased risk of CCA among carriers of the ABO variant (all P > 0.05). Nevertheless, we documented a deviation from Hardy-Weinberg equilibrium in the entire CCA cohort (P = 0.028) and for patients with intrahepatic (P = 0.037) but not extrahepatic tumor localization (P > 0.05). The association tests did not provide evidence for a prominent role of the investigated SNP in the genetic risk of CCA. However, Hardy-Weinberg disequilibrium in the entire cohort and the intrahepatic CCA subgroup warrants future studies investigating a potential CCA risk modulation by individual blood groups. PMID:22147973

  13. Pancreatic cancer risk variant ABO rs505922 in patients with cholangiocarcinoma.

    PubMed

    Krawczyk, Marcin; Mihalache, Florentina; Höblinger, Aksana; Acalovschi, Monica; Lammert, Frank; Zimmer, Vincent

    2011-11-07

    The aim of this study was to investigate an association between the development of cholangiocarcinoma (CCA) and the ABO variant rs505922 (known to increase pancreatic cancer risk) in a large cohort of European individuals with CCA. In total, 180 individuals with CCA and 350 CCA-free controls were included. The ABO variant rs505922 was genotyped using a polymerase chain reaction-based assay. Association between this single nucleotide polymorphism (SNP) and CCA was tested in contingency tables. Neither allele distributions nor association tests and regression analysis provided evidence for an increased risk of CCA among carriers of the ABO variant (all P > 0.05). Nevertheless, we documented a deviation from Hardy-Weinberg equilibrium in the entire CCA cohort (P = 0.028) and for patients with intrahepatic (P = 0.037) but not extrahepatic tumor localization (P > 0.05). The association tests did not provide evidence for a prominent role of the investigated SNP in the genetic risk of CCA. However, Hardy-Weinberg disequilibrium in the entire cohort and the intrahepatic CCA subgroup warrants future studies investigating a potential CCA risk modulation by individual blood groups.

  14. Hepatic cholangiocarcinoma and testicular mesothelioma in a wild-caught blue shark, Prionace glauca (L.).

    PubMed

    Borucinska, J D; Harshbarger, J C; Bogicevic, T

    2003-01-01

    An adult male blue shark, Prionace glauca (L.), caught in July 2000 by a recreational fisherman off Long Island, New York, USA, had a retained fishing hook from a previous capture. The hook penetrated the gastric wall and lacerated the right liver lobe. Macroscopic lesions consisted of transmural gastritis and peritonitis. Alteromonas sp. and Vibrio alginolyticus were isolated from the peritoneal fluid. In addition, a well delineated, sessile mass was found on the otherwise normal serosa of the right testis. Histopathological findings included mesothelial hyperplasia and hypertrophy involving diffusely the gastric, hepatic and parietal serosae, and forming a discrete testicular capsular mass compatible with mesothelioma. In the liver an intrahepatic cholangiocarcinoma, chronic hepatitis, biliary hyperplasia and increased numbers of melanomacrophages were found. In addition organisms compatible with histozoic and coelozoic myxosporeans were found within the skeletal muscle of the abdomen and intrahepatic bile ducts, respectively. This is the third literature report of a liver tumour and the first report of a coelomic mesothelioma from a shark.

  15. Revealing gene clusters associated with the development of cholangiocarcinoma, based on a time series analysis.

    PubMed

    Wu, Jianyu; Xiao, Zhifu; Zhao, Xiulei; Wu, Xiangsong

    2015-05-01

    Cholangiocarcinoma (CC) is a rapidly lethal malignancy and currently is considered to be incurable. Biomarkers related to the development of CC remain unclear. The present study aimed to identify differentially expressed genes (DEGs) between normal tissue and intrahepatic CC, as well as specific gene expression patterns that changed together with the development of CC. By using a two‑way analysis of variance test, the biomarkers that could distinguish between normal tissue and intrahepatic CC dissected from different days were identified. A k‑means cluster method was used to identify gene clusters associated with the development of CC according to their changing expression pattern. Functional enrichment analysis was used to infer the function of each of the gene sets. A time series analysis was constructed to reveal gene signatures that were associated with the development of CC based on gene expression profile changes. Genes related to CC were shown to be involved in 'mitochondrion' and 'focal adhesion'. Three interesting gene groups were identified by the k‑means cluster method. Gene clusters with a unique expression pattern are related with the development of CC. The data of this study will facilitate novel discoveries regarding the genetic study of CC by further work.

  16. Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma; its synthesis is reduced favoring cholangiocarcinoma growth

    PubMed Central

    Han, Yuyan; DeMorrow, Sharon; Invernizzi, Pietro; Jing, Qing; Glaser, Shannon; Renzi, Anastasia; Meng, Fanyin; Venter, Julie; Bernuzzi, Francesca; White, Mellanie; Francis, Heather; Lleo, Ana; Marzioni, Marco; Onori, Paolo; Alvaro, Domenico; Torzilli, Guido; Gaudio, Eugenio

    2011-01-01

    Cholangiocarcinoma (CCA) is a devastating biliary cancer. Melatonin is synthesized in the pineal gland and peripheral organs from serotonin by two enzymes, serotonin N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT). Cholangiocytes secrete neuroendocrine factors, including serotonin-regulating CCA growth by autocrine mechanisms. Melatonin exerts its effects by interaction with melatonin receptor type 1A/1B (MT1/MT2) receptors. We propose that 1) in CCA, there is decreased expression of AANAT and ASMT and secretion of melatonin, changes that stimulate CCA growth; and 2) in vitro overexpression of AANAT decreases CCA growth. We evaluated the 1) expression of AANAT, ASMT, melatonin, and MT1/MT2 in human nonmalignant and CCA lines and control and CCA biopsy samples; 2) melatonin levels in nonmalignant and CCA lines, and bile and serum from controls and patients with intrahepatic CCA; 3) effect of melatonin on the growth and expression of AANAT/ASMT and MT1/MT2 in CCA lines implanted into nude mice; and 4) effect of AANAT overexpression on the proliferation, apoptosis, and expression of MT1/MT2 in Mz-ChA-1 cells. The expression of AANAT, ASMT, and melatonin decreased, whereas MT1/MT2 expression increased in CCA lines and biopsy samples. Melatonin secretion decreased in the supernatant of CCA lines and bile of CCA patients. Melatonin decreased xenograft CCA tumor growth in nude mice by increased AANAT/ASMT and melatonin, along with reduced MT1/MT2 expression. Overexpression of AANAT in Mz-ChA-1 cells inhibited proliferation and MT1/MT2 expression and increased apoptosis. There is dysregulation of the AANAT/ASMT/melatonin → melatonin receptor axis in CCA, which inhibited melatonin secretion and subsequently enhanced CCA growth. PMID:21778461

  17. Intrahepatic splenosis in a dog.

    PubMed

    Knostman, K A B; Weisbrode, S E; Marrie, P A; Worman, J L

    2003-11-01

    A 10-year-old castrated male Standard Poodle presented with an acute onset of lethargy and abdominal pain. The animal had a history of traumatic splenic rupture requiring splenectomy 5 years previously. Surgical exploration revealed multiple cystic red nodules involving all liver lobes, several of which were submitted for histopathology. Microscopically, the cystic nodules were dilated bile ducts and lymphatics surrounded by ectopic splenic tissue. A diagnosis of intrahepatic splenosis was made.

  18. Scintigraphic differentiation of intrahepatic tumors

    SciTech Connect

    Creutzig, H.; Brolsch, C.; Gratz, K.; Neuhaus, P.; Muller, St.; Schober, O.; Lang, W.; Hundeshagen, H.; Pichlmayr, R.

    1984-01-01

    Intrahepatic tumors in asymptomatic patients are seen with increasing frequency. Treatment is dependent of the histology; while follicular nodular hyperplasia (FNH) and hemangiomas need no further treatment, all other tumors should be resected. In a prospective study we investigated the usefulness of two-stage scintigraphy (TSS) for the differentiation. The cholescintigraphy was started with a perfusion study, followed by a scan in the parenchymal phase and in the excretion phase. There is a typical scintigraphic pattern for FNH (hyperperfusion, normal parenchymal uptake delayed excretion) and hemangioma (hypoperfusion, no uptake), while all other tumors may have a mixed pattern. Therefore a blood pool is added to look for a hemangioma, if there is no typical pattern for FNH in the cholescintigraphy. The TSS classified correct 21 of 23 patients with FNH, 17 of 18 with hemangiomas, all 3 with adenoma and 36 of 37 with primary malignant intrahepatic tumors. The TSS is more accurate than CT or sonography, safe and inexpensive and therefore the method of first choice in the differentiation of intrahepatic tumors.

  19. Bile duct lymphoma disguised as cholangiocarcinoma

    PubMed Central

    Jaiswal, Deepna; Wong, Lucas

    2017-01-01

    We present a case of intrabiliary primary B-cell lymphoma masked as a cholangiocarcinoma in an HIV-positive patient. The two entities have similar symptoms, laboratory findings, and imaging findings but require very different treatments. The case highlights the need to confirm the diagnosis by biopsy. PMID:28405078

  20. Huge hepatocellular carcinoma with multiple intrahepatic metastases: An aggressive multimodal treatment.

    PubMed

    Yasuda, Satoshi; Nomi, Takeo; Hokuto, Daisuke; Yamato, Ichiro; Obara, Shinsaku; Yamada, Takatsugu; Kanehiro, Hiromichi; Nakajima, Yoshiyuki

    2015-01-01

    Huge hepatocellular carcinoma (HCC) possesses a potential risk for spontaneous rupture, which leads to a life-threatening complication with a high mortality rate. In addition, a large HCC is frequently accompanied by intrahepatic metastases. We describe, the case of a 74-year-old woman with a huge extrahepatically expanding HCC with multiple intrahepatic metastases who was treated by liver resection with repeated transcatheter arterial chemoembolization (TACE). To prevent tumor rupture or bleeding, we performed right hepatectomy. After the operation, TACE was applied for multiple intrahepatic metastases in the remnant liver. Furthermore, the elevated protein induced vitamin K absence (PIVKA II) level had decreased to limits within the normal range. Three months after the first TACE, computed tomography revealed several recurrences in the liver. TACE was applied for the second and third time and the tumors were well controlled. Although, liver resection is occasionally performed for patients with huge HCC to avoid spontaneous tumor rupture, only surgical approach might not be sufficient for such advanced HCC. To achieve long-term survival, it is necessary to control the residual intrahepatic tumors. We could control multiple intrahepatic metastases with repeated TACEs after hepatectomy. Multimodal treatment involving hepatectomy and TACE might be a good treatment strategy for patients with huge HCC with multiple intrahepatic metastases if the tumors are localized in the liver without distant or peritoneal metastasis. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Treatment of Leptomeningeal Carcinomatosis in a Patient With Metastatic Cholangiocarcinoma

    PubMed Central

    McNeill, Katharine; Volpicelli, Frank M.; Warltier, Karin; Iturrate, Eduardo; Okamura, Charles; Adler, Nicole; Smith, Joshua; Sigmund, Alana; Mednick, Aron; Wertheimer, Benjamin; Hochman, Katherine

    2014-01-01

    A 49-year-old woman with cholangiocarcinoma metastatic to the lungs presented with new-onset unrelenting headaches. A lumbar puncture revealed malignant cells consistent with leptomeningeal metastasis from her cholangiocarcinoma. Magnetic resonance imaging (MRI) of the brain revealed leptomeningeal enhancement. An intrathecal (IT) catheter was placed and IT chemotherapy was initiated with methotrexate. Her case is notable for the rarity of cholangiocarcinoma spread to the leptomeninges, the use of IT chemotherapy with cytologic and potentially symptomatic response, and a possible survival benefit in comparison to previously reported cases of leptomeningeal carcinomatosis secondary to cholangiocarcinoma. PMID:26157901

  2. The pathophysiology of intrahepatic cholestasis of pregnancy.

    PubMed

    Dixon, Peter H; Williamson, Catherine

    2016-04-01

    A number of liver disorders are specific to pregnancy. Amongst these, intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis (OC), is the commonest, affecting approximately 1 in 140 UK pregnancies. Patients commonly present in the third trimester with severe pruritus and deranged serum liver tests; bile acids are elevated, in severe cases >40 μmol/L. Although the disease is considered relatively benign for the mother, increased rates of adverse fetal outcomes, including stillbirth, are associated with ICP. As our knowledge of the mechanisms underlying bile acid homeostasis has advanced in the last 15 years our understanding of ICP has grown, in particular with respect to genetic influences on susceptibility to the disease, the role of reproductive hormones and their metabolites and the possible identity of the pruritic agents. In this review, we will describe recent advances in the understanding of this condition with a particular emphasis on how aspects of genetic and reproductive hormone involvement in pathophysiology have been elucidated. We also review recent developments regarding our knowledge of placental and fetal pathophysiology and the long-term health consequences for the mother and child. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  3. Spanish Experience in Liver Transplantation for Hilar and Peripheral Cholangiocarcinoma

    PubMed Central

    Robles, Ricardo; Figueras, Joan; Turrión, Victor S.; Margarit, Carlos; Moya, Angel; Varo, Evaristo; Calleja, Javier; Valdivieso, Andres; Valdecasas, Juan Carlos G.; López, Pedro; Gómez, Manuel; de Vicente, Emilio; Loinaz, Carmelo; Santoyo, Julio; Fleitas, Manuel; Bernardos, Angel; Lladó, Laura; Ramírez, Pablo; Bueno, F S.; Jaurrieta, Eduardo; Parrilla, Pascual

    2004-01-01

    Objective: To assess the real utility of orthotopic liver transplantation (OLT) in patients with cholangiocarcinoma, we need series with large numbers of cases and long follow-ups. The aim of this paper is to review the Spanish experience in OLT for hilar and peripheral cholangiocarcinoma and to try to identify the prognostic factors that could influence survival. Summary Background Data: Palliative treatment of nondisseminated irresectable cholangiocarcinoma carries a zero 5-year survival rate. The role of OLT in these patients is controversial, due to the fact that the survival rate is lower than with other indications for transplantation and due to the lack of organs. Methods: We retrospectively reviewed 59 patients undergoing OLT in Spain for cholangiocarcinoma (36 hilar and 23 peripheral) over a period of 13 years. We present the results and prognostic factors that influence survival. Results: The actuarial survival rate for hilar cholangiocarcinoma at 1, 3, and 5 years was 82%, 53%, and 30%, and for peripheral cholangiocarcinoma 77%, 65%, and 42%. The main cause of death, with both types of cholangiocarcinoma, was tumor recurrence (present in 53% and 35% of patients, respectively). Poor prognosis factors were vascular invasion (P < 0.01) and IUAC classification stages III–IVA (P < 0.01) for hilar cholangiocarcinoma and perineural invasion (P < 0.05) and stages III-IVA (P < 0.05) for peripheral cholangiocarcinoma. Conclusions: OLT for nondisseminated irresectable cholangiocarcinoma has higher survival rates at 3 and 5 years than palliative treatments, especially with tumors in their initial stages, which means that more information is needed to help better select cholangiocarcinoma patients for transplantation. PMID:14745336

  4. Interactive role of diabetes mellitus and female sex in the risk of cholangiocarcinoma: A population-based nested case-control study

    PubMed Central

    Huang, Yan-Jiun; Wu, Alexander TH; Chiou, Hung-Yi; Chuang, Ming-Tsang; Meng, Tzu-Ching

    2017-01-01

    Diabetes mellitus (DM) has been associated with an increased risk of extrahepatic cholangiocarcinoma (ECC) and intrahepatic cholangiocarcinoma (ICC). However, the role of DM in a population with a lower incidence of ECC remains unclear. We investigated the role of DM and other risk factors for ECC and ICC by conducting a population-based, nested, case–control study in Taiwan, a region with a lower incidence but a higher proportion of ICC. We identified patients who received a diagnosis of cholangiocarcinoma (CC) from the Taiwan Cancer Registry between 2003 and 2009. A total of 6,093 CC cases (ICC: 4,695; ECC: 1,396) and 60,906 matched controls were included. Compared with the controls, the patients with ICC and ECC were more likely to have DM, with an adjusted OR of 1.22 [95% confidence interval (CI): 1.07–1.39] and 1.48 (95% CI: 1.18–1.85), respectively. DM was associated with an increased risk of CC in the women and patients without a history of biliary tract diseases. Moreover, compared with the controls, DM was not associated with an increased risk of ECC in the patients who received cholecystectomy. These findings strongly support the positive association between DM and the increased risk of both ICC and ECC; however, this association was not observed in the patients who received cholecystectomy. PMID:28036262

  5. Outcome of Transplant-fallout Patients With Unresectable Cholangiocarcinoma

    PubMed Central

    Sio, Terence T.; Haddock, Michael G.; Novotny, Paul J.; Gores, Gregory J.; Alberts, Steven R.; Miller, Robert C.; Heimbach, Julie K.; Rosen, Charles B.

    2016-01-01

    Objectives: The aim of this was to determine survival after starting neoadjuvant therapy for patients who became ineligible for orthotopic liver transplantation (OLT). Methods and Materials: Since January 1993, 215 patients with unresectable cholangiocarcinoma began treatment with planned OLT. Treatment included external-beam radiation therapy (EBRT) with fluorouracil, bile duct brachytherapy, and postradiotherapy fluorouracil or capecitabine before OLT. Adverse findings at the staging operation, death, and other factors precluded OLT in 63 patients (29%), of whom 61 completed neoadjuvant chemoradiation. Results: By October 2012, 56 (89%) of the 63 patients unable to undergo OLT had died. Twenty-two patients (35%) became ineligible for OLT before the staging operation, 38 (60%) at the staging operation, and 3 (5%) after staging. From the date of diagnosis, median overall survival was 12.3 months. Survival was 17% at 18 months and 7% at 24 months. Median survival after fallout was 6.8 months. Median survival after the staging operation was 6 months. Two patients lived for 3.7 and 8.7 years before dying of cancer or liver failure caused by persistent biliary stricture at the site of the original cancer, respectively. Univariate analysis showed that time from diagnosis to fallout correlated with overall survival (P=0.04). Conclusions: In highly selected patients initially suitable for OLT, the mortality rate for cholangiocarcinoma was high in patients who became ineligible for OLT. Their survival, however, was comparable to expected survival for patients with locally advanced or metastatic disease treated with nontransplant therapies. The most common reason for patient fallout was adverse findings at the staging operation. PMID:24921218

  6. Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma.

    PubMed

    Wu, Hao; Liu, Yan; Jiang, Xiao-Wei; Li, Wen-Fang; Guo, Gang; Gong, Jian-Ping; Ding, Xiong

    2016-10-01

    Hepatocellular carcinoma (HCC) and hepatic cholangiocarcinoma (CC) are the most aggressive malignancies with a poor prognosis in humans, and hepatic cholangiocarcinoma (CC) exhibits greater malignant behaviour. Yes-associated protein (YAP) is an important downstream target of the Hippo signalling pathway. As an oncogene, it plays a vital role in the occurrence and development of tumours. Our study focuses on the clinical significance of YAP protein expression in HCC and CC. Furthermore, we sought to explore the different survival rates between HCC and CC. A total of 137 patients with HCC and 122 with CC after resection were evaluated by immunohistochemistry for the expression of YAP. Our results showed that positive expression rates of YAP were more frequently noted in CC 67.2 % (82/122) than in HCC 56.9 % (78/137) (P = 0.024). High YAP expression in HCC and CC was significantly associated with tumour size (P < 0.001 and P = 0.019, respectively), liver cirrhosis (P = 0.002 and P = 0.009, respectively), vascular invasion (P = 0.047 and P = 0.018, respectively), multiplicity (P = 0.019 and P = 0.015, respectively), and intrahepatic metastasis (P = 0.015 and P = 0.047, respectively). Importantly, recurrence-free survival and disease-specific survival rates were lower in CC with high YAP expression than in HCC with high YAP expression (P < 0.001 and P < 0.001, respectively). Overall, high YAP expression was more frequently found in CC than in HCC, and YAP overexpression was associated with poor survival rates in patients with HCC and CC. Targeting YAP treatment requires further prospective investigations in larger patient populations.

  7. Long Noncoding RNA AFAP1-AS1 Promoted Tumor Growth and Invasion in Cholangiocarcinoma.

    PubMed

    Lu, Xu; Zhou, Chuang; Li, Renfeng; Deng, Yilei; Zhao, Longshuan; Zhai, Wenlong

    2017-01-01

    Long non-coding RNAs (lncRNAs) have been shown to play important roles in a wide range of pathophysiological processes, including cancer progression. Our previous study has shown that AFAP1-AS1 was upregulated and acted as an oncogene in hepatocellular carcinoma. However, the expression and biological functions of lncRNA AFAP1-AS1 in intrahepatic cholangiocarcinoma (CCA) remains largely unknown. The expression level of AFAP1-AS1 was measured in 56 pairs of human cholangiocarcinoma tumor tissues and corresponding adjacent normal bile duct tissues. The correlation between AFAP1-AS1 and the clinicopathological features were evaluated by chi-square test. The effects of AFAP1-AS1 on CCA cells were determined by CCK-8 assay, clone formation assay, flow cytometry and transwell assay. Finally, to determine the effect of AFAP1-AS1 on tumor growth in vivo, AFAP1-AS1 knockdowned CCLP-1 cells were subcutaneously into nude mice to evaluate tumor growth. In this study, we found that lncRNA AFAP1-AS1 was increased in CCA tissues and patients with high AFAP1-AS1 expression had a shorter overall survival. SiRNA-mediated AFAP1-AS1 knockdown significantly decreased cell proliferation of the CCA cells, with downregulation of C-myc and Cycling D1 in vitro. Furthermore, AFAP1-AS1 silencing inhibited cell migration partly due to decrease the expression of MMP-2 and MMP-9. In addition, CCLP-1 cells with AFAP1-AS1 knockdown were injected into nude mice to investigate the effect of AFAP1-AS1 on the tumorigenesis in vivo. Taken together, our findings suggested that AFAP1-AS1 might promote the CCA progression and provided a novel potential therapeutic target for CCA. © 2017 The Author(s). Published by S. Karger AG, Basel.

  8. Secular Trends in the Incidence of Cholangiocarcinoma in the USA and the Impact of Misclassification

    PubMed Central

    Ilyas, Jawad A.; Duan, Zhigang; Green, Linda K.; Younes, Mamoun; El-Serag, Hashem B.; Davila, Jessica A.

    2016-01-01

    Background and Aims It has been reported that the incidence of intrahepatic cholangiocarcinoma (ICC) has increased in the USA, while extrahepatic cholangiocarcinoma (ECC) has decreased or remained stable. However, neither the recent trends nor the effects of the misclassification of Klatskin tumors are known. Methods Using the Surveillance, Epidemiology, and End Results program databases, we calculated the average annual age-adjusted incidence rates (AA-IRs) of ICC and ECC in 4-year time periods (1992–1995, 1996–1999, 2000–2003, 2004–2007). These AA-IRs were calculated with misclassified as well as correctly classified Klatskin tumors. AA-IRs were also calculated based on age, sex, and race. Multivariable Poisson regression models were used to evaluate the secular trends of ICC and ECC. Results The AA-IR of ICC was 0.92 in 1992–1995 and 0.93 in 2004–2007, while the AA-IR of ECC increased from 0.70 in 1992–1995 to 0.95 in 2004–2007. There was no significant trend in AA-IR of ICC (p = 0.07), while there was a significant increase in ECC across the 4-year time periods (p < 0.001). Klatskin tumors comprised 6.7 % of CCs with approximately 90 and 45 % misclassified as ICC during 1992–2000 and 2001–2007, respectively. Adjusted Poisson models showed no significant differences in the temporal trend of ICC or ECC due to misclassification of Klatskin tumors. Conclusions The incidence of ICC has remained stable between 1992 and 2007 with only slight fluctuations, while the incidence of ECC has been increasing. Misclassification of Klatskin tumors does not appear to play a significant role in the trends of CCs. PMID:25204668

  9. Role of intrahepatic tumor control in the prognosis of patients with hepatocellular carcinoma and extrahepatic metastases.

    PubMed

    Jung, Seung Min; Jang, Jeong Won; You, Chan Ran; Yoo, Sun Hong; Kwon, Jung Hyun; Bae, Si Hyun; Choi, Jong Young; Yoon, Seung Kew; Chung, Kyu Won; Kay, Chul Seung; Jung, Hyun Suk

    2012-04-01

    There has been little information about the long-term outcome and prognostic factors in patients with hepatocellular carcinoma (HCC) and extrahepatic metastases. The purpose of this study was to investigate the clinical factors affecting survival after extrahepatic metastasis and to determine the survival benefit of controlling intrahepatic HCC. Between 2004 and 2009, a total of 240 consecutive patients with HCC and extrahepatic metastasis were recruited. Based on tumor extent, performance, and hepatic function, the patients underwent locoregional and/or systemic treatments. The treatment response of the intrahepatic tumor after extrahepatic metastasis and other prognostic parameters were analyzed retrospectively. During the mean follow up of 276 days, 222 patients died; the median survival time was 146 days. Multivariate analysis revealed that Child-Pugh class A, smaller hepatic tumor size, absence of portal venous invasion, single metastatic organ involvement, and objective treatment response of the intrahepatic tumor were the favorable prognostic factors for survival. Of the 183 evaluable patients, 24 achieved complete or partial response for intrahepatic tumors after treatment. The overall survival for the 24 responders was significantly improved, with a median of 521 days, as compared to 170 days for the remaining 159 patients without objective tumor response. The leading cause of death was progressive intrahepatic tumor. Intrahepatic tumor status and hepatic reserve are among the significant predictors of survival in patients with HCC and extrahepatic metastases. This study indicates that even in patients with metastases from advanced HCC, therapeutic approaches to control intrahepatic tumors are important in improving patient survival. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

  10. Hilar cholangiocarcinoma with intratumoral calcification: A case report

    PubMed Central

    Inoko, Kazuho; Tsuchikawa, Takahiro; Noji, Takehiro; Kurashima, Yo; Ebihara, Yuma; Tamoto, Eiji; Nakamura, Toru; Murakami, Soichi; Okamura, Keisuke; Shichinohe, Toshiaki; Hirano, Satoshi

    2015-01-01

    This report describes a rare case of hilar cholangiocarcinoma with intratumoral calcification that mimicked hepatolithiasis. A 73-year-old man presented to a local hospital with a calcified lesion in the hepatic hilum. At first, hepatolithiasis was diagnosed, and he underwent endoscopic stone extraction via the trans-papillary route. This treatment strategy failed due to biliary stricture. He was referred to our hospital, and further examination suggested the existence of cholangiocarcinoma. He underwent left hepatectomy with caudate lobectomy and extrahepatic bile duct resection. Pathological examination revealed hilar cholangiocarcinoma with intratumoral calcification, while no stones were found. To the best of our knowledge, only one case of calcified hilar cholangiocarcinoma has been previously reported in the literature. Here, we report a rare case of calcified hilar cholangiocarcinoma and reveal its clinicopathologic features. PMID:26478684

  11. [Control of Opisthorchis viverrini infection for cholangiocarcinoma prevention].

    PubMed

    Buisson, Y

    2017-02-01

    The International Agency for Research on Cancer (IARC) has classified two liver flukes as carcinogenic to humans (Group 1): Opisthorchis viverrini in 1994 and Clonorchis sinensis in 2009. This review is focused on O. viverrini, the most studied of these two trematodes, which infects nearly 10 million people in Southeast Asia. The life cycle involves two intermediate hosts living in fresh water: a snail of the genus Bithynia and a ciprinid fish. The definitive hosts (human, cat, dog) become infected by ingesting raw fish containing metacercariae, the infective stage of the parasite. Adult flukes attach to the epithelium of the bile ducts where they feed for as long as 10 to 30 years, resulting in chronic inflammation, epithelial hyperplasia, periductal fibrosis and formation of granuloma. For a long asymptomatic, the distomatosis is revealed by a chronic cholangitis when the parasite load becomes high. Complications can occur with time: gallstones, cholangitis, liver abscess, pancreatitis and, after a few decades, cholangiocarcinoma (CCA). The epidemiological correlation between the prevalence of O. viverrini infection and the incidence of CCA has been demonstrated in the northeast of Thailand. Specifically, the Khon Kaen province has the highest incidence rate in the world. The CCA can develop asymptomatically for a long time, especially in intrahepatic locations. It is often discovered at a late stage, unresectable. Its prognosis is dreadful with a survival rate less than 5% at 5 years. The phenomenon of carcinogenesis induced by O. viverrini is multifactorial. It has been specially studied using experimental infection on the Syrian golden hamster. Three intricated mechanisms are involved: (i) the direct damage caused by adult worms on the bile duct epithelium, (ii) the immunopathologic processes related to chronic inflammation (oxidative stress) and (iii) the mitogenic and anti-apoptotic effects of the proteins secreted by the parasite. Exogenous cofactors are

  12. Intrahepatic cholestasis with parental alimentation.

    PubMed

    Rodgers, B M; Hollenbeck, J I; Donnelly, W H; Talbert, J L

    1976-02-01

    From July 1971 to March 1975, elevan infants receiving total or partial parenteral alimentation at the University of Florida showed histologic evidence of intrahepatic cholestasis. The clinical records of these patients have been examined. These infants were critically ill and had protracted hospital courses with only two survivors. Liver biopsies demonstrated marked cholestasis with some fibrosis and thickening of the limiting membrane of the hepatocyte. In those patients in whom serial liver biopsies were obtained, hepatic histology returned toward normal, paralleling improvement in liver function studies, as intravenous alimentation was discontinued. Careful monitoring of the liver function tests is essential to detect this progressive abnormality as early as possible and discontinue intravenous alimentation. Follow-up as long as two and a half years in the two surviving patients has demonstrated no chronic dysfunction.

  13. Multiple intrahepatic pseudocysts in acute pancreatitis

    PubMed Central

    Casado, David; Sabater, Luis; Calvete, Julio; Mayordomo, Empar; Aparisi, Luis; Sastre, Juan; Lledo, Salvador

    2007-01-01

    Liver pseudocysts are a very rare complication in acute pancreatitis with only a few cases previously described. The lack of experience and literature on this condition leads to difficulties in the differential diagnosis and management. We report herein a case of acute pancreatitis who developed multiple intrahepatic pseudocysts. After complete imaging evaluation, the diagnosis was still unclear and the patient was operated on. The presence of liver lesions in patients with acute pancreatitis should raise the possibility of intrahepatic pseudocysts. PMID:17729426

  14. Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma.

    PubMed

    Arbelaiz, Ander; Azkargorta, Mikel; Krawczyk, Marcin; Santos-Laso, Alvaro; Lapitz, Ainhoa; Perugorria, Maria J; Erice, Oihane; Gonzalez, Esperanza; Jimenez-Agüero, Raul; Lacasta, Adelaida; Ibarra, Cesar; Sanchez-Campos, Alberto; Jimeno, Juan P; Lammert, Frank; Milkiewicz, Piotr; Marzioni, Marco; Macias, Rocio I R; Marin, Jose J G; Patel, Tushar; Gores, Gregory J; Martinez, Ibon; Elortza, Félix; Falcon-Perez, Juan M; Bujanda, Luis; Banales, Jesus M

    2017-10-01

    Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. Several conditions, such as primary sclerosing cholangitis (PSC), are risk factors. Noninvasive differential diagnosis between intrahepatic CCA and hepatocellular carcinoma (HCC) is sometimes difficult. Accurate noninvasive biomarkers for PSC, CCA, and HCC are not available. In the search for novel biomarkers, serum extracellular vesicles (EV) were isolated from CCA (n = 43), PSC (n = 30), or HCC (n = 29) patients and healthy individuals (control, n = 32); and their protein content was characterized. By using nanoparticle tracking analysis, serum EV concentration was found to be higher in HCC than in all the other groups. Round morphology (by transmission electron microscopy), size (∼180 nm diameter by nanoparticle tracking analysis), and markers (clusters of differentiation 9, 63, and 81 by immunoblot) indicated that most serum EV were exosomes. Proteome profiles (by mass spectrometry) revealed multiple differentially expressed proteins among groups. Several of these proteins showed high diagnostic values with maximum area under the receiver operating characteristic curve of 0.878 for CCA versus control, 0.905 for CCA stage I-II versus control, 0.789 for PSC versus control, 0.806 for noncirhottic PSC versus control, 0.796 for CCA versus PSC, 0.956 for CCA stage I-II versus PSC, 0.904 for HCC versus control, and 0.894 for intrahepatic CCA versus HCC. Proteomic analysis of EV derived from CCA human cells in vitro revealed higher abundance of oncogenic proteins compared to EV released by normal human cholangiocytes. Orthotopic implant of CCA human cells in the liver of immunodeficient mice resulted in the release to serum of EV containing some similar human oncogenic proteins. Proteomic signatures found in serum EV of CCA, PSC, and HCC patients show potential usefulness as diagnostic tools. (Hepatology 2017;66:1125-1143). © 2017 by the American Association for the Study

  15. Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression.

    PubMed

    Erice, O; Labiano, I; Arbelaiz, A; Santos-Laso, A; Munoz-Garrido, P; Jimenez-Agüero, R; Olaizola, P; Caro-Maldonado, A; Martín-Martín, N; Carracedo, A; Lozano, E; Marin, J J; O'Rourke, C J; Andersen, J B; Llop, J; Gómez-Vallejo, V; Padro, D; Martin, A; Marzioni, M; Adorini, L; Trauner, M; Bujanda, L; Perugorria, M J; Banales, J M

    2017-09-13

    Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated. FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro. FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism. Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma

    PubMed Central

    Chen, Ming-Huang; Chiang, Kun-Chun; Cheng, Chi-Tung; Huang, Shih-Chiang; Chen, Yeng-Yang; Chen, Tsung-Wen; Yeh, Ta-Sen; Jan, Yi-Yin; Wang, Hsi-Ming; Weng, Jiang-Jie; Chang, Peter Mu-Hsin; Liu, Chun-Yu; Li, Chung-Pin; Chao, Yee; Chen, Ming-Han; Huang, Chi-Ying F.; Yeh, Chun-Nan

    2014-01-01

    The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination. Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment. PMID:24796583

  17. Brachytherapy in the Treatment of Cholangiocarcinoma

    SciTech Connect

    Shinohara, Eric T.; Guo Mengye; Mitra, Nandita; Metz, James M.

