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Sample records for advanced intrahepatic cholangiocarcinoma

  1. Intrahepatic Cholangiocarcinoma.

    PubMed

    Padia, Siddharth A

    2015-12-01

    Cholangiocarcinoma is a rare malignancy that arises from epithelial cells of the biliary system. Its desmoplastic histology and the heterogeneity of its presentation have contributed to its poor prognosis, with limited therapeutic options previously available. However, recent advances using locoregional therapy may expand the treatment arsenal used to manage this resistant malignancy. Although surgical resection has previously been reserved for relatively few patients because of inadequate hepatic reserve, portal vein embolization can induce contralateral hepatic lobe hypertrophy to increase the number of patients eligible for resection. For unresectable cases, both transarterial chemoembolization and yttrium-90 radioembolization have shown effectiveness in controlling tumor growth and prolonging survival. PMID:26615163

  2. Disease control with sunitinib in advanced intrahepatic cholangiocarcinoma resistant to gemcitabine-oxaliplatin chemotherapy

    PubMed Central

    Dreyer, Chantal; Sablin, Marie-Paule; Bouattour, Mohamed; Neuzillet, Cindy; Ronot, Maxime; Dokmak, Safi; Belghiti, Jacques; Guedj, Nathalie; Paradis, Valérie; Raymond, Eric; Faivre, Sandrine

    2015-01-01

    Advanced cholangiocarcinoma is associated with poor prognostic survival and has limited therapeutic options available at present. The importance of angiogenesis and expression of pro-angiogenic factors in intrahepatic forms of cholangiocarcinoma suggest that therapies targeting angiogenesis might be useful for the treatment of this disease. Here we report three cases of patients with advanced intrahepatic cholangiocarcinoma progressive after standard chemotherapy and treated with sunitinib 50 mg/d in 6-wk cycles of 4 wk on treatment followed by 2 wk off treatment (Schedule 4/2). In all three patients, sunitinib treatment was associated with a sustained disease control superior to 4 mo, patients achieving either a partial response or stable disease. A reduction in tumor size and density was observed in all cases, suggesting tumor necrosis as a result of sunitinib treatment in these patients. In addition, sunitinib was generally well tolerated and the occurrence of side effects was managed with standard medical interventions, as required. Our results suggest that sunitinib therapy may be associated with favorable outcomes and tolerability in patients with advanced cholangiocarcinoma. Those observations contributed to launch a prospective phase II multicenter trial investigating sunitinib in advanced intrahepatic cholangiocarcinoma (SUN-CK study; NCT01718327). PMID:25937868

  3. [Resection of Advanced Intrahepatic Cholangiocarcinoma after an Effective Response to S-1 and Gemcitabine Combination Therapy].

    PubMed

    Kuga, Yoshio; Moriya, Takashi; Fukuda, Saburo; Nishida, Toshihiro

    2016-06-01

    We report curative resection of an advanced intrahepatic cholangiocarcinoma that responded well to combined S-1 and gemcitabine chemotherapy(GS therapy). A 67-year-old woman was admitted to our hospital in July 2011 for upper right abdominal pain. She was diagnosed with intrahepatic cholangiocarcinoma with abdominal para-aortic lymph node metastasis on the basis of the computed tomography (CT) findings. She was treated with GS therapy. One course of S-1(80 mg/m(3)) consisted of the administration of the drug for 14 days, followed by 14 days of rest; GEM(1,000 mg/m(3)) was administered on days 1 and 15 after initiating S-1. After 2 courses of treatment, the sizes of the primary tumor and the lymph node metastasis were observed to be reduced on CT. In September, partial hepatectomy and regional lymph node dissection were performed. The patient subsequently received 22 postoperative courses of GS therapy. The patient's postoperative course was uneventful, and she remains free of recurrence 49 months since diagnosis. Therefore, GS therapy is a possible option for the management of advanced intrahepatic cholangiocarcinoma. PMID:27306819

  4. Molecular diagnosis of intrahepatic cholangiocarcinoma

    PubMed Central

    Haga, Hiroaki; Patel, Tushar

    2015-01-01

    Intrahepatic cholangiocarcinomas (iCCA) are primary intrahepatic malignancies originating from biliary epithelia. While both hepatocellular cancer and iCCA can present as mass lesions within the liver, these cancers are distinct in their morphology, etiology, pathology, natural history and response to therapy. There is a need for accurate and sensitive molecular markers for the diagnosis of iCCA. Recent advances in elucidating molecular and genetic characteristics of iCCA offer the potential of molecular-based diagnosis of iCCA. Specific genetic mutations of IDH1/2, BAP1, p53, and KRAS, FGFR gene fusions and alterations in microRNA have all been described in iCCA. Although there are no accurate serum or biliary biomarkers currently available for diagnosis of iCCA, several potential candidates have been identified. Knowledge of specific genetic or molecular abnormalities offers potential for individualized approaches for the treatment of patients with iCCA in the future. PMID:25267595

  5. Percutaneous microwave ablation combined with simultaneous transarterial chemoembolization for the treatment of advanced intrahepatic cholangiocarcinoma

    PubMed Central

    Yang, Guo-Wei; Zhao, Qing; Qian, Sheng; Zhu, Liang; Qu, Xu-Dong; Zhang, Wei; Yan, Zhi-Ping; Cheng, Jie-Min; Liu, Qing-Xin; Liu, Rong; Wang, Jian-Hua

    2015-01-01

    Aim To retrospectively evaluate the safety and efficacy of ultrasound-guided percutaneous microwave ablation (MWA) combined with simultaneous transarterial chemoembolization (TACE) in the treatment of patients with advanced intrahepatic cholangiocarcinoma (ICC). Methods All patients treated with ultrasound-guided percutaneous MWA combined with simultaneous TACE for advanced ICC at our institution were included. Posttreatment contrast-enhanced computed tomography and/or magnetic resonance imaging were retrieved and reviewed for tumor response to the treatment. Routine laboratory studies, including hematology and liver function tests were collected and analyzed. Procedure-related complications were reviewed and survival rates were analyzed. Results From January 2011 to December 2014, a total of 26 advanced ICC patients were treated at our single institute with ultrasound-guided percutaneous MWA combined with simultaneous TACE. There were 15 males and eleven females with an average age of 57.9±10.4 years (range, 43–75 years). Of 26 patients, 20 (76.9%) patients were newly diagnosed advanced ICC without any treatment, and six (23.1%) were recurrent and treated with surgical resection of the original tumor. The complete ablation rate was 92.3% (36/39 lesions) for advanced ICC. There were no major complications observed. There was no death directly from the treatment. Median progression-free survival and overall survival were 6.2 and 19.5 months, respectively. The 6-, 12-, and 24-month survival rates were 88.5%, 69.2%, and 61.5%, respectively. Conclusion The study suggests that ultrasound-guided percutaneous MWA combined with simultaneous TACE therapy can be performed safely in all patients with advanced ICC. The complete ablation rate was high and there was no major complication. The overall 24-month survival was 61.5%. PMID:26060410

  6. Intrahepatic sarcomatoid cholangiocarcinoma.

    PubMed

    Kaibori, Masaki; Kawaguchi, Yusai; Yokoigawa, Norio; Yanagida, Hidesuke; Takai, Soichiro; Kwon, A-Hon; Uemura, Yoshiko; Kamiyama, Yasuo

    2003-01-01

    A 69-year-old woman was admitted to our hospital with fever and abdominal pain in the epigastric region. Abdominal ultrasonography demonstrated a well-defined hypoechoic mass in the epigastric region with encasement of the left hepatic lobe and stomach. Computed tomography confirmed a low-density mass, 20 cm in diameter, with enhancing peripheral areas. Angiography revealed the tumor to be hypovascular. After admission, the patient had a persistent fever and anemia that required transfusions of concentrated red blood cells. On the twelfth day after admission, she suffered disseminated intravascular coagulation and underwent an emergency operation. A lateral segmentectomy with dissection of lymph nodes, cholecystectomy, and hemigastrectomy were carried out. The size of the tumor was 22 x 17 x 15 cm. Macroscopically, a cross-section revealed massive necrosis with hemorrhage. Histological examination of the tumor showed a malignant neoplasm with a carcinomatous component and a sarcomatous component, which were partly intermingled. The former consisted of moderately differentiated adenocarcinoma, while the latter consisted of pleomorphic spindle cells. Immunohistochemical examination of the sarcomatous component showed positive staining for vimentin, epithelial membrane antigen, and cytokeratin. The tumor was diagnosed as cholangiocarcinoma with extensive sarcomatous changes, based on these histological and immunohistochemical findings. The patient had an uneventful postoperative course. However, she died 3 months after surgery from dissemination of the carcinoma. The literature on this rare disease is reviewed and discussed. PMID:14673730

  7. Surgical management of intrahepatic cholangiocarcinoma in the modern era: advances and challenges.

    PubMed

    Konstantinidis, Ioannis T; Arkadopoulos, Nikolaos; Ferrone, Cristina R

    2016-02-01

    Intrahepatic cholangiocarcinoma (ICC) is one of the few gastrointestinal cancers with increasing incidence and mortality worldwide. Unlike hepatocellular carcinoma (HCC) which arises usually in a cirrhotic environment ICC frequently arises in the context of normal hepatic parenchyma. Surgical resection represents the mainstay of curative treatment, with minimally invasive approaches being increasingly utilized. Despite good surgical outcomes, most patients suffer from disease recurrence and eventually succumb to their disease. Effective adjuvant treatments are therefore needed. For unresectable disease hepatic artery utilization techniques are becoming more widely used. New treatments for non metastatic disease such as proton beam therapy (PBT) are also emerging. Systemic chemotherapy is also changing and targeted biologic agents are being added to conventional chemotherapeutic agents. PMID:26932433

  8. Intrahepatic Cholangiocarcinoma Masquerading as Liver Abscess

    PubMed Central

    Shah, Vinit; Arora, Anil; Tyagi, Pankaj; Sharma, Praveen; Bansal, Naresh; Singla, Vikas; Bansal, Rinkesh K.; Gupta, Varun; Kumar, Ashish

    2015-01-01

    Malignancy masquerading as liver abscess, and presenting with fever, is mainly described in patients with colorectal cancers with liver metastasis. Primary liver tumors such as hepatocellular carcinoma or intrahepatic cholangiocarcinoma presenting as non-resolving liver abscess is extremely uncommon and carries a dismal prognosis. We present a rare case of non-resolving liver abscess as a presenting manifestation of intrahepatic cholangiocarcinoma. PMID:25941437

  9. Serum markers of intrahepatic cholangiocarcinoma.

    PubMed

    Malaguarnera, Giulia; Paladina, Isabella; Giordano, Maria; Malaguarnera, Michele; Bertino, Gaetano; Berretta, Massimiliano

    2013-01-01

    Cholangiocarcinoma (CCA) is a relatively rare type of primary liver cancer that originates in the bile duct epithelium. It is an aggressive malignancy typified by unresponsiveness to chemotherapy and radiotherapy. Despite advances in radiologic techniques and laboratory diagnostic test, the diagnosis of CCA remains highly challenging. Development in molecular techniques has led to go into the possible use of serum markers in diagnosing of cholangiocarcinoma. This review summarizes the principal characteristics of serum markers of cholangiocarcinoma. The tumour markers used frequently such as Carbohydrate antigen 19-9 (CA 19-9), Carcinogenic Embryonic antigen (CEA), and Cancer Antigen 125 have shown sufficient sensitivity and specificity to detect and monitor CCA. In particular, the combination of these tumour markers seems to increase their efficiency in diagnosing of cholangiocarcinoma. New markers such as Soluble fragment of cytokeratin 19 (CYFRA 21-1) Mucins, Tumour Markers_{2} pyruvate-Kinase (TuM_{2-} PK) and metalloproteinase-7 (MMP-7) have been recently shown to help in the diagnosis of CCA, with in some cases a prognostic value. PMID:23396291

  10. Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma.