    2010-11-01

    Purpose: To examine the role of brachytherapy in the treatment of cholangiocarcinomas in a relatively large group of patients. Methods and Materials: Using the Surveillance, Epidemiology and End Results database, a total of 193 patients with cholangiocarcinoma treated with brachytherapy were identified for the period 1988-2003. The primary analysis compared patients treated with brachytherapy (with or without external-beam radiation) with those who did not receive radiation. To try to account for confounding variables, propensity score and sensitivity analyses were used. Results: There was a significant difference between patients who received radiation (n = 193) and those who did not (n = 6859) with regard to surgery (p < 0.0001), race (p < 0.0001), stage (p < 0.0001), and year of diagnosis (p <0.0001). Median survival for patients treated with brachytherapy was 11 months (95% confidence interval [CI] 9-13 months), compared with 4 months for patients who received no radiation (p < 0.0001). On multivariable analysis (hazard ratio [95% CI]) brachytherapy (0.79 [0.66-0.95]), surgery (0.50 [0.46-0.53]), year of diagnosis (1998-2003: 0.66 [0.60-0.73]; 1993-1997: (0.96 [0.89-1.03; NS], baseline 1988-1992), and extrahepatic disease (0.84 [0.79-0.89]) were associated with better overall survival. Conclusions: To the authors' knowledge, this is the largest dataset reported for the treatment of cholangiocarcinomas with brachytherapy. The results of this retrospective analysis suggest that brachytherapy may improve overall survival. However, because of the limitations of the Surveillance, Epidemiology and End Results database, these results should be interpreted cautiously, and future prospective studies are needed.

  18. [Occupational cholangiocarcinoma in a printer that responded to neoadjuvant chemoradiotherapy].

    PubMed

    Nakagawa, Kei; Katayose, Yu; Ishida, Kazuyuki; Hayashi, Hiroki; Morikawa, Takanori; Yoshida, Hiroshi; Motoi, Fuyuhiko; Naitoh, Takeshi; Kubo, Shoji; Unno, Michiaki

    2015-07-01

    A 42-year-old man working at a printing company was referred to our hospital for examination and treatment of icterus. We diagnosed resectable hilar cholangiocarcinoma and provided neoadjuvant chemoradiotherapy, extended right hepatectomy, and extrahepatic bile duct resection. A detailed history revealed that he had used 1,2-dichloropropane as part of his work as an offset colour proof-printer, and he has subsequently been recognized as having occupational cholangiocarcinoma. He has survived without recurrence for more than 2 and half years since the liver resection. In the present report, we describe our valuable experience of neoadjuvant chemoradiotherapy for occupational cholangiocarcinoma.

  19. Matrix proteins of basement membrane of intrahepatic bile ducts are degraded in congenital hepatic fibrosis and Caroli's disease.

    PubMed

    Yasoshima, Mitsue; Sato, Yasunori; Furubo, Shinichi; Kizawa, Kazuo; Sanzen, Takahiro; Ozaki, Satoru; Harada, Kenichi; Nakanuma, Yasuni

    2009-02-01

    Congenital hepatic fibrosis (CHF) and Caroli's disease are though to result from ductal plate malformation, and the basal laminar components play important roles in biliary differentiation during development. To clarify the involvement of basal laminar components in the ductal plate malformation, this study examined the immunohistochemical expression of laminin and type IV collagen in the livers of CHF and Caroli's disease. Using the polycystic kidney (PCK) rat, an animal model of Caroli's disease with CHF, in vivo and in vitro experiments were also performed. Immunostaining showed that basement membrane expression of laminin and type IV collagen around intrahepatic bile ducts was degraded in CHF, Caroli's disease, and the PCK rats. The degradation of laminin and type IV collagen around bile ducts was also observed in foci of cholangiocarcinoma in situ of Caroli's disease. In vitro, PCK cholangiocytes were found to overexpress plasminogen and a serine proteinase, the tissue-type plasminogen activator (tPA). When PCK cholangiocytes were cultured in Matrigel, the amounts of laminin and collagen in the gel were significantly reduced, and addition of alpha2-antiplasmin in the culture medium inhibited the degradation of laminin and collagen in Matrigel. These results suggest that biliary overexpression of plasminogen and tPA leads to the generation of excessive amounts of plasmin, and subsequent plasmin-dependent lysis of the extracellular matrix molecules may contribute to the biliary dysgenesis in CHF and Caroli's disease, including progressive cystic dilatation of the intrahepatic bile ducts in Caroli's disease. In addition, it is suggested that once cholangiocarcinoma in situ develops in the biliary epithelium of CHF and Caroli's disease, it tends to transform into invasive carcinoma, due to instability of the basement membrane of the bile ducts.

  20. Metastatic colon cancer from extrahepatic cholangiocarcinoma presenting as painless jaundice: case report and literature review.

    PubMed

    Vabi, Benjamin W; Carter, Jeffrey; Rong, Rong; Wang, Minhua; Corasanti, James G; Gibbs, John F

    2016-04-01

    Cholangiocarcinoma (CCA) is a rare cancer of the biliary epithelium comprising only about 3% of all gastrointestinal malignancies. It is a highly aggressive malignancy and confers a dismal prognosis with majority of patients presenting with metastatic disease. Metastatic CCA to the colon is extremely rare with only few cases reported in the literature. We present a 61-year-old patient with incidental synchronous metastatic colonic adenocarcinoma from extra-hepatic CCA. Laboratory data revealed significant indirect hyperbilirubinemia and transaminitis. Imaging study showed intrahepatic bile ducts prominence without mass lesions. Incidentally, there was diffuse colonic thickening without mass lesions or obstruction. Endoscopic retrograde cholangiopancreatography (ERCP) showed a common bile duct stricture. Brushings were consistent with CCA. Screening colonoscopy identified nodularity and biopsy and immunostaining were consistent with CCA metastasis to colon. The patient elected for palliative and comfort care. Metastatic CCA to the colon is a rare pattern of distant spread that may pose a diagnostic challenge. Some salient characteristics may assist in the differentiation of primary colon cancer and metastatic colon cancer from CCA. Little remains known about the pathogenic behavior of metastatic secondary colorectal cancer. And more so, the management approach to such metastatic cancer still remains to be defined. Screening colonoscopy in patients presenting with resectable CCA may alter management. Furthermore, whether patients with history of resected CCA may benefit from a more frequent screening colonoscopy remains to be validated.

  1. Resistin as an Intrahepatic Cytokine

    PubMed Central

    Bertolani, Cristiana; Sancho-Bru, Pau; Failli, Paola; Bataller, Ramon; Aleffi, Sara; DeFranco, Raffaella; Mazzinghi, Benedetta; Romagnani, Paola; Milani, Stefano; Ginés, Pere; Colmenero, Jordi; Parola, Maurizio; Gelmini, Stefania; Tarquini, Roberto; Laffi, Giacomo; Pinzani, Massimo; Marra, Fabio

    2006-01-01

    Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-κB. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-κB activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca2+/NF-κB-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis. PMID:17148667

  2. Cholangiocarcinoma with metastasis in a captive Adelie penguin (Pygoscelis adeliae).

    PubMed

    Renner, M S; Zaias, J; Bossart, G D

    2001-09-01

    A captive male Adelie penguin (Pygoscelis adeliae), wild caught in 1976, died unexpectedly. Necropsy revealed cholangiocarcinoma with metastases to lung, pancreas, mesentery, and cloaca, the first known case of a penguin hepatic tumor.

  3. Role of Endoscopic Ultrasonography in the Evaluation of Extrahepatic Cholangiocarcinoma

    PubMed Central

    Strongin, Anna; Singh, Harkirat; Eloubeidi, Mohamad A.; Siddiqui, Ali A.

    2013-01-01

    Cholangiocarcinoma is a malignancy that arises from biliary epithelium and is associated with a poor prognosis. Accurate preopera-tive diagnosis and staging of cholangiocarcinoma continues to remain difficult. Endoscopic retrograde cholangiopancreatography (ERCP) is the most commonly performed procedure for cholangiocarcinoma and can provide a tissue diagnosis through brush cytology of the bile duct. However, the sensitivity of biliary brush cytology to diagnose cholangiocarcinoma may be as low as 30%. Endoscopic ultrasound (EUS) is a diagnostic modality which may overcome the limitations of other imaging and biopsy techniques in this setting. EUS can complement the role of ERCP and provide a tissue diagnosis through fine needle aspiration (FNA) and staging through ultrasound imaging. There is currently a paucity of data about the exact role of EUS for the diagnosis of cholan-giocarcinoma in patients with indeterminate extrahepatic biliary strictures. Although multiple studies have shown that EUS is more accurate than ERCP and radiologic imaging for identifying a biliary mass and diagnosing cholangiocarcinoma, the sensitivities are variable. More importantly, the incidence of false negative results is not negligible, though the specificity is close to 100%. There is also controversy regarding the role of EUS-FNA, since even though this may increase diagnosis, it can also lead to tumor seeding. PMID:24949368

  4. Delayed intrahepatic subcapsular hematoma after laparoscopic cholecystectomy.

    PubMed

    de Castro, Steve M M; Reekers, Jim A; Dwars, Boudewijn J

    2012-01-01

    Intrahepatic subcapsular hematoma after laparoscopic cholecystectomy is a rare complication and is potentially life threatening. When radiologic studies confirm the presence of the hematoma, the decision to follow a conservative treatment should involve clinical monitoring. If there are signs of infection, the collection can safely be drained percutaneously. If there are signs of active bleeding, a selective embolization should be attempted first. If unsuccessful, subsequent surgical evacuation should be performed. We report the case of a patient with an intrahepatic subcapsular hematoma after laparoscopic cholecystectomy, which occurred 6 weeks after surgery, and review the literature concerning the management of these bleedings.

  5. Four Major Factors Contributing to Intrahepatic Stones

    PubMed Central

    Ran, Xi; Yin, Baobing

    2017-01-01

    Intrahepatic stone is prevalent in Asian countries; though the incidence declines in recent years, the number of patients is still in a large quantity. Because of multiple complications, high recurrence rates, serious systemic damage, and a lack of extremely effective procedure for the management, it is more important to find out the etiology and pathogenesis of intrahepatic stones to prevent the disease from happening and developing rather than curing. A number of factors contribute to the development of the disease, such as cholestasis, infection, and anatomic abnormity of bile duct and bile metabolic defect. The four factors and possible pathogenesis will be discussed in detail in the review. PMID:28163717

  6. The molecular genetics of intrahepatic cholestasis of pregnancy

    PubMed Central

    Dixon, P H; Williamson, C

    2008-01-01

    Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, causes maternal pruritus and liver impairment, and may be complicated by spontaneous preterm labour, fetal asphyxial events and intrauterine death. Our understanding of the aetiology of this disease has expanded significantly in the last decade due to a better understanding of the role played by genetic factors. In particular, advances in our knowledge of bile homeostasis has led to the identification of genes that play a considerable role in susceptibility to ICP. In this review we consider these advances and discuss the disease in the context of bile synthesis and metabolism, focusing on the genetic discoveries that have shed light on the molecular aetiology and pathophysiology of the condition. PMID:27582788

  7. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited.

    PubMed

    Boulter, Luke; Guest, Rachel V; Kendall, Timothy J; Wilson, David H; Wojtacha, Davina; Robson, Andrew J; Ridgway, Rachel A; Samuel, Kay; Van Rooijen, Nico; Barry, Simon T; Wigmore, Stephen J; Sansom, Owen J; Forbes, Stuart J

    2015-03-02

    Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.

  8. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

    PubMed Central

    Boulter, Luke; Guest, Rachel V.; Kendall, Timothy J.; Wilson, David H.; Wojtacha, Davina; Robson, Andrew J.; Ridgway, Rachel A.; Samuel, Kay; Van Rooijen, Nico; Barry, Simon T.; Wigmore, Stephen J.; Sansom, Owen J.; Forbes, Stuart J.

    2015-01-01

    Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC. PMID:25689248

  9. H3 Histamine Receptor–Mediated Activation of Protein Kinase Cα Inhibits the Growth of Cholangiocarcinoma In vitro and In vivo

    PubMed Central

    Francis, Heather; Onori, Paolo; Gaudio, Eugenio; Franchitto, Antonio; DeMorrow, Sharon; Venter, Julie; Kopriva, Shelley; Carpino, Guido; Mancinelli, Romina; White, Mellanie; Meng, Fanyin; Vetuschi, Antonella; Sferra, Roberta; Alpini, Gianfranco

    2009-01-01

    Histamine regulates functions via four receptors (HRH1, HRH2, HRH3, and HRH4). The d-myo-inositol 1,4,5-trisphosphate (IP3)/Ca2+/protein kinase C (PKC)/mitogen-activated protein kinase pathway regulates cholangiocarcinoma growth. We evaluated the role of HRH3 in the regulation of cholangiocarcinoma growth. Expression of HRH3 in intrahepatic and extrahepatic cell lines, normal cholangiocytes, and human tissue arrays was measured. In Mz-ChA-1 cells stimulated with (R)-(α)-(−)-methylhistamine dihydrobromide (RAMH), we measured (a) cell growth, (b) IP3 and cyclic AMP levels, and (c) phosphorylation of PKC and mitogen-activated protein kinase isoforms. Localization of PKCα was visualized by immunofluorescence in cell smears and immunoblotting for PKCα in cytosol and membrane fractions. Following knockdown of PKCα, Mz-ChA-1 cells were stimulated with RAMH before evaluating cell growth and extracellular signal–regulated kinase (ERK)-1/2 phosphorylation. In vivo experiments were done in BALB/c nude mice. Mice were treated with saline or RAMH for 44 days and tumor volume was measured. Tumors were excised and evaluated for proliferation, apoptosis, and expression of PKCα, vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF receptor 2, and VEGF receptor 3. HRH3 expression was found in all cells. RAMH inhibited the growth of cholangiocarcinoma cells. RAMH increased IP3 levels and PKCα phosphorylation and decreased ERK1/2 phosphorylation. RAMH induced a shift in the localization of PKCα expression from the cytosolic domain into the membrane region of Mz-ChA-1 cells. Silencing of PKCα prevented RAMH inhibition of Mz-ChA-1 cell growth and ablated RAMH effects on ERK1/2 phosphorylation. In vivo, RAMH decreased tumor growth and expression of VEGF and its receptors; PKCα expression was increased. RAMH inhibits cholangiocarcinoma growth by PKCα-dependent ERK1/2 dephosphorylation. Modulation of PKCα by histamine receptors may be important in regulating

  10. Cediranib Maleate and Combination Chemotherapy in Treating Patients With Advanced Biliary Cancers

    ClinicalTrials.gov

    2017-02-10

    Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Unresectable Adult Primary Liver Cancer; Periampullary Adenocarcinoma; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  11. Unusual causes of intrahepatic cholestatic liver disease

    PubMed Central

    Mazokopakis, Elias E; Papadakis, John A; Kofteridis, Diamantis P

    2007-01-01

    We report five cases with unusual causes of intrahepatic cholestasis, including consumption of Teucrium polium (family Lamiaceae) in the form of tea, Stauffer’s syndrome, treatment with tamoxifen citrate for breast cancer, infection with Coxiella Burnetii (acute Q fever), and infection with Brucella melitensis (acute brucellosis). PMID:17465487

  12. Cancer biomarker discovery for cholangiocarcinoma: the high-throughput approaches

    PubMed Central

    Silsirivanit, Atit; Sawanyawisuth, Kanlayanee; Riggins, Gregory J.; Wongkham, Chaisiri

    2015-01-01

    Cholangiocarcinoma (CCA) is difficult to diagnose at an early stage and most tumors are detected at late stage where surgery or other therapy is ineffective. Many advanced techniques are applied to diagnose CCA; however, most are expensive and have varying degrees of accuracy. A less invasive and simpler procedure such as serum markers would be of substantial clinical benefit for diagnosis, monitoring, and predicting outcome for CCA patients. Recent advances in “Omics” technologies offer remarkable opportunities for establishment of biomarker-related to diseases. In this review, the potential biomarkers obtained from proteomics and glycomic studies are evaluated. Several protein markers were discovered from patient specimen, using two dimensional-differential gel electrophoresis couple with liquid chromatography tandem mass spectrometry (2D-DIGE/LC-MS-MS), matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS), surface enhanced laser desorption/ionization (SELDI)-TOF-MS and capillary electrophoresis (CE)-MS, etc. Newly reported CCA-associated glycobiomarkers were identified using lectin-assisted, monoclonal antibody-assisted or specific-target strategies. The combination between carbohydrate binding-lectin and core protein-binding mAb significantly increased the values for detection of the glyco-biomarkers for CCA. Searching for specific and sensitive molecular markers to be used for population screening is worth being evaluated. This could lead to earlier diagnosis and improve outcome. Further investigation of those biomarker functions is also of value in order to better understand the tumor biology and use them as targets for future therapeutic agents. PMID:24616382

  13. Intrabiliary Hepatic Metastasis of Colorectal Carcinoma Mimicking Primary Cholangiocarcinoma: A Case Report and Review of the Literature

    PubMed Central

    Dong, Yimin; Patel, Hitendra; Patel, Charmi

    2016-01-01

    Intrabiliary metastasis from colorectal carcinoma (CRC) growing within or invading bile ducts is not a very common pattern. However, accurate diagnosis of metastatic lesions is very important for selection of adjuvant therapy and prognosis. We report a case of 71-year-old male who developed painless jaundice due to hepatobiliary obstruction. MRI demonstrated 1.4 cm intraductal mass at hepatic hilum with severe intrahepatic ductal dilation, consistent with cholangiocarcinoma. ERCP (endoscopic retrograde cholangiopancreatography) showed intraductal segmental biliary stricture. Biopsy from the lesion showed adenocarcinoma favoring primary cholangiocarcinoma due to the papillary morphology and location of the mass. His past history was significant for rectosigmoid carcinoma (pT1N0) ten years ago and liver resection for metastatic CRC four years ago. He subsequently underwent central hepatectomy with resection of common bile duct. Grossly, there was a 1.2 cm intraductal mass at the bifurcation of bile ducts with multiple nodules in liver parenchyma. Microscopic examination revealed intraductal carcinoma with papillary architecture colonizing bile duct epithelium with resultant dilation and tortuosity. Occasional liver parenchymal nodules show classical metastatic pattern resembling CRC. Because of two distinct morphologic patterns and patient's past history, immunostains were performed. CK7 stained uninvolved bile duct epithelium with no staining in intrabiliary metastatic growth. CK20 and CDX2 were positive, thus confirming intrabiliary growth as metastatic growth from CRC. In summary, findings from our case indicate that intrabiliary growth of metastatic CRC can easily be overlooked with major duct involvement. Pathologic evaluation with use of immunohistochemical stains is very important to achieve correct diagnosis. PMID:27429820

  14. [Cholangiocarcinoma developing in printing company workers: a new type of occupational cancer].

    PubMed

    Kubo, Shoji; Takemura, Shigekazu; Sakata, Chikaharu; Urata, Yorihisa; Tanaka, Shogo; Nakanuma, Yasuni; Endo, Ginji

    2013-11-01

    The incidence of cholangiocarcinoma among the past or present workers in the department of offset color proof-printing at a printing company in Osaka was extremely high. The workers were relatively young and were exposed to several chemicals including organic solvents such as dichloromethane and 1,2-dichloropropane. Although the exact cause of cholangiocarcinoma in the patients remain unknown, it is likely that the development of cholangiocarcinoma was triggered during exposure to these chemicals. Some chemicals can act as environmental factors that lead to the development of cholangiocarcinoma. Therefore, we believe that cholangiocarcinoma is a new type of occupational cancer.

  15. Cholangiocarcinoma--an automated preliminary detection system using MLP.

    PubMed

    Logeswaran, Rajasvaran

    2009-12-01

    Cholangiocarcinoma, cancer of the bile ducts, is often diagnosed via magnetic resonance cholangiopancreatography (MRCP). Due to low resolution, noise and difficulty is actually seeing the tumor in the images, especially by examining only a single image, there has been very little development of automated systems for cholangiocarcinoma diagnosis. This paper presents a computer-aided diagnosis (CAD) system for the automated preliminary detection of the tumor using a single MRCP image. The multi-stage system employs algorithms and techniques that correspond to the radiological diagnosis characteristics employed by doctors. A popular artificial neural network, the multi-layer perceptron (MLP), is used for decision making to differentiate images with cholangiocarcinoma from those without. The test results achieved was 94% when differentiating only healthy and tumor images, and 88% in a robust multi-disease test where the system had to identify the tumor images from a large set of images containing common biliary diseases.

  16. CPI-613 in Treating Patients With Advanced or Metastatic Bile Duct Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2017-08-14

    Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Unresectable Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Unresectable Extrahepatic Bile Duct Cancer

  17. Progressive familial intrahepatic cholestasis: a personal perspective.

    PubMed

    Knisely, A S

    2000-01-01

    Progressive familial intrahepatic cholestasis (PFIC), originally described as "Byler disease" in an Amish kindred, has been distinguished from other forms of cholestatic liver disease in childhood by clinical findings, clinical-laboratory observations, and morphologic studies in biopsy, hepatectomy, and autopsy specimens. Correlation with genetic analyses has permitted both more precise definition of PFIC and distinctions within PFIC. Two types of PFIC now are recognized: PFIC-1, resulting from mutations in a gene called FIC1 (familial intrahepatic cholestasis, type 1), and PFIC-2, resulting from mutations in a gene called BSEP (bile salt export pump). Other forms of PFIC may yet be identified. The roles of FIC1 and BSEP in the secretion of bile acids into bile and in the post-secretory modification of bile are under study.

  18. Dilated cardiomyopathy and progressive familial intrahepatic cholestasis

    PubMed Central

    James, Stephanie; Waterhouse, Deirdre; McDonald, Kenneth; O'Hanlon, Rory

    2014-01-01

    This case is of a 29-year-old man with progressive familial intrahepatic cholestasis type 1 also known as Byler's disease. At the age of 21, our patient developed non-ischaemic dilated cardiomyopathy. Cardiac MRI demonstrated global wall thinning, with significant areas of myocardial fibrosis in the mid and epicardial walls from base to apex on postgadolinium late contrast enhanced images. No shared genetic loci between dilated cardiomyopathy and Byler's or cholestatic liver disease have yet been found. This presents the first documented case of non-ischaemic dilated cardiomyopathy, with evidence of mid wall fibrosis, in association with an established diagnosis of progressive familial intrahepatic cholestasis type 1 since childhood. PMID:24654243

  19. Cholangiocarcinoma among workers in the printing industry: using the NOCCA database to elucidate the generalisability of a cluster report from Japan.

    PubMed

    Vlaanderen, Jelle; Straif, Kurt; Martinsen, Jan Ivar; Kauppinen, Timo; Pukkala, Eero; Sparén, Pär; Tryggvadottir, Laufey; Weiderpass, Elisabete; Kjaerheim, Kristina

    2013-12-01

    A cluster of 11 cases of cholangiocarcinoma (CC) was observed in a small Japanese printing firm. To elucidate whether the identified cluster is indicative of an elevated risk of CC among workers in the printing industry at large, we explored the risk of cancer of the liver and CC among individuals employed in the printing industry in a large cohort set-up in four Nordic countries (Finland, Iceland, Norway and Sweden) over a period of 45 years. The cohort was set-up by linking occupational information from censuses to national cancer registry data utilising personal identity codes in use in all Nordic countries. We calculated standardised incidence ratios (SIRs) for men and women working in the printing industry, and stratified by occupational category (typographers, printers, lithographers, bookbinders). Among men, we observed elevated SIRs for cancer of the liver (1.35, 95% CI 1.14 to 1.60; 142 cases), specifically intrahepatic CC (2.34, 95% CI 1.45 to 3.57; 21 cases). SIRs for liver cancer were especially elevated among printers and lithographers, and SIRs for intrahepatic CC among typographers and printers. SIRs for extrahepatic CC were not elevated. SIRs for women followed a similar pattern but the number of cases was low. Our study supports the notion that the finding of excess CC risk among workers in a small Japanese printing firm possibly extends beyond this specific firm and country. Further studies should focus on the specific exposures that occur in the printing industry.

  20. Multimodality therapy for locoregional extrahepatic cholangiocarcinoma: a population based analysis

    PubMed Central

    Fuller, Clifton D.; Wang, Samuel J.; Choi, Mehee; Czito, Brian G.; Cornell, John; Welzel, Tania M.; McGlynn, Katherine A.; Luh, Join Y.; Thomas, Charles R.

    2009-01-01

    Introduction: While surgical resection is the mainstay of treatment for extrahepatic cholangiocarcinoma (EHCC), most patients present with advanced disease. Owing in part to numerical rarity, the optimum role of radiotherapy (RT) for EHCC, as well as its relative benefit is an area of debate. The specific aim of this series is to estimate survival for EHCC patients receiving surgery and adjuvant RT using a robust population based dataset. Methods: Data was extracted from the Surveillance, Epidemiology, and End Results (SEER) limited-use dataset for selected EHCC cases. Lognormal multivariate survival analysis was implemented to estimate survival for patients for treatment cohorts based on extent of surgical intervention and RT. Results: Parametric estimated median survival for patients receiving total/radical resection+RT was 26 months, 25 months for total/radical resection alone, 25 months for subtotal/debulking resection+RT, 21 months for subtotal/debulking resection, 12 months for RT alone, and 9 months for those not receiving surgery or RT. Parametric multivariate analysis revealed age, AJCC Stage, grade, and surgical/radiation regimen as statistically significant covariates with survival. Surgery-alone and adjuvant radiotherapy cohorts showed evidence of improved survival compared to no treatment; comparatively, radiation alone was associated with survival decrement. Early improvement in survival in adjuvant cohorts was not observed at later time-points. Conclusions: Survival estimates using SEER data suggest an early survival advantage for adjuvant radiotherapy for locoregional EHCC. While future prospective series are needed to confirm these observations, SEER data represents the largest domestic population-based EHCC cohort, and may provide useful baseline survival estimates for future studies. PMID:19637356

  1. Survival and quality of life of cholangiocarcinoma patients: a prospective study over a 4 year period.

    PubMed

    Mihalache, Florentina; Tantau, Marcel; Diaconu, Brindusa; Acalovschi, Monica

    2010-09-01

    Cholangiocarcinomas (CCAs) are tumors with a poor prognosis and a lower quality of life (QoL). The aim of this study was to evaluate the survival rate and quality of life in CCA patients. We prospectively enrolled 133 patients diagnosed with CCA in the 3rd Medical Clinic, Cluj Napoca, over a 4-year period (2005-2009). The QoL was evaluated by means of a QoL questionnaire (EORTC QLQ-C30). The mean age of the patients was 65 +/- 10.6 years: 55% were males. 71% of the patients had hilar tumor (Klatskin), 23% distal and 6% intrahepatic CCA (IH). Only 11.3% of the patients were eligible to receive curative treatment. The 1-year overall survival was 22.3 +/- 4.4% and the 2-year survival was 3.4 +/- 2.1%. The patients receiving metallic stents had better survival than those receiving plastic stents (40.4% vs 12.5% at 1 year, 9.1% vs 5.0% at 2 years, respectively). The 1-year survival was significantly improved for patients who underwent surgery plus adjuvant chemotherapy. The post-therapy QoL demonstrated a less improvement in Klatskin tumor patients than in patients with other types of tumors. Endoscopic palliative therapy allowed a faster community reintegration, but with variable evolution. The highest 2-year survival rate was 5.5%. Slightly longer survival was recorded when chemotherapy was added and also after endoscopic placement of metallic stents. Endoscopic biliary decompression improved the QoL faster than surgery.

  2. Polo-Like Kinase 2 Is a Mediator of Hedgehog Survival Signaling in Cholangiocarcinoma

    PubMed Central

    Fingas, Christian D.; Mertens, Joachim C.; Razumilava, Nataliya; Sydor, Svenja; Bronk, Steven F.; Christensen, John D.; Rizvi, Sumera H.; Canbay, Ali; Treckmann, Jürgen W.; Paul, Andreas; Sirica, Alphonse E.; Gores, Gregory J.

    2013-01-01

    Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2). We employed 50 human CCA samples (25 intrahepatic and 25 extrahepatic CCA) as well as human KMCH-1, Mz-CHA-1, and HUCCT-1 CCA cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. In human samples, polo-like kinase (PLK)1/2/3-immunoreactive cancer cells were present in the preponderance of intra- and extrahepatic CCA specimens. Inhibition of Hh signaling by cyclopamine reduced PLK2, but not PLK1 or PLK3, messenger RNA and protein expression in vehicle-treated and sonic Hh–treated CCA cells, confirming our previous microarray study. PLK2 regulation by Hh signaling appears to be direct, because the Hh transcription factors, glioma-associated oncogene 1 and 2, bind to the PLK2 promotor. Moreover, inhibition of PLK2 by the PLK inhibitor, BI 6727 (volasertib), or PLK2 knockdown was proapoptotic in CCA cells. BI 6727 administration or PLK2 knockdown decreased cellular protein levels of antiapoptotic myeloid cell leukemia 1 (Mcl-1), an effect reversed by the proteasome inhibitor, MG-132. Finally, BI 6727 administration reduced Mcl-1 protein expression in CCA cells, resulting in CCA cell apoptosis and tumor suppression in vivo. Conclusion PLK2 appears to be an important mediator of Hh survival signaling. These results suggest PLK inhibitors to be of therapeutic value for treatment of human CCA. PMID:23703673

  3. Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans

    PubMed Central

    Che, L; Fan, B; Pilo, M G; Xu, Z; Liu, Y; Cigliano, A; Cossu, A; Palmieri, G; Pascale, R M; Porcu, A; Vidili, G; Serra, M; Dombrowski, F; Ribback, S; Calvisi, D F; Chen, X

    2016-01-01

    Intrahepatic cholangiocarcinoma (ICC) is a rare yet deadly malignancy with limited treatment options. Activation of the Notch signalling cascade has been implicated in cholangiocarcinogenesis. However, while several studies focused on the Notch receptors required for ICC development, little is known about the upstream inducers responsible for their activation. Here, we show that the Jagged 1 (Jag1) ligand is almost ubiquitously upregulated in human ICC samples when compared with corresponding non-tumorous counterparts. Furthermore, we found that while overexpression of Jag1 alone does not lead to liver tumour development, overexpression of Jag1 synergizes with activated AKT signalling to promote liver carcinogenesis in AKT/Jag1 mice. Histologically, tumours consisted exclusively of ICC, with hepatocellular tumours not occurring in AKT/Jag1 mice. Furthermore, tumours from AKT/Jag1 mice exhibited extensive desmoplastic reaction, an important feature of human ICC. At the molecular level, we found that both AKT/mTOR and Notch cascades are activated in AKT/Jag1 ICC tissues, and that the Notch signalling is necessary for ICC development in AKT/Jag1 mice. In human ICC cell lines, silencing of Jag1 via specific small interfering RNA reduces proliferation and increases apoptosis. Finally, combined inhibition of AKT and Notch pathways is highly detrimental for the in vitro growth of ICC cell lines. In summary, our study demonstrates that Jag1 is an important upstream inducer of the Notch signalling in human and mouse ICC. Targeting Jag1 might represent a novel therapeutic strategy for the treatment of this deadly disease. PMID:27918553

  4. Asbestos: a hidden player behind the cholangiocarcinoma increase? Findings from a case-control analysis.

    PubMed

    Brandi, Giovanni; Di Girolamo, Stefania; Farioli, Andrea; de Rosa, Francesco; Curti, Stefania; Pinna, Antonio Daniele; Ercolani, Giorgio; Violante, Francesco Saverio; Biasco, Guido; Mattioli, Stefano

    2013-05-01

    We conducted a case-control analysis to explore the association between occupational exposure to asbestos and cholangiocarcinoma (CC). The study was based on historical data from 155 consecutive patients with CC [69 intrahepatic CC (ICC) and 86 extrahepatic CC (ECC)] referred to Sant'Orsola-Malpighi University Hospital between 2006 and 2010. The cases were individually matched by calendar period of birth, sex, and region of residence to historical hospital and population controls. Occupational exposure to asbestos was retrospectively assessed considering job titles obtained from work histories. Separate conditional logistic regression models were applied for ECC and ICC. Estimates were adjusted for smoking status and socioeconomic class. We matched 149 controls (median birth year: 1947; males: 56 %) to 41 cases of ICC (median birth year: 1946; males: 56 %) and 212 controls (median birth year: 1945; males: 48 %) to 59 cases of ECC (median birth year: 1945; males 51 %); 53 cases were not matched due to residence or birth year. We found an increased risk of ICC in workers exposed to asbestos (adjusted OR 4.81, 95 % CI 1.73-13.33); we also observed suggestive evidence that asbestos exposure might be associated with ECC (adjusted OR 2.09, 95 % CI 0.83-5.27). Sensitivity analysis restricted to patients from the Province of Bologna produced confirmatory figures. Our findings suggest that ICC could be associated with asbestos exposure; a chronic inflammatory pathway is hypothesized. Exposure to asbestos could be one of the determinants of the progressive rise in the incidence of ICC during the last 30 years.

  5. Progressive familial intrahepatic cholestasis and benign recurrent intrahepatic cholestasis: a review.

    PubMed

    Strubbe, B; Geerts, A; Van Vlierberghe, H; Colle, I

    2012-12-01

    Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are two rare autosomal recessive disorders, characterized by cholestasis. They are related to mutations in hepatocellular transport system genes involved in bile formation. The differentiation between PFIC and BRIC is based on phenotypic presentation: PFIC is a progressive disease, with evolution to end-stage liver disease. BRIC is characterized by intermittent recurrent cholestatic episodes, with irresistible pruritus, mostly without evident liver damage. Between symptomatic periods, patients are completely asymptomatic. In this article, a short overview of the aetiology, the clinical and diagnostic characteristics and the therapy of both PFIC and BRIC are given.

  6. Genetic Factors in the Pathogenesis of Cholangiocarcinoma

    PubMed Central

    Wadsworth, Christopher A.; Dixon, Peter H.; Wong, Jason H.; Chapman, Michael H.; McKay, Siobhan C.; Sharif, Amar; Spalding, Duncan R.; Pereira, Stephen P.; Thomas, Howard C.; Taylor-Robinson, Simon D.; Whittaker, John; Williamson, Catherine; Khan, Shahid A.

    2011-01-01

    Background Cholangiocarcinoma (CC) is increasing in incidence, but its pathogenesis remains poorly understood. Chronic inflammation of the bile duct and cholestasis are major risk factors, but most cases in the West are sporadic. Genetic polymorphisms in biliary transporter proteins have been implicated in benign biliary disease and, in the case of progressive familial cholestasis, have been associated with childhood onset of CC. In the current study, five biologically plausible candidate genes were investigated: ABCB11 (BSEP), ABCB4 (MDR3), ABCC2 (MRP2), ATP8B1 (FIC1) and NR1H4 (FXR). Methods DNA was collected from 172 Caucasian individuals with confirmed CC. A control cohort of healthy Caucasians was formed. Seventy-three SNPs were selected using the HapMap database to capture genetic variation around the five candidate loci. Genotyping was undertaken with a competitive PCR-based system. Confirmation of Hardy-Weinberg equilibrium and Cochran-Armitage trend testing were performed using PLINK. Haplotype frequencies were compared using haplo.stats. Results All 73 SNPs were in Hardy-Weinberg equilibrium. Four SNPs in ABCB11 were associated with altered susceptibility to CC, including the V444A polymorphism, but these associations did not retain statistical significance after Bonferroni correction for multiple testing. Haplotype analysis of the genotyped SNPs in ATP8B1 identified significant differences in frequencies between cases and controls (global p value of 0.005). Conclusion Haplotypes in ATP8B1 demonstrated a significant difference between CC and control groups. There was a trend towards significant association of V444A with CC. Given the biological plausibility of polymorphisms in ABCB11 and ATP8B1 as risk modifiers for CC, further study in a validation cohort is required. PMID:21691113

  7. Hepatitis C virus infection of cholangiocarcinoma cell lines.

    PubMed

    Fletcher, Nicola F; Humphreys, Elizabeth; Jennings, Elliott; Osburn, William; Lissauer, Samantha; Wilson, Garrick K; van IJzendoorn, Sven C D; Baumert, Thomas F; Balfe, Peter; Afford, Simon; McKeating, Jane A

    2015-06-01

    Hepatitis C virus (HCV) infects the liver and hepatocytes are the major cell type supporting viral replication. Hepatocytes and cholangiocytes derive from a common hepatic progenitor cell that proliferates during inflammatory conditions, raising the possibility that cholangiocytes may support HCV replication and contribute to the hepatic reservoir. We screened cholangiocytes along with a panel of cholangiocarcinoma-derived cell lines for their ability to support HCV entry and replication. While primary cholangiocytes were refractory to infection and lacked expression of several entry factors, two cholangiocarcinoma lines, CC-LP-1 and Sk-ChA-1, supported efficient HCV entry; furthermore, Sk-ChA-1 cells supported full virus replication. In vivo cholangiocarcinomas expressed all of the essential HCV entry factors; however, cholangiocytes adjacent to the tumour and in normal tissue showed a similar pattern of receptor expression to ex vivo isolated cholangiocytes, lacking SR-BI expression, explaining their inability to support infection. This study provides the first report that HCV can infect cholangiocarcinoma cells and suggests that these heterogeneous tumours may provide a reservoir for HCV replication in vivo.

  8. Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy.

    PubMed

    Ha, Hyerim; Nam, Ah-Rong; Bang, Ju-Hee; Park, Ji-Eun; Kim, Tae-Yong; Lee, Kyung-Hun; Han, Sae-Won; Im, Seock-Ah; Kim, Tae-You; Bang, Yung-Jue; Oh, Do-Youn

    2016-11-22

    Programmed death-ligand 1 (PD-L1) expression in tumor tissue is under investigation as a candidate biomarker in immuno-oncology dug development. The soluble form of PD-L1 (sPDL1) is suggested to have immunosuppressive activity. In this study, we measured the serum level of sPDL1 and evaluated its prognostic implication in biliary tract cancer (BTC). Blood was collected from 158 advanced BTC patients (68 intrahepatic cholangiocarcinoma, 56 gallbladder cancer, 22 extrahepatic cholangiocarcinoma and 12 ampulla of vater cancer) before initiation of palliative chemotherapy. Serum sPDL1 was measured using an enzyme-linked immunosorbent assay. Clinical data included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, neutrophil × platelet/lymphocyte). The patients were assigned to two cohorts (training and validation cohort) using a simple random sampling method to validate the cut-off value of each marker. Validation was performed using a twofold cross-validation method. Overall survival (OS) of all patients was 9.07 months (95% CI: 8.20-11.33). Median sPDL1 was 1.20 ng/mL (range 0.03-7.28, mean 1.50, SD 1.22). Median NLR, PLR and SII were 2.60, 142.85 and 584.93, respectively. Patients with high sPDL1 (≥0.94 ng/mL) showed worse OS than patients with low sPDL1 (7.93 vs. 14.10 months, HR 1.891 (1.35-2.65), p<0.001). In multivariate analysis, high sPDL1 and NLR were independent poor prognostic factors. In conclusion, serum sPDL1 can be measured and has significant role on the prognosis of advanced BTC patients treated with palliative chemotherapy.

  9. Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy

    PubMed Central

    Ha, Hyerim; Nam, Ah-Rong; Bang, Ju-Hee; Park, Ji-Eun; Kim, Tae-Yong; Lee, Kyung-Hun; Han, Sae-Won; Im, Seock-Ah; Kim, Tae-You; Bang, Yung-Jue; Oh, Do-Youn

    2016-01-01

    Programmed death-ligand 1 (PD-L1) expression in tumor tissue is under investigation as a candidate biomarker in immuno-oncology dug development. The soluble form of PD-L1 (sPDL1) is suggested to have immunosuppressive activity. In this study, we measured the serum level of sPDL1 and evaluated its prognostic implication in biliary tract cancer (BTC). Blood was collected from 158 advanced BTC patients (68 intrahepatic cholangiocarcinoma, 56 gallbladder cancer, 22 extrahepatic cholangiocarcinoma and 12 ampulla of vater cancer) before initiation of palliative chemotherapy. Serum sPDL1 was measured using an enzyme-linked immunosorbent assay. Clinical data included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, neutrophil × platelet/lymphocyte). The patients were assigned to two cohorts (training and validation cohort) using a simple random sampling method to validate the cut-off value of each marker. Validation was performed using a twofold cross-validation method. Overall survival (OS) of all patients was 9.07 months (95% CI: 8.20-11.33). Median sPDL1 was 1.20 ng/mL (range 0.03-7.28, mean 1.50, SD 1.22). Median NLR, PLR and SII were 2.60, 142.85 and 584.93, respectively. Patients with high sPDL1 (≥0.94 ng/mL) showed worse OS than patients with low sPDL1 (7.93 vs. 14.10 months, HR 1.891 (1.35-2.65), p<0.001). In multivariate analysis, high sPDL1 and NLR were independent poor prognostic factors. In conclusion, serum sPDL1 can be measured and has significant role on the prognosis of advanced BTC patients treated with palliative chemotherapy. PMID:27780932

  10. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma

    PubMed Central

    Goyal, Lipika; Saha, Supriya K.; Liu, Leah Y.; Siravegna, Giulia; Leshchiner, Ignaty; Ahronian, Leanne G.; Lennerz, Jochen K.; Vu, Phuong; Deshpande, Vikram; Kambadakone, Avinash; Mussolin, Benedetta; Reyes, Stephanie; Henderson, Laura; Sun, Jiaoyuan Elisabeth; Van Seventer, Emily E.; Gurski, Joseph M.; Baltschukat, Sabrina; Schacher-Engstler, Barbara; Barys, Louise; Stamm, Christelle; Furet, Pascal; Ryan, David P.; Stone, James R.; Iafrate, A. John; Getz, Gad; Porta, Diana Graus; Tiedt, Ralph; Bardelli, Alberto; Juric, Dejan; Corcoran, Ryan B.; Bardeesy, Nabeel; Zhu, Andrew X.

    2017-01-01

    Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intra-lesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation lead to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide development of future therapeutic strategies. PMID:28034880

  11. Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition through heme oxygenase-1 blockage in cholangiocarcinoma cells

    PubMed Central

    Yun, Bo-Ra; Lee, Mi-Jin; Kim, Jong-Hyun; Kim, In-Hee; Yu, Goung-Ran

    2010-01-01

    Cholangiocarcinoma (CC) is a chemoresistant intrahepatic bile duct carcinoma with a poor prognosis. The aims of this study were to identify molecular pathways that enhance sesquiterpene lactone parthenolide (PTL)-induced anticancer effects on CC cells. The effects of PTL on apoptosis and hemoxygenase-1 (HO-1) induction were examined in CC cell lines. The enhancement of PTL-mediated apoptosis by modulation of HO-1 expression and the mechanisms involved were also examined in an in vitro cell system. Low PTL concentrations (5 to 10 µM) led to Nrf2-dependent HO-1 induction, which attenuated the apoptogenic effect of PTL in Choi-CK and SCK cells. PTL-mediated apoptosis was enhanced by the protein kinase C-alpha inhibitor Ro317549 (Ro) through inhibition of expression and nuclear translocation of Nrf2, resulting in blockage of HO-1 expression. Finally, HO-1 silencing resulted in enhancement of apoptotic cell death in CC cells. The combination of PTL and Ro efficiently improved tumor growth inhibition compared to treatment with either agent alone in an in vivo subcutaneous tumor model. In conclusion, the modulation of HO-1 expression substantially improved the anticancer effect of PTL. The combination of PTL and Ro could prove to be a valuable chemotherapeutic strategy for CC. PMID:20938215

  12. Nal-IRI With 5-fluorouracil (5-FU) and Leucovorin or Gemcitabine Plus Cisplatin in Advanced Biliary-tract Cancer

    ClinicalTrials.gov

    2017-02-03

    Adenocarcinoma Metastatic; Biliary Tract Cancer; Adenocarcinoma of the Biliary Tract; Adenocarinoma Locally Advanced; Non-Resectable Hepatocellular Carcinoma; Intrahepatic Bile Duct Carcinoma; Extrahepatic Bile Duct Carcinoma

  13. Intrahepatic cholelithiasis in dogs and cats: A case series.

    PubMed

    Kanemoto, Hideyuki; Fukushima, Kenjiro; Tsujimoto, Hajime; Ohno, Koichi

    2017-09-01

    A retrospective study of intrahepatic cholelithiasis (IC) in 9 dogs and 2 cats was conducted. Only 1 dog showed clinical signs related to hepatobiliary disease before referral and during the follow-up period. Intrahepatic cholelithiasis might be a subclinical finding in both dogs and cats.

  14. New Insights on Intrahepatic Cholestasis of Pregnancy.

    PubMed

    Floreani, Annarosa; Gervasi, Maria Teresa

    2016-02-01

    Intrahepatic cholestasis of pregnancy (ICP) is characterized by maternal pruritus, and elevated serum transaminases and bile acids. Genetic defects in at least 6 canalicular transporters have been found. Association studies stress the variability of genotypes, different penetrance, and influence of environmental factors. Serum autotaxin is a sensitive, specific, and robust diagnostic marker. Elevated maternal bile acids correlate with fetal complications. Long-term sequelae for mothers include the gallstone risk and chronic liver disease. There is an association between ICP and hepatitis C. Current treatment is ursodeoxycholic acid, owing to benefits on pruritus, liver function, safety, and decreased rates of adverse effects.

  15. Long-term survival after intraluminal brachytherapy for inoperable hilar cholangiocarcinoma: A case report

    PubMed Central

    Chan, Siu-Yin; Poon, Ronnie T.; Ng, Kelvin K.; Liu, Chi-Leung; Chan, Raymond T.; Fan, Sheung-Tat

    2005-01-01

    Surgical resection with a tumor-free margin is the only curative treatment for hilar cholangiocarcinoma (Klatskin tumor). However, over half of the patients present late with unresectable tumors. Radiotherapy using external beam irradiation or intraluminal brachytherapy (ILBT) has been used to treat unresectable hilar cholangiocarcinoma with satisfactory outcome. We reported a patient with unresectable hilar cholangiocarcinoma surviving more than 6 years after combined external beam irradiation and ILBT. PMID:15918211

  16. Menopause after a history of intrahepatic cholestasis of pregnancy.

    PubMed

    Turunen, Kaisa; Helander, Kristiina; Mattila, Kari J; Sumanen, Markku

    2013-11-01

    Intrahepatic cholestasis of pregnancy is a hormone-provoked disorder that fades quickly after parturition. The aim of this study was to establish whether a history of intrahepatic cholestasis of pregnancy reduces the use of hormone therapy for menopausal symptoms and, irrespective of hormone therapy, whether intrahepatic cholestasis is associated with other health aspects after menopause. In 2010, questionnaires were sent to a cohort of women who delivered in Tampere University Hospital, Finland, from 1969 to 1988. The study population comprised postmenopausal women with a history of intrahepatic cholestasis of pregnancy (n = 189) and their controls (n = 416). The main outcome measures were the use of hormone therapy and other means of alleviating menopausal symptoms, and the diseases the women reported. There were no differences in the use of hormone therapy between the two groups. Of the diseases reported, breast cancer, hepatobiliary diseases, and hypothyroidism were more frequent among women with a history of intrahepatic cholestasis of pregnancy, whereas cardiac arrhythmia was less frequent. With respect to other diseases, there were no differences. A history of intrahepatic cholestasis of pregnancy does not reduce the use of hormone therapy. However, when physicians prescribe hormone therapy for these women, a history of intrahepatic cholestasis of pregnancy calls for attention in view of its association with gallstones.

  17. Computed tomography of localized dilatation of the intrahepatic bile ducts

    SciTech Connect

    Araki, T.; Itai Y.; Tasaka, A.

    1981-12-01

    Twenty-nine patients showed localized dilatation of the intrahepatic bile ducts on computed tomography, usually unaccompanied by jaundice. Congenital dilatation was diagnosed when associated with a choledochal cyst, while cholangiographic contrast material was helpful in differentiating such dilatation from a simple cyst by showing its communication with the biliary tract when no choledochal cyst was present. Obstructive dilatation was associated with intrahepatic calculi in 4 cases, hepatoma in 9, cholangioma in 5, metastatic tumor in 5, and polycystic disease in 2. Cholangioma and intrahepatic calculi had a greater tendency to accompany such localized dilatation; in 2 cases, the dilatation was the only clue to the underlying disorder.

  18. Common Hepatic Duct Mixed Adenoneuroendocrine Carcinoma Masquerading as Cholangiocarcinoma

    PubMed Central

    Priyanka Akhilesh, Sali; Kamal Sunder, Yadav; Chandralekha, Tampi; Samir, Parikh; Prasad Kashinath, Wagle

    2016-01-01

    Bile duct mixed adenoneuroendocrine carcinoma (MANEC) is a rare entity. It is defined as having mixed elements of both neuroendocrine tumors (NET) and an adenocarcinoma element, the lesser component forming at least 30% of the tumor. It is a subtype of neuroendocrine carcinoma (NEC) showing both gland-forming epithelial tumor cells and neuroendocrine cells. It is generally misdiagnosed as cholangiocarcinoma on imaging studies. The preoperative pathological workup from the endoscopic retrograde cholangiography brush cytology usually misses the NET/NEC component since it often lies deeper in the tumor. However, it is reported that it is the NEC component that defines the prognosis of the tumor; hence, it is vital to identify the NEC component. We present a rare case of common hepatic duct (CHD) MANEC that was preoperatively misdiagnosed as cholangiocarcinoma. PMID:27375908

  19. Spinal cord infarct as a presentation of cholangiocarcinoma with metastases.

    PubMed

    Thar, Yu Yu; Tun, Aung Myint; Huang, Tiangui; Bordia, Sonal; Guevara, Elizabeth

    2015-11-01

    It is well-known that malignancies, particularly pancreatic and brain cancers, often present as venous thromboembolism. However, stroke and angina attributable to arterial occlusion are relatively common presentations as well. We are reporting a patient, with treatment-naïve hepatitis C and multiple liver nodules, was admitted for deep vein thrombosis (DVT) and pulmonary embolism (PE). Subsequently, she developed an ascending paralysis due to spinal cord infarct (SCI) despite adequate anticoagulation. She also had an enlargement of left supraclavicular lymph node, which was confirmed histologically metastatic cholangiocarcinoma. To our best knowledge, this is the first literature report showing the association linking SCI to metastatic cholangiocarcinoma as a consequence of hypercoagulable state of malignancy.

  20. Spinal cord infarct as a presentation of cholangiocarcinoma with metastases

    PubMed Central

    Tun, Aung Myint; Huang, Tiangui; Bordia, Sonal; Guevara, Elizabeth

    2015-01-01

    It is well-known that malignancies, particularly pancreatic and brain cancers, often present as venous thromboembolism. However, stroke and angina attributable to arterial occlusion are relatively common presentations as well. We are reporting a patient, with treatment-naïve hepatitis C and multiple liver nodules, was admitted for deep vein thrombosis (DVT) and pulmonary embolism (PE). Subsequently, she developed an ascending paralysis due to spinal cord infarct (SCI) despite adequate anticoagulation. She also had an enlargement of left supraclavicular lymph node, which was confirmed histologically metastatic cholangiocarcinoma. To our best knowledge, this is the first literature report showing the association linking SCI to metastatic cholangiocarcinoma as a consequence of hypercoagulable state of malignancy. PMID:26697480

  1. Liver carcinogenesis: Rodent models of hepatocarcinoma and cholangiocarcinoma

    PubMed Central

    Minicis, Samuele De; Kisseleva, Tatiana; Francis, Heather; Baroni, Gianluca Svegliati; Benedetti, Antonio; Brenner, David; Alvaro, Domenico; Alpini, Gianfranco; Marzioni, Marco

    2013-01-01

    Hepatocellular carcinoma and cholangiocarcinoma are primary liver cancers, both represent a growing challenge for clinicians due to their increasing morbidity and mortality. In the last few years a number of in vivo models of hepatocellular carcinoma and cholangiocarcinoma have been developed. The study of these models is providing a significant contribution in unveiling the pathophysiology of primary liver malignancies. They are also fundamental tools to evaluate newly designed molecules to be tested as new potential therapeutic agents in a pre-clinical set. Technical aspects of each model are critical steps, and they should always be considered in order to appropriately interpret the findings of a study or its planning. The purpose of this review is to describe the technical and experimental features of the most significant rodent models, highlighting similarities or differences between the corresponding human diseases. The first part is dedicated to the discussion of models of hepatocellular carcinoma, developed using toxic agents, or through dietary or genetic manipulations. In the second we will address models of cholangiocarcinoma developed in rats or mice by toxin administration, genetic manipulation and/or bile duct incannulation or surgery. Xenograft or syngenic models are also proposed. PMID:23177172

  2. Clinical features, histology, and histogenesis of combined hepatocellular-cholangiocarcinoma

    PubMed Central

    Gera, Shweta; Ettel, Mark; Acosta-Gonzalez, Gabriel; Xu, Ruliang

    2017-01-01

    Combined hepatocellular-cholangiocarcinoma (CHC) is a rare tumor with poor prognosis, with incidence ranging from 1.0%-4.7% of all primary hepatic tumors. This entity will be soon renamed as hepato-cholangiocarcinoma. The known risk factors for hepatocellular carcinoma (HCC) have been implicated for CHC including viral hepatitis and cirrhosis. It is difficult to diagnose this tumor pre-operatively. The predominant histologic component within the tumor largely determines the predominant radiographic features making it a difficult distinction. Heterogeneous and overlapping imaging features of HCC and cholangiocarcinoma should raise the suspicion for CHC and multiple core biopsies (from different areas of tumor) are recommended before administering treatment. Serum tumor markers CA19-9 and alpha-fetoprotein can aid in the diagnosis, but it remains a challenging diagnosis prior to resection. There is sufficient data to support bipotent hepatic progenitor cells as the cell of origin for CHC. The current World Health Organization classification categorizes two main types of CHC based on histo-morphological features: Classical type and CHC with stem cell features. Liver transplant is one of the available treatment modalities with other management options including transarterial chemoembolization, radiofrequency ablation, and percutaneous ethanol injection. We present a review paper on CHC highlighting the risk factors, origin, histological classification and therapeutic modalities. PMID:28293379

  3. Clinical grading of intrahepatic cholestasis pregnancy.

    PubMed

    Pradhan, Meena; Shao, Yong

    2013-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is the pregnancy induced liver disorder causing intense itching of palm, sole or even whole body especially in the evening at late second and third trimester. This disease is categorized into mild and severe ICP according to raised level of LFT including serum level of bile acid and cholic acid. ICP has less morbidity to mother but significant risk to fetus in uterus. The predisposing element to cause intense pruritus is because of high amount of bile acid in maternal serum. Toxic bile acids affect fetal cardiomyocytes retained in fetus body causing sudden intrauterine fetal death. ICP is commonly found in winter months and mostly itching of body occurs in the evening after sunset. Fetus in uterus is unsafe if mother's bile acid exceeds normal value. ICP is successfully treated with Ursodeoxycholic acid (UDCA), S-adenosyl methionine (SAME), Dexamethasone and vitamin K.

  4. Management of intrahepatic cholestasis of pregnancy.

    PubMed

    Marschall, Hanns-Ulrich

    2015-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy, characterized by otherwise unexplained pruritus in late second and third trimester of pregnancy and elevated bile acids and/or transaminases. ICP is associated with an increased risk of adverse perinatal outcomes for the fetus and the later development of hepatobiliary disease for the mother. Bile acids should be monitored throughout pregnancy since fetal risk is increased at serum bile acids >40 µmol/l. Management of ICP consists of treatment with ursodeoxycholic acid, which reduces pruritus. Early elective delivery is common practice but should be performed on an individualized basis as long as strong evidence supporting this practice is lacking. Mothers should be followed-up for normalization of liver function tests 6-12 weeks after delivery. Future research in large-scale studies is needed to address the impact of ursodeoxycholic acid and early elective delivery on fetal outcome.

  5. [Risks of intrahepatic cholestasis of pregnancy].

    PubMed

    Bolier, A Ruth; Jebbink, Jiska M; van der Post, Joris A M; Oude Elferink, Ronald P J; Beuers, Ulrich

    2014-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus during pregnancy in the absence of primary skin lesions, combined with an increase in serum total bile salts and/or abnormal serum liver tests. This article provides an insight into the diagnostic and therapeutic considerations by presenting two cases. ICP usually presents around 34 weeks of gestation, but can be present early in pregnancy as described in a 32-year-old patient pregnant after in-vitro fertilization. DNA analysis showed a mutation in the ABCB4 gene, causing MDR3 deficiency. Ursodeoxycholic acid treatment seems to alleviate maternal pruritus and possibly reduces perinatal risks related to the severe form of ICP, defined as fasted serum bile salt levels of ≥ 40 μmol/l at any point during the pregnancy. Short-term rifampicin treatment can be considered in patients with persistent pruritus. Induction of labour is advised only after 37 weeks of gestation in patients with severe ICP.

  6. Dramatic response to dabrafenib and trametinib combination in a BRAF V600E-mutated cholangiocarcinoma: implementation of a molecular tumour board and next-generation sequencing for personalized medicine

    PubMed Central

    Loaiza-Bonilla, Arturo; Clayton, Erica; Furth, Emma; O’Hara, Mark; Morrissette, Jennifer

    2014-01-01

    This is the case of a 47-year-old woman diagnosed with chemotherapy and radiation-refractory BRAF V600E mutant, poorly differentiated intrahepatic cholangiocarcinoma (ICC), with multiple metastatic lesions within the liver, lungs, pleura, and bone, stage IV. Discussion of her malignancy’s next-generation sequencing genomic information at a multidisciplinary molecular tumour board took place. The patient was considered a suitable candidate for dual BRAF and MEK inhibition, with the intent to prolong her survival and optimize the quality of life. We report her excellent tolerance and exceptional response to dual therapy with dabrafenib and trametinib, including symptomatic and sustained near-complete radiological improvement. We also briefly review the current knowledge of the genomics of cholangiocarcinoma with a focus on BRAF mutations, and make a point of the importance of the establishment of a molecular tumour board for personalized genomic medicine approaches. To our knowledge, this is the first reported case of the use of personalized genomic information for the successful management of a patient with ICC, and it is also the first description of dual BRAF and MEK targeted therapy in this malignancy, leading to what is considered an exceptional response. PMID:25435907

  7. Immunoglobulin G4-mediated sclerosing cholangitis as a risk factor for cholangiocarcinoma: A case report

    PubMed Central

    Koopman, Karin E.; Bloemena, Elisabeth; Kazemier, Geert; Klemt-Kropp, Michael

    2016-01-01

    Immunoglobulin (Ig)G4-mediated disease is a systemic autoimmune disease, which occasionally presents solely as sclerosing cholangitis (SC). IgG4-mediated SC is challenging to diagnose, as it may mimic cholangiocarcinoma radiologically, and carcinoma cells may produce IgG4. The diagnosis of IgG4-mediated disease is based on histological consensus criteria and response to corticosteroids. In addition to the radiological and histological overlap between IgG4-mediated SC and cholangiocarcinoma, IgG4-mediated SC may be considered as a risk factor for the development of cholangiocarcinoma. We herein present the case of a patient in whom cholangiocarcinoma developed in two lesions previously characterized as IgG4-mediated SC, including a suggested mechanism underlying the contribution of IgG4-mediated SC to the development of cholangiocarcinoma. PMID:28105357

  8. Prognostic Significance of Neutrophil to Lymphocyte Ratio in Oncologic Outcomes of Cholangiocarcinoma: A Meta-analysis.

    PubMed

    Tan, De-Wen; Fu, Yan; Su, Qi; Guan, Ming-Jun; Kong, Po; Wang, Sheng-Qiang; Wang, He-Ling

    2016-10-03

    Increasing evidence indicates that the neutrophil to lymphocyte ratio (NLR) is a useful biomarker of long-term outcomes in patients with cholangiocarcinoma. However, the prognostic role of NLR in patients with cholangiocarcinoma remains unclear. Thus, the current meta-analysis was undertaken to clarify the correlation between NLR and overall survival (OS) in cholangiocarcinoma, and a comprehensive literature research was conducted to understand the association of NLR and prognosis of cholangiocarcinoma. The hazard ratio (HR) with 95% confidence interval (CI) was used to assess OS. The synthesized HR of 1.449 (95% CI: 1.296-1.619, P < 0.001) indicated that a high NLR had an unfavourable effect on OS. Overall, this meta-analysis suggested that elevated preoperative NLR is associated with poorer rates of survival in cholangiocarcinoma patients.

  9. What we learned from difficult hepatectomies in patients with advanced hepatic malignancy

    PubMed Central

    Jung, Bo Hyun; Lee, Jae Hoon; Lee, Sang Yeup; Song, Dae Keun; Hwang, Ji Woong; Hwang, Dae Wook; Lee, Young-Joo

    2011-01-01

    Backgrounds/Aims By reviewing difficult resections for advanced hepatic malignancies, we discuss the effectiveness and extended indications for hepatectomy in such patients. Methods We reviewed 7 patients who underwent extensive surgery between July 2008 and March 2011 for advanced hepatic malignancies. They had stage IV disease, except for in one case that was a stage IIIC (T4N0M0) hepatocellular carcinoma (HCC). Results Patient 1 with intrahepatic cholangiocarcinoma (IHCC) underwent right hemihepatectomy and resection of the bile duct and left portal vein. At 39 months after surgery, she had no recurrence or metastasis. Patient 2 with HCC underwent palliative right trisectionectomy. At 38 months after surgery, he is alive despite residual pulmonary metastases. Patient 3 with HCC invading the hepatic vein and diaphragm underwent right trisectionectomy and caval venoplasty. At 12 months after surgery, he had no recurrence or metastasis. Patient 4, who had 2 large HCCs and pulmonary thromboembolism, underwent a right trisectionectomy. At 7 months after surgery, he had no evidence of recurred HCC. Patient 5, who had IHCC invading her inferior vena cava and main portal vein, underwent preoperative radiotherapy, left hemihepatectomy, and caval resection. At 20 months after surgery, she is well despite a caval thrombus. Patient 6 and 7 underwent repeated surgery due to a recurred IHCC and metastatic colon cancer, respectively. In addition, they are alive during each 20 and 17 months after surgery. Conclusions Despite macroscopic extrahepatic metastases or major vessel involvement, extensive surgery for advanced hepatic malignancy may result in relatively favorable outcomes and be important modality for improving of survival in such patients. PMID:26421042

  10. Combined hepatocellular-cholangiocarcinoma with stem cell features, ductal plate malformation subtype: a case report and proposal of a new subtype.

    PubMed

    Terada, Tadashi

    2013-01-01

    In the current WHO blue book, combined hepatocellular-cholangiocarcinoma (C-HCC-CC) was classified into two types; classical type and type with stem cell features. The latter is extremely rare, and is subcategorized into the following three subtypes; typical subtype, intermediate cell subtype, and cholangiocellular subtype. Recently, intrahepatic cholangiocarcinoma (ICC) with features of ductal plate malformations (DPM) have been reported, and the ICC with DPM was proposed as a subtype of ICC. The author herein reports a case of C-HCC-CC with stem cell features. Characteristically, the CC element showed features of DPM. A 51-year-old man of HBV carrier was found to have high AFP. A laboratory test showed an elevated AFP (395 ng/ml, normal 9-10) and hepatitis B virus-related antigens and antibodies. Liver and ductal enzymes and PIVKAII were within normal ranges. Imaging modalities including CT identified a small liver tumor. Hepatocellular carcinoma (HCC) was suspected, and the resection of the hepatic tumor was performed. Grossly, the liver tumor is well-defined white solid tumor measuring 22x16x23 mm. Microscopically, the tumor was a C-HCC-CC, and was composed of following three elements: well differentiated HCC, well differentiated cholangiocarcinoma (CC), and intermediate tumor element. Characteristically, the CC cells formed tortuous markedly irregular tubules with intraluminal cell projections, bridge formations, intraluminal tumor biliary cells; such features very resembled the ductal plate (DP) and DPM. Immunohistochemically, the cells of CC element were positive for stem cell antigens (KIT (CD117), CD56, EMA, CD34), HepPar1, EpCAM, cytokeratin (CK) CAM5.2, AE1/3, CK34BE12 (focal), CK7, CK8, CK18, CK19, CA19-9, p53, MUC1, MUC2, MUC5AC, MUC6, and Ki-67 (labeling=25%). They were negative for CEA, CK5/6, CK20, NSE, chromogranin, synaptophysin, and p63. No mucins were found by histochemically. The background liver showed chronic hepatitis B (a1, f3). Very

  11. Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma.

    PubMed

    Goyal, Lipika; Saha, Supriya K; Liu, Leah Y; Siravegna, Giulia; Leshchiner, Ignaty; Ahronian, Leanne G; Lennerz, Jochen K; Vu, Phuong; Deshpande, Vikram; Kambadakone, Avinash; Mussolin, Benedetta; Reyes, Stephanie; Henderson, Laura; Sun, Jiaoyuan Elisabeth; Van Seventer, Emily E; Gurski, Joseph M; Baltschukat, Sabrina; Schacher-Engstler, Barbara; Barys, Louise; Stamm, Christelle; Furet, Pascal; Ryan, David P; Stone, James R; Iafrate, A John; Getz, Gad; Porta, Diana Graus; Tiedt, Ralph; Bardelli, Alberto; Juric, Dejan; Corcoran, Ryan B; Bardeesy, Nabeel; Zhu, Andrew X

    2017-03-01

    Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252-63. ©2016 AACR.See related commentary by Smyth et al., p. 248This article is highlighted in the In This Issue feature, p. 235.

  12. Type II diabetes mellitus is associated with a reduced risk of cholangiocarcinoma in patients with biliary tract diseases.

    PubMed

    Tsai, Ming-Shian; Lee, Po-Huang; Lin, Cheng-Li; Peng, Chiao-Ling; Kao, Chia-Hung

    2015-05-15

    It has not yet been reported whether Type II diabetes mellitus (DM) is associated with an increased cholangiocarcinoma (CC) risk in patients with biliary tract diseases. We identified 123,050 patients concomitantly diagnosed with biliary tract diseases and DM between 1998 and 2010. The control cohort consisted of 122,721 individuals with biliary tract diseases but not DM. Both cohorts were followed-up until the end of 2010 to estimate the risk of CC. We also compared the risk of CC between DM and non-DM cohorts without biliary tract diseases. Overall, the incidence of CC was 21% lower among the DM patients than among the control patients (1.11 vs. 1.41 per 1,000 person-years). DM cohorts exhibited significantly reduced risks for both intrahepatic and extrahepatic CC. A multivariable Cox proportional hazards regression model was used, and the adjusted hazard ratio (HR) of CC was 0.74 (95% confidence interval [CI], 0.66-0.82) for the DM cohort in comparison with the control cohort. The age-specific data indicated that compared with the control patients, the adjusted HRs for the DM patients were significantly lower among patients 50-64 (adjusted HR = 0.67; 95% CI = 0.55-0.82) and 65-74 years old (adjusted HR = 0.70; 95% CI, 0.59-0.84). Furthermore, DM was associated with a lower risk of CC among patients with biliary diseases, regardless of the presence of comorbidities and the status of cholecystectomy. In the patients without biliary tract diseases, DM is associated with significantly increased risk of CC (adjusted HR = 1.58; 95% CI, 1.37-1.82).

  13. An S100P-positive biliary epithelial field is a preinvasive intraepithelial neoplasm in nodular-sclerosing cholangiocarcinoma.

    PubMed

    Nakanuma, Yasuni; Uchida, Tsuneyuki; Sato, Yasunori; Uesaka, Katsuhiko

    2017-02-01

    Nodular-sclerosing cholangiocarcinoma (NS-CCA) is a common CCA of the intrahepatic large, perihilar, and distal bile ducts. Intraepithelial biliary neoplasms, such as the mucosal extension of carcinoma and preinvasive neoplastic lesions (ie, biliary intraepithelial neoplasia) reportedly occur in the bile ducts around CCA. In the present study, we collectively refer to these intraepithelial lesions as "intraepithelial neoplasms of the bile duct (IENBs)". We examined the IENBs in 57 surgically resected cases of NS-CCA. S100P immunostaining was used to help detect IENBs. The IENBs formed field(s) of continuous neoplastic biliary epithelial cells and showed a flat, micropapillary, or papillotubular configuration. IENBs could be classified into 3 categories based on their atypia: group A (neoplastic but not enough for malignancy), B (neoplastic and sufficiently well differentiated for high-grade dysplasia), and C (overtly malignant and variably differentiated). IENB was found in 31 of 57 cases, with group C the most common (26 cases) followed by group B (22 cases) and group A (16 cases). The expression of cancer-related molecules and MIB-1 index of groups A and B differed from those of invasive CCA, whereas these features of group C were relatively similar to those of invasive CCA. In conclusion, IENB was not infrequently found in NS-CCA and could be classified into 3 grades. Preinvasive lesions (biliary intraepithelial neoplasias) are likely to be found in groups A and B, whereas cancerization would be included in group C. The classification of IENB may be useful for future studies of the preinvasive intraepithelial neoplastic lesions of NS-CCAs.