    PubMed

    Esnaola, Nestor F; Meyer, Joshua E; Karachristos, Andreas; Maranki, Jennifer L; Camp, E Ramsay; Denlinger, Crystal S

    2016-05-01

    Cholangiocarcinomas are rare biliary tract tumors that are often challenging to diagnose and treat. Cholangiocarcinomas are generally categorized as intrahepatic or extrahepatic depending on their anatomic location. The majority of patients with cholangiocarcinoma do not have any of the known or suspected risk factors and present with advanced disease. The optimal evaluation and management of patients with cholangiocarcinoma requires thoughtful integration of clinical information, imaging studies, cytology and/or histology, as well as prompt multidisciplinary evaluation. The current review focuses on recent advances in the diagnosis and treatment of patients with cholangiocarcinoma and, in particular, on the role of endoscopy, surgery, transplantation, radiotherapy, systemic therapy, and liver-directed therapies in the curative or palliative treatment of these individuals. Cancer 2016;122:1349-1369. © 2016 American Cancer Society. PMID:26799932

  11. Intrahepatic cholangiocarcinoma: expert consensus statement.

    PubMed

    Weber, Sharon M; Ribero, Dario; O'Reilly, Eileen M; Kokudo, Norihiro; Miyazaki, Masaru; Pawlik, Timothy M

    2015-08-01

    An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists met on 15 January 2014 to review current evidence on the management of intrahepatic cholangiocarcinoma (ICC) in order to establish practice guidelines and to agree on consensus statements. The treatment of ICC requires a coordinated, multidisciplinary approach to optimize survival. Biopsy is not necessary if the surgeon suspects ICC and is planning curative resection, although biopsy should be obtained before systemic or locoregional therapies are initiated. Assessment of resectability is best accomplished using cross-sectional imaging [computed tomography (CT) or magnetic resonance imaging (MRI)], but the role of positron emission tomography (PET) is unclear. Resectability in ICC is defined by the ability to completely remove the disease while leaving an adequate liver remnant. Extrahepatic disease, multiple bilobar or multicentric tumours, and lymph node metastases beyond the primary echelon are contraindications to resection. Regional lymphadenectomy should be considered a standard part of surgical therapy. In patients with high-risk features, the routine use of diagnostic laparoscopy is recommended. The preoperative diagnosis of combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) by imaging studies is extremely difficult. Surgical resection remains the mainstay of treatment, but survival is worse than in HCC alone. There are no adequately powered, randomized Phase III trials that can provide definitive recommendations for adjuvant therapy for ICC. Patients with high-risk features (lymphovascular invasion, multicentricity or satellitosis, large tumours) should be encouraged to enrol in clinical trials and to consider adjuvant therapy. Cisplatin plus gemcitabine represents the standard-of-care, front-line systemic therapy for metastatic ICC. Genomic analyses of biliary cancers support the development of targeted therapeutic interventions. PMID

  12. 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

  13. Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase (IDH) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma

    PubMed Central

    Goyal, Lipika; Govindan, Aparna; Sheth, Rahul A.; Nardi, Valentina; Blaszkowsky, Lawrence S.; Faris, Jason E.; Clark, Jeffrey W.; Ryan, David P.; Kwak, Eunice L.; Allen, Jill N.; Murphy, Janet E.; Saha, Supriya K.; Hong, Theodore S.; Wo, Jennifer Y.; Ferrone, Cristina R.; Tanabe, Kenneth K.; Chong, Dawn Q.; Deshpande, Vikram; Borger, Darrell R.; Iafrate, A. John; Bardeesy, Nabeel; Zheng, Hui

    2015-01-01

    Background. Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with advanced-stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC. Methods. Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging. Results. Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p = .17). The pretreatment serum carbohydrate antigen 19-9 (CA19-9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p = .04). Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status. Conclusion. The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19-9 level at presentation. Implications for Practice: Previous studies assessing the prognostic impact of the isocitrate dehydrogenase (IDH) gene mutation in intrahepatic cholangiocarcinoma (ICC) mainly focused on patients with early-stage disease who have undergone resection. These studies offer conflicting results. The target population for clinical trials of IDH inhibitors is patients with

  14. Multimodality treatment of intrahepatic cholangiocarcinoma: A review.

    PubMed

    Simo, Kerri A; Halpin, Laura E; McBrier, Nicole M; Hessey, Jacob A; Baker, Erin; Ross, Samuel; Swan, Ryan Z; Iannitti, David A; Martinie, John B

    2016-01-01

    Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary hepatic cancer in the United States. Currently, curative treatment involves aggressive surgery. Chemotherapy and radiation treatments have been used for unresectable tumors with some success. Optimizing the use of current and developing novel multimodality treatment for iCCA is essential to improving outcomes. PMID:26797780

  15. Molecular pathogenesis of intrahepatic cholangiocarcinoma.

    PubMed

    Andersen, Jesper B

    2015-02-01

    Cholangiocarcinoma (CCA) is an orphan cancer of the hepatobiliary tract, the incidence of which has increased in the past decade. The molecular pathogenesis of this treatment-refractory disease is poorly understood. Desmoplasia is a key causal feature of CCA; however, a majority of tumors develop with no apparent etiological background. The impact of the stromal compartment on tumor progression as well as resistance to therapy is in vogue, and the epithelial-stromal crosstalk may present a target for novel treatment strategies. As such, the complexity of tumor cellularity and the molecular mechanisms underlying the diversity of growth patterns of this malignancy remain a clinical concern. It is crucial to advance our present understanding of the molecular pathogenesis of CCA to improve current clinical strategies and patient outcome. This will facilitate the delineation of patient subsets and individualization for precision therapies. Many questions persevere as to the evolutionary process and cellular origin of the initial transforming event, the context of intratumoral plasticity and the causal driver action. Next-generation sequencing has begun to underline the persistent alterations, which may be the trigger of acquired drug resistance, and the cause of metastasis and disease recurrence. A complex issue that remains is to account for the heterogeneous pool of "backseat" aberrations, which in chromosomal proximity to the causative variant are likely to influence, for example, drug response. This review explores the recent advances in defining the molecular pathways implicated in the development of this devastating disease and, which present putative clinical strategies. PMID:25174625

  16. Clinical Diagnosis and Staging of Intrahepatic Cholangiocarcinoma.

    PubMed

    Bartella, Isabel; Dufour, Jean-François

    2015-12-01

    Intrahepatic cholangiocarcinomas are the second most common primary liver malignancies with an increasing incidence over the past decades. Due to a lack of early symptoms and their aggressive oncobiological behavior, the diagnostic approach is challenging and the outcome remains unsatisfactory with a poor prognosis. Thus, a consistent staging system for a comparison between different therapeutic approaches is needed, but independent predictors for worse survival are still controversial. Currently, four different staging systems are primarily used, which differ in the way they determine the 'T' category. Furthermore, different nomograms and prognostic models have been recently proposed and may be helpful in providing additional information for predicting the prognosis and therefore be helpful in approaching an adequate treatment strategy. This review will discuss the diagnostic approach to intrahepatic cholangiocarcinoma as well as compare and contrast the most current staging systems and prognostic models. PMID:26697575

  17. A case of intrahepatic clear cell cholangiocarcinoma

    PubMed Central

    Toriyama, Eo; Nanashima, Atsushi; Hayashi, Hideyuki; Abe, Kuniko; Kinoshita, Naoe; Yuge, Shunsuke; Nagayasu, Takeshi; Uetani, Masataka; Hayashi, Tomayoshi

    2010-01-01

    Intrahepatic clear cell cholangiocarcinoma is very rare - only 8 cases have been reported. A 56-year-old Japanese man with chronic hepatitis B infection was diagnosed with a 2.2 cm hepatocellular carcinoma on imaging, and hepatic segmentectomy was performed. Histopathologically, the tumor cells had copious clear cytoplasm and formed glandular structures or solid nests. These pathological findings suggested the tumor was a clear cell variant of intrahepatic cholangiocarcinoma. Particular stains and radiological images suggested that the cause of the clear cell change had been glycogen, not mucin nor lipid. On immunohistochemical staining, cytokeratin (CK) 7 and CK19 were positive, whereas CK20 was negative. Vimentin was detected on the cell membranes, and CD56 was focally positive. The patient was given adjuvant chemotherapy and is currently free from the tumor 7 mo postoperatively. Careful follow-up with adequate postoperative supplementary chemotherapy is necessary because the characteristics of this type of tumor are unknown. PMID:20503460

  18. Congenital dilatation of the intrahepatic bile ducts with cholangiocarcinoma

    PubMed Central

    Gallagher, P. J.; Millis, R. R.; Mitchinson, M. J.

    1972-01-01

    Intrahepatic cholangiocarcinomas were found at necropsy in two previously reported cases of congenital dilatation of the intrahepatic bile ducts. The nature of the developmental abnormality is discussed and compared with other forms of biliary dilatation. Slow-flowing bile for many years probably leads to cholangiocarcinoma. Images PMID:4343747

  19. Transarterial therapies for the treatment of intrahepatic cholangiocarcinoma.

    PubMed

    Zechlinski, Joseph J; Rilling, William S

    2013-03-01

    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

  20. 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

  1. 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

  2. A case of advanced intrahepatic cholangiocarcinoma accidentally, but successfully, treated with capecitabine plus oxaliplatin (CAPOX) therapy combined with bevacizumab: a case report.

    PubMed

    Uji, Masahito; Mizuno, Takashi; Ebata, Tomoki; Sugawara, Gen; Igami, Tsuyoshi; Uehara, Keisuke; Nagino, Masato

    2016-12-01

    Although surgical resection is the only way to cure biliary tract cancer (BTC), most BTCs are unresectable by the time they are diagnosed. Chemotherapy is usually used to treat unresectable BTC, but its impact on survival is small. Here, we report the case of a 70-year-old woman with a locally advanced intrahepatic cholangiocarcinoma that was initially diagnosed as an unresectable liver metastasis from colon cancer that had invaded all of the major hepatic veins. However, the tumor was noticeably reduced after treatment with CAPOX plus bevacizumab, which is an uncommon therapy for BTC. The tumor was finally resected by inferior right hepatic vein-preserving left hepatic trisectionectomy combined with a resection of the right hepatic vein after a right hepatic vein embolization. PMID:27342988

  3. Evaluation of efficacy, safety and tolerability of high dose-intermittent calcitriol supplementation to advanced intrahepatic cholangiocarcinoma patients--a pilot study.

    PubMed

    Sookprasert, Aumkhae; Pugkhem, Ake; Khuntikeo, Narong; Chur-in, Siri; Chamadol, Nittaya; Prawan, Auemduan; Janeklang, Somkid; Vaeteewoottacharn, Kulthida; Kukongviriyapan, Veerapol; Pairojkul, Chawalit; Bhudhisawasdi, Vajarabhongsa; Wongkham, Sopit

    2012-01-01

    Antitumor activity (growth suppression) of vitamin D has been demonstrated using cholangiocarcinoma (CCA) cell lines, CCA cell-grafted animal models, and human CCA tissue cultures. The present study aimed to determine the toxicity and tolerability of intermittent-high dose calcitriol in advanced inoperable intrahepatic CCA patients and to evaluate the therapeutic efficacy of combinations of calcitriol and 5-fluorouracil-based chemotherapeutic drugs. The patients were divided into 3 groups: the first (n=2) received intermittent-high dose oral calcitriol 12 μg/day for 3 days, i.e. Monday-Wednesday, per week up to 3 months. The treatment did not cause any serious adverse events, except hypercalcemia grade I, once in 72 administrations. The second group (n=3) received chemotherapeutic drugs (5-fluorouracil, Mitomycin C and Leucovorin) for 3 cycles, one patient showing a partial response. The third group (n=4) received high dose calcitriol in combination with chemotherapeutic-drugs. All 4 patients encountered serious adverse events and two of them were withdrawn after the first drug cycle. This pilot study suggests that, although high dose-intermittent calcitriol appeared to be safe and tolerated well in advanced intrahepatic CCA patients, co-administration with 5-fluorouracil-based chemotherapeutic drugs caused unexpected potentiation of their toxicity. Adjustment of the doses of both drugs is required to avoid such toxicity and to optimize therapeutic efficacy of anticancer drugs when they were combined with high dose-intermittent calcitriol. PMID:23480759

  4. Outcomes following resection of intrahepatic cholangiocarcinoma

    PubMed Central

    Tabrizian, Parissa; Jibara, Ghalib; Hechtman, Jaclyn F; Franssen, Bernardo; Labow, Daniel M; Schwartz, Myron E; Thung, Swan N; Sarpel, Umut

    2015-01-01

    Objectives The aim of this analysis was to examine prognostic features and outcomes in patients undergoing resection for intrahepatic cholangiocarcinoma (ICC). Methods A retrospective chart review was performed in all patients who underwent R0 or R1 resection for primary ICC between 1995 and 2011. Clinical data were abstracted and statistical analyses were conducted in the standard fashion. Results A total of 82 patients underwent curative hepatectomy for primary ICC; 51 patients in this cohort developed recurrence. The median follow-up of survivors was 27 months (range: 1–116 months). Recurrences were intrahepatic (65%), associated with multiple tumours (54%) and occurred during the first 2 years after hepatectomy (86%). The main factor associated with recurrence after resection was the presence of satellite lesions. Overall 5-year disease-free survival after primary resection was 16%. Factors associated with poor survival were transfusion and perineural invasion. Treatment of recurrence was undertaken in 89% of patients and repeat surgical resection was performed in 15 patients. The 3-year survival rate after recurrence was 25%. Prolonged survival after recurrence was associated with a solitary tumour recurrence. Conclusions Despite curative resection of ICC, recurrence can be expected to occur in 79% of patients at 5 years. Predictors of survival and recurrence after resection vary in the literature. In patients with recurrence, selection of the optimal treatment remains challenging. PMID:25395176

  5. Intrahepatic cholangiocarcinoma: radiologic-pathologic correlation.

    PubMed

    Ros, P R; Buck, J L; Goodman, Z D; Ros, A M; Olmsted, W W

    1988-06-01

    Seventeen proved cases of intrahepatic cholangiocarcinoma (ICAC) were reviewed to establish a radiologic-pathologic correlation. The most common appearance of ICAC at computed tomography (CT) is that of a single, homogeneous low-attenuation mass. Multiple low-attenuation lesions were present in four cases. Calcification was depicted by CT in three cases. At angiography, ICAC has a variable appearance with avascular, hypovascular, and hypervascular patterns possible. Portal obstruction was seen in only one case. The most common appearance of ICAC at sonography is that of a homogeneously hyperechoic mass, either single or multiple. In only one case was ICAC hypoechoic. Plain abdominal radiography demonstrated calcification in three patients and evidence of Thorotrast (thorium dioxide) deposition in one. Upper gastrointestinal series demonstrated abnormal gastric folds in two cases, corresponding to gastric invasion by ICAC. There were no characteristic radiographic findings, but the following features may be helpful in differentiating ICAC from other primary intrahepatic tumors, particularly typical hepatocellular carcinoma: a homogeneously echogenic or high-attenuation appearance on images that reflects the uniform nature observed at pathologic examination, the presence of calcification, and the uncommon invasion of portal or hepatic veins. Conversely, the presence of satellite lesions may blur the the distinction between ICAC and metastatic liver disease. PMID:2834769

  6. Hepatitis B virus infection and intrahepatic cholangiocarcinoma

    PubMed Central

    Zhou, Hua-Bang; Hu, Jing-Yi; Hu, He-Ping

    2014-01-01

    Intrahepatic cholangiocarcinoma (ICC) is a devastating malignant tumor arising from the peripheral intrahepatic bile duct epithelium. The incidence and mortality of ICC is markedly increasing over the past two decades worldwide, though the cause for this rise in incidence is unclear, thus intensifying the search for alternative etiological agents and pathogenetic mechanisms. Hepatolithiasis, primary sclerosing cholangitis, parasitic infection (Opisthorchis viverrini or Clonorchis sinensis), fibropolycystic liver disease, and chemical carcinogen exposure are thought to be the risk factors for ICC. Nevertheless, the majority of ICC patients do not have any of these risk factors, and none of the established risk factors can explain the recent increasing trend of ICC. Therefore, identifying other risk factors may lead to the prevention and early detection of ICC. Chronic hepatitis B virus (HBV) infection is the predominant cause of hepatocellular carcinoma in HBV-endemic areas. This review discusses the evidence implicating chronic HBV infection as a likely etiology of ICC and the pathogenetic mechanisms that might be involved. PMID:24914333

  7. Intrahepatic cholangiocarcinoma: Epidemiology, risk factors, diagnosis and surgical management.

    PubMed

    Zhang, Han; Yang, Tian; Wu, Mengchao; Shen, Feng

    2016-09-01

    Intrahepatic cholangiocarcinoma (ICC), the least common form of cholangiocarcinomas, is a rare hepatobiliary malignancy that arises from the epithelial cells of the intrahepatic bile ducts. The incidence of ICC has been rising in the global scale over the last twenty years, which may reflect both a true increase and the trend of earlier detection of the disease. Other than some well recognized causative risk factors, the association between viral and metabolic factors and ICC pathogenesis has been increasingly identified recently. Surgical resection is currently the only feasible modality with a curative ability, but the resectability and curability remain low. The high invasiveness of ICC predisposes the tumors to multifocality, node metastasis and vascular invasions, leading to poor long-term survival after resection. The role of liver transplantation is controversial, while locoregional treatments and systematic therapies may provide survival benefits, especially in patients with unresectable and advanced tumors. The present review discussed the epidemiology, risk factors, surgical and multimodal management of ICCs, which mainly focused on the outcomes and factors associated with surgical treatment. PMID:26409434

  8. Radiofrequency ablation of intrahepatic cholangiocarcinoma: preliminary experience.

    PubMed

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

    2010-08-01

    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. PMID:20411389

  9. 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.

  10. 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

  11. Locoregional intra-arterial therapies for unresectable intrahepatic cholangiocarcinoma.

    PubMed

    Hong, Kelvin; Geschwind, Jean-Francois H

    2010-04-01

    Intrahepatic cholangiocarcinoma (ICC) is a rare hepatic malignancy that for patients with unresectable disease is uniformly fatal. Only approximately 30% of patients are eligible for resection because of the advanced nature of the disease at the time of diagnosis. Systemic chemotherapy has been disappointing in regard to its efficacy, with most regimens resulting in a median survival of 6 to12 months. There has been great interest in other modalities of treatment, particularly intra-arterial therapies, which consist of a catheter-based group of treatments where therapeutic and/or embolic agents are intra-arterially injected to target the liver tumors. In this report, we attempt to employ an evidence-based approach to critically review and comprehend the current role and future potential of intra-arterial therapies for ICC. PMID:20494703

  12. The miRNAome of Opisthorchis viverrini induced intrahepatic cholangiocarcinoma

    PubMed Central

    Peng, Jin; Feng, Yanjun; Rinaldi, Gabriel; Yonglitthipagon, Ponlapat; Easley, Samantha E.; Laha, Therawach; Pairojkul, Chawalit; Bhudhisawasdi, Vajarabhongsa; Sripa, Banchob; Brindley, Paul J.; Mulvenna, Jason P.; Bethony, Jeffrey M.; Plieskatt, Jordan L.

    2014-01-01

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer, arising in the biliary ducts that extend into the liver. The highest incidence of ICC occurs in Southeast Asia, particularly in the Mekong River Basin countries of Thailand, Laos, Cambodia, and Vietnam, where it is strongly associated with chronic infection by the food-borne liver fluke Opisthorchis viverrini (OV), one of only three eukaryote pathogens considered Group one carcinogens. Intrahepatic cholangiocarcinoma is usually diagnosed at an advanced stage, with a poor prognosis and survival often less than 24 months. Hence, biomarkers that enable the early detection of ICC would be desirable and have a potentially important impact on the public health in the resource-poor regions where this cancer is most prevalent. As microRNAs (miRNAs) remain well preserved after formalin fixation, there is much interest in developing them as biomarkers that can be investigated using tumor biopsy samples preserved in formalin fixed paraffin embedded (FFPE) tumor blocks. Recently, we reported the first comprehensive profiling of tissue-based miRNA expression using FFPE from the three most common subtypes of OV-induced ICC tumors: moderately differentiated ICC, papillary ICC, and well-differentiated ICC. We observed that each subtype of OV-induced ICC exhibited a distinct miRNA profile, which suggested the involvement of specific sets of miRNAs in the progression of this cancer. In addition, non-tumor tissue adjacent to ICC tumor tissue on the same FFPE block shared a similar miRNA dysregulation profile with the tumor tissue than with normal (non-tumor) liver tissue (individuals without ICC or OV infection). Herein, we provide a detailed description of the microarray analysis procedures used to derive these findings. PMID:26484108

  13. Prevalence of Nonalcoholic Steatohepatitis Among Patients with Resectable Intrahepatic Cholangiocarcinoma

    PubMed Central

    Reddy, Srinevas K.; Hyder, Omar; Marsh, J. Wallis; Sotiropoulos, Georgios C.; Paul, Andreas; Alexandrescu, Sorin; Marques, Hugo; Pulitano, Carlo; Barroso, Eduardo; Aldrighetti, Luca; Geller, David A.; Sempoux, Christine; Herlea, Vlad; Popescu, Irinel; Anders, Robert; Rubbia-Brandt, Laura; Gigot, Jean-Francois; Mentha, Giles; Pawlik, Timothy M.

    2014-01-01

    Background and Aims The objective of this report was to determine the prevalence of underlying nonalcoholic steatohepatitis in resectable intrahepatic cholangiocarcinoma. Methods Demographics, comorbidities, clinicopathologic characteristics, surgical treatments, and outcomes from patients who underwent resection of intrahepatic cholangiocarcinoma at one of eight hepatobiliary centers between 1991 and 2011 were reviewed. Results Of 181 patients who underwent resection for intrahepatic cholangiocarcinoma, 31 (17.1 %) had underlying nonalcoholic steatohepatitis. Patients with nonalcoholic steatohepatitis were more likely obese (median body mass index, 30.0 vs. 26.0 kg/m2, p<0.001) and had higher rates of diabetes mellitus (38.7 vs. 22.0 %, p=0.05) and the metabolic syndrome (22.6 vs. 10.0 %, p=0.05) compared with those without nonalcoholic steatohepatitis. Presence and severity of hepatic steatosis, lobular inflammation, and hepatocyte ballooning were more common among nonalcoholic steatohepatitis patients (all p<0.001). Macrovascular (35.5 vs. 11.3 %, p=0.01) and any vascular (48.4 vs. 26.7 %, p=0.02) tumor invasion were more common among patients with nonalcoholic steatohepatitis. There were no differences in recurrence-free (median, 17.0 versus 19.4 months, p=0.42) or overall (median, 31.5 versus 36.3 months, p=0.97) survival after surgical resection between patients with and without nonalcoholic steatohepatitis. Conclusions Nonalcoholic steatohepatitis affects up to 20 % of patients with resectable intrahepatic cholangiocarcinoma. PMID:23355033

  14. A case of occult intrahepatic cholangiocarcinoma diagnosed by autopsy.

    PubMed

    Oda, Eri; Hashimoto, Daisuke; Shiomi, Yuko; Ohnishi, Koji; Hayashi, Hiromitsu; Chikamoto, Akira; Takeya, Motohiro; Baba, Hideo

    2015-12-01

    Cancer of unknown primary is associated with unknown biology and dismal prognosis. The most common primary sites of cancer of unknown primary were usually the lungs in autopsy studies, and intrahepatic cholangiocarcinoma is rare. We describe the case of a 57-year-old male patient with systemic lymph node metastasis. Imaging examination failed to reveal primary cancer; however, immunostaining of cytokeratins 7, 19, and 20 of a metastatic axillary lymph node suggested a pancreaticobiliary cancer as a primary lesion. He died of liver abscess and sepsis, and then, autopsy indicated occult intrahepatic cholangiocarcinoma. We discuss the clinical course of this rare cholangiocarcinoma including the diagnostic procedure and also present a review of the English literature regarding patients with cancer of unknown primary. PMID:26943425