  14. Comorbidity negatively influences prognosis in patients with extrahepatic cholangiocarcinoma

    PubMed Central

    Fernández-Ruiz, Mario; Guerra-Vales, Juan-Manuel; Colina-Ruizdelgado, Francisco

    2009-01-01

    AIM: To study the outcome and prognostic factors in a series of patients with extrahepatic cholangiocarcinoma and determine the impact of comorbidity on survival. METHODS: A retrospective analysis of 68 patients with extrahepatic cholangiocarcinoma (perihilar, n = 37; distal, n = 31) seen at a single tertiary-care institution during the period 1999-2003 was performed. Data on presentation, management, and outcome were assessed by chart review. Pathologic confirmation was obtained in 37 cases (54.4%). Comorbidity was evaluated by using the Charlson comorbidity index (CCI). RESULTS: Mean age at diagnosis was 73.4 ± 11.5 years. Jaundice was the most common symptom presented (86.8%). Median CCI score was 1 (range, 0 to 4). Nineteen patients (27.9%) underwent tumor resection. Palliative biliary drainage was performed in 39 patients (57.4%), and 6 patients (8.8%) received only best supportive care. Tumor-free margin status (R0) was achieved in 15 cases (78.9% of resection group). Baseline serum carbohydrate antigen 19-9 (CA 19-9) level was revealed to be an independent predictor of surgical treatment (P = 0.026). Overall median survival was 3.1 ± 0.9 mo, with 1- and 2-year survival rates of 21% and 7%, respectively. In the univariate analysis, tumor resection, CCI score, and serum CA 19-9 levels correlated significantly with outcome. In the multivariate analysis, only resection (HR 0.10; 95% CI, 0.02-0.51, P = 0.005) and a CCI score ≥ 2 (HR 3.36; 95% CI, 1.0-10.9, P = 0.045) were found to independently predict survival. CONCLUSION: Tumor resection and comorbidity emerged as significant prognostic variables in extrahepatic cholangiocarcinoma. Comorbidity evaluation instruments should be applied in the clinical management of such patients. PMID:19908335

  15. Sustained IL-6/STAT-3 Signaling in Cholangiocarcinoma Cells due to SOCS-3 Epigenetic Silencing

    PubMed Central

    Isomoto, Hajime; Mott, Justin L.; Kobayashi, Shogo; Werneburg, Nathan W.; Bronk, Steve F.; Haan, Serge; Gores, Gregory J.

    2008-01-01

    Background and aims IL-6 mediated STAT-3 phosphorylation (activation) is aberrantly sustained in cholangiocarcinoma cells resulting in enhanced Mcl-1 expression and resistance to apoptosis. Because SOCS-3 controls the IL-6/STAT-3 signaling pathway by a classic feedback loop, the aims of this study were to examine SOCS-3 regulation in human cholangiocarcinoma. Methods SOCS-3 expression was assessed in human cholangiocarcinoma tissue and the Mz-ChA-1 and CCLP1 human cholangiocarcinoma cell lines. Results An inverse correlation was observed between phospho-STAT-3 and SOCS-3 protein expression in cholangiocarcinoma. In those cancers failing to express SOCS-3, extensive methylation of the SOCS-3 promoter was demonstrated in tumor but not in paired non-tumor tissue. Likewise, methylation of the socs-3 promoter was also identified in two cholangiocarcinoma cell lines. Treatment with a demethylating agent, 5-aza-2′-deoxycytidine (DAC), restored IL-6 induction of SOCS-3, terminated the phospho-STAT-3 response, and reduced cellular levels of Mcl-1. Enforced expression of SOCS-3 also reduced IL-6 induction of phospho-STAT-3 and Mcl-1. Either DAC treatment or enforced SOCS-3 expression sensitized the cells to TRAIL-mediated apoptosis. Conclusion SOCS-3 epigenetic silencing is responsible for sustained IL-6/STAT-3 signaling and enhanced Mcl-1 expression in cholangiocarcinoma. PMID:17241887

  16. Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes

    PubMed Central

    Mimaki, Sachiyo; Totsuka, Yukari; Suzuki, Yutaka; Nakai, Chikako; Goto, Masanori; Kojima, Motohiro; Arakawa, Hirofumi; Takemura, Shigekazu; Tanaka, Shogo; Marubashi, Shigeru; Kinoshita, Masahiko; Matsuda, Tomonari; Shibata, Tatsuhiro; Nakagama, Hitoshi; Ochiai, Atsushi; Kubo, Shoji; Nakamori, Shoji; Esumi, Hiroyasu; Tsuchihara, Katsuya

    2016-01-01

    Cholangiocarcinoma is a relatively rare cancer, but its incidence is increasing worldwide. Although several risk factors have been suggested, the etiology and pathogenesis of the majority of cholangiocarcinomas remain unclear. Recently, a high incidence of early-onset cholangiocarcinoma was reported among the workers of a printing company in Osaka, Japan. These workers underwent high exposure to organic solvents, mainly haloalkanes such as 1,2-dichloropropane (1,2-DCP) and/or dichloromethane. We performed whole-exome analysis on four cases of cholangiocarcinoma among the printing workers. An average of 44.8 somatic mutations was detected per Mb in the genome of the printing workers’ cholangiocarcinoma tissues, approximately 30-fold higher than that found in control common cholangiocarcinoma tissues. Furthermore, C:G-to-T:A transitions with substantial strand bias as well as unique trinucleotide mutational changes of GpCpY to GpTpY and NpCpY to NpTpY or NpApY were predominant in all of the printing workers’ cholangiocarcinoma genomes. These results were consistent with the epidemiological observation that they had been exposed to high concentrations of chemical compounds. Whole-genome analysis of Salmonella typhimurium strain TA100 exposed to 1,2-DCP revealed a partial recapitulation of the mutational signature in the printing workers’ cholangiocarcinoma. Although our results provide mutational signatures unique to occupational cholangiocarcinoma, the underlying mechanisms of the disease should be further investigated by using appropriate model systems and by comparison with genomic data from other cancers. PMID:27267998

  17. Liver transplantation and transjugular intrahepatic portosystemic shunt.

    PubMed

    Moreno, A; Meneu, J C; Moreno, E; Fraile, M; García, I; Loinaz, C; Abradelo, M; Jiménez, C; Gomez, R; García-Sesma, A; Manrique, A; Gimeno, A

    2003-08-01

    Describe the results of liver transplantation after installing Transjugular Intrahepatic Portosystemic Shunt (TIPS) and compare them with those of a control group in a comparative, longitudinal, retrospective study. Between April 1986 and October 2002, we performed 875 liver transplantations. Between January 1996 and October 2002, 26 transplantations were performed on TIPS carriers. This group was compared with a control cohort of 50 randomly selected patients who underwent transplantation in this period (non-TIPS carriers). Both groups were homogeneous with no significant differences between age, sex United Network for Organ Sharing (UNOS) score, Child stage, or etiology. Actuarial survival rates at 1 and 3 years: TIPS group 96.15% and 89.29% versus control cohort 87.8% and 81%, respectively. In 73.9%, the TIPS was clearly effective; in 88.9%, a postoperative Doppler revealed normal flow. There were no statistically significant differences compared with time on the waiting list for transplant, duration of the operation, ischemia times, intraoperative consumption of hemoderivates, vascular or nonvascular postoperative complications, duration of stay in the intensive care unit, hospital stay, or retransplantation rate. In our experience, TIPS insertion does not affect either the intraoperative or postoperative evolution and is not associated with an increased time on the liver transplant waiting list.

  18. Health history after intrahepatic cholestasis of pregnancy.

    PubMed

    Turunen, Kaisa; Mölsä, Anni; Helander, Kristiina; Sumanen, Markku; Mattila, Kari J

    2012-06-01

    To establish whether intrahepatic cholestasis of pregnancy (ICP) is associated with other diseases during a woman's lifetime. Prospective controlled cohort study. University Hospital in Finland. A total of 575 women with ICP and 1374 control women, all having delivered in 1969-1988. Questionnaires were sent to 544 ICP patients and 1235 control women. Responses were received from 1178 (66.4%). Questionnaire survey in autumn 2010. Perceived health, symptoms and complaints, diseases diagnosed by a doctor and use of medicines. No statistically significant differences were detected in perceived health. Differences in recent symptoms and complaints were small. Diagnoses made by a doctor showed higher frequencies in the ICP group than in control women for other hepatobiliary diseases, breast cancer and hypothyreosis. Diagnosed hypertension and high cholesterol requiring medication as well as cardiac arrhythmia were less frequent in the ICP group. Women in this group used antacid medicines more often than control women. There were few differences between the ICP patients and control women except for a higher frequency of later hepatobiliary disease, breast cancer and hypothyreosis. Women with a history of ICP should be screened for hypothyreosis more readily than those without. The higher frequency of breast cancer warrants further research. © 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.

  19. [Intrahepatic cholestasis of pregnancy : Rare but important].

    PubMed

    Kremer, A E; Wolf, K; Ständer, S

    2017-02-01

    Intrahepatic cholestasis of pregnancy (ICP) is a liver-specific disorder occurring in approximately 0.5-2.0% of all pregnancies with a considerable variation in certain ethnic groups. ICP usually runs a benign course for the mother and is characterized by maternal pruritus mainly in the third trimester, elevated transaminases and fasting total serum bile salts and increased fetal adverse events. The etiology of ICP is only partially understood but seems to be multifactorial. Cholestasis-inducing effects of certain female sex hormones and their metabolites play an important role in genetically susceptible women. The mechanisms resulting in fetal complications such as spontaneous preterm labour, antepartum passage of meconium, asphyxia events, still birth and fetal death are not well understood. Certain sulfated progesterone metabolites are likely to play a role in the pathogenesis of pruritus in ICP. In contrast to pregnancy-related dermatoses, pruritus does not present with primary skin alterations. However, intense scratching may cause secondary skin changes such as abrasions, excoriations and sometimes prurigo nodularis. Treatment is based on ursodeoxycholate treatment to reduce pruritus and hepatic impairment as well as elective delivery between gestation week 37-38 to pre-empt potential stillbirths. This article reviews clinical symptoms, diagnosis, treatment and in particular pathogenesis of pruritus in ICP.

  20. Thalidomide decreases intrahepatic resistance in cirrhotic rats.

    PubMed

    Yang, Ying-Ying; Huang, Yi-Tsau; Lin, Han-Chieh; Lee, Fa-Yauh; Lee, Kuei-Chuan; Chau, Ga-Yang; Loong, Che-Chuan; Lai, Chiung-Ru; Lee, Shou-Dong

    2009-03-13

    Increased intrahepatic resistance (IHR) within cirrhotic liver is caused by increased endotoxemia, cytokines tumor necrosis factor-alpha (TNF-alpha), vasoconstrictor thromboxane A(2) (TXA(2)), and disrupted microvasculatures. We evaluated the effects of thalidomide-related inhibition of TNF-alpha upon the hepatic microcirculation of cirrhosis in rats. Portal venous pressure (PVP), hepatic TNF-alpha, expression of thromboxane synthase (TXS), and leukocyte common antigen (LCA) were measured in bile-duct-ligated (BDL) rats receiving 1 month of thalidomide (BDL-thalido rats). Portal perfusion pressure (PPP), IHR, and hepatic TXA(2) production were measured in the isolated liver perfusion system. Intravital microscopy was used to examine hepatic microvascular disruptions. In BDL-thalido rats, PVP, PPP, IHR, hepatic TXA(2) and TNF-alpha, hydroxyproline content, expression of TXS and LCA, and LPS-induced leukocyte recruitment were significantly decreased. Conversely, hepatic microvascular density and perfused sinusoids were significantly increased. Thalidomide decreased PVP and IHR by reducing hepatic TXA(2) and improving hepatic microvascular disruptions in rats with biliary cirrhosis.

  1. Selective internal radiotherapy (SIRT) versus transarterial chemoembolization (TACE) for the treatment of intrahepatic cholangiocellular carcinoma (CCC): study protocol for a randomized controlled trial.

    PubMed

    Kloeckner, Roman; Ruckes, Christian; Kronfeld, Kai; Wörns, Marcus Alexander; Weinmann, Arndt; Galle, Peter Robert; Lang, Hauke; Otto, Gerd; Eichhorn, Waltraud; Schreckenberger, Mathias; Dueber, Christoph; Pitton, Michael Bernhard

    2014-08-06

    Cholangiocellular carcinoma is the second most common primary liver cancer after hepatocellular carcinoma. Over the last 30 years, the incidence of intrahepatic cholangiocellular carcinoma has risen continuously worldwide. Meanwhile, the intrahepatic cholangiocellular carcinoma has become more common than the extrahepatic growth type and currently accounts for 10-15% of all primary hepatic malignancies. Intrahepatic cholangiocellular carcinoma is typically diagnosed in advanced stages due to late clinical symptoms and an absence of classic risk factors. A late diagnosis precludes curative surgical resection. There is evidence that transarterial chemoembolization leads to better local tumor control and prolongs survival compared to systemic chemotherapy. New data indicates that selective internal radiotherapy, also referred to as radioembolization, provides promising results for treating intrahepatic cholangiocellular carcinoma. This pilot study is a randomized, controlled, single center, phase II trial. Twenty-four patients with intrahepatic cholangiocellular carcinoma will be randomized in a 1:1 ratio to receive either chemoembolization or radioembolization. Randomization will be stratified according to tumor load. Progression-free survival is the primary endpoint; overall survival and time to progression are secondary endpoints. To evaluate treatment success, patients will receive contrast enhanced magnetic resonance imaging every 3 months. Currently, chemoembolization is routinely performed in many centers instead of systemic chemotherapy for treating intrahepatic cholangiocellular carcinoma confined to the liver. Recently, radioembolization has been increasingly applied to cholangiocellular carcinoma as second line therapy after TACE failure or even as an alternative first line therapy. Nonetheless, no randomized studies have compared radioembolization and chemoembolization. Considering all this background information, we recognized a strong need for a

  2. Upregulation of transferrin receptor-1 induces cholangiocarcinoma progression via induction of labile iron pool.

    PubMed

    Jamnongkan, Wassana; Thanan, Raynoo; Techasen, Anchalee; Namwat, Nisana; Loilome, Watcharin; Intarawichian, Piyapharom; Titapun, Attapol; Yongvanit, Puangrat

    2017-07-01

    Labile iron pool is a cellular source of ions available for Fenton reactions resulting in oxidative stress. Living organisms avoid an excess of free irons by a tight control of iron homeostasis. We investigated the altered expression of iron regulatory proteins and iron discrimination in the development of liver fluke-associated cholangiocarcinoma. Additionally, the levels of labile iron pool and the functions of transferrin receptor-1 on cholangiocarcinoma development were also identified. Iron deposition was determined using the Prussian blue staining method in human cholangiocarcinoma tissues. We investigated the alteration of iron regulatory proteins including transferrin, transferrin receptor-1, ferritin, ferroportin, hepcidin, and divalent metal transporter-1 in cholangiocarcinoma tissues using immunohistochemistry. The clinicopathological data of cholangiocarcinoma patients and the expressions of proteins were analyzed. Moreover, the level of intracellular labile iron pool in cholangiocarcinoma cell lines was identified by the RhoNox-1 staining method. We further demonstrated transferrin receptor-1 functions on cell proliferation and migration upon small interfering RNA for human transferrin receptor 1 transfection. Results show that Iron was strongly stained in tumor tissues, whereas negative staining was observed in normal bile ducts of healthy donors. Interestingly, high iron accumulation was significantly correlated with poor prognosis of cholangiocarcinoma patients. The expressions of iron regulatory proteins in human cholangiocarcinoma tissues and normal liver from cadaveric donors revealed that transferrin receptor-1 expression was increased in the cancer cells of cholangiocarcinoma tissues when compared with the adjacent normal bile ducts and was significantly correlated with cholangiocarcinoma metastasis. Labile iron pool level and transferrin receptor-1 expression were significantly increased in KKU-214 and KKU-213 when compared with cholangiocyte

  3. Positioning high-dose radiation in multidisciplinary management of unresectable cholangiocarcinomas: review of current evidence.

    PubMed

    Chopra, Supriya; Mathew, Ashwathy S; Engineer, Reena; Shrivastava, Shyam K

    2014-09-01

    Cholangiocarcinoma is a rare malignancy of the bile ducts. The current standard of care for unresectable nonmetastatic disease is doublet systemic chemotherapy, which provides a median survival of 11.7 months. Although chemoradiation is a therapeutic option that provides almost equivalent or superior survival, the lack of level I evidence presents a major hurdle in routinely recommending it within multidisciplinary clinics. This mini review presents the current evidence on the use of chemoradiation for unresectable nonmetastatic cholangiocarcinoma and rationale for positioning it within multidisciplinary management of unresectable cholangiocarcinomas.

  4. Primary sclerosing cholangitis and cholangiocarcinoma as a diagnostic and therapeutic dilemma.

    PubMed

    van Leeuwen, D J; Reeders, J W

    1999-01-01

    Differentiating primary sclerosing cholangitis (PSC) from cholangiocarcinoma (CC) can be a diagnostic challenge with major therapeutic implications. In case of advanced or symptomatic PSC, liver transplantation (OLTx) can be life saving with excellent long-term outcome. However, the outcome of CC diagnosed prior or during OLTx is dismal. PSC is a premalignant condition associated with a risk of developing cholangio- or hepatocellular carcinoma in > 15% of patients. Imaging diagnoses should be integrated into the further clinical data. It is the sudden, rapid and irreversible deterioration of the patient's condition, and the rapid progression of cholangiographic abnormalities, which may strongly point towards a malignancy or a malignant evolution in case of PSC. Brush cytology, (guided) biopsy, and tumor markers such as Ca 19.9 and CEA levels can be of some help, but confirmation of malignancy is often associated with a poor outcome and exclusion from liver transplantation. Clinical deterioration of the PSC patient and signs indicating advanced liver damage are a justification to evaluate patients for liver transplantation. Early transplantation should be considered in appropriate patients.

  5. Transjugular intrahepatic portosystemic shunts and portal hypertension-related complications

    PubMed Central

    Siramolpiwat, Sith

    2014-01-01

    Portal hypertension (PH) plays an important role in the natural history of cirrhosis, and is associated with several clinical consequences. The introduction of transjugular intrahepatic portosystemic shunts (TIPS) in the 1980s has been regarded as a major technical advance in the management of the PH-related complications. At present, polytetrafluoroethylene-covered stents are the preferred option over traditional bare metal stents. TIPS is currently indicated as a salvage therapy in patients with bleeding esophageal varices who fail standard treatment. Recently, applying TIPS early (within 72 h after admission) has been shown to be an effective and life-saving treatment in those with high-risk variceal bleeding. In addition, TIPS is recommended as the second-line treatment for secondary prophylaxis. For bleeding gastric varices, applying TIPS was able to achieve hemostasis in more than 90% of patients. More trials are needed to clarify the efficacy of TIPS compared with other treatment modalities, including cyanoacrylate injection and balloon retrograde transvenous obliteration of gastric varices. TIPS should also be considered in bleeding ectopic varices and refractory portal hypertensive gastropathy. In patients with refractory ascites, there is growing evidence that TIPS not only results in better control of ascites, but also improves long-term survival in appropriately selected candidates. In addition, TIPS is a promising treatment for refractory hepatic hydrothorax. However, the role of TIPS in the treatment of hepatorenal and hepatopulmonary syndrome is not well defined. The advantage of TIPS is offset by a risk of developing hepatic encephalopathy, the most relevant post-procedural complication. Emerging data are addressing the determination the optimal time and patient selection for TIPS placement aiming at improving long-term treatment outcome. This review is aimed at summarizing the published data regarding the application of TIPS in the management of

  6. Stent Placement With or Without Photodynamic Therapy Using Porfimer Sodium as Palliative Treatment in Treating Patients With Stage III or Stage IV Cholangiocarcinoma That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2013-04-02

    Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer

  7. Colon Mass as a Secondary Metastasis from Cholangiocarcinoma: A Diagnostic and Therapeutic Dilemma.

    PubMed

    Niazi, Azfar; Saif, Muhammad W

    2016-07-22

    Cholangiocarcinoma (bile ducts cancer) is a rare and aggressive form of cancer. It metastasizes frequently to liver, peritoneum, and lungs. Colon metastasis is extremely uncommon. We report here a 70-year-old male who was diagnosed with cholangiocarcinoma for which he underwent a Whipple procedure. Fifteen months later, a CT scan revealed mural thickening in the colon; this was supplemented with a PET scan, which confirmed this mass. Histological diagnosis of metastatic cholangiocarcinoma to the colon was made and the patient was treated with chemotherapy. Although rare, cholangiocarcinoma metastasis can be found in the colon. A high index of suspicion is required to diagnose and treat early. More cases need to be reported to find out further about the prognosis of the disease.

  8. Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy

    PubMed Central

    Krekorian, Massis; Alles, Lindy K.; van Wijk, Albert C.; Mackaaij, Claire; Verheij, Joanne; van der Wal, Allard C.; van Gulik, Thomas M.; Storm, Gert; Heger, Michal

    2016-01-01

    Background: Photodynamic therapy (PDT) induces tumor cell death by oxidative stress and hypoxia but also survival signaling through activation of hypoxia-inducible factor 1 (HIF-1). Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression levels of HIF-1-associated proteins in human perihilar cholangiocarcinomas, (2) investigate the role of HIF-1 in PDT-treated human perihilar cholangiocarcinoma cells, and (3) determine whether HIF-1 inhibition reduces survival signaling and enhances PDT efficacy. Results: Increased expression of VEGF, CD105, CD31/Ki-67, and GLUT-1 was confirmed in human perihilar cholangiocarcinomas. PDT with liposome-delivered zinc phthalocyanine caused HIF-1α stabilization in SK-ChA-1 cells and increased transcription of HIF-1α downstream genes. Acriflavine was taken up by SK-ChA-1 cells and translocated to the nucleus under hypoxic conditions. Importantly, pretreatment of SK-ChA-1 cells with acriflavine enhanced PDT efficacy via inhibition of HIF-1 and topoisomerases I and II. Methods: The expression of VEGF, CD105, CD31/Ki-67, and GLUT-1 was determined by immunohistochemistry in human perihilar cholangiocarcinomas. In addition, the response of human perihilar cholangiocarcinoma (SK-ChA-1) cells to PDT with liposome-delivered zinc phthalocyanine was investigated under both normoxic and hypoxic conditions. Acriflavine, a HIF-1α/HIF-1β dimerization inhibitor and a potential dual topoisomerase I/II inhibitor, was evaluated for its adjuvant effect on PDT efficacy. Conclusions: HIF-1, which is activated in human hilar cholangiocarcinomas, contributes to tumor cell survival following PDT in vitro. Combining PDT with acriflavine pretreatment improves PDT efficacy in cultured cells and therefore warrants further preclinical validation for therapy-recalcitrant perihilar cholangiocarcinomas. PMID:26657503

  9. Paraneoplastic Necrotizing Autoimmune Myopathy in a Patient Undergoing Laparoscopic Pancreatoduodenectomy for Distal Cholangiocarcinoma

    PubMed Central

    van Dijk, Stefan; van der Kooi, Anneke J.; Aronica, Eleonora; van Gulik, Thomas M.; Busch, Olivier R.; Besselink, Marc G.

    2016-01-01

    A 73-year-old male presented with jaundice and severe muscle weakness. He was diagnosed with distal cholangiocarcinoma and paraneoplastic necrotizing autoimmune myopathy (NAM). Treatment of NAM consisted of dexamethasone pulse therapy, prednisone, and single-dose intravenous immunoglobulin. The distal cholangiocarcinoma was resected through a total laparoscopic pancreatoduodenectomy. After hospital discharge, muscle strength initially increased postoperatively; however, pneumonia resulted in the deterioration of his general condition and death 5 months after the diagnosis of paraneoplastic NAM. PMID:27843429

  10. Pesticides, fresh water fish, liver flukes and nitrosamines: A story of cholangiocarcinoma development in Thailand.

    PubMed

    Wiwanitkit, Viroj

    2009-01-01

    Cholangiocarcinoma is a common hepatobiliary carcinoma in Thailand. It is believed that both chronic exposure to liver fluke infestation and nitrosamine exposure are the two main underlying factors leading to the carcinogenesis. Here, the author further extrapolates and proposes a new hypothesis based on the environmental ecological data that the stimulation of fresh water fish by contaminated pesticide in water reservoirs might be a possible background of the high prevalence of cholangiocarcinoma in Thailand.

  11. Intra-hepatic arterioportal shunt mimicking a metastatic liver tumor: report of a case.

    PubMed

    Haruki, Koichiro; Wakiyama, Shigeki; Shiba, Hiroaki; Ishida, Yuichi; Yanaga, Katsuhiko

    2012-04-01

    The differential diagnosis of an arterioportal shunt (APS) is difficult and important. We report a case of an intra-hepatic APS mimicking a metastatic liver tumor on imaging scans in a patient without hepatic cirrhosis. The patient was a 64-year-old woman, who had undergone low anterior resection of the rectum for advanced rectal cancer, followed 2 months later by right hemihepatectomy, including the middle hepatic vein, for a synchronous metastatic liver tumor. About 2 years after the hepatectomy, a follow-up CT scan showed a new mass in the remnant liver, suggestive of a metastatic liver tumor, the assumption of which was further supported by an elevated serum carcinoembryonic antigen (CEA) level. However, the findings of magnetic resonance imaging were not consistent with a malignant tumor, and Doppler ultrasonography showed a low echoic area connected with the portal vein branch and the hepatic artery branch. Thus, we diagnosed intra-hepatic APS. The patient remains well without signs of growth of the hepatic lesion, although with fluctuating serum CEA levels.

  12. ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics

    SciTech Connect

    Fan, Zhongqi; Yu, Huimei; Cui, Ni; Kong, Xianggui; Liu, Xiaomin; Chang, Yulei; Wu, Yao; Sun, Liankun; Wang, Guangyi

    2015-07-01

    Cholangiocarcinoma responses weakly to cisplatin. Mitochondrial dynamics participate in the response to various stresses, and mainly involve mitophagy and mitochondrial fusion and fission. Bcl-2 family proteins play critical roles in orchestrating mitochondrial dynamics, and are involved in the resistance to cisplatin. Here we reported that ABT737, combined with cisplatin, can promote cholangiocarcinoma cells to undergo apoptosis. We found that the combined treatment decreased the Mcl-1 pro-survival form and increased Bak. Cells undergoing cisplatin treatment showed hyperfused mitochondria, whereas fragmentation was dominant in the mitochondria of cells exposed to the combined treatment, with higher Fis1 levels, decreased Mfn2 and OPA1 levels, increased ratio of Drp1 60 kD to 80 kD form, and more Drp1 located on mitochondria. More p62 aggregates were observed in cells with fragmented mitochondria, and they gradually translocated to mitochondria. Mitophagy was induced by the combined treatment. Knockdown p62 decreased the Drp1 ratio, increased Tom20, and increased cell viability. Our data indicated that mitochondrial dynamics play an important role in the response of cholangiocarcinoma to cisplatin. ABT737 might enhance cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics and the balance within Bcl-2 family proteins. Furthermore, p62 seems to be critical in the regulation of mitochondrial dynamics. - Highlights: • Cholangiocarcinoma may adapt to cisplatin through mitochondrial fusion. • ABT737 sensitizes cholangiocarcinoma to cisplatin by promoting fission and mitophagy. • p62 might participate in the regulation of mitochondrial fission and mitophagy.

  13. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA).

    PubMed

    Banales, Jesus M; Cardinale, Vincenzo; Carpino, Guido; Marzioni, Marco; Andersen, Jesper B; Invernizzi, Pietro; Lind, Guro E; Folseraas, Trine; Forbes, Stuart J; Fouassier, Laura; Geier, Andreas; Calvisi, Diego F; Mertens, Joachim C; Trauner, Michael; Benedetti, Antonio; Maroni, Luca; Vaquero, Javier; Macias, Rocio I R; Raggi, Chiara; Perugorria, Maria J; Gaudio, Eugenio; Boberg, Kirsten M; Marin, Jose J G; Alvaro, Domenico

    2016-05-01

    Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.

  14. A Multicenter Phase II Study of Gemcitabine, Capecitabine, and Bevacizumab for Locally Advanced or Metastatic Biliary Tract Cancer.

    PubMed

    Iyer, Renuka V; Pokuri, Venkata K; Groman, Adrienne; Ma, Wen W; Malhotra, Usha; Iancu, Dan M; Grande, Catherine; Saab, Tanios B

    2016-11-15

    Vascular endothelial growth factor overexpression, seen in 42% to 76% of biliary tract cancers (BTCs), correlates with poor survival. We explored the safety/efficacy and potential biomarkers for bevacizumab in combination with gemcitabine-capecitabine in advanced BTCs. Inoperable stage III/IV BTC patients in our prospective study were given 1000 mg/m of gemcitabine (on days 1, 8), 650 mg/m of capecitabine (on days 1 to 14), and 15 mg/kg of bevacizumab (on day 1) in 21-day cycles. Circulating tumor cells and quality of life were assessed at baseline and before cycle 2 and 3. In total, 50 patients with gallbladder cancer (22%), intrahepatic (58%), and extrahepatic (20%) cholangiocarcinoma, received a median of 8 treatment cycles for median treatment duration of 5.8 months. Common grade 3/4 toxicities were neutropenia (36%), thrombocytopenia (16%), fatigue (20%), infections (14%), and hand-foot syndrome (10%). There were 12 partial response (24%), 24 stable disease (48%) with clinical benefit rate of 72%. Median progression-free survival was 8.1 months (95% confidence interval, 5.3-9.9). Median overall survival was 10.2 months (95% confidence interval, 7.5-13.7). Circulating tumor cells were identified at baseline in 21/46 patients (46%), who had lower median overall survival compared with those without (9.4 vs. 13.7 mo; P=0.29). Patients with quality of life scores greater than the group median by the end of first cycle of treatment had improved survival compared with those who did not (13.3 vs. 9.4 mo; P=0.39). Addition of bevacizumab to gemcitabine/capecitabine did not improve outcome in an unselected group of patients with advanced BTC compared with historical controls. The selective benefit of vascular endothelial growth factor inhibition in BTC remains to be explored.

  15. A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours.

    PubMed

    Papadopoulos, K P; El-Rayes, B F; Tolcher, A W; Patnaik, A; Rasco, D W; Harvey, R D; LoRusso, P M; Sachdev, J C; Abbadessa, G; Savage, R E; Hall, T; Schwartz, B; Wang, Y; Kazakin, J; Shaib, W L

    2017-10-03

    ARQ 087 is an orally administered pan-FGFR inhibitor with multi-kinase activity. This Phase 1 study evaluated safety, pharmacokinetics, and pharmacodynamics of ARQ 087 and defined the recommended Phase 2 dose (RP2D). Patients with advanced solid tumours received ARQ 087 administered initially at 25 mg every other day and dose-escalated from 25 to 425 mg daily (QD) continuous dosing. FGF19, 21, 23, and serum phosphate were assessed as potential biomarkers of target engagement. 80 patients were enrolled, 61 in dose-escalation/food-effect cohorts and 19 with pre-defined tumour types in the expansion cohort. The most common ARQ 087-related adverse events were fatigue (49%), nausea (46%), aspartate aminotransferase (AST) increase (30%), and diarrhoea (23%). Four patients (5%) experienced grade 1 treatment-related hyperphosphataemia. Dose-limiting toxicity was reversible grade 3 AST increase. The RP2D was 300 mg QD. Pharmacokinetics were linear and dose-proportional from 25 to 325 mg QD, and were unaffected by food. Statistically significant changes (P-value<0.05) suggest phosphate and FGF19 levels as markers of target engagement. In 18 evaluable patients with FGFR genetic alterations, 3 confirmed partial responses (two intrahepatic cholangiocarcinomas (iCCA) with FGFR2 fusions and one urothelial cancer with FGFR2 and FGF19 amplification) and two durable stable disease at ⩾16 weeks with tumour reduction (FGFR2 fusion-positive iCCA and adrenocortical carcinoma with FGFR1 amplification) were observed. ARQ 087 had manageable toxicity at the RP2D of 300 mg QD, showed pharmacodynamics effects, and achieved objective responses, notably in patients with FGFR2 genetic alterations.British Journal of Cancer advance online publication, 3 October 2017; doi:10.1038/bjc.2017.330 www.bjcancer.com.

  16. Embolization of nonvariceal portosystemic collaterals in transjugular intrahepatic portosystemic shunts

    SciTech Connect

    Bilbao, Jose Ignacio; Arias, Mercedes; Longo, Jesus Maria; Alejandre, Pedro Luis; Betes, Maria Teresa; Elizalde, Arlette Maria

    1997-03-15

    Percutaneous embolization of large portosystemic collaterals was performed in three patients following placement of a transjugular intrahepatic portosystemic shunt in order to improve hepatopetal portal flow. Improved hepatic portal perfusion was achieved in these cases, thereby theoretically reducing the risk of chronic hepatic encephalopathy.

  17. Transjugular Intrahepatic Portosystemic Shunt Complications: Prevention and Management

    PubMed Central

    Suhocki, Paul V.; Lungren, Matthew P.; Kapoor, Baljendra; Kim, Charles Y.

    2015-01-01

    Transjugular intrahepatic portosystemic shunt (TIPS) insertion has been well established as an effective treatment in the management of sequelae of portal hypertension. There are a wide variety of complications that can be encountered, such as hemorrhage, encephalopathy, TIPS dysfunction, and liver failure. This review article summarizes various approaches to preventing and managing these complications. PMID:26038620

  18. Spontaneous Intrahepatic Portal Venous Shunt: Presentation and Endovascular Treatment.

    PubMed

    Sheth, Nakul; Sabbah, Nathanael; Contractor, Sohail

    2016-07-01

    Spontaneous intrahepatic portal venous shunts are rare with only few case reports published. Treatments using various endovascular techniques have been described, although no single technique has been shown to be preferred. We present a patient who was referred for treatment of a spontaneous portal venous shunt and describe our treatment approach and present a review on previously reported cases.