  15. 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

  16. Transarterial chemoembolization (TACE) for inoperable intrahepatic cholangiocarcinoma.

    PubMed

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

    2007-01-01

    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

  17. Primary hepatic tuberculosis mimicking intrahepatic cholangiocarcinoma: report of two cases

    PubMed Central

    2015-01-01

    Hepatic tuberculosis (TB) is usually associated with pulmonary or miliary TB, but primary hepatic TB is very uncommon even in countries with high prevalence of TB. The clinical manifestation of primary hepatic TB is atypical and imaging modalities are unhelpful for differential diagnosis of the liver mass. Image-guided needle biopsy is the best diagnostic method for primary hepatic TB. In the cases presented here, we did not perform liver biopsy because we believed the liver masses were cholangiocarcinoma, but primary hepatic TB was ultimately confirmed by postoperative pathology. Here we report two cases of patients who were diagnosed with primary hepatic TB mimicking mass-forming intrahepatic cholangiocarcinoma. PMID:26236700

  18. 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

  19. 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

  20. Hepatolithiasis and intrahepatic cholangiocarcinoma: A review.

    PubMed

    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

    2015-12-28

    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

  1. Molecular Pathogenesis and Current Therapy in Intrahepatic Cholangiocarcinoma.

    PubMed

    Høgdall, Dan; O'Rourke, Colm J; Taranta, Andrzej; Oliveira, Douglas V N P; Andersen, Jesper B

    2016-01-01

    Intrahepatic cholangiocarcinoma (iCCA) comprises one of the most rapidly evolving cancer types. An underlying chronic inflammatory liver disease that precedes liver cancer development for several decades and creates a pro-oncogenic microenvironment frequently impairs progress in therapeutic approaches. Depending on the cellular target of malignant transformation, a large spectrum of molecular and morphological patterns is observed. As such, it is crucial to advance our existing understanding of the molecular pathogenesis of iCCA, particularly its genomic heterogeneity, to improve current clinical strategies and patient outcome. This was achieved for other cancers, such as breast carcinoma, facilitated by the delineation of patient subsets and of precision therapies. In iCCA, many questions persevere as to the evolutionary process and cellular origin of the initial transforming event, the context of tumor plasticity and the causative features driving the disease. Molecular profiling and pathological techniques have begun to underline persistent alterations that may trigger inherited drug resistance (a hallmark of hepatobiliary and pancreatic cancers), metastasis and disease recurrence. In this review, we will focus on the key molecular achievements that are currently advancing the characterization and stratification of iCCA. We will discuss current clinical practice and how genomic achievements may advance diagnosis and therapy as well as ultimately improve patient outcome. PMID:27170400

  2. Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma.

    PubMed

    Ettel, Mark; Eze, Ogechukwu; Xu, Ruliang

    2015-11-01

    Cholangiocarcinoma (CC) is primarily a malignant tumor of older adults most prevalent in Southeast Asia, where liver fluke infestation is high. However the etiology in western countries is unknown. Although the incidence of extrahepatic cholangiocarcinoma has remained constant, incidence of intrahepatic CC (ICC) which differs in morphology, pathogenesis, risk factors, treatment and prognosis is increasing. While this increase is associated with hepatitis C virus infection, chronic nonalcoholic liver disease, obesity, and smoking, the pathogenesis of ICC and molecular alterations underlying the carcinogenesis are not completely elucidated. Benign biliary lesions such as biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, von Meyenburg complex or bile duct hamartoma, and bile duct adenoma have been associated with ICC. For each of these entities, evidence suggests or supports a role as premalignant lesions. This article summarized the important biological significance of the precursor lesions of ICC and the molecular mechanisms that may be involved in intrahepatic cholangiocarcinogenesis. PMID:26557948

  3. Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma

    PubMed Central

    Ettel, Mark; Eze, Ogechukwu; Xu, Ruliang

    2015-01-01

    Cholangiocarcinoma (CC) is primarily a malignant tumor of older adults most prevalent in Southeast Asia, where liver fluke infestation is high. However the etiology in western countries is unknown. Although the incidence of extrahepatic cholangiocarcinoma has remained constant, incidence of intrahepatic CC (ICC) which differs in morphology, pathogenesis, risk factors, treatment and prognosis is increasing. While this increase is associated with hepatitis C virus infection, chronic nonalcoholic liver disease, obesity, and smoking, the pathogenesis of ICC and molecular alterations underlying the carcinogenesis are not completely elucidated. Benign biliary lesions such as biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, von Meyenburg complex or bile duct hamartoma, and bile duct adenoma have been associated with ICC. For each of these entities, evidence suggests or supports a role as premalignant lesions. This article summarized the important biological significance of the precursor lesions of ICC and the molecular mechanisms that may be involved in intrahepatic cholangiocarcinogenesis. PMID:26557948

  4. Stereotactic Body Radiotherapy (SBRT) for Intrahepatic and Hilar Cholangiocarcinoma

    PubMed Central

    Mahadevan, Anand; Dagoglu, Nergiz; Mancias, Joseph; Raven, Kristin; Khwaja, Khalid; Tseng, Jennifer F; Ng, Kimmie; Enzinger, Peter; Miksad, Rebecca; Bullock, Andrea; Evenson, Amy

    2015-01-01

    Background: Unresectable intrahepatic and hilar cholangiocarcinomas carry a dismal prognosis. Systemic chemotherapy and conventional external beam radiation and brachytherapy have been used with limited success. We explored the use of stereotactic body radiotherapy (SBRT) for these patients. Methods: Patients with unresectable intrahepatic or hilar cholangiocarcinoma or those with positive margins were included in this study. Systemic therapy was used at the discretion of the medical oncologist. The CyberknifeTM stereotactic body radiotherapy system used to treat these patients. Patients were treated with three daily fractions. Clinical and radiological follow-up were performed every three months. Results: 34 patients (16 male and 18 female) with 42 lesions were included in this study. There were 32 unresectable tumors and two patients with resected tumors with positive margins. The median SBRT dose was 30Gy in three fractions. The median follow-up was 38 months (range 8-71 months). The actuarial local control rate was 79%. The median overall survival was 17 months and the median progression free survival was ten months. There were four Grade III toxicities (12%), including duodenal ulceration, cholangitis and liver abscess. Conclusions: SBRT is an effective and reasonably safe local therapy option for unresectable intrahepatic or hilar cholangiocarcinoma. PMID:26516357

  5. 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. PMID:24063104

  6. Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma.

    PubMed

    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

    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

  7. Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma.

    PubMed

    Moeini, Agrin; Sia, Daniela; Bardeesy, Nabeel; Mazzaferro, Vincenzo; Llovet, Josep M

    2016-01-15

    Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous hepatobiliary neoplasm with poor prognosis and limited therapeutic options. The incidence of this neoplasm is growing globally. One third of iCCA tumors are amenable to surgical resection, but most cases are diagnosed at advanced stages with chemotherapy as the only established standard of practice. No molecular therapies are currently available for the treatment of this neoplasm. The poor understanding of the biology of iCCA and the lack of known oncogenic addiction loops has hindered the development of effective targeted therapies. Studies with sophisticated animal models defined IDH mutation as the first gatekeeper in the carcinogenic process and led to the discovery of striking alternative cellular origins. RNA- and exome-sequencing technologies revealed the presence of recurrent novel fusion events (FGFR2 and ROS1 fusions) and somatic mutations in metabolic (IDH1/2) and chromatin-remodeling genes (ARID1A, BAP1). These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA. More than 100 clinical trials testing molecular therapies alone or in combination with chemotherapy including iCCA patients have not reported conclusive clinical benefits. Recent discoveries have shown that up to 70% of iCCA patients harbor potential actionable alterations that are amenable to therapeutic targeting in early clinical trials. Thus, the first biomarker-driven trials are currently underway. PMID:26405193

  8. 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

  9. 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

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

    PubMed

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

    2016-04-01

    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

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

    PubMed Central

    2014-01-01

    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. PMID:24980217

  12. Review to better understand the macroscopic subtypes and histogenesis of intrahepatic cholangiocarcinoma

    PubMed Central

    Sanada, Yuichi; Kawashita, Yujo; Okada, Satomi; Azuma, Takashi; Matsuo, Shigetoshi

    2014-01-01

    Intrahepatic cholangiocarcinoma is macroscopically classified into three subtypes, mass-forming-type, periductal infiltrating-type, and intraductal growth-type. Each subtype should be preoperatively differentiated to perform the valid surgical resection. Recent researches have revealed the clinical, radiologic, pathobiological characteristics of each subtype. We reviewed recently published studies covering various aspects of intrahepatic cholangiocarcinoma (ICC), focusing especially on the macroscopic subtypes and stem cell features to better understand the pathophysiology of ICC and to establish the valid therapeutic strategy. PMID:25133021

  13. 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

  14. Multiple cellular origins and molecular evolution of intrahepatic cholangiocarcinoma.

    PubMed

    Wei, Miaoyan; Lü, Lisheng; Lin, Peiyi; Chen, Zhisheng; Quan, Zhiwei; Tang, Zhaohui

    2016-09-01

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy associated with unfavorable prognosis and for which no effective treatments are available. Its molecular pathogenesis is poorly understood. Genome-wide sequencing and high-throughput technologies have provided critical insights into the molecular basis of ICC while sparking a heated debate on the cellular origin. Cancer exhibits variabilities in origin, progression and cell biology. Recent evidence suggests that ICC has multiple cellular origins, including differentiated hepatocytes; intrahepatic biliary epithelial cells (IBECs)/cholangiocytes; pluripotent stem cells, such as hepatic stem/progenitor cells (HPCs) and biliary tree stem/progenitor cells (BTSCs); and peribiliary gland (PBG). However, both somatic mutagenesis and epigenomic features are highly cell type-specific. Multiple cellular origins may have profoundly different genomic landscapes and key signaling pathways, driving phenotypic variation and thereby posing significant challenges to personalized medicine in terms of achieving the optimal drug response and patient outcome. Considering this information, we have summarized the latest experimental evidence and relevant literature to provide an up-to-date view of the cellular origin of ICC, which will contribute to establishment of a hierarchical model of carcinogenesis and allow for improvement of the anatomical-based classification of ICC. These new insights have important implications for both the diagnosis and treatment of ICC patients. PMID:26940139

  15. Radiofrequency Ablation for Postoperative Recurrences of Intrahepatic Cholangiocarcinoma

    PubMed Central

    Fu, Ying; Yang, Wei; Wu, Wei; Yan, Kun; Xing, Bao-cai

    2011-01-01

    Objective Most recurrent intrahepatic cholangiocarcinoma (RICC) lost the opportunity of radical resection while most nonsurgical management failed to prolong patients’ survival. The efficacy and safety of radiofrequency ablation (RFA) as a local treatment for recurrent hepatocellular carcinoma have been confirmed by many clinical studies. The purpose of this study was to evaluate the efficacy, long-term survival and complications of RFA for RICC. Methods A total of 12 patients with 19 RICCs after radical resection were included in this study. The tumors were 1.9-6.8 cm at the maximum diameter (median, 3.2±1.6 cm). All patients were treated with ultrasound guided RFA. There were two RFA approaches including percutaneous and open. Results A total of 18 RFA treatment sessions were performed. Ablation was successful (evaluated by 1-month CT after the initial RFA procedure) in 18 (94.7%) of 19 tumors. By a median follow-up period of 29.9 months after RFA, 5 patients received repeated RFA because of intrahepatic lesion recurrence. The median local recurrence-free survival period and median event-free survival period after RFA were 21.0 months and 13.0 months, respectively. The median overall survival was 30 months, and the 1- and 3-year survival rates were 87.5% and 37.5%, respectively. The complication rate was 5.6% (1/18 sessions). The only one major complication was pleural effusion requiring thoracentesis. Conclusion This study showed RFA may effectively and safely manage RICC with 3-year survival of 37.5%. It provides a treatment option for these RICC patients who lost chance for surgery. PMID:23359754

  16. Intrahepatic cholangiocarcinoma with increased serum CYFRA 21-1 level.

    PubMed

    Kashihara, T; Ohki, A; Kobayashi, T; Sato, T; Nishizawa, H; Ogawa, K; Tako, H; Kawakami, F; Tsuji, M; Tamaoka, K

    1998-06-01

    CYFRA 21-1 is a fragment of cytokeratin 19 (CK 19). Four patients with large intrahepatic (or peripheral) cholangiocarcinoma (CC) and high serum levels of CYFRA 21-1 (normal, < or = 2 ng/ml) are reported. CYFRA 21-1 levels exceeded 9 ng/ml in all 4 patients. Carcinoembryonic antigen (CEA), was high in 1 (CEA; normal range, < or = 5.0 ng/ml) and carbohydrate antigen 19-9 (CA 19-9) was high in 3 (CA19-9; normal range, < or = 36 U/ml). We also measured serum levels of CYFRA 21-1 in 13 patients with hepatocellular carcinoma (HCC) more than 5 cm in diameter. Levels of CYFRA 21-1 exceeded 2 ng/ml in 9 of the HCC patients and were higher than 9 ng/ml in 2 of the HCC patients. Levels of alpha fetoprotein (AFP) and/or protein induced by vitamin K absence or antagonist II (PIVKA II) were elevated in all HCC patients (AFP, PIVKA II, respectively; normal range, < or = 10.0 ng/ml and < or = 0.1 AU/ml) CYFRA 21-1 levels were measured twice or three times during the clinical course in 2 CC patients and in 6 HCC patients, and increased gradually with tumor growth in the 2 CC patients and in 3 of the 6 HCC patients. Marked increases in serum CYFRA 21-1 levels in patients with large liver cancers, particularly in those with normal levels of AFP and PIVKA II, would suggest the existence of intrahepatic CC rather than HCC. PMID:9658330

  17. Intraoperative Conversion to ALPPS in a Case of Intrahepatic Cholangiocarcinoma.

    PubMed

    Oldhafer, F; Ringe, K I; Timrott, K; Kleine, M; Ramackers, W; Cammann, S; Jäger, M D; Klempnauer, J; Bektas, H; Vondran, F W R

    2015-01-01

    Background. Surgical resection remains the best treatment option for intrahepatic cholangiocarcinoma (ICC). Two-stage liver resection combining in situ liver transection with portal vein ligation (ALPPS) has been described as a promising method to increase the resectability of liver tumors also in the case of ICC. Presentation of Case. A 46-year-old male patient presented with an ICC-typical lesion in the right liver. The indication for primary liver resection was set and planed as a right hepatectomy. In contrast to the preoperative CT-scan, the known lesion showed further progression in a macroscopically steatotic liver. Therefore, the decision was made to perform an ALPPS-procedure to avoid an insufficient future liver remnant (FLR). The patient showed an uneventful postoperative course after the first and second step of the ALPPS-procedure, with sufficient increase of the FLR. Unfortunately, already 2.5 months after resection the patient had developed new tumor lesions found by the follow-up CT-scan. Discussion. The presented case demonstrates that an intraoperative conversion to an ALPPS-procedure is safely applicable when the FLR surprisingly seems to be insufficient. Conclusion. ALPPS should also be considered a treatment option in well-selected patients with ICC. However, the experience concerning the outcome of ALPPS in case of ICC remains fairly small. PMID:26649219

  18. Intrahepatic cholangiocarcinoma with extensive sarcomatous change: report of a case.

    PubMed

    Matsuo, S; Shinozaki, T; Yamaguchi, S; Takami, Y; Obata, S; Tsuda, N; Kanematsu, T

    1999-01-01

    A 77-year-old woman was admitted to our hospital with severe upper abdominal pain. Ultrasonography showed a well-defined hypoechoic mass with heterogeneity in the left lobe of the liver, and computed tomography demonstrated a low-density mass with enhanced peripheral areas. Magnetic resonance imaging revealed a mass with iso- to low signal intensity on T1-weighted images (WI) and heterogeneous high and low signal intensity on T2 WI. The tumor was found to be hypovascular by angiography. During 5 months of observation, the tumor increased in size, which strongly suggested malignancy. A laparotomy was performed under the provisional diagnosis of a neoplasm other than hepatocellular carcinoma, revealing that the hepatic mass had invaded the gastric wall. Therefore, a left hepatic lobectomy with dissection of the lymph nodes and hemigastrectomy was carried out. Histologically, the tumor was found to be composed of a large amount of sarcomatous elements and a small amount of adenocarcinomatous elements, both of which were partly intermingled. Immunohistochemically, the sarcomatous element demonstrated the features of malignant fibrous histiocytoma (MFH). Thus, a diagnosis of intrahepatic cholangiocarcinoma with MFH-like sarcomatous change was confirmed. PMID:10385374

  19. Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma.

    PubMed

    Peng, Hong; Zhang, Qiuyang; Li, Jiali; Zhang, Ning; Hua, Yunpeng; Xu, Lixia; Deng, Yubin; Lai, Jiaming; Peng, Zhenwei; Peng, Baogang; Chen, Minhu; Peng, Sui; Kuang, Ming

    2016-03-29

    Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC. PMID:26967384

  20. Intraoperative Conversion to ALPPS in a Case of Intrahepatic Cholangiocarcinoma

    PubMed Central

    Oldhafer, F.; Ringe, K. I.; Timrott, K.; Kleine, M.; Ramackers, W.; Cammann, S.; Jäger, M. D.; Klempnauer, J.; Bektas, H.; Vondran, F. W. R.

    2015-01-01

    Background. Surgical resection remains the best treatment option for intrahepatic cholangiocarcinoma (ICC). Two-stage liver resection combining in situ liver transection with portal vein ligation (ALPPS) has been described as a promising method to increase the resectability of liver tumors also in the case of ICC. Presentation of Case. A 46-year-old male patient presented with an ICC-typical lesion in the right liver. The indication for primary liver resection was set and planed as a right hepatectomy. In contrast to the preoperative CT-scan, the known lesion showed further progression in a macroscopically steatotic liver. Therefore, the decision was made to perform an ALPPS-procedure to avoid an insufficient future liver remnant (FLR). The patient showed an uneventful postoperative course after the first and second step of the ALPPS-procedure, with sufficient increase of the FLR. Unfortunately, already 2.5 months after resection the patient had developed new tumor lesions found by the follow-up CT-scan. Discussion. The presented case demonstrates that an intraoperative conversion to an ALPPS-procedure is safely applicable when the FLR surprisingly seems to be insufficient. Conclusion. ALPPS should also be considered a treatment option in well-selected patients with ICC. However, the experience concerning the outcome of ALPPS in case of ICC remains fairly small. PMID:26649219

  1. SALL4 is a novel therapeutic target in intrahepatic cholangiocarcinoma

    PubMed Central

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

    2015-01-01

    Intrahepatic cholangiocarcinoma (ICC) is the most common and deadly disease of the biliary tree due to its poor prognosis. Sal-like protein 4 (SALL4), a stem cell marker, has been identified as a potential target for aggressive hepatocellular carcinoma (HCC). In our study, 175 ICC cases with an average age of 55 years were included, and 53% (93/175) were male. And 28 adjacent non-tumor tissues were also collected. The SALL4-positive immunoreactivity was detected in a total of 102 ICC cases (58%), whereas all 28 adjacent tissues showed negative staining. Univariate analysis, showed that the SALL4-positive ICC cases had significantly more frequent lymph nodal metastasis (P = 0.0460), vascular invasion (P < 0.0001), and nerve invasion (P < 0.0001). Furthermore, the strong SALL4-positive cases (n = 7, 5 months) had shorter overall survival, when compared to moderate SALL4-positive (n = 46, 9 months) or SALL4-negative cases (n = 73, 7 months), respectively. Our data also suggest that SALL4 may be involved in the regulation of epithelial-mesenchymal transition (EMT) in ICC. Those results for the first time indicate an oncogenic role of SALL4 in ICC. Therefore, SALL4 may serve as a promising therapeutic target for ICC. PMID:26317546

  2. Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma

    PubMed Central

    Zhang, Ning; Hua, Yunpeng; Xu, Lixia; Deng, Yubin; Lai, Jiaming; Peng, Zhenwei; Peng, Baogang; Chen, Minhu; Peng, Sui; Kuang, Ming

    2016-01-01

    Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC. PMID:26967384

  3. Chemotherapy Outcomes for the Treatment of Unresectable Intrahepatic and Hilar Cholangiocarcinoma: A Retrospective Analysis

    PubMed Central

    Eckmann, Karen R.; Patel, Dina K.; Landgraf, Andrea; Slade, Julian H.; Lin, E.; Kaur, Harmeet; Loyer, Evelyne; Weatherly, Jacqueline M.; Javle, Milind

    2011-01-01

    ABSTRACT Background: Recent clinical trials for “biliary cancers” include a heterogenous group of patients with cholangiocarcinoma, gallbladder, and ampullary cancers. Limited data exist regarding the relative effectiveness of known chemotherapeutic regimens specifically in intrahepatic or hilar cholangiocarcinoma. Methods: Records of M D Anderson Cancer Center patients with unresectable intrahepatic and hilar cholangiocarcinoma who received first-line chemotherapy from January 1, 2005, to October 31, 2009, were retrospectively reviewed. The primary objective of this research was to determine overall tumor control rates with chemotherapeutic regimens used for first-line treatment of unresectable intrahepatic and hilar cholangiocarcinoma. Secondary objectives included duration of response, overall survival, and prognostic factors. Results: Eighty-five patients met inclusion criteria and were eligible for analysis. The most commonly used regimen was gemcitabine/cisplatin (62%), followed by oxaliplatin and capecitabine (16%). There was no significant difference between tumor control rates with gemcitabine/cisplatin (72% PR + SD) and other regimens (69% PR + SD). There was no significant difference between overall survival with the use of gemcitabine/cisplatin (15.2 months) or alternative regimens (13.9 months). A decrease in overall survival was seen with elevated baseline CA 19–9 (p < .0001), an initial diagnosis of unknown primary tumor (p = .0001), and prior treatment with chemoradiation (p = .0018). Conclusion: In this retrospective review, both gemcitabine/cisplatin and alternative doublets (including capecitabine/oxaliplatin, gemcitabine/capecitabine, and gemcitabine/oxaliplatin) were effective regimens in maintaining disease control in intrahepatic and hilar cholangiocarcinoma. PMID:22295126

  4. Synchronous occurrence of gastrointestinal stromal tumor and intrahepatic cholangiocarcinoma: A case report

    PubMed Central

    NAM, SEUNG-JOO; CHOI, HYUK SOON; KIM, EUN SUN; KEUM, BORA; JEEN, YOON TAE; CHUN, HOON JAI

    2015-01-01

    Various cases of gastrointestinal stromal tumor (GIST) coinciding with other gastrointestinal malignancies have been reported to date, however, the synchronous occurrence of GIST and intrahepatic cholangiocarcinoma (ICC) is exceptionally rare and, to the best of our knowledge, has only been reported once. The coinciding malignancy has usually been encountered incidentally during surgical exploration. Thus, this is the first report where a targeted biopsy of the clinically suspicious lesion was used to determine the diagnosis of ICC concurrent with GIST. The liver is the most frequent metastatic site of GIST, therefore, additional hepatic masses may be mistakenly diagnosed as metastatic disease, rather than the presentation of multiple primary tumors. This subsequently delays the accurate diagnosis and complicates the performance of a curable resection. The current study reports a case of advanced synchronous GIST and ICC, which was operable at initial presentation, but progressed to become surgically unresectable. PMID:25435952

  5. Prognostic significance of NQO1 expression in intrahepatic cholangiocarcinoma

    PubMed Central

    Wakai, Toshifumi; Shirai, Yoshio; Sakata, Jun; Matsuda, Yasunobu; Korit, Pavel V; Takamura, Masaaki; Ajioka, Yoichi; Hatakeyama, Katsuyoshi