  19. Photodynamic Therapy Plus Chemotherapy Compared with Photodynamic Therapy Alone in Hilar Nonresectable Cholangiocarcinoma

    PubMed Central

    Wentrup, Robert; Winkelmann, Nicola; Mitroshkin, Andrey; Prager, Matthias; Voderholzer, Winfried; Schachschal, Guido; Jürgensen, Christian; Büning, Carsten

    2016-01-01

    Background/Aims Standard treatments are not available for hilar nonresectable cholangiocarcinoma (NCC). It is unknown whether combination therapy of photodynamic therapy (PDT) plus systemic chemotherapy is superior to PDT alone. Methods We retrospectively reviewed 68 patients with hilar NCC treated with either PDT plus chemotherapy (PTD-C) or PDT monotherapy (PDT-M). The primary endpoint was the mean overall survival rate. Secondary endpoints included the 1-year survival rate, risk of cholangitic complications, and outcomes, which were evaluated according to the chemotherapy protocol. Results More than 90% of the study population had advanced hilar NCC Bismuth type III or IV. In the PDT-M group (n=35), the mean survival time was 374 days compared with 520 days in the PDT-C group (n=33, p=0.021). The 1-year survival rate was significantly higher in the PDT-C group compared with the PDT-M group (88% vs 58%, p=0.001) with a significant reduction of mortality (hazard ratio, 0.20; 95% confidence interval, 0.07 to 0.58; p=0.003). Gemcitabine monotherapy resulted in a shorter survival time compared with the gemcitabine combination therapy (mean, 395 days vs 566 days; p=0.09). Cholangitic complications were observed at a similar frequency in the PDT-C and PDT-M groups. Conclusions Combining repeated PDT with a gemcitabine-based combination therapy might offer a significant survival benefit in patients with hilar NCC. PMID:26814610

  20. Photodynamic Therapy Plus Chemotherapy Compared with Photodynamic Therapy Alone in Hilar Nonresectable Cholangiocarcinoma.

    PubMed

    Wentrup, Robert; Winkelmann, Nicola; Mitroshkin, Andrey; Prager, Matthias; Voderholzer, Winfried; Schachschal, Guido; Jürgensen, Christian; Büning, Carsten

    2016-05-23

    Standard treatments are not available for hilar nonresectable cholangiocarcinoma (NCC). It is unknown whether combination therapy of photodynamic therapy (PDT) plus systemic chemotherapy is superior to PDT alone. We retrospectively reviewed 68 patients with hilar NCC treated with either PDT plus chemotherapy (PTD-C) or PDT monotherapy (PDT-M). The primary endpoint was the mean overall survival rate. Secondary endpoints included the 1-year survival rate, risk of cholangitic complications, and outcomes, which were evaluated according to the chemotherapy protocol. More than 90% of the study population had advanced hilar NCC Bismuth type III or IV. In the PDT-M group (n=35), the mean survival time was 374 days compared with 520 days in the PDT-C group (n=33, p=0.021). The 1-year survival rate was significantly higher in the PDT-C group compared with the PDT-M group (88% vs 58%, p=0.001) with a significant reduction of mortality (hazard ratio, 0.20; 95% confidence interval, 0.07 to 0.58; p=0.003). Gemcitabine monotherapy resulted in a shorter survival time compared with the gemcitabine combination therapy (mean, 395 days vs 566 days; p=0.09). Cholangitic complications were observed at a similar frequency in the PDT-C and PDT-M groups. Combining repeated PDT with a gemcitabine-based combination therapy might offer a significant survival benefit in patients with hilar NCC.

  1. Classification of Gemcitabine resistant Cholangiocarcinoma cell lines using synchrotron FTIR microspectroscopy.

    PubMed

    Wongwattanakul, Molin; Hahnvajanawong, Chariya; Tippayawat, Patcharaporn; Chio-Srichan, Sirinart; Leelayuwat, Chanvit; Limpaiboon, Temduang; Jearanaikoon, Patcharee; Heraud, Philip

    2017-03-01

    Cholangiocarcinoma (CCA), a cancer of bile duct epithelium, is a major health problem in Thailand especially in the northeast. Overall treatment outcomes have not shown much improvement because the disease is usually detected at an advanced stage and often shows chemotherapeutic resistance. High-throughput Fourier Transform Infrared (FTIR) microspectroscopy can be used for cell classification and has the potential to diagnose cancer and possibly predict chemo-response. This study was aimed to differentiate gemcitabine-sensitive and gemcitabine-resistant induction in two CCA cell lines (KKU-M139 and KKU-M214) and xenograft tissues using synchrotron-FTIR microspectroscopy. Partial Least Squares Discriminant Analysis (PLS-DA) could discriminate between chemo-sensitive and chemo-resistant cells in the FTIR fingerprint spectral region (1800-1000 cm(-1) ) with more than 90% sensitivity and specificity. The chemo-resistant and chemo-sensitive phenotypes were different in protein (amide I, amide II), lipids (carbonyl group and CH3 deformation) and phosphodiester from nucleic acids. Additionally, spectra from xenograft tissues showed similar results to the cell line study with marked differences between chemo-resistant and chemo-sensitive CCA tissues, and PLS-DA could discriminate the chemotherapeutic response with 98% sensitivity and specificity. This is the first study to demonstrate the use of FTIR microspectroscopy to assess chemo-response both in vitro and in vivo. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Factors affecting survival time of cholangiocarcinoma patients: a prospective study in Northeast Thailand.

    PubMed

    Woradet, Somkiattiyos; Promthet, Supannee; Songserm, Nopparat; Parkin, Donald Maxwell

    2013-01-01

    Cholangiocarcinoma (CCA) is a major health problem and cause of death among people in Northeastern Thailand. In this prospective study 171 patients newly diagnosed with CCA by physicians in 5 tertiary hospitals in four provinces of northeastern of Thailand between February and July 2011 were followed up to January 2012. The outcome was survival time from diagnosis to death. A total of 758.4 person-months of follow-up were available. The mortality rate was 16.9 per 100 person-months (95%CI: 14.1-20.1). The median survival time among CCA patients was 4.3 months (95%CI: 3.3-5.1). Cox's proportional hazard model was used to study the independent effects of factors affecting survival time among patients. Statistically significant factors included advanced stage at diagnosis (HR: 2.5, 95%CI: 1.7-3.8), presentation with jaundice (HR: 1.7, 95%CI: 1.1-2.4) or ascites (HR: 2.8, 95%CI: 1.8-4.4), and positive serum carcinoembryonic antigen (HR: 2.3, 95%CI: 1.2-4.3). Patients who had received standard treatment had a better prognosis that those who did not (HR: 0.5, 95%CI: 0.3-0.7).

  3. Roles of liver fluke infection as risk factor for cholangiocarcinoma.

    PubMed

    Sithithaworn, Paiboon; Yongvanit, Puangrat; Duenngai, Kunyarat; Kiatsopit, Nadda; Pairojkul, Chawalit

    2014-05-01

    Several factors are known to be associated with risk of cholangiocarcinoma (CCA) and infection with the liver flukes, Opisthorchis viverrini and Clonorchis sinensis, has often been singled out as the leading risk factor in east and southeast Asia. In this review, current knowledge of their biology, life cycle, and pathogenesis of O. viverrini, and its role as a carcinogenic parasite are presented. The trends of age-specific incidence of liver cancer in Khon Kaen, northeast Thailand are considered and compared with the prevalence profiles of O. viverrini. Potential impacts of the liver fluke control program particularly by mass drug administration (MDA) and public health education in the past and a recent drop of incidence of CCA are discussed in relation to primary prevention and control of this fatal bile duct cancer. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  4. Combined hepatocellular-cholangiocarcinoma in a lesser flamingo (Phoenicopterus minor).

    PubMed

    Van Wettere, A J; Degernes, L A; Barnes, H John

    2010-08-01

    A case of combined hepatocellular-cholangiocarcinoma (CHCC) in an adult male lesser flamingo (Phoenicopterus minor) that was part of a breeding programme at a private facility is reported. Grossly, the liver was markedly enlarged with multifocal, well-circumscribed, pinpoint to 2 cm diameter pale tan nodular masses. Histologically, the hepatic parenchyma was replaced by neoplastic cells that demonstrated hepatocellular and, less frequently, biliary epithelial cell differentiation. Positive pan-cytokeratin (AE1/AE3/PCK26) immunolabelling of the neoplastic cells forming bile ducts with the scattered immunoreactivity of cells forming glandular structures within the areas of hepatocellular differentiation supported the diagnosis. No metastases were detected. CHCC is a rare neoplasm in mammals and birds. This is the first report where gross, histological, and immunohistochemical characteristics of CHCC in a bird are described, and the first report of CHCC in a lesser flamingo.

  5. Autocrine and Paracrine Mechanisms Promoting Chemoresistance in Cholangiocarcinoma

    PubMed Central

    Cadamuro, Massimiliano; Brivio, Simone; Spirli, Carlo; Joplin, Ruth E.; Strazzabosco, Mario; Fabris, Luca

    2017-01-01

    Resistance to conventional chemotherapeutic agents, a typical feature of cholangiocarcinoma, prevents the efficacy of the therapeutic arsenal usually used to combat malignancy in humans. Mechanisms of chemoresistance by neoplastic cholangiocytes include evasion of drug-induced apoptosis mediated by autocrine and paracrine cues released in the tumor microenvironment. Here, recent evidence regarding molecular mechanisms of chemoresistance is reviewed, as well as associations between well-developed chemoresistance and activation of the cancer stem cell compartment. It is concluded that improved understanding of the complex interplay between apoptosis signaling and the promotion of cell survival represent potentially productive areas for active investigation, with the ultimate aim of encouraging future studies to unveil new, effective strategies able to overcome current limitations on treatment. PMID:28098760

  6. Systemic therapy of cholangiocarcinoma: From chemotherapy to targeted therapies.

    PubMed

    Schweitzer, N; Vogel, A

    2015-04-01

    Cholangiocarcinomas (CCA) are rare tumors of the liver with poor prognosis. The standard of care in patients with unresectable tumors or metastatic disease is combination chemotherapy (CT) with gemcitabine and cisplatin. Targeted therapies inhibiting EGFR, VEGF, MEK and others are broadly tested in CCA but to date, the existing data from randomized and nonrandomized trials do not justify the application of small molecules outside of clinical trials. In clinical practice, many patients receive second-line CT after failure of gemcitabine/cisplatin, although there is so far no evidence to support second-line CT. This review summarizes current chemotherapy protocols and ongoing studies, including conventional chemotherapy and targeted therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Coenzyme Q in pregnant women and rats with intrahepatic cholestasis.

    PubMed

    Martinefski, Manuela R; Contin, Mario D; Rodriguez, Myrian R; Geréz, Estefanía M; Galleano, Mónica L; Lucangioli, Silvia E; Bianciotti, Liliana G; Tripodi, Valeria P

    2014-08-01

    Intrahepatic cholestasis of pregnancy is a high-risk liver disease given the eventual deleterious consequences that may occur in the foetus. It is accepted that the abnormal accumulation of hydrophobic bile acids in maternal serum are responsible for the disease development. Hydrophobic bile acids induce oxidative stress and apoptosis leading to the damage of the hepatic parenchyma and eventually extrahepatic tissues. As coenzyme Q (CoQ) is considered an early marker of oxidative stress in this study, we sought to assess CoQ levels, bile acid profile and oxidative stress status in intrahepatic cholestasis. CoQ, vitamin E and malondialdehyde were measured in plasma and/or tissues by HPLC-UV method whereas serum bile acids by capillary electrophoresis in rats with ethinyl estradiol-induced cholestasis and women with pregnancy cholestasis. CoQ and vitamin E plasma levels were diminished in both rats and women with intrahepatic cholestasis. Furthermore, reduced CoQ was also found in muscle and brain of cholestatic rats but no changes were observed in heart or liver. In addition, a positive correlation between CoQ and ursodeoxycholic/lithocholic acid ratio was found in intrahepatic cholestasis suggesting that increased plasma lithocholic acid may be intimately related to CoQ depletion in blood and tissues. Significant CoQ and vitamin E depletion occur in both animals and humans with intrahepatic cholestasis likely as the result of increased hydrophobic bile acids known to produce significant oxidative stress. Present findings further suggest that antioxidant supplementation complementary to traditional treatment may improve cholestasis outcome. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events

    PubMed Central

    Huang, Li; Frampton, Gabriel; Rao, Arundhati; Zhang, Kun-song; Chen, Wei; Lai, Jia-ming; Yin, Xiao-yu; Walker, Kimberly; Culbreath, Brianne; Leyva-Illades, Dinorah; Quinn, Matthew; McMillin, Matthew; Bradley, Michelle; Liang, Li-Jian; DeMorrow, Sharon

    2014-01-01

    Objectives The secretion of dopamine and serotonin is increased in cholangiocarcinoma, which has growth-promoting effects. Monoamine oxidase A (MAOA), the degradation enzyme of serotonin and dopamine, is suppressed in cholangiocarcinoma via an unknown mechanism. The aims of this study were to (i) correlate MAOA immunoreactivity with pathophysiological parameters of cholangiocarcinoma, (ii) determine the mechanism by which MAOA expression is suppressed and (iii) evaluate the consequences of restored MAOA expression in cholangiocarcinoma. Design MAOA expression was assessed in cholangiocarcinoma and non-malignant controls. The control of MAOA expression by promoter hypermethylation was evaluated and the contribution of IL-6 signaling to the suppression of MAOA expression was determined. The effects of MAOA overexpression on cholangiocarcinoma growth and invasion were also assessed. Results MAOA expression is correlated with differentiation, invasion and survival in cholangiocarcinoma. The MAOA promoter was hypermethylated immediately upstream of the start codon in cholangiocarcinoma samples and cell lines but not in non-malignant counterparts. IL-6 signaling also decreased MAOA expression via a mechanism independent of hypermethylation, involving the regulation of the balance between SP-1 transcriptional activity and its inhibitor, R1 repressor. Inhibition of both IL-6 signaling and DNA methylation restored MAOA levels to those observed in cholangiocytes. Forced MAOA overexpression inhibited cholangiocarcinoma growth and invasion. Conclusions MAOA expression is suppressed by the coordinated control of promoter hypermethylation and IL-6 signaling. MAOA may be a useful prognostic marker in the management of cholangiocarcinoma, and therapies designed to increase MAOA expression might prove beneficial in the treatment of cholangiocarcinoma. PMID:22906985

  9. Untangling the Complexity of Liver Fluke Infection and Cholangiocarcinoma in NE Thailand Through Transdisciplinary Learning.

    PubMed

    Ziegler, A D; Echaubard, P; Lee, Y T; Chuah, C J; Wilcox, B A; Grundy-Warr, C; Sithithaworn, P; Petney, T N; Laithevewat, L; Ong, X; Andrews, R H; Ismail, T; Sripa, B; Khuntikeo, N; Poonpon, K; Tungtang, P; Tuamsuk, K

    2016-06-01

    This study demonstrates how a transdisciplinary learning approach provided new insights for explaining persistent Opisthorchis viverrini infection in northern Thailand, as well as elucidating problems of focusing solely on the parasite as a means of addressing high prevalence of cholangiocarcinoma. Researchers from diverse backgrounds collaborated to design an investigative homestay program for 72 Singaporean and Thai university students in five northeast Thai villages. The students explored how liver fluke infection and potential cholangiocarcinoma development are influenced by local landscape dynamics, aquatic ecology, livelihoods, food culture and health education. Qualitative fieldwork was guided daily by the researchers in a collaborative, co-learning process that led to viewing this health issue as a complex system, influenced by interlinked multidimensional factors. Our transdisciplinary experience has led us to believe that an incomplete understanding of these linkages may reduce the efficacy of interventions. Further, viewing liver fluke infection and cholangiocarcinoma as the same issue is inadvisable. Although O. viverrini infection is an established risk factor for the development of cholangiocarcinoma, multiple factors are known to influence the likelihood of acquiring either. Understanding the importance of the current livelihood transition, landscape modification and the resulting mismatch between local cultures and new socio-ecological settings on cholangiocarcinoma initiation and liver fluke transmission is of critical importance as it may help readjust our view of the respective role of O. viverrini and other socioeconomic risk factors in cholangiocarcinoma etiology and refine intervention strategies. As demonstrated in this study, transdisciplinary approaches have the potential to yield more nuanced perspectives to complex diseases than research that focuses on specific aspects of their epidemiology. They may therefore be valuable when designing

  10. Prognostic significance of peroxiredoxin 1 and ezrin-radixin-moesin-binding phosphoprotein 50 in cholangiocarcinoma.

    PubMed

    Yonglitthipagon, Ponlapat; Pairojkul, Chawalit; Chamgramol, Yaovalux; Loukas, Alex; Mulvenna, Jason; Bethony, Jeffrey; Bhudhisawasdi, Vajarabhongsa; Sripa, Banchob

    2012-10-01

    We performed a comparative proteomic analysis of protein expression profiles in 4 cholangiocarcinoma cell lines: K100, M156, M213, and M139. The H69 biliary cell line was used as a control. Peroxiredoxin 1 and ezrin-radixin-moesin-binding phosphoprotein 50 were selected for further validation by immunohistochemistry using a cholangiocarcinoma tissue microarray (n = 301) to assess their prognostic value in this cancer. Both peroxiredoxin 1 and ezrin-radixin-moesin-binding phosphoprotein 50 were overexpressed in cholangiocarcinoma tissues compared with normal liver tissues. Of the 301 cholangiocarcinoma cases, overexpression of peroxiredoxin 1 in 103 (34.3%) was associated with an age-related effect in young patients (P = .011) and the absence of cholangiocarcinoma in lymphatic vessels and perineural tissues (P = .004 and P = .037, respectively). Expression of radixin-moesin-binding phosphoprotein 50 correlated with histopathologic type, with 180 (59.8%) of moderately or poorly differentiated tumors (P = .039) being higher, and was associated with the presence of cholangiocarcinoma in lymphatic and vascular vessels (P < .001 and P < .001, respectively). The high expression of radixin-moesin-binding phosphoprotein 50 and the low expression of peroxiredoxin 1 correlated with reduced survival by univariate analysis (P = .017 and P = .048, respectively). Moreover, the impact of peroxiredoxin 1 and radixin-moesin-binding phosphoprotein 50 expression on patient survival was an independent predictor in multivariate analyses (P = .004 and P = .025, respectively). Therefore, altered expression of peroxiredoxin 1 and radixin-moesin-binding phosphoprotein 50 may be used as prognostic markers in cholangiocarcinoma.

  11. Fluorogenic 2D Peptidosheet Unravels CD47 as a Potential Biomarker for Profiling Hepatocellular Carcinoma and Cholangiocarcinoma Tissues.

    PubMed

    Ma, Yun-Han; Dou, Wei-Tao; Pan, Yu-Fei; Dong, Li-Wei; Tan, Ye-Xiong; He, Xiao-Peng; Tian, He; Wang, Hong-Yang

    2017-02-01

    A 2D peptidosheet unravels CD47 as a potential biomarker to image hepatocarcinoma and cholangiocarcinoma cells and tissues. Supramolecular assembly between water-soluble 2D MoS2 and a peptide probe produces the 2D peptidosheet suited for the profiling of hepatocarcinoma and cholangiocarcinoma tissues over healthy tissues on clinical specimens.

  12. Dual Inhibition of PI3K-AKT-mTOR- and RAF-MEK-ERK-signaling is synergistic in cholangiocarcinoma and reverses acquired resistance to MEK-inhibitors.

    PubMed

    Ewald, Florian; Nörz, Dominik; Grottke, Astrid; Hofmann, Bianca T; Nashan, Björn; Jücker, Manfred

    2014-12-01

    Until today, there is no systemic treatment available for advanced cholangiocarcinoma (CCA). Recent studies have shown a frequent upregulation of the PI3K-AKT-mTOR and RAF-MEK-ERK pathways in this type of cancer. However, considering their high extend of redundancy and cross-talk, targeting only one pathway is likely to result in therapy failure and emergence of resistances. To provide a rationale for treatment of CCA with inhibitors of these respective pathways, we analyzed the effects of AKT inhibitor MK-2206, MEK inhibitor AZD6244 (ARRY-142886) and mTOR kinase inhibitor AZD8055 on three CCA cell lines in vitro, concerning proliferation, cell signaling and apoptosis. Furthermore, AZD6244 resistant cell lines have been generated to investigate, how their response may be affected by prolonged treatment with only a single inhibitor. Our data demonstrates that co-targeting of both, the PI3K/AKT/mTOR and RAF-MEK-ERK pathway, as well as vertical targeting of AKT and mTOR results in strong synergistic effects on proliferation and cell survival with combination indices below 0.3. Mechanistically, the combinatorial treatment with MK-2206 in addition to AZD8055 is necessary because AKT kinase activity was quickly restored after mTOR kinase inhibition. Interestingly, acquired MEK inhibitor resistance to AZD6244 was reversed by combined treatment with AZD6244 and either MK-2206 or AZD8055. Our data suggest that a combination of inhibitors targeting those respective pathways may be a viable approach for future application in patients with cholangiocarcinoma. AKT, mTOR and MEK are promising targets for a combinatorial treatment of cholangiocarcinoma cells even after acquisition of MEK inhibitor resistance.

  13. Biological effects of RNAi targeted inhibiting Tiam1 gene expression on cholangiocarcinoma cells.

    PubMed

    Cheng, Wei; Liu, Yaling; Zuo, Zhi; Yin, Xinmin; Jiang, Bo; Chen, Daojin; Peng, Chuang; Yang, Jianhui

    2015-01-01

    To investigate the characteristics of Tiam1 gene expression in human cholangiocarcinoma tissues and benign bile duct tissues, and to analyze the correlations between Tiam1 gene expression and the degree of tumor differentiation, invasive and metastatic abilities. To explore the effect of targeted inhibiting Tiam1 gene expression on proliferation and migration activity of human cholangiocarcinoma cells. Expression of Tiam1 in 83 cases of cholangiocarcinoma tissues and 25 cases of benign bile tissues was detected using immunohistochemistry. The clinical data of patients with cholangiocarcinoma were collected. The correlations between Tiam1 gene expression and the clinicopathologic features in patients with cholangiocarcinoma were analyzed. The human cholangiocarcinoma RBE cells were divided into 3 groups. Cells in experimental group and control group were respectively transfected with Tiam1 shRNA lentiviral vectors and negative shRNA lentiviral control vectors. Cells in blank group received no treatment. Real-time PCR endogenesis was used to verify Tiam1 gene expression. Cell cycle experiments and MTT assay were used to measure cell proliferation activity. Transwell test was used to detect cell migration activity. The negative rate Tiam1 protein expression in cholangiocarcinoma tissues was significantly higher than that in benign bile tissues (P<0.001). Tiam1 protein expression in cholangiocarcinoma tissues had correlations with cholangiocarcinoma differentiation degree, TNM stage and lymph node metastasis (P<0.05), and had no significant correlations with gender, age and distant metastasis (P>0.05). Real-time PCR detection indicated that Tiam1 expression of experimental group was significantly lower than that in control group and blank group (P<0.05), demonstrating that Tiam1 shRNA was effective on Tiam1 gene silencing in RBE cells. Cell cycle experiment showed that the percentage of S phase in cell cycle in experimental group was lower than that in control group

  14. Biological effects of RNAi targeted inhibiting Tiam1 gene expression on cholangiocarcinoma cells

    PubMed Central

    Cheng, Wei; Liu, Yaling; Zuo, Zhi; Yin, Xinmin; Jiang, Bo; Chen, Daojin; Peng, Chuang; Yang, Jianhui

    2015-01-01

    Objective: To investigate the characteristics of Tiam1 gene expression in human cholangiocarcinoma tissues and benign bile duct tissues, and to analyze the correlations between Tiam1 gene expression and the degree of tumor differentiation, invasive and metastatic abilities. To explore the effect of targeted inhibiting Tiam1 gene expression on proliferation and migration activity of human cholangiocarcinoma cells. Methods: Expression of Tiam1 in 83 cases of cholangiocarcinoma tissues and 25 cases of benign bile tissues was detected using immunohistochemistry. The clinical data of patients with cholangiocarcinoma were collected. The correlations between Tiam1 gene expression and the clinicopathologic features in patients with cholangiocarcinoma were analyzed. The human cholangiocarcinoma RBE cells were divided into 3 groups. Cells in experimental group and control group were respectively transfected with Tiam1 shRNA lentiviral vectors and negative shRNA lentiviral control vectors. Cells in blank group received no treatment. Real-time PCR endogenesis was used to verify Tiam1 gene expression. Cell cycle experiments and MTT assay were used to measure cell proliferation activity. Transwell test was used to detect cell migration activity. Results: The negative rate Tiam1 protein expression in cholangiocarcinoma tissues was significantly higher than that in benign bile tissues (P<0.001). Tiam1 protein expression in cholangiocarcinoma tissues had correlations with cholangiocarcinoma differentiation degree, TNM stage and lymph node metastasis (P<0.05), and had no significant correlations with gender, age and distant metastasis (P>0.05). Real-time PCR detection indicated that Tiam1 expression of experimental group was significantly lower than that in control group and blank group (P<0.05), demonstrating that Tiam1 shRNA was effective on Tiam1 gene silencing in RBE cells. Cell cycle experiment showed that the percentage of S phase in cell cycle in experimental group was lower

  15. Macrophage stimulating protein variation enhances the risk of sporadic extrahepatic cholangiocarcinoma.

    PubMed

    Krawczyk, Marcin; Höblinger, Aksana; Mihalache, Florentina; Grünhage, Frank; Acalovschi, Monica; Lammert, Frank; Zimmer, Vincent

    2013-07-01

    Primary sclerosing cholangitis confers risk of cholangiocarcinoma. Here, we assessed the primary sclerosing cholangitis-associated variant rs3197999 in the MST1 gene, coding for RON receptor tyrosine kinase ligand macrophage stimulating protein, in a large European cholangiocarcinoma cohort. 223 cholangiocarcinoma patients including three primary sclerosing cholangitis individuals and 355 cancer- and primary sclerosing cholangitis-free controls were genotyped for MST1 rs3197999. The cancer group departed from Hardy-Weinberg equilibrium (p = 0.022) and exhibited a trend for rs3197999 [A] overrepresentation (31% vs. 26%: p = 0.10). Homozygous rs3197999 [AA] carrier status significantly increased overall (OR = 1.97; p = 0.023) and primary sclerosing cholangitis-unrelated biliary tract cancer risk (OR = 1.84; p = 0.044), relative to homozygous common allele carriers. The association was most pronounced in patients with extrahepatic tumours. This finding was robust to multivariate analysis (p < 0.05), validating the [AA] genotype as an independent cholangiocarcinoma risk factor. These results suggest that the [AA] genotype of the common MST1 variant rs3197999 enhances genetic risk of sporadic extrahepatic cholangiocarcinoma irrespective of primary sclerosing cholangitis status, presumably by modulating inflammatory responses and/or altered MSP/RON signalling. Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  16. Mass spectrometry-based proteomic analysis of formalin-fixed paraffin-embedded extrahepatic cholangiocarcinoma.

    PubMed

    Maeda, Shimpei; Morikawa, Takanori; Takadate, Tatsuyuki; Suzuki, Takashi; Minowa, Takashi; Hanagata, Nobutaka; Onogawa, Tohru; Motoi, Fuyuhiko; Nishimura, Toshihide; Unno, Michiaki

    2015-09-01

    Extrahepatic cholangiocarcinoma is very difficult to diagnose at an early stage, and has a poor prognosis. Novel markers for diagnosis and optimal treatment selection are needed. However, there has been very limited data on the proteome profile of extrahepatic cholangiocarcinoma. This study was designed to unravel the proteome profile of this disease and to identify overexpressed proteins using mass spectrometry-based proteomic approaches. We analyzed a discovery set of formalin-fixed paraffin-embedded tissues of 14 extrahepatic cholangiocarcinomas using shotgun mass spectrometry, and compared proteome profiles with those of seven controls. Then, selected candidates were verified by quantitative analysis using scheduled selected reaction monitoring-based mass spectrometry. Furthermore, immunohistochemical staining used a validation set of 165 cases. In total, 1,992 proteins were identified and 136 proteins were overexpressed. Verification of 58 selected proteins by quantitative analysis revealed 11 overexpressed proteins. Immunohistochemical validation for 10 proteins showed positive rates of S100P (84%), CEAM5 (75%), MUC5A (62%), OLFM4 (60%), OAT (42%), CAD17 (41%), FABPL (38%), AOFA (30%), K1C20 (25%) and CPSM (22%) in extrahepatic cholangiocarcinomas, which were rarely positive in controls. We identified 10 proteins associated with extrahepatic cholangiocarcinoma using proteomic approaches. These proteins are potential targets for future diagnostic biomarkers and therapy. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  17. Multiple Intrahepatic Artery Aneurysms in a Patient with Behcet's Disease: Use of Transcatheter Embolization for Rupture

    SciTech Connect

    Ahmed, Irfan; Fotiadis, Nikolas I. Dilks, Phil; Kocher, Hemant M.; Fotheringham, Tim; Matson, Matthew

    2010-04-15

    Intrahepatic artery aneuryms are a rare and potentially life-threatening condition. We present the first case in the English literature of multiple intrahepatic artery aneuryms in a patient with Behcet's disease who presented acutely with rupture. The ruptured aneurysm was treated successfully with transcatheter arterial coil embolization-CT and clinical follow-up confirming a good result. We discuss the management dilemma with regard to prophylactic embolization of the numerous other small asymptomatic intrahepatic aneurysms in this same patient.

  18. The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration.

    PubMed

    Leelawat, Surang; Leelawat, Kawin; Narong, Siriluck; Matangkasombut, Oraphan

    2010-05-01

    Currently, only gemcitabine plus platinum demonstrates the considerable activity for cholangiocarcinoma. The anticancer effect of Delta (9)-tetrahydrocannabinol (THC), the principal active component of cannabinoids has been demonstrated in various kinds of cancers. We therefore evaluate the antitumor effects of THC on cholangiocarcinoma cells. Both cholangiocarcinoma cell lines and surgical specimens from cholangiocarcinoma patients expressed cannabinoid receptors. THC inhibited cell proliferation, migration and invasion, and induced cell apoptosis. THC also decreased actin polymerization and reduced tumor cell survival in anoikis assay. pMEK1/2 and pAkt demonstrated the lower extent than untreated cells. Consequently, THC is potentially used to retard cholangiocarcinoma cell growth and metastasis.

  19. Immunological Basis in the Pathogenesis of Intrahepatic Cholestasis of Pregnancy

    PubMed Central

    Larson, Spencer P; Kovilam, Oormila; Agrawal, Devendra K

    2016-01-01

    Summary Intrahepatic cholestasis of pregnancy poses a great risk to both maternal and fetal health. Despite extensive research, much of the pathogenesis of this disorder is unknown. The increase in bile acids observed in patients with intrahepatic cholestasis of pregnancy has been noted to cause a change in the immune system from the normally mediated TH2 response to one that is more oriented towards TH1. In this literature review, we have critically reviewed the current literature regarding the changes in the immune system and the potential effects of immunological changes in the management of the patient. The current treatment, ursodeoxycholic acid, is also discussed along with potential combination therapies and future directions for research. PMID:26469633

  20. Immunological basis in the pathogenesis of intrahepatic cholestasis of pregnancy.

    PubMed

    Larson, Spencer P; Kovilam, Oormila; Agrawal, Devendra K

    2016-01-01

    Intrahepatic cholestasis of pregnancy poses a great risk to both maternal and fetal health. Despite extensive research, much of the pathogenesis of this disorder is unknown. The increase in bile acids observed in patients with intrahepatic cholestasis of pregnancy has been noted to cause a change in the immune system from the normally mediated TH2 response to one that is more oriented towards TH1. In this literature review, we have critically reviewed the current literature regarding the changes in the immune system and the potential effects of immunological changes in the management of the patient. The current treatment, ursodeoxycholic acid, is also discussed along with potential combination therapies and future directions for research.

  1. Intrahepatic Duct Stones Harboring Ascariasis Ova: A Case Report.

    PubMed

    Lee, Chen-Fang; Lee, Wei-Chen; Wu, Ren-Chin; Chen, Tse-Ching

    2016-03-01

    Ascariasis lumbricoides is one of the most common helminthic infestations in humans. Despite the fact that the prevalence of ascariasis in developed countries has been decreasing, biliary ascariasis can cause serious complications, such as acute cholangitis, pancreatitis, and liver abscess. Here we presented a rare ascariasis-related complication-hepatolithiasis.A 60-year-old female patient had symptoms of recurrent cholangitis. Abdominal computed tomography scan revealed left intrahepatic duct stones with left liver lobe atrophy. Endoscopic retrograde cholangiopancreatography was performed, but the stones could not be removed due to left main intrahepatic duct stenosis. The patient was treated with left hemi-hepatectomy. Unexpectedly, Ascaris ova were found on the histopathological examination. She received antihelminthic therapy orally and was on regular follow-up without any complications.Our study indicates that clinicians should be aware of biliary ascariasis in patients with hepatolithiasis, though not living in endemic areas.

  2. Septic candidasis with intrahepatic cholestasis and immunoglobuline deficiency after renal transplantation.

    PubMed

    Zazgornik, J; Schmidt, P; Kopsa, H; Fill, W; Deutsch, E

    1975-10-01

    Two renal allograft recipients with acquired immunoglobulin deficiency had a disseminated infection with candida albicans. Septic fever, intrahepatic cholestasis and pulmonary mycotic disease were the prominent clinical symptoms. Recurrence of septic fever during the clinical course was associated with increase of intrahepatic cholestasis. On the other hand there was an amelioration of cholestasis when effective antimycotic therapy was instituted. In our patients there was no evidence that intrahepatic cholestasis was drug-related. It was assumed that toxic metabolits of candida albicans were responsible for intrahepatic cholestasis.

  3. Cardiac Perforation and Tamponade During Transjugular Intrahepatic Portosystemic Shunt Placement

    SciTech Connect

    McCowan, Timothy C.; Hummel, Michael M.; Schmucker, Tracey; Goertzen, Timothy C.; Culp, William C.; Habbe, Thomas G.

    2000-07-15

    A patient developed acute severe hemodynamic compromise during a transjugular intrahepatic portosystemic shunt (TIPS) procedure for intractable ascites. Rapid clinical and radiographic evaluation of the patient disclosed pericardial blood and cardiac tamponade as the cause, probably due to right heart perforation from guidewire and catheter manipulation. The tamponade was successfully treated percutaneously, and the patient survived. Cardiac tamponade should be considered in the differential diagnosis of patients who develop hypotension during TIPS placement.