    2011-01-01

    This study aimed to evaluate the association between the immunohistochemical expression of NAD(P) H:quinone oxidoreductase-1 (NQO1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in resected specimens of intrahepatic cholangiocarcinoma (ICC) and to elucidate the prognostic value of NQO1 and Nrf2 expression. A retrospective analysis was conducted of 34 consecutive patients who underwent surgical resection for ICC. Immunohistochemistry of the resected specimens was conducted using each of the following primary monoclonal antibodies against NQO1 and Nrf2. Of the 34 patients, 23 were classified as having tumors with NQO1-positive expression and 11 had tumors with loss of NQO1 expression, whereas 22 patients had tumors with Nrf2-positive expression and 12 had tumors with loss of Nrf2 expression. NQO1 expression showed a positive association with Nrf2 expression (p=0.005). Loss of NQO1 expression was more frequent in tumor specimens that were moderately or poorly differentiated (11/26; 42%) than in well-differentiated tumors (0/8; 0%; p=0.034). Post-resection survival was significantly worse in patients with tumors with loss of NQO1 expression than in patients with NQO1-positive tumors (cumulative 5 -year survival rate of 0% and 51%, respectively; p=0.005). Nrf2 expression was not associated with survival after resection (p=0.287). The Cox proportional hazards regression analysis revealed that lymph node involvement (p<0.001) and loss of NQO1 expression (p<0.001) had an independent adverse effect on survival. Loss of NQO1 expression reflects dedifferentiation and thus indicates a poor prognosis for patients undergoing resection for ICC. PMID:21577322

  6. Clinicopathological significance of aberrant Notch receptors in intrahepatic cholangiocarcinoma

    PubMed Central

    Wu, Wen-Rui; Shi, Xiang-De; Zhang, Rui; Zhu, Man-Sheng; Xu, Lei-Bo; Yu, Xian-Huan; Zeng, Hong; Wang, Jie; Liu, Chao

    2014-01-01

    Notch signaling has been reported to be activated to promote biliary epithelial cell differentiation and tubulogenesis during bile duct development. In this study, clinicopathological significance of aberrant expression of Notch receptors in intrahepatic cholangiocarcinoma (ICC) was investigated. Thus, forty-one ICC specimens were examined by immunohistochemistry using anti-Notch1-4 antibodies, respectively. Expression of Notch receptors was scored by percentage of positive tumor cells and intensity of immunostaining. Clinicopathological parameters and survival data were compared with the expression of Notch receptors, respectively. Expression of Notch receptors was identified in cancer cells, as well as in non-neoplastic cells. Compared with adjacent non-tumor liver tissues, Notch1 and 4 were up regulated, and Notch2 and 3 were relatively weaker. Positive immunostaining of Notch1 in ICC cells was detected in 34 cases (82.9%), Notch2 in 23 (56.1%), Notch3 in 16 (39.0%) and Notch4 in 14 (34.1%). Notch1 was overexpressed in cases with tumor size > 5 cm (P = 0.036). Expression of Notch2 was correlated inversely with histological grade (P = 0.016). Overexpression of Notch4 was more common in cases with serum CA125 > 35 U/ml than cases with CA125 ≤ 35 U/ml (P = 0.048). Expression of Notch3 was not correlated with any other clinicopathological parameters. Moreover, Notch4 was related to poor survival (P < 0.001). To conclude, this study reveals that aberrant expression of Notch receptors 1 and 4 might play important roles during ICC progression. PMID:25031748

  7. 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. PMID:26297049

  8. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.

    PubMed

    Jiao, Yuchen; Pawlik, Timothy M; Anders, Robert A; Selaru, Florin M; Streppel, Mirte M; Lucas, Donald J; Niknafs, Noushin; Guthrie, Violeta Beleva; Maitra, Anirban; Argani, Pedram; Offerhaus, G Johan A; Roa, Juan Carlos; Roberts, Lewis R; Gores, Gregory J; Popescu, Irinel; Alexandrescu, Sorin T; Dima, Simona; Fassan, Matteo; Simbolo, Michele; Mafficini, Andrea; Capelli, Paola; Lawlor, Rita T; Ruzzenente, Andrea; Guglielmi, Alfredo; Tortora, Giampaolo; de Braud, Filippo; Scarpa, Aldo; Jarnagin, William; Klimstra, David; Karchin, Rachel; Velculescu, Victor E; Hruban, Ralph H; Vogelstein, Bert; Kinzler, Kenneth W; Papadopoulos, Nickolas; Wood, Laura D

    2013-12-01

    Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas. PMID:24185509

  9. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas

    PubMed Central

    Selaru, Florin M; Streppel, Mirte M; Lucas, Donald J; Niknafs, Noushin; Guthrie, Violeta Beleva; Maitra, Anirban; Argani, Pedram; Offerhaus, G Johan A; Roa, Juan Carlos; Roberts, Lewis R; Gores, Gregory J; Popescu, Irinel; Alexandrescu, Sorin T; Dima, Simona; Fassan, Matteo; Simbolo, Michele; Mafficini, Andrea; Capelli, Paola; Lawlor, Rita T; Ruzzenente, Andrea; Guglielmi, Alfredo; Tortora, Giampaolo; de Braud, Filippo; Scarpa, Aldo; Jarnagin, William; Klimstra, David; Karchin, Rachel; Velculescu, Victor E; Hruban, Ralph H; Vogelstein, Bert; Kinzler, Kenneth W; Papadopoulos, Nickolas; Wood, Laura D

    2014-01-01

    Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas. PMID:24185509

  10. Gab1 regulates proliferation and migration through the PI3K/Akt signaling pathway in intrahepatic cholangiocarcinoma.

    PubMed

    Sang, Haiquan; Li, Tingting; Li, Hangyu; Liu, Jingang

    2015-11-01

    Intrahepatic cholangiocarcinoma is the second most common primary malignant tumor of the liver, and it originates from the intrahepatic biliary duct epithelium. Prognosis is poor due to lack of effective comprehensive treatments. In this study, we assessed the expression of Gab1, VEGFR-2, and MMP-9 in intrahepatic cholangiocarcinoma solid tumors by immunohistochemistry and determined whether their expression was associated with clinical and pathological features. We found that expression of Gab1, VEGFR-2, and MMP-9 was highly and positively correlated with each other and with lymph node metastasis and TNM stage in intrahepatic cholangiocarcinoma tissues. Interference of Gab1 and VEGFR-2 expression via siRNA in the intrahepatic cholangiocarcinoma cell line RBE resulted in decreased PI3K/Akt pathway activity. Inhibition of Gab1 and VEGFR-2 expression also caused decreased cell proliferation, cell cycle arrested in G1 phase, increased apoptosis, and decreased invasion in RBE cells. These results suggest that Gab1, VEGFR-2, and MMP-9 contribute significantly to the highly malignant behavior of intrahepatic cholangiocarcinoma. The regulation of growth, apoptosis, and invasion by Gab1 through the VEGFR-2/Gab1/PI3K/Akt signaling pathway may represent potential targets for improving the treatment of intrahepatic cholangiocarcinoma. PMID:26014518

  11. 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

  12. 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

  13. Geographic Variation of Intrahepatic Cholangiocarcinoma, Extrahepatic Cholangiocarcinoma, and Hepatocellular Carcinoma in the United States

    PubMed Central

    Cuccinelli, James E.; Zou, Zhaohui; Tatalovich, Zaria; McGlynn, Katherine A.

    2015-01-01

    Background Intrahepatic (ICC) and extrahepatic cholangiocarcinomas (ECC) are tumors that arise from cholangiocytes in the bile duct, but ICCs are coded as primary liver cancers while ECCs are coded as biliary tract cancers. The etiology of these tumors is not well understood. It has been suggested that the etiology of ICC is more similar to that of another type of liver cancer, hepatocellular carcinoma (HCC), than to the etiology of ECC. If this is true, geographic incidence patterns and trends in ICC incidence should be more similar to that of HCC than ECC. Methods To examine this hypothesis, data from the North American Association of Central Cancer Registries Cancer in North America data file were analyzed. Incidence rates and joinpoint trends were calculated by demographic subgroup. County-level incidence rates were mapped. Results Overall incidence rates, racial distribution, male:female ratio, and peak ages were more similar between ICC and ECC than with HCC. During 2000–2009, average annual incidence rates of ECC increased. During 2005–2009, average annual ICC incidence rates also increased. High rates for all three cancer sites were found in the Pacific region, particularly Hawaii and Alaska. Rates of ICC and ECC were also high in the Northeast and the upper Midwest, while rates of HCC were high in the South. Conclusions Demographic patterns and geographical variation were more closely related between ICC and ECC than HCC, suggesting that the etiology of ICC and ECC may be similar. Increasing rates of both tumors suggest that further etiology studies are warranted. PMID:25837669

  14. Utility of immunocytochemistry in diagnosing leptomeningeal metastases from an intrahepatic cholangiocarcinoma.

    PubMed

    Chaudhary, Shweta; Klein, Melissa; Mehrotra, Bhoomi; Morgenstern, Nora J

    2014-01-01

    Isolated spinal leptomeningeal metastases (LMM) without brain metastases are infrequent, accounting for about 1% of all solid tumors. In LMM, cerebrospinal fluid (CSF) analyses are mostly abnormal. Demonstrations of intrathecal tumor markers are highly suggestive, but only a positive cytology is diagnostic. The initial CSF cytology can give a false negative result in up to 40-50% of patients with pathologically proven LMM on autopsy. We report a case of intrahepatic cholangiocarcinoma with spinal LMM confirmed using cytokeratin7 and pancytokeratin (AE1/AE3) immunocytochemical studies on paucicellular cerebrospinal fluid cytospin preparation. Given the paucicellularity of the smears and difficult morphologic categorization, immunocytochemistry is vital for confirmatory diagnosis and can help reduce false negative results. To the best of our knowledge this is the first case report of cytologically confirmed LMM from an intrahepatic cholangiocarcinoma while the patient was undergoing treatment. PMID:23341095

  15. [A case of intrahepatic cholangiocarcinoma effectively treated by hepatic arterial infusion chemotherapy].

    PubMed

    Nishizawa, Toshihiro; Higuchi, Hajime; Takaishi, Hiromasa; Iizuka, Hideko; Izumiya, Motoko; Yamagishi, Yoshiyuki; Hisamatsu, Tadakazu; Suzuki, Hidekazu; Masaoka, Tatsuhiro; Iwasaki, Eisuke; Nagata, Hiroshi; Hibi, Toshifumi

    2006-11-01

    The patient was a 50-year-old woman who suffered from gastric discomfort. She was first diagnosed as intrahepatic cholangiocarcinoma with hepatic, paraaortic lymphnodal and bone metastasis. Initial systemic chemotherapy using gemcitabine (GEM) and 5-FU failed to control the disease activity. Then she was given GEM and cisplatin (CDDP) combination chemotherapy. The response was assessed as stable disease (SD), but grade 4 leukopenia was seen. Then systemic therapy using GEM, and hepatic arterial infusion therapy with CDDP, l-leucovorin and 5-FU were continued biweekly. Partial response (PR) was achieved six months later, and her disease status was maintained as SD. This hepatic arterial infusion chemotherapy would be safe and feasible as therapy for inoperable intrahepatic cholangiocarcinoma. PMID:17108736

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

    PubMed Central

    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. PMID:27152236

  17. 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. PMID:27152236

  18. Trousseau's Syndrome Caused by Intrahepatic Cholangiocarcinoma: An Autopsy Case Report and Literature Review

    PubMed Central

    Yuri, Takashi; Kato, Kouta; Hirohara, y; Kinoshita, Yuichi; Emoto, Yuko; Yuki, Michiko; Yoshizawa, Katsuhiko; Tsubura, Airo