  4. Intrahepatic Cholestasis as a Side-Effect of Drug Therapy

    PubMed Central

    Feuer, G.; Dhami, M.S.I.

    1982-01-01

    Drug-induced hepatotoxicity causes 2-5% of hospitalization for jaundice; in the elderly this figure is close to 20%. The liver is particularly susceptible to drug damage because its blood supply delivers drugs in higher concentrations, and because of its role in metabolizing drugs. This article reviews the morphological, biochemical and clinical features of intrahepatic cholestasis, outlining the hypotheses for this frequent side-effect of drug therapy. PMID:21286123

  5. Intrahepatic cholestasis of pregnancy: a critical clinical review.

    PubMed

    Gabzdyl, Elizabeth M; Schlaeger, Judith M

    2015-01-01

    Intrahepatic cholestasis of pregnancy is the most common liver disease of pregnancy. It is characterized by pruitus, elevated levels of maternal serum bile salts, and normal or mildly elevated liver enzymes occurring after 30 weeks of pregnancy. The primary risks associated with this condition include preterm delivery, meconium-stained amniotic fluid, and stillbirth. Management of intrahepatic cholestasis of pregnancy utilizes a 2-prong approach of oral medications and comfort measures along with active management close to term. The goal of active management has been to deliver women between 37 and 39 weeks of gestation in order to prevent the risk of stillbirth. Currently, expert opinions vary as to recommendations for fetal surveillance and induction of labor. Controversy exists as to whether there is an increased incidence of stillbirth between 37 and 39 weeks of gestation. This critical clinical review is a comprehensive overview of intrahepatic cholestasis of pregnancy, including background, controversies, and care of the pregnant woman with this condition and how to provide appropriate follow-up care later after delivery.

  6. A case of distal extrahepatic cholangiocarcinoma with two positive resection margins

    PubMed Central

    Warner, Wayne A.; Ramcharan, Wesley; Harnanan, Dave; Umakanthan, Srikanth; Maharaj, Ravi

    2016-01-01

    Cholangiocarcinoma is an uncommon primary malignancy of the biliary tract that is challenging to diagnose and treat effectively due to its relatively silent and late clinical presentation. The present study reports a case of a 60-year-old male with distal extrahepatic cholangiocarcinoma with a 3-week history of painless obstructive jaundice symptoms and subjective weight loss. Imaging revealed an obstructing lesion in the common bile duct, just distal to the entrance of the cystic duct. Pathology revealed moderately differentiated cholangiocarcinoma with two positive proximal resection margins. The two positive resection margins presented a challenge during surgery and points to an urgent need for further studies to better illuminate diagnostic and therapeutic options for patients with similar clinicopathological presentation. PMID:27895774

  7. Cholangiocarcinoma cell line TK may be useful for the pharmacokinetic study of the chemotherapeutic agent gemcitabine.

    PubMed

    Kamada, Minori; Akiyoshi, Kohei; Akiyama, Nobutake; Funamizu, Naotake; Watanabe, Michiko; Fujioka, Kouki; Ikeda, Kei-Ichi; Manome, Yoshinobu

    2014-08-01

    Cholangiocarcinoma is a disease with a poor prognosis. A human cholangiocarcinoma cell line, TK, was previously established to enable further understanding of the disease. We conducted this investigation to determine whether or not the TK line is useful for pharmacokinetic study of the chemotherapeutic agent gemcitabine (GEM). Along with the BXPC3 human pancreatic adenocarcinoma cell line, the sensitivity to and effects on the TK cell line of GEM were compared. The influence of deoxycytidine kinase (dCK) transduction was also comparatively investigated. The effects of GEM in terms of drug sensitivity of the TK cell line, cell cycle and levels of transcripts of key enzymes were comparable to the BXPC3 cell line. Responses to the drug were similar in both cell lines. In contrast to pancreatic carcinoma, cell lines for research on cholangiocarcinoma have been limited. This study suggests the application of the TK cell line to the pharmacokinetic study of the chemosensitization of therapeutic drugs, such as GEM.

  8. Potential targeted therapy for liver fluke associated cholangiocarcinoma.

    PubMed

    Vaeteewoottacharn, Kulthida; Seubwai, Wunchana; Bhudhisawasdi, Vajarabhongsa; Okada, Seiji; Wongkham, Sopit

    2014-06-01

    Biliary tree cancer or cholangiocarcinoma (CCA) is an unusual subtype of liver cancer with exceptionally poor prognosis. Lack of specific symptoms and availability of early diagnostic markers account for late diagnosis of CCA. Surgical treatment is a gold standard choice but few patients are candidates and local recurrence after surgery is high. Benefit of systemic chemotherapy is limited; hence, better treatment options are required. The differences in etiology, anatomical positions and pathology make it difficult to generalize all CCA subtypes for a single treatment regimen. Herein, we review the uniqueness of molecular profiling identified by multiple approaches, for example, serial analysis of gene expression, exome sequencing, transcriptomics/proteomics profiles, protein kinase profile, etc., that provide the opportunity for treatment of liver fluke-associated CCA. Anti-inflammatory, immunomodulator/immunosuppressor, epidermal growth factor receptor or platelet-derived growth factor receptor inhibitors, multi-targeted tyrosine kinase inhibitor, IL6 antagonist, nuclear factor-κB inhibitor, histone modulator, proteasome inhibitor as well as specific inhibitors suggested from various study approaches, such as MetAP2 inhibitor, 1,25(OH)2 D3 and cyclosporine A are suggested in this review for the treatments of this specific CCA subtype. This might provide an alternative treatment option for CCA patients; however, clinical trials in this specific CCA group are required. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  9. Tumor-related gene changes in immunosuppressive Syrian hamster cholangiocarcinoma.

    PubMed

    Juasook, Amornrat; Aukkanimart, Ratchadawan; Boonmars, Thidarut; Sudsarn, Pakkayanee; Wonkchalee, Nadchanan; Laummaunwai, Porntip; Sriraj, Pranee

    2013-10-01

    The results of a previous study demonstrated that prednisolone enhanced cholangiocarcinogenesis. Therefore, to clarify molecular changes during immunosuppressive cholangiocarcinogenesis, Syrian hamsters were divided into 8 groups: uninfected controls; immunosuppressed Syrian hamsters using prednisolone (P); normal Syrian hamsters administered N-nitrosodimethylamine (ND); immunosuppressed Syrian hamsters administered N-nitrosodimethylamine (NDis); normal Syrian hamsters infected with Opisthorchis viverrini (OV); immunosuppressed Syrian hamsters infected with O. viverrini (OVis); normal Syrian hamsters infected with O. viverrini and administered N-nitrosodimethylamine (CCA); and immunosuppressed Syrian hamsters infected with O. viverrini and administered N-nitrosodimethylamine (CCAis). Syrian hamster livers were used for analysis of tumor-related gene expression and immunohistochemistry through cytokeratin 19 (CK19) and proliferating cell nuclear antigen (PCNA) staining. The tumor-related gene expression results show that CCAis groups at all time points exhibited upregulation of COX-2, IL-6, SOD1, CAT and iNOS and downregulation of p53, which correlated with the predominant expression of CK19 and PCNA in liver tissue. These results suggest that prednisolone enhances cholangiocarcinoma development, which was confirmed by molecular changes.

  10. Opisthorchiasis and Opisthorchis-associated cholangiocarcinoma in Thailand and Laos

    PubMed Central

    Sripa, Banchob; Bethony, Jeffrey M.; Sithithaworn, Paiboon; Kaewkes, Sasithorn; Mairiang, Eimorn; Loukas, Alex; Mulvenna, Jason; Laha, Thewarach; Hotez, Peter J.; Brindley, Paul J.

    2010-01-01

    Liver fluke infection caused by Opisthorchis viverrini is a major public health problem in Thailand and the Lao People’s Democratic Republic (Lao PDR; Laos). Currently, more than 600 million people are at risk of infection with these fish-borne trematodes and/or their close relatives. Opisthorchiasis has been studied extensively in Thailand, where about 8 million people are infected with the liver fluke. Here we review the pathogenesis, control and re-emergence of O. viverrini infection, in particular in Thailand and, to a lesser extent in Lao PDR given the contiguous geographical range of O. viverrini through these two regions. We also review the association of O. viverrini infection and cholangiocarcinoma, bile duct cancer, and highlight new findings on pathogenesis of liver fluke induced cholangiocarcinogenesis. Last, we comment on national control strategies in Thailand for the control of O. viverrini infection aimed at reduction in the prevalence of O. viverrini-associated liver cancer in the longer term. PMID:20655862

  11. The search for novel diagnostic and prognostic biomarkers in cholangiocarcinoma.

    PubMed

    Macias, Rocio I R; Banales, Jesus M; Sangro, Bruno; Muntané, Jordi; Avila, Matias A; Lozano, Elisa; Perugorria, Maria J; Padillo, Francisco J; Bujanda, Luis; Marin, Jose J G

    2017-08-04

    The poor prognosis of cholangiocarcinoma (CCA) is in part due to late diagnosis, which is currently achieved by a combination of clinical, radiological and histological approaches. Available biomarkers determined in serum and biopsy samples to assist in CCA diagnosis are not sufficiently sensitive and specific. Therefore, the identification of new biomarkers, preferably those obtained by minimally invasive methods, such as liquid biopsy, is important. The development of innovative technologies has permitted to identify a significant number of genetic, epigenetic, proteomic and metabolomic CCA features with potential clinical usefulness in early diagnosis, prognosis or prediction of treatment response. Potential new candidates must be rigorously evaluated prior to entering routine clinical application. Unfortunately, to date, no such biomarker has achieved validation for these purposes. This review is an up-to-date of currently used biomarkers and the candidates with promising characteristics that could be included in the clinical practice in the next future. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Tumor reactive stroma in cholangiocarcinoma: The fuel behind cancer aggressiveness

    PubMed Central

    Brivio, Simone; Cadamuro, Massimiliano; Strazzabosco, Mario; Fabris, Luca

    2017-01-01

    Cholangiocarcinoma (CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although mechanisms underpinning CCA progression are still a conundrum, it is now increasingly recognized that the desmoplastic microenvironment developing in conjunction with biliary carcinogenesis, recently renamed tumor reactive stroma (TRS), behaves as a paramount tumor-promoting driver. Indeed, once being recruited, activated and dangerously co-opted by neoplastic cells, the cellular components of the TRS (myofibroblasts, macrophages, endothelial cells and mesenchymal stem cells) continuously rekindle malignancy by secreting a huge variety of soluble factors (cyto/chemokines, growth factors, morphogens and proteinases). Furthermore, these factors are long-term stored within an abnormally remodeled extracellular matrix (ECM), which in turn can deleteriously mold cancer cell behavior. In this review, we will highlight evidence for the active role played by reactive stromal cells (as well as by the TRS-associated ECM) in CCA progression, including an overview of the most relevant TRS-derived signals possibly fueling CCA cell aggressiveness. Hopefully, a deeper knowledge of the paracrine communications reciprocally exchanged between cancer and stromal cells will steer the development of innovative, combinatorial therapies, which can finally hinder the progression of CCA, as well as of other cancer types with abundant TRS, such as pancreatic and breast carcinomas. PMID:28396716

  13. The anticancer effects of Resina Draconis extract on cholangiocarcinoma.

    PubMed

    Wen, Feng; Zhao, Xiangxuan; Zhao, Yun; Lu, Zaiming; Guo, Qiyong

    2016-11-01

    Cholangiocarcinoma (CCA) is a relatively rare, heterogeneous malignant tumor with poor clinical outcomes. Because of high insensitivity to chemotherapy and radiotherapy, there are no effective treatment options. Efforts to identify and develop new agents for prevention and treatment of this deadly disease are urgent. Here, we assessed the apoptotic cytotoxicity of Resina Draconis extract (RDE) using in vitro and in vivo assays and identified the mechanisms underlying antitumor effects of RDE. RDE was obtained via vacuum distillation of Resina Draconis with 75 % ethanol. The ethanol extract could inhibit CCA cell proliferation and trigger apoptotic cell death in both QBC939 and HCCC9810 cell lines in a time- and concentration-dependent manner. RDE treatment resulted in intracellular caspase-8 and poly (ADP-ribose) polymerase protease activation. RDE significantly downregulated antiapoptotic protein survivin expression and upregulated proapoptotic protein Bak expression. RDE also inhibited CCA tumor growth in vivo. We observed that human CCA tissues had much higher survivin expression than did paired adjacent normal tissue. Taken together, the current data suggested that RDE has anticancer effects on CCA, and that RDE could function as a novel anticancer agent to benefit patients with CCA.

  14. Notch3 drives development and progression of cholangiocarcinoma.

    PubMed

    Guest, Rachel V; Boulter, Luke; Dwyer, Benjamin J; Kendall, Timothy J; Man, Tak-Yung; Minnis-Lyons, Sarah E; Lu, Wei-Yu; Robson, Andrew J; Gonzalez, Sofia Ferreira; Raven, Alexander; Wojtacha, Davina; Morton, Jennifer P; Komuta, Mina; Roskams, Tania; Wigmore, Stephen J; Sansom, Owen J; Forbes, Stuart J

    2016-10-25

    The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt. We use genetic KO studies to show that tumor growth significantly attenuates after Notch3 deletion and demonstrate signaling occurs via a noncanonical pathway independent of the mediator of classical Notch, Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). These data present an opportunity in this aggressive cancer to selectively target Notch, bypassing toxicities known to be RBPJ dependent.

  15. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation.

    PubMed

    Boberg, K M; Bergquist, A; Mitchell, S; Pares, A; Rosina, F; Broomé, U; Chapman, R; Fausa, O; Egeland, T; Rocca, G; Schrumpf, E

    2002-10-01

    Primary sclerosing cholangitis (PSC) confers a high risk of cholangiocarcinoma (CC) development. Since patients at risk of CC may be selected for early liver transplantation, it is a challenge to identify any predisposing factors. We compared the presentation and natural history of a large number of PSC patients with and without later CC development to identify features associated with risk of CC. Clinical and laboratory data from presentation and follow-up were collected from 394 PSC patients from five European countries. The cohort included 48 (12.2%) patients with CC. CC was diagnosed within the first year after diagnosis of PSC in 24 (50%) cases and in 13 (27%) patients at intended liver transplantation. Jaundice, pruritus, abdominal pain and fatigue were significantly more frequent at diagnosis of PSC in the group that developed CC, but not after exclusion of cases diagnosed within the first year. Inflammatory bowel disease was diagnosed at least 1 year before PSC more often among patients with CC development than among those without (90% and 65%, respectively: P = 0.001). The duration of inflammatory bowel disease before diagnosis of PSC was significantly longer in patients who developed CC than in the remaining group (17.4 years and 9.0 years, respectively: P=0.009 in multivariate analysis). A high proportion of CC cases is diagnosed within the first year after diagnosis of PSC. A long history of inflammatory bowel disease is a risk factor for CC development.

  16. Notch3 drives development and progression of cholangiocarcinoma

    PubMed Central

    Guest, Rachel V.; Dwyer, Benjamin J.; Kendall, Timothy J.; Man, Tak-Yung; Minnis-Lyons, Sarah E.; Lu, Wei-Yu; Robson, Andrew J.; Gonzalez, Sofia Ferreira; Raven, Alexander; Wojtacha, Davina; Morton, Jennifer P.; Komuta, Mina; Roskams, Tania; Wigmore, Stephen J.; Sansom, Owen J.; Forbes, Stuart J.

    2016-01-01

    The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt. We use genetic KO studies to show that tumor growth significantly attenuates after Notch3 deletion and demonstrate signaling occurs via a noncanonical pathway independent of the mediator of classical Notch, Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). These data present an opportunity in this aggressive cancer to selectively target Notch, bypassing toxicities known to be RBPJ dependent. PMID:27791012

  17. Induction of biliary cholangiocarcinoma cell apoptosis by 103Pd cholangial radioactive stent gamma-rays.

    PubMed

    He, Gui-jin; Sun, Dan-dan; Ji, Da-wei; Sui, Dong-ming; Yu, Fa-qiang; Gao, Qin-yi; Dai, Xian-wei; Gao, Hong; Jiang, Tao; Dai, Chao-liu

    2008-06-05

    In recent years, interventional tumor therapy, involving implantation of intra-cholangial metal stents through percutaneous trans-hepatic punctures, has provided a new method for treating cholangiocarcinoma. (103)Pd cholangial radioactive stents can concentrate high radioactive dosages into the malignant tumors and kill tumor cells effectively, in order to prevent re-stenosis of the lumen caused by a relapsed tumor. The aim of the present study was to investigate the efficacy of gamma-rays released by the (103)Pd biliary duct radioactive stent in treating cholangiocarcinoma via induction of biliary cholangiocarcinoma cell apoptosis. A group of biliary duct cancer cells was collectively treated with a dose of gamma-rays. Cells were then examined by the 3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl terazolium-bromide (MTT) technique for determining the inhibition rate of the biliary duct cancer cells, as well as with other methods including electron microscopy, DNA agarose gel electrophoresis, and flow cytometry were applied for the evaluation of their morphological and biochemical characteristics. The growth curve and the growth inhibition rate of the cells were determined, and the changes in the ultrastructure of the cholangiocarcinoma cells and the DNA electrophoresis bands were examined under a UV-lamp. The gamma-ray released by (103)Pd inhibited cholangiocarcinoma cell growth, as demonstrated when the growth rate of the cells was stunned by a gamma-ray with a dosage larger than 197.321 MBq. Typical features of cholangiocarcinoma cell apoptosis were observed in the 197.321 MBq dosage group, while cell necrosis was observed when irradiated by a dosage above 245.865 MBq. DNA agarose gel electrophoresis results were different between the 197.321 MBq irradiation dosage group, the 245.865 MBq irradiation dosage group, and the control group. (103)Pd radioactive stents which provide a radioactive dosage of 197.321 MBq are effective in the treatment of cholangiocarcinoma

  18. Elevated red blood cell distribution width is associated with intrahepatic cholestasis of pregnancy.

    PubMed

    Vural Yilmaz, Zehra; Gencosmanoglu Turkmen, Gulenay; Daglar, Korkut; Yılmaz, Elif; Kara, Ozgur; Uygur, Dilek

    2017-01-01

    Intrahepatic cholestasis of pregnancy is the most common pregnancy specific liver disease and related with adverse maternal and perinatal outcome. Red blood cell distribution width, an anisocytosis marker in a complete blood count, has been used as an inflammation marker in various diseases. However the association of red blood cell distribution width with intrahepatic cholestasis of pregnancy is unknown. We aimed to evaluate the relationship between red blood cell distribution width and intrahepatic cholestasis of pregnancy. Ninety pregnant women with intrahepatic cholestasis of pregnancy and ninety healthy pregnant women were included in the study. Their clinical and laboratory characteristics including red blood cell distribution width, liver function tests, fasting and postprandial bile acid concentrations were analyzed. Serum red blood cell distribution width cell levels were significantly higher in pregnants with intrahepatic cholestasis of pregnancy than healthy pregnants. We also demonstrated that red blood cell distribution Width levels were higher in severe disease than mild disease and was significantly correlated with fasting and postprandial bile acid concentration in intrahepatic cholestasis of pregnancy group. Our study showed that red blood cell distribution width, an easy and inexpensive marker; were associated with intrahepatic cholestasis of pregnancy and can be used as a diagnostic and prognostic marker in intrahepatic cholestasis of pregnancy.

  19. [Intrahepatic pregnancy cholestasis. A contribution to the casuistics of the disease (author's transl)].

    PubMed

    Beckmann, M; Hanker, J P

    1979-02-01

    Jaundice, or icterus, during pregnancy is frequently a symptom of an intrahepatic cholestasis. It is evident from the literature that intrahepatic pregancy cholestasis represents a risk pregnancy with moderate risk to the mother and high risk to the foetus. Although diagnostic clarification is necessary, the authors sound a warning against liver biopsy during pregnancy.

  20. Intrahepatic Tissue Implantation Represents a Favorable Approach for Establishing Orthotopic Transplantation Hepatocellular Carcinoma Mouse Models

    PubMed Central

    Zuo, Bingfeng; Gao, Xianjun; Zhang, Ti; Du, Zhi; Wu, Chenxuan; Yin, HaiFang

    2016-01-01

    Mouse models are commonly used for studying hepatocellular carcinoma (HCC) biology and exploring new therapeutic interventions. Currently three main modalities of HCC mouse models have been extensively employed in pre-clinical studies including chemically induced, transgenic and transplantation models. Among them, transplantation models are preferred for evaluating in vivo drug efficacy in pre-clinical settings given the short latency, uniformity in size and close resemblance to tumors in patients. However methods used for establishing orthotopic HCC transplantation mouse models are diverse and fragmentized without a comprehensive comparison. Here, we systemically evaluate four different approaches commonly used to establish HCC mice in preclinical studies, including intravenous, intrasplenic, intrahepatic inoculation of tumor cells and intrahepatic tissue implantation. Four parameters—the latency period, take rates, pathological features and metastatic rates—were evaluated side-by-side. 100% take rates were achieved in liver with intrahepatic, intrasplenic inoculation of tumor cells and intrahepatic tissue implantation. In contrast, no tumor in liver was observed with intravenous injection of tumor cells. Intrahepatic tissue implantation resulted in the shortest latency with 0.5cm (longitudinal diameter) tumors found in liver two weeks after implantation, compared to 0.1cm for intrahepatic inoculation of tumor cells. Approximately 0.1cm tumors were only visible at 4 weeks after intrasplenic inoculation. Uniform, focal and solitary tumors were formed with intrahepatic tissue implantation whereas multinodular, dispersed and non-uniform tumors produced with intrahepatic and intrasplenic inoculation of tumor cells. Notably, metastasis became visible in liver, peritoneum and mesenterium at 3 weeks post-implantation, and lung metastasis was visible after 7 weeks. T cell infiltration was evident in tumors, resembling the situation in HCC patients. Our study

  1. Low dose mTHPC photodynamic therapy for cholangiocarcinoma

    NASA Astrophysics Data System (ADS)

    Stepp, Herbert; Kniebühler, Gesa; Pongratz, Thomas; Betz, Christian S.; Göke, Burkhard; Sroka, Ronald; Schirra, Jörg

    2013-06-01

    Objective: Demonstration of whether a low dose of mTHPC (temoporfin , Foscan) is sufficient to induce an efficient clinical response in palliative PDT of non-resectable cholangiocarcinoma (CC), while showing a low side effect profile as compared to the standard Photofrin PDT. Materials and Methods: 13 patients (14 treatment sessions) with non-resectable CC were treated with stenting and PDT (3 mg Foscan per treatment, 0.032-0.063 mg/kg body weight, 652 nm, 50 J/cm). Fluorescence measurements were performed with a single bare fiber for 5/13 patients prior to PDT at the tumor site to determine the fluorescence contrast. For another 7/13 patients, long-term fluorescence-kinetics were measured on the oral mucosa to determine the time of maximal relative fluorescence intensity. Results: Foscan fluorescence could clearly be identified spectroscopically as early as 20 hours after administration. It was not significantly different between lesion and normal tissue within the bile duct. Fluorescence kinetics assessed at the oral mucosa were highest at 72-96 hours after administration. The DLI was therefore extended from 20 hours to approx. 70 hours for the last 5 patients treated. The treatment effect was promising with a median survival of 11 months for the higher grade tumors (Bismuth types III and IV). Local side effects occurred in one patient (pancreatitis), systemic side effects were much reduced compared to prior experience with Photofrin. Conclusion: Combined stenting and photodynamic therapy (PDT) performed with a low dose of Foscan results in comparable survival times relative to standard Photofrin PDT, while lowering the risk of side effects significantly.

  2. Metformin Inhibits Migration and Invasion of Cholangiocarcinoma Cells

    PubMed

    Trinh, Son Xuan; Nguyen, Huyen Thi Bich; Saimuang, Kween; Prachayasittikul, Virapong; Chan On, Waraporn

    2017-02-01

    Background: Metformin is an oral anti-diabetic agent that has been widely prescribed for treatment of type II diabetes. Anti-cancer properties of metformin have been revealed for numerous human malignancies including cholangiocarcinoma (CCA) with anti-proliferative effects in vitro. However, effects on CCA cell migration and invasion have not been fully investigated. The present study aimed to explore the inhibitory effects of metformin on motility, migration and invasion of the CCA cell line HuCCT1, and examine molecular mechanisms underlying metformin effects. Methods: HuCCT1 cells were exposed to increasing doses of metformin. Viability and growth of HuCCT1 cells were assessed by MTS and colony formation assays, respectively. Motility, migration and invasion of metformin-treated HuCCT1 cells were determined in vitro using wound healing, transwell migration and matrigel invasion assays. Expression of signaling molecules and epithelial-mesenchymal transition (EMT) markers was assessed by Western blotting. Results: It was observed that metformin significantly decreased HuCCT1 cell viability and colony formation. The agent also markedly reduced wound closure, migration and invasion of HuCCT1 cells. Furthermore, metformin exposure resulted in decreased STAT3 activation and down-regulation of anti-apoptotic protein Bcl-2 and Mcl-1 expression. In addition, it upregulated the expression of E-cadherin, while downregulating that of N-cadherin, Snail, and MMP-2. Conclusion: These results demonstrated inhibitory effects of metformin on CCA cell migration and invasion, possibly involving the STAT3 pathway and reversal of EMT markers expression. They further suggest that metformin may be useful for CCA management.

  3. Molecular mechanisms of cholangiocarcinoma cell inhibition by medicinal plants

    PubMed Central

    Leelawat, Surang; Leelawat, Kawin

    2017-01-01

    Cholangiocarcinoma (CCA) is one of the most common causes of cancer-associated mortality in Thailand. Certain phytochemicals have been demonstrated to modulate apoptotic signaling pathways, which may be targeted for the prevention and treatment of cancer. Therefore, the aim of the present study was to investigate the effect of specific medicinal plants on the inhibition of CCA cell proliferation, and to identify the molecular mechanisms underlying this. A WST-1 cell proliferation assay was performed using an RMCCA1 cell line, and apoptotic signaling pathways were also investigated using a PathScan Stress and Apoptosis Signaling Antibody Array Kit. The cell proliferation assay indicated that extracts from the Phyllanthus emblica fruit pulp (PEf), Phyllanthus emblica seed (PEs), Terminalia chebula fruit pulp (TCf), Terminalia chebula seed (TCs), Areca catechu seed (ACs), Curcuma longa (CL) and Moringa oleifera seed (MOs) exerted anti-proliferative activity in RMCCA1 cells. In addition, the PathScan assay revealed that certain pro-apoptotic molecules, including caspase-3, poly (ADP-ribose) polymerase, checkpoint kinase 2 and tumor protein 53, exhibited increased activity in RMCCA1 cells treated with the aforementioned selected plant extracts, with the exception of PEf. The mitogen-activated protein kinase (MAPK) pathways (including ERK1/2 and p38 MAPK) expression level was significantly increased in RMCCA1 cells pre-treated with extracts of PEs, TCf, CL and MOs. The activation of protein kinase B (Akt) was significantly demonstrated in RMCCA1 cells pre-treated with extracts of TCf, ACs and MOs. In summary, the present study demonstrated that extracts of PEs, TCf, TCs, ACs, CL and MOs exhibited anti-proliferative effects in CCA cells by inducing pro-apoptotic signals and modulating signal transduction molecules. Further studies in vivo are required to demonstrate the potential applications of specific plant extracts for the treatment of human cancer. PMID:28356985

  4. Matrine induces RIP3-dependent necroptosis in cholangiocarcinoma cells

    PubMed Central

    Xu, Beibei; Xu, Minying; Tian, Yuan; Yu, Qiang; Zhao, Yujie; Chen, Xiong; Mi, Panying; Cao, Hanwei; Zhang, Bing; Song, Gang; Zhan, Yan-yan; Hu, Tianhui

    2017-01-01

    The development of acquired resistance to pro-apoptotic antitumor agents is a major impediment to the cure of cholangiocarcinoma (CCA). Antitumor drugs inducing non-apoptotic cell death are considered as a new approach to overcome such drug resistance. Here, we reported for the first time that matrine-induced necroptosis in CCA cell lines, differing from its classical role to induce apoptosis in many other kinds of cancer cells. CCA cells under matrine treatment exhibited typical necrosis-like but not apoptotic morphologic change. These matrine-induced morphologic change and cell death in CCA cells were greatly attenuated by necroptosis inhibitor necrostatin-1, but not apoptosis inhibitor z-VAD-fmk. Unlike many cancer cells with negative receptor-interacting protein 3 (RIP3) expression, moderate expression of RIP3 in CCA cells was observed and was required for matrine to induce necroptosis, which was switched to apoptosis after knocking down endogenous RIP3. Moreover, matrine could increase RIP3 expression level, which may facilitate the necroptosis process. Translocation of mixed lineage kinase-domain like (MLKL) from cytoplasm to plasma membrane as a downstream event of RIP3, as well as the increased production of reactive oxygen species (ROS) by RIP3/MLKL, was critical for matrine to induce necroptosis. In clinical study, we found RIP3 was lower but still moderately expressed in most CCA tissue samples compared with adjacent normal tissues. Taken together, we identified matrine as a necroptosis inducer in CCA by enhancing RIP3 expression and the following RIP3/MLKL/ROS signaling pathway, which provided new individualized strategies based on RIP3 expression to overcome chemoresistance in CCA therapy. PMID:28179994

  5. A Novel Predictive Equation for Potential Diagnosis of Cholangiocarcinoma

    PubMed Central

    Kraiklang, Ratthaphol; Pairojkul, Chawalit; Khuntikeo, Narong; Imtawil, Kanokwan; Wongkham, Sopit; Wongkham, Chaisiri

    2014-01-01

    Cholangiocarcinoma (CCA) is the second most common-primary liver cancer. The difficulties in diagnosis limit successful treatment of CCA. At present, histological investigation is the standard diagnosis for CCA. However, there are some poor-defined tumor tissues which cannot be definitively diagnosed by general histopathology. As molecular signatures can define molecular phenotypes related to diagnosis, prognosis, or treatment outcome, and CCA is the second most common cancer found after hepatocellularcarcinoma (HCC), the aim of this study was to develop a predictive model which differentiates CCA from HCC and normal liver tissues. An in-house PCR array containing 176 putative CCA marker genes was tested with the training set tissues of 20 CCA and 10 HCC cases. The molecular signature of CCA revealed the prominent expression of genes involved in cell adhesion and cell movement, whereas HCC showed elevated expression of genes related to cell proliferation/differentiation and metabolisms. A total of 69 genes differentially expressed in CCA and HCC were optimized statistically to formulate a diagnostic equation which distinguished CCA cases from HCC cases. Finally, a four-gene diagnostic equation (CLDN4, HOXB7, TMSB4 and TTR) was formulated and then successfully validated using real-time PCR in an independent testing set of 68 CCA samples and 77 non-CCA controls. Discrimination analysis showed that a combination of these genes could be used as a diagnostic marker for CCA with better diagnostic parameters with high sensitivity and specificity than using a single gene marker or the usual serum markers (CA19-9 and CEA). This new combination marker may help physicians to identify CCA in liver tissues when the histopathology is uncertain. PMID:24586698

  6. Differential Diagnosis of Immunoglobulin G4-associated Cholangitis From Cholangiocarcinoma

    PubMed Central

    Du, Shunda; Liu, Gang; Cheng, Xinqi; Li, Yue; Wang, Qian; Li, Ji; Lu, Xin; Zheng, Yongchang; Xu, Haifeng; Chi, Tianyi; Zhao, Haitao; Xu, Yiyao; Sang, Xinting; Zhong, Shouxian

    2016-01-01

    Background and Aim: Immunoglobulin G4-associated cholangitis (IAC) shares many similar symptoms with cholangiocarcinoma (CCA). However, the treatment and the prognosis are substantially different. This study aimed to identify the important markers for the differential diagnosis of these 2 diseases. Methods: Thirty IAC patients and 275 CCA patients were reviewed retrospectively for their clinical symptoms, serological tests, and imaging characteristics. Posttreatment responses were also studied. Results: IgG4 had 100% specificity for IAC at a cutoff of 6 times the upper normal limit. IAC patients had a significantly higher incidence of weight loss (P=0.025) and a higher level of weight loss (P=0.008) than CCA patients. The positive rates of biological markers CA199, CA242, and CEA in CCA and IAC were 81.5% versus 42.9%, 45.5% versus 4.5%, and 29.2% versus 7.1%, respectively. Levels of these tumor markers in CCA were significantly higher than in IAC (P<0.05). The thickened wall [17/18 (94.4%) vs. 3/10 (30%), P=0.001] and the occupying lesion on the bile duct [1/18 (5.6%) vs. 8/10 (80%), P<0.001] were found to be significantly different in IAC and CCA, respectively, by endoscopic ultrasonography. Autoimmune pancreatitis was the most frequently observed comorbidity of IAC (25/30). All IAC patients respond positively to steroid treatment. Conclusions: Increased tumor markers, 6-fold higher levels of serum IgG4, and other organs’ involvement could be the reference factors for a differential diagnosis of IAC and CCA. Endoscopic ultrasonography might be an effective imaging tool for diagnosis, although clinical signs and symptoms of IAC and CCA are similar. Experimental steroid treatment can be useful in the diagnosis for certain difficult cases. PMID:26974756

  7. The diagnostic performance of serum MUC5AC for cholangiocarcinoma

    PubMed Central

    Xuan, Ji; Li, Jing; Zhou, Zhirui; Zhou, Renrong; Xu, Huabing; Wen, Wei

    2016-01-01

    Abstract Specific diagnostic biomarker for cholangiocarcinoma (CCA) has been lacking. This systematic review and meta-analysis was performed aiming to investigate serum MUC5AC's diagnostic performance on CCA. Studies investigating serum MUC5AC's diagnostic value on CCA were retrieved from Pubmed, Embase, and Cochrane Library. The methodology quality of included studies was assessed according to QUADAS-2. Diagnostic 2 × 2 table was extracted from each eligible study, Meta-disc 1.4 was used for statistical analysis, data synthesis was done using a random-effects model. Subgroup analyses were conducted according to region and array method. Six eligible studies were identified, a total of 1213 patients were involved in the meta-analysis. The AUC on SROC was 0.9138, and the Q∗ was 8463. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (DOR) were 0.69 (95% CI: 0.65–0.73), 0.93 (95% CI: 0.91–0.95), 8.99 (95% CI: 5.65–14.30), 0.33 (95% CI: 0.24–0.46), and 33.98 (95% CI: 20.12–57.40), respectively. Targeting MUC5AC's epitope has a higher pooled sensitivity than targeting MUC5AC protein (0.77 vs 0.63). There was substantial cross-study heterogeneity. Serum MUC5AC might be potentially used as a surrogate marker in the diagnosis of CCA. However, the appropriate array method and the optimum cut-off value are yet to be decided. PMID:27310944