    2014-01-01

    An autopsy case report of Trousseau's syndrome caused by intrahepatic cholangiocarcinoma is presented, and seven previously reported cases are reviewed. A 73-year-old woman experiencing light-headedness and dementia of unknown cause for 6 months developed severe hypotonia. A hypointense lesion compatible with acute cerebral infarction was detected by magnetic resonance imaging. Abdominal computed tomography revealed an ill-defined large liver mass in the right lobe. The mass was not further investigated because of the patient's poor condition. She died of multiple organ failure, and an autopsy was conducted. Postmortem examination revealed intrahepatic cholangiocarcinoma, fibrous vegetations on the mitral valves and multiple thromboemboli in the cerebrum, spleen and rectum. Trousseau's syndrome is defined as an idiopathic thromboembolism in patients with undiagnosed or concomitantly diagnosed malignancy. This syndrome is encountered frequently in patients with mucin-producing carcinomas, while the incidence in patients with intrahepatic cholangiocarcinoma is uncommon. We found that tissue factor and mucin tumor marker (CA19-9, CA15-3 and CA-125) expression in cancer cells may be involved in the pathogenesis of thromboembolism. A patient with unexplained thromboembolism may have occult visceral malignancy; thus, mucin tumor markers may indicate the origin of a mucin-producing carcinoma, and postmortem examination may play an important role in revealing the hidden malignancy. PMID:24987359

  19. MTSS1 is an independent prognostic biomarker for survival in intrahepatic cholangiocarcinoma patients

    PubMed Central

    Shi, Wei; Hasimu, Gulimire; Wang, Yan; Li, Ning; Chen, Mingquan; Zhang, Hao

    2015-01-01

    MTSS1 is a possible metastasis suppressor which has been proved to play a key role in metastasis of various tumors, yet its role in intrahepatic cholangiocarcinoma (ICC) remains unclear. In present study, we reported detection of MTSS1 expression in ICC and explored its clinical significances. Tissue microarrays containing 93 cases with ICC were constructed and immunohistochemistry was performed to detect MTSS1 expression on these arrays. PcDNA3.1-MTSS1 was transfected into QBC939 cell lines and cell function was measured by transwell assay. Data showed that MTSS1 expression was barely detectable in 56 cases (60.0%) of the 93 primary tumors and that lacking MTSS1 expression was significantly associated with tumor size, nodal metastases and advanced disease stage. In addition, survival analysis demonstrated that lacking MTSS1 expression also correlated significantly with tumor recurrence and poor outcome of patients with ICC. Meanwhile, enhanced expression of MTSS1 leaded to inhibition of the migration of QBC939 cell lines in vitro. These findings together support that MTSS1 may serve as a useful biomarker in predicting tumor recurrence and prognosis of ICC. PMID:26692940

  20. The Ser326Cys polymorphism of hOGG1 is associated with intrahepatic cholangiocarcinoma susceptibility in a Chinese population

    PubMed Central

    Ding, Xiangmin; Wang, Ke; Wu, Zhengshan; Yao, Aihua; Li, Jiaxin; Jiao, Chengyu; Qian, Jianjun; Bai, Dousheng; Li, Xiangcheng

    2015-01-01

    Objective: Intrahepatic cholangiocarcinoma is a rare disease whose etiology is far from clear, the Ser326Cys polymorphism in human 8-hydroxyguanine glycosylase (hOGG1) has been shown associated with various cancers, however, the association of Ser326Cys (rsl052133) polymorphism and intrahepatic cholangiocarcinoma susceptibility has not been clarified. The purpose of this study is to investigate whether this polymorphism is related to the genetic susceptibility of intrahepatic cholangiocarcinoma. Methods: A total 150 patients and 150 normal people were included in this study, the Ser326Cys polymorphisms in each group were genotyped using PCR-RFLP method. Results: We found that individuals carrying Cys/Cys genotype were exposed to higher riskof intrahepatic cholangiocarcinoma (OR=2.924, 95% CI=1.475-5.780) compared with the individuals with wild type genotype Ser/Ser. Further analysis revealed that male individuals carrying Cys/Cys genotype also had increased risk (OR=2.762, 95% CI=1.233-6.173), whereas no significant difference was observed in female group. Conclusions: Therefore, our data indicates that the Ser326Cys (rs1052133) polymorphism is associated with intrahepatic cholangiocarcinoma susceptibility, and it shows preference in male population. PMID:26629147

  1. One case of intrahepatic cholangiocarcinoma amenable to resection after radioembolization

    PubMed Central

    Servajean, Cecilia; Gilabert, Marine; Piana, Gilles; Monges, Geneviève; Delpero, Jean-Robert; Brenot, Isabelle; Raoul, Jean-Luc

    2014-01-01

    We report the case of a 57-year-old man who was diagnosed with a large unresectable cholangiocarcinoma associated with 2 satellite nodules and without clear margins with the right hepatic vein. Despite 4 cycles of GEMOX (stopped due to a hypertransaminasemia believed to be due to gemcitabine) and 4 cycles of FOLFIRINOX, the tumor remained stable and continued to be considered unresectable. Radioembolization (resin microspheres, SIRS-spheres®) targeting the left liver (474 MBq) and segment IV (440 MBq) was performed. This injection was very well tolerated, and 4 more cycles of FOLFIRINOX were given while waiting for radioembolization efficacy. On computed tomography scan, a partial response was observed; the tumor was far less hypervascularized, and a margin was observed between the tumor and the right hepatic vein. A left hepatectomy enlarged to segment VIII was performed. On pathological exam, most of the tumor was acellular, with dense fibrosis around visible microspheres. Viable cells were observed only at a distance from beads. Radioembolization can be useful in the treatment of cholangiocarcinoma, allowing in some cases a secondary resection. PMID:24803830

  2. FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma

    PubMed Central

    Guion-Dusserre, Jean-Florian; Lorgis, Veronique; Vincent, Julie; Bengrine, Leila; Ghiringhelli, Francois

    2015-01-01

    AIM: To evaluate the efficacy and tolerance of FOLFIRI plus bevacizumab treatment outcome as second-line treatment for metastatic intrahepatic cholangiocarcinoma. METHODS: Thirteen consecutive patients with metastatic intrahepatic cholangiocarcinoma who were refractory to first-line therapy consisting of gemcitabine plus oxaliplatin-based first-line chemotherapy given intravenously via intra-arterial infusion were treated with FOLFIRI [irinotecan (180 mg/m² i.v. over 90 min) concurrently with folinic acid (400 mg/m² i.v. over 120 min) followed by fluorouracil (400 mg/m² i.v. bolus) then fluorouracil 2400 mg/m² intravenous infusion over 46 h] and bevacizumab (5 mg/kg) every 2 wk. Tumor response was evaluated by computed tomography scan every 4 cycles. RESULTS: The best tumor responses using response evaluation criteria in solid tumor criteria were: complete response for 1 patient, partial response for 4 patients, and stable disease for 6 patients after 6 mo of follow-up. The response rate was 38.4% (95%CI: 12.5-89) and the disease control rate was 84.5% (95%CI: 42-100). Seven deaths occurred at the time of analysis, progression free survival was 8 mo (95%CI: 7-16), and median overall survival was 20 mo (95%CI: 8-48). No grade 4 toxic events were observed. Four grade 3 hematological toxicities and one grade 3 digestive toxicity occurred. An adaptive reduction in chemotherapy dosage was required in 2 patients due to hematological toxicity, and a delay in chemotherapy cycles was required for 3 patients. CONCLUSION: FOLFIRI plus bevacizumab combination treatment showed promising efficacy and safety as second-line treatment for metastatic intrahepatic cholangiocarcinoma after failure of the first-line treatment of gemcitabine plus oxaliplatin chemotherapy. PMID:25717243

  3. Cavernous hemangioma with extensive sclerosis masquerading as intrahepatic cholangiocarcinoma — A pathologist's perspective

    PubMed Central

    Andeen, Nicole K.; Bhargava, Puneet; Park, James O.; Moshiri, Mariam; Westerhoff, Maria

    2015-01-01

    A patient presented with an acute episode of bright red blood in her stool. The incidental liver mass seen in segment 4 was suspected to represent a cholangiocarcinoma due to associated mild intrahepatic biliary ductal dilatation and suspicion for capsular retraction. Pathology confirmed that this lesion represented a sclerosing hemangioma. This case report corroborates prior observations that degenerative changes in hemangiomas—sclerosis, narrowing of vascular channels, thrombosis, infarct, hemorrhage—may produce atypical radiographic findings. Since these atypical radiographic features may suggest a primary or metastatic malignancy, the protean appearance of hemangiomas remains an important consideration in the evaluation of hepatic masses. PMID:27186246

  4. Pancreatic recurrence of intrahepatic cholangiocarcinoma: Case report and review of the literature

    PubMed Central

    Labgaa, Ismaïl; Carrasco-Avino, Gonzalo; Fiel, Maria Isabel; Schwartz, Myron Eliot

    2014-01-01

    Intrahepatic cholangiocarcinomas (ICC) are malignant tumors arising from the intrahepatic bile ducts that frequently recur after resection. The main sites of recurrence are the remnant liver, lymph nodes and lungs. Metastasis to the pancreas has never been reported. This case describes a 24-year-old woman who underwent a hepatic lobectomy in 2008 for an ICC. Almost 4 years after her surgery she presented with a pancreatic mass and lung nodules. An endoscopic ultrasound guided fine needle aspiration of the pancreatic mass and a video-assisted thoracoscopic surgery resection for the lung nodules were performed for diagnostic purposes. Pathological analyses of specimens revealed recurrence of her primary ICC in both pancreas and lungs. Subsequently, the patient received systemic chemotherapy. The patient is currently off chemotherapy and remains well. Moreover, she is pregnant. This is the first report of an ICC with pancreatic metastasis. PMID:24829624

  5. Differentially expressed gene profiles of intrahepatic cholangiocarcinoma, hepatocellular carcinoma, and combined hepatocellular-cholangiocarcinoma by integrated microarray analysis.

    PubMed

    Xue, Tong-Chun; Zhang, Bo-Heng; Ye, Sheng-Long; Ren, Zheng-Gang

    2015-08-01

    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are common primary liver cancers worldwide. However, the survival and prognosis of ICC are much poorer than those of HCC, indicating the different molecular characteristics and mechanisms between ICC and HCC. To identify differentially expressed (DE) genes between ICC and HCC or combined hepatocellular-cholangiocarcinoma (CHC), we performed integrated analysis of publicly available microarray Gene Expression Omnibus (GEO) datasets by MetaOmics. Three GEO datasets comprising 32 ICC biochips, 77 HCC biochips, and 34 CHC biochips were available for the data integration. We identified 7313 DE genes between ICC and HCC, including 3650 upregulated genes and 3663 downregulated genes. The S100 family members on chromosome 1q21 were extensively upregulated in ICC, and S100A11 had the greatest degree of upregulation in ICC. Based on the DE genes, combined gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed the enhanced pathways of local adhesion, ECM-receptor interaction, and regulation of action cytoskeleton, suggesting the enhanced communication between ICC and the microenvironment. Additionally, development-related genes and development-related pathways, including the Notch, Wnt, and TGF-β signaling pathways, were shown to be active prominently in ICC. Taken together, we identified the characteristically upregulated or downregulated DE genes and pathways in ICC compared with HCC or CHC. These DE genes and pathways supply new transcriptomics evidence for ICC and could help identify new therapeutic targets. PMID:25712376

  6. 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. PMID:19727937

  7. Prognosis after resection for hepatitis B virus-associated intrahepatic cholangiocarcinoma

    PubMed Central

    Wu, Zhen-Feng; Wu, Xiao-Yu; Zhu, Nan; Xu, Zhe; Li, Wei-Su; Zhang, Hai-Bin; Yang, Ning; Yao, Xue-Quan; Liu, Fu-Kun; Yang, Guang-Shun

    2015-01-01

    AIM: To investigate the prognostic factors after resection for hepatitis B virus (HBV)-associated intrahepatic cholangiocarcinoma (ICC) and to assess the impact of different extents of lymphadenectomy on patient survival. METHODS: A total of 85 patients with HBV-associated ICC who underwent curative resection from January 2005 to December 2006 were analyzed. The patients were classified into groups according to the extent of lymphadenectomy (no lymph node dissection, sampling lymph node dissection and regional lymph node dissection). Clinicopathological characteristics and survival were reviewed retrospectively. RESULTS: The cumulative 1-, 3-, and 5-year survival rates were found to be 60%, 18%, and 13%, respectively. Multivariate analysis revealed that liver cirrhosis (HR = 1.875, 95%CI: 1.197-3.278, P = 0.008) and multiple tumors (HR = 2.653, 95%CI: 1.562-4.508, P < 0.001) were independent prognostic factors for survival. Recurrence occurred in 70 patients. The 1-, 3-, and 5-year disease-free survival rates were 36%, 3% and 0%, respectively. Liver cirrhosis (HR = 1.919, P = 0.012), advanced TNM stage (stage III/IV) (HR = 2.027, P < 0.001), and vascular invasion (HR = 3.779, P = 0.02) were independent prognostic factors for disease-free survival. Patients with regional lymph node dissection demonstrated a similar survival rate to patients with sampling lymph node dissection. Lymphadenectomy did not significantly improve the survival rate of patients with negative lymph node status. CONCLUSION: The extent of lymphadenectomy does not seem to have influence on the survival of patients with HBV-associated ICC, and routine lymph node dissection is not recommended, particularly for those without lymph node metastasis. PMID:25624728

  8. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas.