  8. Imbalanced adaptive responses associated with microsatellite instability in cholangiocarcinoma

    PubMed Central

    Loilome, Watcharin; Kadsanit, Sasithorn; Muisook, Kanha; Yongvanit, Puangrat; Namwat, Nisana; Techasen, Anchalee; Puapairoj, Anucha; Khuntikeo, Narong; Phonjit, Pichai

    2017-01-01

    The adaptive response of the genome protection mechanism occurs in cells when exposed to genotoxic stress due to the overproduction of free radicals via inflammation and infection. In such circumstances, cells attempt to maintain health via several genome protection mechanisms. However, evidence is increasing that this adaptive response may have deleterious effect; a reduction of antioxidant enzymes and/or imbalance in the DNA repair system generates microsatellite instability (MSI), which has procarcinogenic implications. Therefore, the present study hypothesized that MSI caused by imbalanced responses of antioxidant enzymes and/or DNA repair enzymes as a result of oxidative/nitrative stress arising from the inflammatory response is involved in liver fluke-associated cholangiocarcinogenesis. The present study investigated this hypothesis by identifying the expression patterns of antioxidant enzymes, including superoxide dismutase 2 (SOD2) and catalase (CAT), and DNA repair enzymes, including alkyladenine DNA glycosylase (AAG), apurinic endonuclease (APE) and DNA polymerase β (DNA pol β). In addition, the activities of the antioxidant enzymes, SOD2 and CAT, were examined in human cholangiocarcinoma (CCA) tissues using immunohistochemical staining. MSI was also analyzed in human CCA tissues. The resulting data demonstrated that the expression levels of the SOD2 and CAT enzymes decreased. The activities of SOD2 and CAT decreased significantly in the CCA tissues, compared with the hepatic tissue of cadaveric donors. In the DNA repairing enzymes, it was found that the expression levels of AAG and DNA pol β enzymes increased, whereas the expression of APE decreased. In addition, it was found that MSI-high was present in 69% of patients, whereas MSI-low was present in 31% of patients, with no patients classified as having microsatellite stability. In the patients, a MSI-high was correlated with poor prognosis, indicated by a shorter survival rate. These results

  9. Anticancer activities of epigallocatechin-3-gallate against cholangiocarcinoma cells

    PubMed Central

    Kwak, Tae Won; Park, Su Bum; Kim, Hyun-Jung; Jeong, Young-IL; Kang, Dae Hwan

    2017-01-01

    Purpose Epigallocatechin-3-gallate (EGCG) is an antioxidant agent derived from green tea. Because it has chemopreventive and anti-invasive effect against various cancer cells, EGCG can be used to inhibit proliferation and invasion of cholangiocarcinoma (CCA) cells. Methods The anticancer effects of EGCG were studied using human CCA cells (HuCC-T1). Apoptosis was analyzed by Western blotting. Invasion and migration of cancer cells were assessed with Matrigel® and wound healing assays. An animal tumor xenograft model of HuCC-T1 was used to study the in vivo antitumor activities of EGCG. Results EGCG effectively inhibited the growth of HuCC-T1 cells with no adverse effects on the viability of 293T cells. EGCG induced apoptotic cell death at 5 µg/mL concentration. It inhibited the expression of mutant p53 and induced apoptotic molecular signals such as Bax/Bcl-2, Caspase, and cytochrome C. Furthermore, EGCG dose-dependently inhibited the activity of matrix metalloproteinase (MMP)-2/9, invasion, and migration. In the animal tumor xenograft model of HuCC-T1 cells, EGCG was subcutaneously administered beside the tumor for local treatment. EGCG efficiently inhibited growth of the tumor and suppressed carcinogenic molecular signals such as Notch1, MMP-2/9, and proliferating cell nuclear antigen. Conclusion EGCG induced apoptosis of cancer cells without adverse effects on normal cells. EGCG inhibited growth, invasion, and migration of HuCC-T1 cells. We suggest EGCG as a promising candidate for local treatment of CCA. PMID:28053547

  10. Hepatitis viruses and risk of cholangiocarcinoma in northeast Thailand.

    PubMed

    Srivatanakul, Petcharin; Honjo, Satoshi; Kittiwatanachot, Pacharin; Jedpiyawongse, Adisorn; Khuhaprema, Thiravud; Miwa, Masanao

    2010-01-01

    Liver cancer is the most common cancer in males in Thailand and the third in females. A high incidence of cholangiocarcinoma (CCA) is estimated in the northeast of Thailand. Chronic infection with Opisthorchis viverrini (OV) is the major risk factor for development of CCA. It has been demonstrated that HCV infection is a risk factor for CCA in non - endemic area of OV infection. We examined the association of HBV and HCV and risk of CCA in the northeast Thailand. All cases of CCA were recruited between 1999 and 2001 from Nakhon Phanom provincial hospital and all community hospitals in the province. One control per case was selected, matched by sex, age (∓5 years) and residence. 106 case-control pairs were obtained. Anti-OV, HBsAg, and Anti HCV were determined by ELISA. Among 103 age-sex-place of residence matched case-control pairs, there were 7, 0, 0, 96 pairs for anti-HCV (+) case vs. (-) control, (+) case vs. (+) control, (-) case vs. (+) control and (-) case vs. (-) control combinations (OR=7/0). Among 106 matched pairs, there were 9, 2, 4, 91 pairs for the similar four combinations of HBsAg (OR=2.25 (95%CI: 0.63-10.0). If the subject had anti-HCV and/or HBsAg, the OR for CCA was 4.00 (95%CI: 1.29-16.4). Even after adjustment for anti-OV, risk for HBsAg and/or anti-HCV positive was still marginally increased with an OR of 4.69 although not reaching statistical significance (95%CI: 0.98-22.5). Hepatitis B and C virus infection may also play role in the development of CCA in northeast Thailand.

  11. Effects of systemic hyperthermia and intrahepatic infusion with 5-fluorouracil.

    PubMed

    Daly, J M; Smith, G; Frazier, O H; Dudrick, S J; Copeland, E M

    1982-03-15

    Potential hepatotoxicity from systemic hyperthermia (43 degrees C) +/- simultaneous hepatic artery infusion with 5-FU was evaluated in an animal model. Twenty-two dogs had aorta-vena caval shunts (8 mm Dacron grafts) placed, and 10 of these dogs had silastic catheters inserted in their hepatic arteries. Two weeks later, Group I (n = 8) was heated to 43 degrees C for one hour (distal esophageal + intrahepatic temperature) using the shunts and blood-heat exchangers; Group II (n = 6) was heated to 43 degrees C for one hour with simultaneous intrahepatic infusion of 5-FU (10 mg/kg); Group III (n = 8) was shamheated (37 degrees C) and underwent a one hour intrahepatic infusion with 5-FU (10 mg/kg). Serum alkaline phosphatase, SGOT, SPGT (IU/ml) and bilirubin were measured, and liver biopsies were obtained at 0 and 1 hour, at one and seven days. Mean SGOT levels increased significantly (P less than 0.05) in Group II from 19 +/- 2 to 31 +/- 6 and 63 +/- 18 at one hour and one day; these levels rose slightly in Group I from 31 +/- 5 to 40 +/- 8 and 47 +/- 8 at one hour and one day. Hepatocellular enzyme levels returned to normal at seven days in both groups. Mean SGOT and SGPT levels remained similar in Group III at all time periods. No significant differences in mean serum alkaline phosphatase or bilirubin levels were noted. There was no histologic evidence of hepatocellular necrosis at any time period. Survival was 6/8, 5/6 and 8/8 dogs in Groups I, II, and III, respectively. Systemic hyperthermia to 43 degrees C for one hour in dogs does not adversely affect serum hepatic enzymes or cell structure; reversible serum hepatic enzyme changes occurred when hyperthermia was combined with hepatic artery infusion with 5-FU.

  12. Behavioral Modification Regarding Liver Fluke and Cholangiocarcinoma with a Health Belief Model Using Integrated Learning.

    PubMed

    Phatisena, Panida; Eaksanti, Tawatchai; Wichantuk, Pitsanee; Tritipsombut, Jaruwan; Kaewpitoon, Soraya J; Rujirakul, Ratana; Wakkhuwattapong, Parichart; Tongtawee, Taweesak; Matrakool, Likit; Panpimanmas, Sukij; Norkaew, Jun; Kujapun, Jirawoot; Chavengkun, Wasugree; Kompor, Porntip; Pothipim, Mali; Ponphimai, Sukanya; Padchasuwan, Natnapa; Kaewpitoon, Natthawut

    2016-01-01

    This study aimed to modify behavior regarding liver fluke and cholangiocarcinoma prevention in Chumphuang district, Nakhon Ratchasima province, Thailand through integrated learning. A total of 180 participants were included through purposive selection of high-risk scores on verbal screening. Participants attended the health education program which applied the health belief model included family based, knowledge station based, academic merit based and community based learning. Data were collected using a questionnaire composed of 4 parts: 1) personal information, 2) knowledge, 3) perceived susceptibility, severity, benefits, and barriers, 4) practice regarding liver fluke and cholangiocarcinoma prevention. The result revealed that the majority were female (79.9%), age ≥60 years old (33.2%), primary school educational level (76.1%), and agricultural occupation (70.1%). The mean scores of knowledge, perception, and practice to liver fluke and cholangiocarcinoma prevention, before participated the integrative learning were low, moderate, and low, respectively. Meanwhile, the mean score of knowledge, perceived susceptibility, severity, benefits, and barriers, and practice regarding liver fluke and cholangiocarcinoma prevention, were higher with statistical significance after participation in the integrated learning. This finding indicates that health education programs may successfully modify health behavior in the rural communities. Therefore they may useful for further work behavior modification in other epidemic areas.

  13. Schwannoma of the biliary tract resembling cholangiocarcinoma: A case report and review

    PubMed Central

    Garcia Sanz, I; Muñoz de Nova, JL; Valdés de Anca, A; Martín Pérez, ME

    2016-01-01

    Schwannomas are benign tumours derived from Schwann cells and are extremely rare in the biliary tract. We present the case of a 62-year-old patient with a common bile duct schwannoma that resembled a cholangiocarcinoma. We also review all 17 previously published cases of schwannoma of the biliary tract and discuss the challenges of preoperative diagnosis. PMID:27269434

  14. Is ursodeoxycholic acid effective for intrahepatic cholestasis of pregnancy?

    PubMed

    Sepúlveda Marín, Sebastián; Contreras Maragaño, Valeria; Vera, Claudio

    2016-01-08

    Intrahepatic cholestasis of pregnancy is a condition associated with fetal morbidity and mortality. Ursodeoxycholic acid has been proposed as a treatment alternative, but its use remains controversial. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including eight randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded ursodeoxycholic acid reduces prematurity risk and need for admission in neonatal intensive care units. It might also reduce maternal pruritus.

  15. Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS

    PubMed Central

    Qu, Xianzhi; Sheng, Jiyao; Shen, Luyan; Su, Jing; Xu, Yunjie; Xie, Qi; Wu, Yao; Zhang, Xuewen; Sun, Liankun

    2017-01-01

    The tumor cells have some metabolic characteristics of the original tissues, and the metabolism of the tumor cells is closely related to autophagy. However, the mechanism of autophagy and metabolism in chemotherapeutic drug resistance is still poorly understood. In this study, we investigated the role and mechanism of autophagy and glucose metabolism in chemotherapeutic drug resistance by using cholangiocarcinoma QBC939 cells with primary cisplatin resistance and hepatocellular carcinoma HepG2 cells. We found that QBC939 cells with cisplatin resistance had a higher capacity for glucose uptake, consumption, and lactic acid generation, and higher activity of the pentose phosphate pathway compared with HepG2 cells, and the activity of PPP was further increased after cisplatin treatment in QBC939 cells. It is suggested that there are some differences in the metabolism of glucose in hepatocellular carcinoma and cholangiocarcinoma cells, and the activation of PPP pathway may be related to the drug resistance. Through the detection of autophagy substrates p62 and LC3, found that QBC939 cells have a higher flow of autophagy, autophagy inhibitor chloroquine can significantly increase the sensitivity of cisplatin in cholangiocarcinoma cells compared with hepatocellular carcinoma HepG2 cells. The mechanism may be related to the inhibition of QBC939 cells with higher activity of the PPP, the key enzyme G6PDH, which reduces the antioxidant capacity of cells and increases intracellular ROS, especially mitochondrial ROS. Therefore, we hypothesized that autophagy and the oxidative stress resistance mediated by glucose metabolism may be one of the causes of cisplatin resistance in cholangiocarcinoma cells. It is suggested that according to the metabolism characteristics of tumor cells, inhibition of autophagy lysosome pathway with chloroquine may be a new route for therapeutic agents against cholangiocarcinoma. PMID:28301876

  16. Genomic and Genetic Characterization of Cholangiocarcinoma Identifies Therapeutic Targets for Tyrosine Kinase Inhibitors

    PubMed Central

    Andersen, Jesper B.; Spee, Bart; Blechacz, Boris R.; Avital, Itzhak; Komuta, Mina; Barbour, Andrew; Conner, Elizabeth A.; Gillen, Matthew C.; Roskams, Tania; Roberts, Lewis R.; Factor, Valentina M.; Thorgeirsson, Snorri S.

    2012-01-01

    BACKGROUND & AIMS Cholangiocarcinoma is a heterogeneous disease with a poor outcome that accounts for 5%–10% of primary liver cancers. We characterized its genomic and genetic features and associated these with patient responses to therapy. METHODS We profiled the transcriptomes from 104 surgically resected cholangiocarcinoma samples collected from patients in Australia, Europe, and the United States; epithelial and stromal compartments from 23 tumors were laser capture microdissected. We analyzed mutations in KRAS, epidermal growth factor receptor (EGFR), and BRAF in samples from 69 tumors. Changes in gene expression were validated by immunoblotting and immunohistochemistry; integrative genomics combined data from the patients with data from 7 human cholangiocarcinoma cell lines, which were then exposed to trastuzumab and lapatinib. RESULTS Patients were classified into 2 subclasses, based on 5-year survival rate (72% vs 30%; χ2 = 11.61; P < .0007), time to recurrence (13.7 vs 22.7 months; P < .001), and the absence or presence of KRAS mutations (24.6%), respectively. Class comparison identified 4 survival subgroups (SGI–IV; χ2 = 8.34; P < .03); SGIII was characterized by genes associated with proteasomal activity and the worst prognosis. The tumor epithelium was defined by deregulation of the HER2 network and frequent overexpression of EGFR, the hepatocyte growth factor receptor (MET), pRPS6, and Ki67, whereas stroma was enriched in inflammatory cytokines. Lapatinib, an inhibitor of HER2 and EGFR, was more effective in inhibiting growth of cholangiocarcinoma cell lines than trastuzumab. CONCLUSIONS We provide insight into the pathogenesis of cholangiocarcinoma and identify previously unrecognized subclasses of patients, based on KRAS mutations and increased levels of EGFR and HER2 signaling, who might benefit from dual-target tyrosine kinase inhibitors. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes

  17. Thyroid gland metastasis arising from primary liver cholangiocarcinoma: The first case report involving surgical operation

    PubMed Central

    Park, Min Ho; Cho, Jin Seong; Lee, Ji Shin; Kim, Hee Kyung; Yoon, Jung Han

    2011-01-01

    Introduction A primary cancer causing thyroid metastasis is extremely rare. In western countries, the most common primary tumors causing thyroid metastases include kidney, lung, breast, and gastrointestinal cancers. In contrast, breast is the most common primary site, followed by kidney, colon, and lung cancers in Korea. To the best of our knowledge, surgically confirmed thyroid metastasis from cholangiocarcinoma has not been reported. Herein, we report the first case of thyroid metastasis secondary to cholangiocarcinoma on which surgery was performed. Presentation of case A 55-year-old man was diagnosed with hepatic malignancy in December 2008. He subsequently received 2 cycles of transarterial chemoembolization and 4 cycles of radio-frequency ablation between 2008 and 2010. At follow-up in January 2011, brain metastasis was identified in the right parietal area secondary to cholangiocarcinoma. In April 2011, the patient was found to have palpable masses on the left thyroid and lateral neck. The patient subsequently underwent total thyroidectomy followed by left radical neck dissection. Intraoperatively, an ill-defined mass measuring 6.0 cm was found infiltrating the subcutaneous tissue into the prevertebral fascia. Microscopic and immunohistochemical findings confirmed that the thyroid masses and lymph nodes were metastatic cholangiocarcinoma. Discussion Positive immunohistochemical staining for cytokeratin 7, cytokeratin 19, and AFP and negative results for TG, TTF-1, and cytokeratin 20 can be definitely helpful in arriving at a correct diagnosis. Conclusion To the best of our knowledge, this is the first case report on surgically resected thyroid and lateral neck metastases secondary to cholangiocarcinoma. PMID:22288052

  18. MART-10 represses cholangiocarcinoma cell growth and high vitamin D receptor expression indicates better prognosis for cholangiocarcinoma

    PubMed Central

    Chiang, Kun-Chun; Yeh, Ta-Sen; Huang, Cheng-Cheng; Chang, Yu-Chan; Juang, Horng-Heng; Cheng, Chi-Tung; Pang, Jong-Hwei S.; Hsu, Jun-Te; Takano, Masashi; Chen, Tai C.; Kittaka, Atsushi; Hsiao, Michael; Yeh, Chun-Nan

    2017-01-01

    Cholangiocarcinoma (CCA) is a devastating disease due to no effective treatments available. Since the non-mineral functions of vitamin D emerges, 1α,25(OH)2D3, the active form of vitamin D, has been applied in anti-cancer researches. In this study, we demonstrated that both the 1α,25(OH)2D3 analog, MART-10, and 1α,25(OH)2D3 possessed anti-growth effect on human CCA cells with MART-10 much more potent than 1α,25(OH)2D3. The growth inhibition of both drugs were mediated by induction of G0/G1 cell cycle arrest through upregulation of p27 and downregulation of CDK4, CDK6, and cyclin D3. Human neutrophil gelatinase associated lipocalin (NGAL) was found to be involved in 1α,25(OH)2D3 and MART-10 meditated growth inhibition for CCA as knockdown of NGAL decreased Ki-67 expression in SNU308 cells and rendered SNU308 cells less responsive to 1α,25(OH)2D3 and MART-10 treatment. Vitamin D receptor (VDR) knockdown partly abolished MART-10-induced inhibition of NGAL and cell growth in SNU308 cells. The xenograft animal study demonstrated MART-10 could effectively repressed CCA growth in vivo without inducing obvious side effects. The IHC examination of human CCA specimen for VDR revealed that higher VDR expression was linked with better prognosis. Collectively, our results suggest that MART-10 could be a promising regimen for CCA treatment. PMID:28256614

  19. Progressive familial intrahepatic cholestasis with high gamma-glutamyltranspeptidase levels in Taiwanese infants: role of MDR3 gene defect?

    PubMed

    Chen, H L; Chang, P S; Hsu, H C; Lee, J H; Ni, Y H; Hsu, H Y; Jeng, Y M; Chang, M H

    2001-07-01

    MDR3 P-glycoprotein mediates canalicular phospholipid transport in hepatocytes. Defects in the MDR3 gene have been found to cause a subtype of progressive familial intrahepatic cholestasis (PFIC) with high gamma-glutamyltranspeptidase (GGT) levels. Affected children develop proliferation of biliary epithelium, portal inflammation, and biliary cirrhosis. The frequency of MDR3 mutations in patients with high GGT-PFIC is unclear. There have been no Asian patients reported to carry MDR3 mutations. To determine the role of MDR3 defects in chronic cholestatic patients, we studied six Taiwanese children from five families who presented high GGT-PFIC among 47 patients with infantile onset chronic intrahepatic cholestasis. Sequence analysis of MDR3 cDNA from liver tissues was performed. Only one patient had mutation in the MDR3 gene. This patient had a homozygous 719-bp deletion (nucleotide 287 to 1005) of liver cDNA encompassing exon 5 to 9 and leading to protein truncation. The onset age was 1 y in contrast with the other five patients who presented neonatal cholestasis. Four patients without mutation, including one sibling pair, exhibited histologic features of prominent portal fibrosis leading to advanced biliary cirrhosis that were indistinguishable from the case of MDR3 mutation. We concluded that mutations in MDR3 accounted for approximately 2% (1/47) of infantile onset chronic cholestasis in Taiwan. Those patients presenting high GGT-PFIC with early onset cholestasis but without MDR3 mutation probably had inheritable disorders remaining to be clarified.

  20. Copper chelation therapy in intrahepatic cholestasis of childhood.

    PubMed Central

    Evans, J; Zerpa, H; Nuttall, L; Boss, M; Sherlock, S

    1983-01-01

    The effect of copper chelation was studied in a group of children with intrahepatic cholestasis of childhood (IHCC) and increased liver copper levels. Initial therapy was D-penicillamine (10 mg/kg/day), being replaced by triethylenetetramine dihydrochloride (20 mg/kg/day) when side-effects of D-penicillamine occurred. Eight children completed two years of copper chelation. Pruritus remained the main symptom and did not improve. Two patients developed D-penicillamine side-effects - one patient after nine months (marked anorexia, lassitude) and one other patient after 19 months (thrombocytopenia). Two patients died during the study, in one of these normal hepatic copper concentration was achieved. Hepatic copper concentrations decreased in seven of eight patients from 8.6 (2.7 +/- 16.2) mumol/g to 3.4 (0.6-16.5) mumol/g (median and range (0.05 less than 0.01) and serum aspartate transaminase increased in seven of eight patients (p less than 0.05). Histological assessment of serial liver sections revealed increased fibrosis and cholestasis despite reductions in hepatic copper levels during the study. This study showed that D-penicillamine therapy was associated with significant side-effects, while marked clinical, biochemical, or histological improvement did not follow effective copper chelation therapy in intrahepatic cholestasis of childhood. PMID:6848432

  1. Carbohydrate metabolism in the course of intrahepatic cholestasis in pregnancy.

    PubMed

    Wójcicka-Jagodzińska, J; Kuczyńska-Sicińska, J; Czajkowski, K; Smolarczyk, R

    1989-10-01

    Glucose metabolism was evaluated in pregnant women with clinically and biochemically demonstrated intrahepatic cholestasis. Laboratory investigations included measurements of serum glucose concentrations on fasting and 2 hours after breakfast, the glucose tolerance test (100 gm oral glucose load), and 24-hour glycemia profile. All patients were admitted to the II Department of Obstetrics and Gynecology, Institute of Obstetrics and Gynecology of the Medical School in Warsaw, Poland. None of the patients exhibited manifest diabetes mellitus or had any clinical history suggestive of previous diabetes. The serum samples collected 2 hours after breakfast demonstrated higher glucose concentrations in women with intrahepatic cholestasis when compared with healthy control subjects. The glucose tolerance tests demonstrated consistently higher concentrations of glucose in blood serum samples after loading in the study group. The 24-hour glycemia profile showed greater glucose concentrations in serum samples collected 2 hours after breakfast and after supper. These results suggest that in the course of cholestasis in pregnancy, visible changes occur in the carbohydrate metabolism of the pregnant woman.

  2. [Progressive familial intrahepatic cholestasis presenting as liver failure].

    PubMed

    Sangorrin Iranzo, A; Iriondo Sanz, M; Alvarez García, L; Jara Vega, P; Martín de Carpi, J

    2009-12-01

    Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomic-recessive inherited cholestatic disorders that begin in the neonatal period or in the first years of life. There are three types of PFIC defined by different mutations located in the gene responsible for the bile flow through the intrahepatic canalicular transporter system. These disorders usually present in children or young adults and the main clinical manifestations are cholestasis, jaundice and pruritus, and they progress slowly towards liver fibrosis in adult life. PFIC diagnosis is based on clinical suspicion, biochemical findings (that include normal gamma-glutamyl transpeptidase in type 1 and 2, but increased levels in type 3), image techniques that rule-out other disorders, and histological confirmation. Initial treatment consists of symptomatic relief of cholestatic symptoms with choleretic agents (urso-deoxycholic acid). Partial biliary derivation and ileal bypass are intermediate therapeutic options. In case of no response to these treatments, liver transplantation is indicated. We report the case of a neonate with PFIC type 2 presenting as a liver failure.

  3. Impaired fetal adrenal function in intrahepatic cholestasis of pregnancy

    PubMed Central

    Wang, Chunfang; Chen, Xiaojun; Zhou, Shu-Feng; Li, Xiaotian

    2011-01-01

    Summary Background Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease of unknown etiology. The aim of this study was to investigate the change in maternal and fetal adrenal function in clinical and experimental ICP. Material/Methods The maternal and fetal serum levels of cortisol and dehydroepiandrosterone sulfate (DHEAS) were determined in 14 women with ICP and in pregnant rats with estrogen-induced intrahepatic cholestasis. Results In women with ICP, the fetal serum cortisol and DHEAS levels were significantly higher than those in women with normal pregnancy, after correcting the impact of gestational age at delivery. The relationship between fetal cortisol and maternal cholic acid levels was bidirectional; the fetal cortisol tended to increase in mild ICP, while it decreased in severe ICP. In pregnant rats with estrogen-induced cholestasis, the fetal cortisol level was significantly lower in the group with oxytocin injection, compared with the group without oxytocin injection (191.92±18.86 vs. 272.71±31.83 ng/ml, P<0.05). In contrast, the fetal cortisol concentration was increased after oxytocin injection in normal control rats. Conclusions The data indicate that fetal stress-responsive system is stimulated in mild ICP, but it is suppressed in severe ICP, which might contribute to the occurrence of unpredictable sudden fetal death. Further studies are warranted to explore the role of impaired fetal adrenal function in the pathogenesis of ICP and the clinical implications. PMID:21525808

  4. Giant Intrahepatic Portal Vein Aneurysm: Leave it or Treat it?

    PubMed

    Shrivastava, Amit; Rampal, Jagdeesh S; Nageshwar Reddy, D

    2017-03-01

    Portal vein aneurysm (PVA) is a rare vascular dilatation of the portal vein. It is a rare vascular anomaly representing less than 3% of all visceral aneurysms and is not well understood. Usually, PVA are incidental findings, are asymptomatic, and clinical symptoms are proportionally related to size. Patients present with nonspecific epigastric pain or gastrointestinal bleeding with underlying portal hypertension. PVA may be associated with various complications such as biliary tract compression, portal vein thrombosis/rupture, duodenal compression, gastrointestinal bleeding, and inferior vena cava obstruction. Differential diagnoses of portal vein aneurysms are solid, cystic, and hypervascular abdominal masses, and it is important that the radiologists be aware of their multi-modality appearance; hence, the aim of this article was to provide an overview of the available literature to better simplify various aspects of this rare entity and diagnostic appearance on different modality with available treatment options. In our case, a 55-year-old male patient came to the gastroenterology OPD for further management of pancreatitis with portal hypertension and biliary obstruction with plastic stents in CBD and PD for the same. In this article, we have reported a case of largest intrahepatic portal vein aneurysm and its management by endovascular technique. As per our knowledge, this is the largest intrahepatic portal vein aneurysm and first case where the endovascular technique was used for the treatment of the same.

  5. The Novel Monoclonal Antibody HPC2 and N-cadherin Distinguish Metastatic Pancreatic Ductal Adenocarcinoma from Cholangiocarcinoma

    PubMed Central

    Hooper, Jody E.; Morgan, Terry K.; Grompe, Markus; Sheppard, Brett C.; Troxell, Megan L.; Corless, Christopher L.; Streeter, Philip R.

    2013-01-01

    Metastatic pancreatic ductal adenocarcinoma and primary cholangiocarcinoma are morphologically very similar and therefore challenging to distinguish in liver biopsies. The distinction is important because surgical management and prognosis differ significantly. A number of immunohistochemical markers have been evaluated to aid this diagnosis, but aside from N-cadherin, which labels cholangiocarcinoma, few provide the combination of good sensitivity and specificity. Our laboratory recently developed a novel monoclonal antibody HPC2 that recognizes pancreatic cancer. We hypothesized the combination of our new marker and N-cadherin would reliably distinguish metastatic pancreatic cancer from cholangiocarcinoma. We immunostained 60 pancreatic ductal adenocarcinomas and 31 cholangiocarcinomas for the HPC2 and N-cadherin antigens. We also stained 24 gallbladder adenocarcinomas, 12 ampullary adenocarcinomas, and 10 metastatic colonic adenocarcinomas to the liver. Sections were independently scored by two pathologists with good agreement using both markers (kappa statistics 0.62–0.64, p<0.0001). HPC2 was observed in 80% of pancreatic cancers (48/60), 75% of ampullary (9/12), and 32% (10/31) of cholangiocarcinomas. N-cadherin stained 27% (16/60) of the pancreas cases and 58% (18/31) of the cholangiocarcinomas. Gallbladder and colon cancers were usually double negative (18/24 and 8/10 respectively). Each marker provided significant likelihood ratios to separate pancreatic cancer (HPC2: 2.48 [1.46–4.19], p<0.0001) from cholangiocarcinoma (N-cadherin: 2.17 [1.3–3.64], p<0.01). The combination of both markers provided even better specificity and positive likelihood ratios. We conclude that HPC2 and N-cadherin reliably distinguish pancreatic cancer from cholangiocarcinoma. PMID:22406361

  6. Denosumab is Effective for Controlling Serum Calcium Levels in Patients with Humoral Hypercalcemia of Malignancy Syndrome: A Case Report on Parathyroid Hormone-related Protein-producing Cholangiocarcinoma

    PubMed Central

    Ashihara, Norihiro; Nakajima, Koji; Nakamura, Yoshiyuki; Kobayashi, Mutsuhiro; Shirahata, Kumiko; Maeda, Chika; Uehara, Takeshi; Gomi, Daisuke; Ito, Nobuo

    2016-01-01

    Hypercalcemia resulting in the elevation of serum parathyroid hormone-related protein (PTHrP) and suppression of serum PTH was observed in a patient with advanced cholangiocarcinoma (CCC) and multiple lymph node metastases. We confirmed humoral hypercalcemia of malignancy based on PTHrP-producing CCC. Chemotherapy with gemcitabine and cisplatin could not control the patient's serum PTHrP levels and the patient was affected with bisphosphonate-refractory hypercalcemia. We administered a single dose of denosumab, an anti-receptor activator of nuclear factor-kappaB ligand monoclonal antibody, and the patient's serum calcium levels remained close to the normal range for approximately 3 weeks without additional treatment. PMID:27904108

  7. The etiology of intrahepatic cholestasis of pregnancy: towards solving a monkey puzzle.

    PubMed

    Webb, Gwilym J; Elsharkawy, Ahmed M; Hirschfield, Gideon M

    2014-01-01

    Clinical and epidemiological findings implicate genetic predisposition and the effects of elevated steroids in pregnancy in the pathogenesis of intrahepatic cholestasis of pregnancy. To date, a number of studies have identified polymorphisms encoding biliary canalicular transporters, including those encoded by ABCB4 and ABCB11, which are associated with intrahepatic cholestasis of pregnancy. Questions remain regarding divergent findings between populations and the relative contributions of these polymorphisms. In a large study of Western European women with intrahepatic cholestasis of pregnancy, Dixon et al. (this issue) provide further insights into the genetics of this cholestatic syndrome, which contribute to ongoing evaluation of cholestasis generally.

  8. Arterial Perfusion Imaging-Defined Subvolume of Intrahepatic Cancer

    PubMed Central

    Wang, Hesheng; Farjam, Reza; Feng, Mary; Hussain, Hero; Ten Haken, Randall K.; Lawrence, Theodore S.; Cao, Yue

    2014-01-01

    Purpose To assess whether an increase in a subvolume of intrahepatic tumor with elevated arterial perfusion during radiation therapy (RT) predicts tumor progression post RT. Methods and Materials Twenty patients with unresectable intrahepatic cancers undergoing RT were enrolled in a prospective IRB-approved study. Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) were performed prior to RT (pre-RT), after delivering ~60% of the planned dose (mid-RT) and one month after completion of RT to quantify hepatic arterial perfusion. The arterial perfusions of the tumors at pre-RT were clustered into low-normal and elevated perfusion by a fuzzy clustering-based method, and the tumor subvolumes with elevated arterial perfusion were extracted from the hepatic arterial perfusion images. The percentage changes in the tumor subvolumes and means of arterial perfusion over the tumors from pre-RT to mid-RT were evaluated for predicting tumor progression post-RT. Results Of the 24 tumors, 6 tumors in 5 patients progressed 5–21 months after RT completion. Neither tumor volumes nor means of tumor arterial perfusion at pre-RT were predictive of treatment outcome. The mean arterial perfusion over the tumors increased significantly at mid-RT in progressive tumors comparing to the responsive ones (p=0.006). From pre-RT to mid-RT, the responsive tumors had a decrease in the tumor subvolumes with elevated arterial perfusion (median: −14%, range: −75% – 65%), while the progressing tumors had an increase of the subvolumes (median: 57%, range: −7% – 165%) (p=0.003). Receiver operating characteristic (ROC) analysis of the percentage change in the subvolume for predicting tumor progression post-RT had an area under the curve (AUC) of 0.90. Conclusion The increase in the subvolume of the intrahepatic tumor with elevated arterial perfusion during RT has the potential to be a predictor for tumor progression post-RT. The tumor subvolume could be a radiation boost candidate

  9. Impaired fetal myocardial deformation in intrahepatic cholestasis of pregnancy.

    PubMed

    Fan, Xuemei; Zhou, Qichang; Zeng, Shi; Zhou, Jiawei; Peng, Qinghai; Zhang, Ming; Ding, Yiling

    2014-07-01

    To investigate changes in fetal myocardial deformation in intrahepatic cholestasis of pregnancy. Patients with intrahepatic cholestasis of pregnancy were divided into 2 groups according to the total maternal serum bile acid concentration: mild cholestasis (10-40 μmol/L) and severe cholestasis (>40 μmol/L). Fetal echocardiography and velocity vector imaging were performed on women with cholestasis and control patients. The left ventricular global longitudinal strain and strain rate were measured. Clinical characteristics, maternal serum bile acid levels, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in umbilical vein blood were compared between groups. The relationships among fetal myocardial deformation, maternal total bile acids, and cord NT-proBNP were analyzed. Twenty women with mild cholestasis, 20 with severe cholestasis, and 40 control patients were enrolled. There were no significant differences in maternal and gestational ages between the case and control groups. Maternal bile acids and NT-proBNP were significantly higher in fetuses of mothers with cholestasis than control fetuses. The left ventricular longitudinal strain (-10.56% ± 1.83% versus -18.36% ± 1.11%; P < .01), systolic strain rate (-1.63 ± 0.18 versus -2.04 ± 0.18 secondsz(-1); P < .01), and diastolic strain rate (1.37 ± 0.18 versus 1.83 ± 0.14 seconds(-1); P < .01) were significantly decreased in fetuses with severe cholestasis compared with control fetuses. There were positive correlations between fetal myocardial deformation and maternal total bile acids (r = 0.705, 0.643, and 0.690, respectively; P < .01) and between myocardial deformation and NT-proBNP (r = 0.672, 0.643, and 0.647; P < .01). Fetal myocardial deformation is impaired in severe intrahepatic cholestasis of pregnancy. Further investigation is needed to determine whether fetal echocardiography and velocity vector imaging can help predict which fetuses of mothers with cholestasis are likely to have poor

  10. Intrahepatic cholestasis of pregnancy: When should you look further?

    PubMed Central

    Hardikar, Winita; Kansal, Shivani; Elferink, Ronald P J Oude; Angus, Peter

    2009-01-01

    Pruritis with abnormal liver function tests is the classical presentation of intrahepatic cholestasis of pregnancy (ICP), a condition associated with significant fetal complications. Although the etiology of ICP is unclear in many cases, certain features of the clinical presentation should alert the practitioner to the possibility of an underlying metabolic defect, which may not only affect subsequent pregnancies, but may be an indicator of more serious subsequent liver disease. We report a kindred of Anglo-Celtic descent, among whom many members present with ICP, gallstones or cholestasis related to use of oral contraception. Genetic studies revealed a novel mutation in the ABCB4 gene, which codes for a phospholipid transport protein. The clinical significance of this mutation and the importance of identifying such patients are discussed. PMID:19266607

  11. [INTRAHEPATIC CHOLESTASIS OF PREGNANCY: STATE-OF-THE-ART].

    PubMed

    Maev, I V; Andreev, D N; Dicheva, D T; Kaznacheeva, T V

    2015-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is a relatively benign cholestatic pathology of the liver developing in II or III trimester of pregnancy and characterized by itchy skin and enhanced serum bile acid levels. The cause of ICP is unknown; it may have a multifactor nature involving genetic (ABCB4, EXR, ABCC2 genes), hormonal (estrogens, progesterone), and environmental factors. As a rule, ICP first manifests itself on weeks 28-30 of pregnancy in the form of pruritus especially pronounced at night time. Almost half of the patients develop jaundice, usually within 1-4 weeks after appearance of pruritus. The enhanced serum bile acid level is sometimes the first or the sole laboratory sign of the disease. Ursodeoxycholic acid is currently the drug of choice for the treatment of ICP due to its confirmed effectiveness and safety.

  12. Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy.

    PubMed

    Geenes, Victoria; Chambers, Jenny; Khurana, Rshmi; Shemer, Elisabeth Wikstrom; Sia, Winnie; Mandair, Dalvinder; Elias, Elwyn; Marschall, Hanns-Ulrich; Hague, William; Williamson, Catherine

    2015-06-01

    To describe the use of combined ursodeoxycholic acid (UDCA) and rifampicin treatment in intrahepatic cholestasis of pregnancy (ICP). A questionnaire survey of 27 women with 28 affected pregnancies identified via the UK and International Obstetric Medicine forum. The clinical case notes of women with ICP treated with combined UDCA and rifampicin therapy were reviewed, and data regarding maternal and perinatal outcomes extracted. Serum bile acids remained high whilst taking UDCA as monotherapy. In 14 pregnancies (54%) serum bile acids decreased following the introduction of rifampicin. In 10 pregnancies (38%), there was a 50% reduction in serum bile acids. There were no adverse effects reported with either drug. This is the first report of the use of rifampicin in ICP. The data suggest that combined treatment with UDCA and rifampicin is an effective way of treating women with severe ICP who do not respond to treatment with UDCA alone. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems

    PubMed Central

    Kondrackiene, Jurate; Kupcinskas, Limas

    2008-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal distress, preterm delivery, and sudden intrauterine fetal death. The cause of ICP remains elusive, but there is evidence that mutations in genes encoding hepatobiliary transport proteins can predispose for the development of ICP. Recent data suggest that ursodeoxycholic acid is currently the most effective pharmacologic treatment, whereas obstetric management is still debated. Clinical trials are required to identify the most suitable monitoring modalities that can specifically predict poor perinatal outcome. This article aims to review current achievements and unsolved problems of ICP. PMID:18855975

  14. Congenital intrahepatic portosystemic shunt diagnosed during intrauterine life

    PubMed Central

    Bellettini, Camila Vieira; Wagner, Rafaela; Balzanelo, Aleocídio Sette; Andretta, André Luis de Souza; de Moura, Arthur Nascimento; Fabris, Catia Carolina; Gubert, Eduardo Maranhão

    2016-01-01

    Abstract Objective: To report a patient with prenatal diagnosis of portosystemic shunt; a rare condition in humans. Case description: 17-Day-old female infant admitted for investigation of suspected diagnosis of portosystemic shunt, presumed in obstetric ultrasound. The hypothesis was confirmed after abdominal angiography and liver Doppler. Other tests such as echocardiography and electroencephalogram were performed to investigate possible co-morbidities or associated complications, and were normal. We chose conservative shunt treatment, as there were no disease-related complications and this was intrahepatic shunt, which could close spontaneously by the age of 2 years. Comments: Portosystemic shunt can lead to various complications such as hepatic encephalopathy, hypergalactosemia, liver tumors, and hepatopulmonary syndrome. Most diagnoses are done after one month of age, after such complications occur. The prenatal diagnosis of this patient provided greater security for the clinical picture management, as well as regular monitoring, which allows the anticipation of possible complications and perform interventional procedures when needed. PMID:27133713

  15. Transjugular intrahepatic portosystemic shunt for the management of acute variceal hemorrhage

    PubMed Central

    Loffroy, Romaric; Estivalet, Louis; Cherblanc, Violaine; Favelier, Sylvain; Pottecher, Pierre; Hamza, Samia; Minello, Anne; Hillon, Patrick; Thouant, Pierre; Lefevre, Pierre-Henri; Krausé, Denis; Cercueil, Jean-Pierre

    2013-01-01

    Acute variceal hemorrhage, a life-threatening condition that requires a multidisciplinary approach for effective therapy, is defined as visible bleeding from an esophageal or gastric varix at the time of endoscopy, the presence of large esophageal varices with recent stigmata of bleeding, or fresh blood visible in the stomach with no other source of bleeding identified. Transfusion of blood products, pharmacological treatments and early endoscopic therapy are often effective; however, if primary hemostasis cannot be obtained or if uncontrollable early rebleeding occurs, transjugular intrahepatic portosystemic shunt (TIPS) is recommended as rescue treatment. The TIPS represents a major advance in the treatment of complications of portal hypertension. Acute variceal hemorrhage that is poorly controlled with endoscopic therapy is generally well controlled with TIPS, which has a 90% to 100% success rate. However, TIPS is associated with a mortality of 30% to 50% in such a setting. Emergency TIPS should be considered early in patients with refractory variceal bleeding once medical treatment and endoscopic sclerotherapy failure, before the clinical condition worsens. Furthermore, admission to specialized centers is mandatory in such a setting and regional protocols are essential to be organized effectively. This review article discusses initial management and then focuses on the specific role of TIPS as a primary therapy to control acute variceal hemorrhage, particularly as a rescue therapy following failure of endoscopic approaches. PMID:24115809

  16. The Transjugular Intrahepatic Portosystemic Shunt in the Treatment of Portal Hypertension: Current Status

    PubMed Central

    Pomier-Layrargues, Gilles; Bouchard, Louis; Lafortune, Michel; Bissonnette, Julien; Guérette, Dave; Perreault, Pierre

    2012-01-01

    The transjugular intrahepatic portosystemic shunt (TIPS) represents a major advance in the treatment of complications of portal hypertension. Technical improvements and increased experience over the past 24 years led to improved clinical results and a better definition of the indications for TIPS. Randomized clinical trials indicate that the TIPS procedure is not a first-line therapy for variceal bleeding, but can be used when medical treatment fails, both in the acute situation or to prevent variceal rebleeding. The role of TIPS to treat refractory ascites is probably more justified to improve the quality of life rather than to improve survival, except for patients with preserved liver function. It can be helpful for hepatic hydrothorax and can reverse hepatorenal syndrome in selected cases. It is a good treatment for Budd Chiari syndrome uncontrollable by medical treatment. Careful selection of patients is mandatory before TIPS, and clinical followup is essential to detect and treat complications that may result from TIPS stenosis (which can be prevented by using covered stents) and chronic encephalopathy (which may in severe cases justify reduction or occlusion of the shunt). A multidisciplinary approach, including the resources for liver transplantation, is always required to treat these patients. PMID:22888442

  17. [A case of liver abscess with subcapsular hematoma mimicking ruptured hepatic cholangiocarcinoma].

    PubMed

    Kim, Chung Ho; Kim, Ji Hoon; Lee, Hyun Jung; Lee, Young Sun; Choi, Jong Hwan; Jung, Young Kul; Yeon, Jong Eun; Byun, Kwan Soo

    2009-03-01

    Subcapsular hematoma is a very rare complication of liver abscess. We report a case of liver abscess with subcapsular hematoma mimicking ruptured hepatic cholangiocarcinoma. A 59-year-old man presented with right upper quadrant pain and febrile sense. Computed tomography showed a low attenuated mass with extensive subcapsular hematoma on the right hepatic lobe. The initial impression was a hematoma caused by the rupture of cholangiocarcinoma. Hepatic arteriography was performed, but no active bleeding focus was found. After drainage of the subcapsular hematoma, a hematoma wall biopsy through the drainage catheter and a liver biopsy of the low attenuated mass were performed. The biopsies showed many neutrophils, macrophages, and granulation tissues consistent with an abscess, but no malignant cells were detected. After antibiotics therapy for 6 weeks, computed tomography was performed 4 months later, and revealed complete resolution of the hematoma and the low attenuated hepatic lesion.

  18. Alopecia: a common paraneoplastic manifestation of cholangiocarcinoma in humans and animals

    PubMed Central

    Antoniou, Efstathios; Paraskeva, Panorea; Smyrnis, Anastasios; Konstantopoulos, Kostas

    2012-01-01

    The coincidence of alopecia and a tumour may indicate the paraneoplastic nature of alopecia. Paraneoplastic alopecia is not uncommon in animals, feline paraneoplastic alopecia being the best example known. We present a case of alopecia coinciding with the presentation of a cholangiocarcinoma in a woman. Following surgical resection of the tumour, alopecia resolved spontaneously and it reappeared on local recurrence, 2 years later. As far as pathogenesis is concerned, the coincidence of alopecia and cholangiocarcinoma may indicate the paraneoplastic nature of alopecia as a rare complication of this rare tumour in humans. This also implies that common interspecies mechanism(s) must exist as far as this paraneoplastic complication is concerned. PMID:22717934

  19. Prognostic roles of tetrahydroxy bile acids in infantile intrahepatic cholestasis.

    PubMed

    Lee, Chee-Seng; Kimura, Akihiko; Wu, Jia-Feng; Ni, Yen-Hsuan; Hsu, Hong-Yuan; Chang, Mei-Hwei; Nittono, Hiroshi; Chen, Huey-Ling

    2017-03-01

    Tetrahydroxy bile acids (THBAs) are hydrophilic and are present at minimal or undetectable levels in healthy human adults, but are present at high levels in bile salt export pump (abcb11)-knockout mice. The roles of THBAs in human cholestatic diseases are unclear. We aimed to investigate the presence of THBAs in patients with infantile intrahepatic cholestasis and its correlation with outcome. Urinary bile acids (BAs) were analyzed by GC-MS. Data were compared between good (n = 21) (disease-free before 1 year old) and poor prognosis groups (n = 19). Good prognosis patients had a higher urinary THBA proportion than poor prognosis patients [25.89% (3.45-76.73%) vs. 1.93% (0.05-48.90%)]. A urinary THBA proportion >7.23% predicted good prognosis with high sensitivity (95.24%), specificity (84.21%), and area under the curve (0.91) (P < 0.0001). A THBA proportion 7.23% was an independent factor for decreased transplant-free survival (hazard ratio = 7.16, confidence interval: 1.24-41.31, P = 0.028). Patients with a confirmed ABCB11 or tight junction protein 2 gene mutation (n = 7) had a minimally detectable THBA proportion (0.23-2.99% of total BAs). Three patients with an ATP8B1 mutation had an elevated THBA proportion (7.51-37.26%). In conclusion, in addition to disease entity as a major determinant of outcome, a high THBA level was associated with good outcome in the infantile intrahepatic cholestasis patients.

  20. Solitary hepatic granuloma preoperatively diagnosed as intrahepatic cholangiocellular carcinoma: report of a case.

    PubMed

    Fukushima, Daizo; Iwane, Takeru; Sato, Kazushige; Kawagishi, Naoki; Sekiguchi, Satoshi; Ishida, Kazuyuki; Satomi, Susumu

    2012-12-01

    We herein report the case of a 67-year-old female with a solitary hepatic granuloma preoperatively diagnosed as a mass-forming type of intrahepatic cholangiocellular carcinoma. Magnetic resonance imaging using gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid as a contrast medium is expected to be useful for making a differential diagnosis between hepatic granuloma and other hypovascular liver tumors, such as the mass-forming type of intrahepatic cholangiocellular carcinoma and metastatic liver tumors.

  1. Heterozygosity for the alpha1-antitrypsin Z allele may confer genetic risk of cholangiocarcinoma.

    PubMed

    Mihalache, F; Höblinger, A; Grünhage, F; Krawczyk, M; Gärtner, B C; Acalovschi, M; Sauerbruch, T; Lammert, F; Zimmer, V

    2011-02-01

    Alpha1-antitrypsin (α1AT) deficiency caused by Z allele homozygosity represents a well-established risk factor for hepatocellular carcinoma. Previous studies have also implicated α1AT Z heterozygosity in cholangiocarcinogenesis. To assess the 'common' Z and S alleles as well as the promoter variant rs8004738 for association with cholangiocarcinoma. We genotyped 182 Caucasian patients and 350 controls for rs28929474 (Z), rs17580 (S) and the variant rs8004738. Exploratory analyses were performed in relation to gender and cholangiocarcinoma localisation. rs28929474 was significantly enriched in the cholangiocarcinoma group (4.1 vs. 1.7%; OR 2.46, 95% CI 1.14-5.32; Bonferroni corrected p(c) = 0.036), reinforced by Armitage trend testing (OR 2.53; p(c) = 0.032). The rs8004738 (promoter) minor allele tended to be overrepresented in Z heterozygotes (30.0 vs. 16.7%: P = 0.13). Exploratory data analyses suggested a high genetic risk for extrahepatic tumour localisation (OR 3.0; p(c) = 0.016) and potentially female Z allele carriers (OR 3.37; unadjusted P = 0.022, p(c) = 0.088). These data point to a novel role of α1AT Z heterozygosity as a potential genetic susceptibility factor for cholangiocarcinoma formation and suggest a contribution of aberrant α1AT function in biliary carcinogenesis. However, given the overall low rs28929474 minor allele frequency, larger studies are warranted to confirm and extend our findings. © 2010 Blackwell Publishing Ltd.

  2. Efficacy and safety of photodynamic therapy for unresectable cholangiocarcinoma: A meta-analysis.

    PubMed

    Lu, Yi; Liu, Lei; Wu, Jia-chuan; Bie, Li-Ke; Gong, Biao

    2015-12-01

    Photodynamic therapy with the placement of a biliary stent may improve the prognosis in patients with unresectable cholangiocarcinoma. The aim of this research is to determine the hazard ratio of photodynamic therapy with stent compared to biliary stenting alone or other therapies for the treatment of cholangiocarcinoma. Several databases were searched from inception to December 31 2013 for trials comparing photodynamic therapy+stent vs. stent-only or other treatments for cholangiocarcinoma. The outcomes of interest included patient survival, the changes of serum bilirubin levels, the quality of life (Karnofsky performance status), and adverse events. The hazard ratios (HR) were extracted from the survival curves using Tierney's Method. LnHR and its variance were pooled using an inverse variance-weighted average. Inconsistency was quantified using I(2) statistics. In all, 8 trials comparing PDT+stent with other therapeutic methods were selected. We made a meta-analysis based on the 7 trials, which compared the result of PDT+stent and the stent-only group. HR summarizes the survival for the two groups. Overall survival was significantly better in patients who received photodynamic therapy than those who did not [HR=0.49, 95% confidence interval (CI), 0.33∼0.73, P=0.0005]. Among the 8 trials (642 subjects), 5 assessed the changes of serum bilirubin levels, and/or Karnofsky performance status, as other indications for improvement. In all, the incidence for phototoxic reaction is 11.11%. The incidence for other events in photodynamic therapy and the stent-only group was 13.64% and 12.79%, respectively. The palliative treatment of cholangiocarcinoma, with photodynamic therapy, is associated with an increased survival benefit, an improved biliary drainage, and a better quality of life. However, the quality of this evidence is low. Copyright © 2015. Published by Elsevier Masson SAS.

  3. Effective enrichment of cholangiocarcinoma secretomes using the hollow fiber bioreactor culture system.

    PubMed

    Weeraphan, Churat; Diskul-Na-Ayudthaya, Penchatr; Chiablaem, Khajeelak; Khongmanee, Amnart; Chokchaichamnankit, Daranee; Subhasitanont, Pantipa; Svasti, Jisnuson; Srisomsap, Chantragan

    2012-09-15

    The Northeastern region of Thailand is well known to have high incidence of bile duct cancer known as cholangiocarcinoma. So there is a continued need to improve diagnosis and treatment, and discovery of biomarkers for early detection of bile duct cancer should greatly improve treatment outcome for these patients. The secretome, a collection of proteins secreted from cells, is a useful source for identifying circulating biomarkers in blood secreted from cancer cells. Here a Hollow Fiber Bioreactor culture system was used for enrichment of cholangiocarcinoma secretomes, since this culture system mimics the dense three-dimensional microenvironment of the tumor found in vivo. Two-dimensional fluorescence difference gel electrophoresis using a sensitive Fluor saturation dye staining, followed by LC/MS/MS, was used to compare protein expression in the secretomes of cells cultured in the Hollow Fiber system and cells cultured in the monolayer culture system. For the first time, the 2D-patterns of cholangiocarcinoma secretomes from the two culture systems could be compared. The Hollow Fiber system improved the quality and quantity of cholangiocarcinoma secreted proteins compared to conventional monolayer system, showing less interference by cytoplasmic proteins and yielding more secreted proteins. Overall, 75 spots were analyzed by LC/MS/MS and 106 secreted proteins were identified. Two novel secreted proteins (C19orf10 and cystatin B) were found only in the Hollow Fiber system and were absent from the traditional monolayer culture system. Among the highly expressed proteins, 22 secreted soluble proteins were enriched by 5 fold in Hollow Fiber system compared to monolayer culture system. The Hollow Fiber system is therefore useful for preparing a wide range of proteins from low-abundance cell secretomes. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Perihilar Cholangiocarcinoma: Number of Nodes Examined and Optimal Lymph Node Prognostic Scheme

    PubMed Central

    Bagante, Fabio; Tran, Thuy; Spolverato, Gaya; Ruzzenente, Andrea; Buttner, Stefan; Ethun, Cecilia G; Koerkamp, Bas Groot; Conci, Simone; Idrees, Kamran; Isom, Chelsea A; Fields, Ryan C; Krasnick, Bradley; Weber, Sharon M; Salem, Ahmed; Martin, Robert CG; Scoggins, Charles; Shen, Perry; Mogal, Harveshp D; Schmidt, Carl; Beal, Eliza; Hatzaras, Ioannis; Vitiello, Gerardo; IJzermans, Jan NM; Maithel, Shishir K; Poultsides, George; Guglielmi, Alfredo; Pawlik, Timothy M

    2017-01-01

    BACKGROUND The role of routine lymphadenectomy for perihilar cholangiocarcinoma is still controversial and no study has defined the minimum number of lymph nodes examined (TNLE). We sought to assess the prognostic performance of American Joint Committee on Cancer/Union Internationale Contre le Cancer (7th edition) N stage, lymph node ratio, and log odds (LODDS; logarithm of the ratio between metastatic and nonmetastatic nodes) in patients with perihilar cholangiocarcinoma and identify the optimal TNLE to accurately stage patients. METHODS A multi-institutional database was queried to identify 437 patients who underwent hepatectomy for perihilar cholangiocarcinoma between 1995 and 2014. The prognostic abilities of the lymph node staging systems were assessed using the Harrell’s c-index. A Bayesian model was developed to identify the minimum TNLE. RESULTS One hundred and fifty-eight (36.2%) patients had lymph node metastasis. Median TNLE was 3 (interquartile range, 1 to 7). The LODDS had a slightly better prognostic performance than lymph node ratio and American Joint Committee on Cancer, in particular among patients with <4 TNLE (c-index = 0.568). For 2 TNLE, the Bayesian model showed a poor discriminatory ability to distinguish patients with favorable and poor prognosis. When TNLE was >2, the hazard ratio for N1 patients was statistically significant and the hazard ratio for N1 patients increased from 1.51 with 4 TNLE to 2.10 with 10 TNLE. Although the 5-year overall survival of N1 patients was only slightly affected by TNLE, the 5-year overall survival of N0 patients increased significantly with TNLE. CONCLUSIONS Perihilar cholangiocarcinoma patients undergoing radical resection should ideally have at least 4 lymph nodes harvested to be accurately staged. In addition, although LODDS performed better at determining prognosis among patients with <4 TNLE, both lymph node ratio and LODDS outperformed compared with American Joint Committee on Cancer N stage among

  5. Longitudinal profiles of 15 serum bile acids in patients with intrahepatic cholestasis of pregnancy.

    PubMed

    Tribe, Rachel M; Dann, Anthony T; Kenyon, Anna P; Seed, Paul; Shennan, Andrew H; Mallet, Anthony

    2010-03-01

    Increased maternal serum bile acids are implicated in intrahepatic cholestasis of pregnancy. Individual bile acid profiles and their relationship with disease progression, however, remain unknown. The purpose of this prospective study was to determine the temporal changes in bile acids in normal pregnancy and in pregnancies complicated with intrahepatic cholestasis of pregnancy and pruritus gravidarum. A validated method for the evaluation of 15 bile acids (conjugated and unconjugated) in a single serum sample was developed using high-performance liquid chromatography/mass spectrometry (HPLC-MS) with an electrospray interface. Bile acid concentrations were assessed in samples (16 weeks of gestation to 4 weeks postpartum) from women with, or who later developed, intrahepatic cholestasis of pregnancy (n=63) and were compared with those from normal pregnant women (n=26) and from women with pruritus gravidarum (n=43). Intrahepatic cholestasis of pregnancy was associated with a predominant increase in cholic acid conjugated with taurine and glycine, from 24 weeks of pregnancy. Ursodeoxycholic acid (UDCA) treatment (> or =21 days, n=15) significantly reduced serum taurocholic and taurodeoxycholic acid concentrations (P<0.01). Bile acid profiles were similar in normal pregnancy and pregnancy associated with pruritus gravidarum. The bile acid profiles and effects of treatment by UDCA implicate a role for taurine-conjugated bile acids in the syndrome of intrahepatic cholestasis of pregnancy. [corrected] With regard to individual bile acid profiles, pruritus gravidarum is a disorder quite distinct from intrahepatic cholestasis of pregnancy.

  6. Polymeric photosensitizer-embedded self-expanding metal stent for repeatable endoscopic photodynamic therapy of cholangiocarcinoma.

    PubMed

    Bae, Byoung-chan; Yang, Su-Geun; Jeong, Seok; Lee, Don Haeng; Na, Kun; Kim, Joon Mee; Costamagna, Guido; Kozarek, Richard A; Isayama, Hiroyuki; Deviere, Jacques; Seo, Dong Wan; Nageshwar Reddy, D

    2014-10-01

    Photodynamic therapy (PDT) is a new therapeutic approach for the palliative treatment of malignant bile duct obstruction. In this study, we designed photosensitizer-embedded self-expanding nonvascular metal stent (PDT-stent) which allows repeatable photodynamic treatment of cholangiocarcinoma without systemic injection of photosensitizer. Polymeric photosensitizer (pullulan acetate-conjugated pheophorbide A; PPA) was incorporated in self-expanding nonvascular metal stent. Residence of PPA in the stent was estimated in buffer solution and subcutaneous implantation on mouse. Photodynamic activity of PDT-stent was evaluated through laserexposure on stent-layered tumor cell lines, HCT-116 tumor-xenograft mouse models and endoscopic intervention of PDT-stent on bile duct of mini pigs. Photo-fluorescence imaging of the PDT-stent demonstrated homogeneous embedding of polymeric Pheo-A (PPA) on stent membrane. PDT-stent sustained its photodynamic activities at least for 2 month. And which implies repeatable endoscopic PDT is possible after stent emplacement. The PDT-stent after light exposure successfully generated cytotoxic singlet oxygen in the surrounding tissues, inducing apoptotic degradation of tumor cells and regression of xenograft tumors on mouse models. Endoscopic biliary in-stent photodynamic treatments on minipigs also suggested the potential efficacy of PDT-stent on cholangiocarcinoma. In vivo and in vitro studies revealed our PDT-stent, allows repeatable endoscopic biliary PDT, has the potential for the combination therapy (stent plus PDT) of cholangiocarcinoma. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer

    PubMed Central

    Zabron, Abigail; Edwards, Robert J.; Khan, Shahid A.

    2013-01-01

    Cholangiocarcinoma is a fatal cancer of the biliary epithelium and has an incidence that is increasing worldwide. Survival beyond a year of diagnosis is less than 5%, and therapeutic options are few. Known risk factors include biliary diseases such as primary sclerosing cholangitis and parasitic infestation of the biliary tree, but most cases are not associated with any of these underlying diseases. Numerous in vitro and in vivo models, as well as novel analytical techniques for human samples, are helping to delineate the many pathways implicated in this disease, albeit at a frustratingly slow pace. As yet, however, none of these studies has been translated into improved patient outcome and, overall, the pathophysiology of cholangiocarcinoma is still poorly understood. There remains an urgent need for new approaches and models to improve management of this insidious and devastating disease. In this review, we take a bedside-to-bench approach to discussing cholangiocarcinoma and outline research opportunities for the future in this field. PMID:23520144

  8. Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells

    PubMed Central

    Ding, Xiwei; Chaiteerakij, Roongruedee; Moser, Catherine D.; Shaleh, Hassan; Boakye, Jeffrey; Chen, Gang; Ndzengue, Albert; Li, Ying; Zhou, Yanling; Huang, Shengbing; Sinicrope, Frank A.; Zou, Xiaoping; Thomas, Melanie B.; Smith, Charles D.; Roberts, Lewis R.

    2016-01-01

    Sphingosine kinase 2 (Sphk2) has an oncogenic role in cancer. A recently developed first-in-class Sphk2 specific inhibitor ABC294640 displays antitumor activity in many cancer models. However, the role of Sphk2 and the antitumor activity of its inhibitor ABC294640 are not known in cholangiocarcinoma. We investigated the potential of targeting Sphk2 for the treatment of cholangiocarcinoma. We found that Sphk2 is overexpressed in five established human cholangiocarcinoma cell lines (WITT, HuCCT1, EGI-1, OZ and HuH28) and a new patient-derived cholangiocarcinoma cell line (LIV27) compared to H69 normal cholangiocytes. Inhibition of Sphk2 by ABC294640 inhibited proliferation and induced caspase-dependent apoptosis. Furthermore, we found that ABC294640 inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cholangiocarcinoma cell proliferation and survival. ABC294640 also induced autophagy. Inhibition of autophagy by bafilomycin A1 or chloroquine potentiated ABC294640-induced cytotoxicity and apoptosis. In addition, ABC294640 in combination with sorafenib synergistically inhibited cell proliferation of cholangiocarcinoma cells. Strong decreases in STAT3 phosphorylation were observed in WITT and HuCCT1 cells exposed to the ABC294640 and sorafenib combination. These findings provide novel evidence that Sphk2 may be a rational therapeutic target in cholangiocarcinoma. Combinations of ABC294640 with sorafenib and/or autophagy inhibitors may provide novel strategies for the treatment of cholangiocarcinoma. PMID:26956050

  9. Combined portal vein resection in the treatment of hilar cholangiocarcinoma: a systematic review and meta-analysis.

    PubMed

    Chen, W; Ke, K; Chen, Y L

    2014-05-01

    To analyse the efficacy and safety of portal vein resection for hilar cholangiocarcinoma (HCCA). A thorough search of PubMed, the Cochrane Library, Embase, the Chinese BioMedical Literature (CBM), and the Chinese Medical Current Contents (CMCC) databases was performed to identify comparative studies concerning combined portal vein resection (PVR) versus surgery without portal vein resection (Without PVR) and no surgical tumour resection (NR) in the treatment of HCCA. Thirteen studies with a total of 1921 HCCA cases were included. The results of the meta-analysis revealed that PVR was associated with a poorer overall survival than Without PVR (HR = 1.90; 95%CI 1.59-2.28; P < 0.00001) but was significantly better than NR (HR = 0.33; 95%CI 0.26-0.41; P < 0.00001). The PVR group exhibited significantly higher rates of advanced disease and a higher proportion of lymph node metastasis (OR = 1.50; 95%CI 1.06-2.13; P = 0.02) and perineural invasion (OR = 2.95; 95%CI 1.80-4.84; P < 0.0001), and the PVR group exhibited a lower curative resection rate (OR = 0.65; 95%CI 0.46-0.91; P = 0.01). No significant differences were found between the two groups with respect to postoperative mortality and morbidity. Combined PVR is safe and feasible in the treatment of HCCA when the portal vein is grossly involved. For advanced HCCA when the portal vein is grossly involved, surgical resection including PVR can benefit the overall survival in certain patients. However, further randomised controlled trials are necessary to determine the prognostic effects of the addition of PVR to the surgical procedure. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Sodium Iodide Symporter and Phosphatase and Tensin Homolog Deleted on Chromosome Ten Expression in Cholangiocarcinoma Analysis with Clinicopathological Parameters

    PubMed Central

    Kim, Jong Han; Lee, Sung Wook; Baek, Yang Hyun; Kim, Ha Yoen; Kim, Jong Han; Jeong, Jin Sook; Roh, Young Hoon; Kim, Young Hoon; Park, Byung Ho; Kwon, Hee Jin; Cho, Jin Han; Nam, Kyung Jin

    2012-01-01

    Background/Aims This study was performed to investigate the correlation of sodium iodide symporter (NIS) expression with the functionality and loss of phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression in human cholangiocarcinoma (CCA). Methods Immunohistochemistry for the expression of NIS and PTEN was performed in 60 biopsy specimens of CCA. The clinicopathological parameters were retrospectively identified from medical records. The expression pattern of NIS and loss of PTEN expression were analyzed in association with the clinicopathological characteristics, including survival. Results Normal biliary trees displayed NIS expression, but hepatocytes did not. NIS expression was divided into two patterns: cytoplasmic and membranous. Fifty-nine cases, all except for one case, displayed NIS expression in tumor cells. Twenty-two cases (33.3%) were mixed pattern, and 39 cases (65.05%) were cytoplasmic pattern; the pure membranous pattern was not noted. There was no association between the NIS expression pattern and clinicopathological parameters, including age, sex, differentiation grade, T stage and tumor, node, metastasis stage (p>0.05). The survival rates were similar among various NIS expression patterns. Normal hepatocytes and biliary trees exhibited PTEN expression in the nucleus and cytoplasm. CCA cells displayed nuclear staining. Thirty-six (60.0%) of 60 cases displayed a loss of PTEN expression. The loss of PTEN expression was observed in the advanced T-stage group (p=0.0036), but there was no association between the loss of PTEN expression and other clinicopathological parameters (p>0.05). No association between the loss of PTEN expression and survival was noted. Conclusions NIS is expressed in most types of human CCA. The expression pattern suggests a role in cancer development. PTEN loss expression is common in the context of human CCA, especially in the advanced T stage. PMID:22844568

  11. Lipocalin 2 (LCN2) is a promising target for cholangiocarcinoma treatment and bile LCN2 level is a potential cholangiocarcinoma diagnostic marker

    PubMed Central

    Chiang, Kun-Chun; Yeh, Ta-Sen; Wu, Ren-Chin; Pang, Jong-Hwei S.; Cheng, Chi-Tung; Wang, Shang-Yu; Juang, Horng-Heng; Yeh, Chun-Nan

    2016-01-01

    Cholangiocarcinoma (CCA) is a devastating disease due to resistance to traditional chemotherapies and radiotherapies. New therapeutic strategies against CCA are urgently needed. This study investigated the role of lipocalin-2 (LCN2) in human cholangiocarcinoma as a potential therapeutic target and diagnostic marker. So far, the role of LCN2 in cancer is still controversial and studies regarding the role of LCN2 in CCA are limited. LCN2 knockdown inhibited CCA cell growth in vitro and in vivo through induction of cell cycle arrest at G0/G1 phases and decreased metastatic potential due to repression of epithelial-mesenchymal transition (EMT). Overexpression of LCN2 in CCA cells increased cell metastatic potential. We showed for the first time that the N-myc downstream regulated gene 1 (NDRG1) and NDRG2, known as tumor suppressor genes, are negatively regulated by LCN2 in CCA cells. LCN2 concentration in bile was higher in patients with CCA than that in patients with gallstones, with a cutoff value of 20.08 ng/ml making this a potential diagnostic marker. Higher LCN2 expression was associated with worse survival in patients with CCA. LCN2 is a promising target for CCA treatment and bile LCN2 level is a potential diagnostic marker for CCA. PMID:27782193