    PubMed

    Wang, P; Dong, Q; Zhang, C; Kuan, P-F; Liu, Y; Jeck, W R; Andersen, J B; Jiang, W; Savich, G L; Tan, T-X; Auman, J T; Hoskins, J M; Misher, A D; Moser, C D; Yourstone, S M; Kim, J W; Cibulskis, K; Getz, G; Hunt, H V; Thorgeirsson, S S; Roberts, L R; Ye, D; Guan, K-L; Xiong, Y; Qin, L-X; Chiang, D Y

    2013-06-20

    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 and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (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 were 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 2309 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

  9. 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. PMID:24849871

  10. Fascioliasis simulating an intrahepatic cholangiocarcinoma-Case report with imaging and pathology correlation.

    PubMed

    Losada, Héctor; Hirsch, Michael; Guzmán, Pablo; Fonseca, Flery; Hofmann, Edmundo; Alanís, Martín

    2015-02-01

    Human fascioliasis is a rare zoonosis in Chile. Clinically it presents with a highly polymorphous group of symptoms that evolve in two periods. The first, acute or a result of hepatic invasion, lasts 2 weeks to 4 months and is characterized essentially by pain in the right hypochondrium and/or epigastrium, continuous fever and painful hepatomegaly. This clinical picture, associated with eosinophilia and a history of raw watercress consumption, corresponds to the classic presentation of the disease in its initial stage. We report the case of a 57-year-old female patient with no risk factors for and no clinical signs of fascioliasis, with a lesion in the right hepatic lobe compatible with intrahepatic cholangiocarcinoma, studied with computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET-CT). With the clinical suspicion of intrahepatic cholangiocarcinoma, a regulated right hepatectomy was performed, the pathological study of which revealed cholangitis and granulomatous pericholangitis resulting from trematode eggs, compatible with Fasciola hepatica. PMID:25713810

  11. CA9 overexpression is an independent favorable prognostic marker in intrahepatic cholangiocarcinoma

    PubMed Central

    Gu, Mijin

    2015-01-01

    The aim of this study is to evaluate the expression of carbonic anhydrase IX (CA9) and to identify its prognostic significance in intrahepatic cholangiocarcinoma (IHCC). We performed immunohistochemistry (IHC) for CA9 in a total of 85 IHCCs. CA9 overexpression was observed in 38 of 85 (44.7%) IHCCs. CA9 overexpression was related to tumors with intraductal growth than mass forming or periductal infiltrative type. CA9 overexpression was more observed in tumors with well/moderate differentiation than poor differentiation and without lymph node metastasis. No significant correlation was observed in CA9 overexpression with tumor size, pT, stage and lymphovascular invasion. Intrahepatic cholangiocarcinomas with CA9 overexpression showed better overall survival than that without expression (P = 0.001). In multivariate analysis, lymph node metastasis (95% CI: 2.103 (1.167-3.791), P = 0.013) was an independent poor prognostic factor. IHCC with CA9 overexpression showed a 0.5-fold (95% confidence interval, 0.328-0.944) lower risk of death compared with those of no or weak expression. CA9 overexpression was related to histologic differentiation and an independent good prognostic factor. PMID:25755787

  12. 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

  13. 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

  14. 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

  15. What Are the Precursor and Early Lesions of Peripheral Intrahepatic Cholangiocarcinoma?

    PubMed Central

    Nakanuma, Yasuni; Tsutsui, Akemi; Sasaki, Motoko

    2014-01-01

    Cholangiocarcinoma (CC) is divided into distal, perihilar, and intrahepatic CCs (ICCS), and are further subdivided into large bile duct ICC and peripheral ICC. In distal and perihilar CC and large duct ICC, biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm (IPN) have been proposed as precursor lesions. Peripheral ICC, bile duct adenoma (BDA), biliary adenofibroma (BAF), and von Meyenburg complexes (VMCs) are reportedly followed by development of ICCs. Herein, we surveyed these candidate precursor lesions in the background liver of 37 cases of peripheral ICC and controls (perihilar CC, 34 cases; hepatocellular carcinoma, 34 cases and combined hepatocellular cholangiocarcinoma, 25 cases). In the background liver of peripheral ICC, BDA and BAF were not found, but there were not infrequently foci of BDA-like lesions and atypical bile duct lesions involving small bile ducts (32.4% and 10.8%, resp.). VMCs were equally found in peripheral CCs and also control CCs. In conclusion, BDA, BAF, and VMCs are a possible precursor lesion of a minority of peripheral CCs, and BDA-like lesions and atypical bile duct lesions involving small bile ducts may also be related to the development of peripheral ICC. Further pathologic studies on these lesions are warranted for analysis of development of peripheral ICCs. PMID:24860673

  16. Intrahepatic cholangiocarcinoma in a patient with Wilson's disease: a case report.

    PubMed

    Mukai, Yosuke; Wada, Hiroshi; Eguchi, Hidetoshi; Yamada, Daisaku; Asaoka, Tadafumi; Noda, Takehiro; Kawamoto, Koichi; Gotoh, Kunihito; Takeda, Yutaka; Tanemura, Masahiro; Umeshita, Koji; Hori, Yumiko; Morii, Eiichi; Doki, Yuichiro; Mori, Masaki

    2016-12-01

    The incidence of hepatobiliary malignancies, and especially intrahepatic cholangiocarcinoma (ICC), for patients with Wilson's disease (WD), is very low, even for cirrhotic patients. A 44-year-old male was admitted to our department for treatment of a liver tumor. He was diagnosed with WD at the age of 15. According to radiological findings, his liver tumor was a suspected hepatocellular carcinoma (HCC) or a combined hepatocellular and cholangiocellular carcinoma. A partial resection of liver segments 8 (S8) and 5 (S5) was subsequently performed due to the intraoperative suspicion of intrahepatic metastasis at the surface of S5. Postoperative histology revealed that the resected portion of S8 contained an ICC; the removed S5 portion comprised a regenerative nodule with hemosiderosis. To date, the patient has survived without tumor recurrence for more than 44 months following surgery. A survey of the literature, inclusive of case reports, would suggest that surgical resection is the primary course of action for a WD patient with ICC, if liver function can be preserved and curative resection performed. PMID:27005296

  17. 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

  18. 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. PMID:21354945

  19. Adjuvant Transarterial Chemoembolization Following Liver Resection for Intrahepatic Cholangiocarcinoma Based on Survival Risk Stratification

    PubMed Central

    Li, Jun; Wang, Qing; Lei, Zhengqing; Wu, Dong; Si, Anfeng; Wang, Kui; Wan, Xuying; Wang, Yizhou; Yan, Zhenlin; Xia, Yong; Lau, Wan Yee; Wu, Mengchao

    2015-01-01

    Background. The effectiveness of adjuvant transarterial chemoembolization (TACE) for intrahepatic cholangiocarcinoma (ICC) after hepatectomy remains unclear. This study was performed to identify ICC patients who would benefit from adjuvant TACE. Patients and Methods. The study included 553 patients who underwent hepatectomy for ICC between January 2008 and February 2011 at the Eastern Hepatobiliary Surgery Hospital and who were treated with or without TACE (122 with TACE and 431 without TACE). Survival risk stratification was performed using the established prognostic nomogram (ICC nomogram). The predictive performance was evaluated by concordance index and calibration. The tumor recurrence and overall survival (OS) rates were analyzed by the Kaplan-Meier method before and after propensity score matching (PSM). Results. The predictive performance of the ICC nomogram was demonstrated by the well-fitted calibration curves and an optimal c-index of 0.71 for OS prediction. In the whole cohort, the 5-year recurrence and OS rates between the TACE and non-TACE groups were significantly different (5-year recurrence: 72.9% vs. 78.1%; OS: 38.4% vs. 29.7%). After 1:1 PSM, the TACE and non-TACE groups (122 patients each) had similar 5-year recurrence and OS rates (5-year recurrence: 72.9% vs. 74.2%; OS: 38.4% vs. 36.0%). By survival risk stratification based on ICC nomogram, only the patients in the lowest tertile (nomogram scores ≥77) benefited from adjuvant TACE (TACE vs. non-TACE groups: 90.4% vs. 95.9% for 5-year recurrence; 21.3% vs. 6.2% for 5-year OS). Conclusion. Adjuvant TACE following liver resection might be suitable for ICC patients with high ICC nomogram scores (≥77). Implications for Practice: The accurate predictive performance of the established prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) following liver resection was reconfirmed in an independent cohort with 553 patients. Based on the survival risk stratification using the nomogram

  20. Multimodal treatment strategies for advanced hilar cholangiocarcinoma.

    PubMed

    Weiss, Matthew J; Cosgrove, David; Herman, Joseph M; Rastegar, Neda; Kamel, Ihab; Pawlik, Timothy M

    2014-08-01

    Cholangiocarcinoma (CCA) is the second most common primary malignancy of the liver arising from malignant transformation and growth of biliary ductal epithelium. Approximately 50-70 % of CCAs arise at the hilar plate of the biliary tree, which are termed hilar cholangiocarcinoma (HC). Various staging systems are currently employed to classify HCs and determine resectability. Depending on the pre-operative staging, the mainstays of treatment include surgery, chemotherapy, radiation therapy, and photodynamic therapy. Surgical resection offers the only chance for cure of HC and achieving an R0 resection has demonstrated improved overall survival. However, obtaining longitudinal and radial surgical margins that are free of tumor can be difficult and frequently requires extensive resections, particularly for advanced HCs. Pre-operative interventions may be necessary to prepare patients for major hepatic resections, including endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, and portal vein embolization. Multimodal therapy that combines chemotherapy with external beam radiation, stereotactic body radiation therapy, bile duct brachytherapy, and/or photodynamic therapy are all possible strategies for advanced HC prior to resection. Orthotopic liver transplantation is another therapeutic option that can achieve complete extirpation of locally advanced HC in judiciously selected patients following standardized neoadjuvant protocols. PMID:24962146

  1. Distinguishing intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma using precontrast and gadoxetic acid-enhanced MRI

    PubMed Central

    Asayama, Yoshiki; Nishie, Akihiro; Ishigami, Kousei; Ushijima, Yasuhiro; Takayama, Yukihisa; Fujita, Nobuhiro; Kubo, Yuichiro; Aishima, Shinichi; Shirabe, Ken; Yoshiura, Takashi; Honda, Hiroshi

    2015-01-01

    PURPOSE We aimed to gain further insight in magnetic resonance imaging characteristics of mass-forming intrahepatic cholangiocarcinoma (mICC), its enhancement pattern with gadoxetic acid contrast agent, and distinction from poorly differentiated hepatocellular carcinoma (pHCC). METHODS Fourteen mICC and 22 pHCC nodules were included in this study. Two observers recorded the tumor shape, intratumoral hemorrhage, fat on chemical shift imaging, signal intensity at the center of the tumor on T2-weighted image, fibrous capsule, enhancement pattern on arterial phase of dynamic study, late enhancement three minutes after contrast injection (dynamic late phase), contrast uptake on hepatobiliary phase, apparent diffusion coefficient, vascular invasion, and intrahepatic metastasis. RESULTS Late enhancement was more common in mICC (n=10, 71%) than in pHCC (n=3, 14%) (P < 0.001). A fat component was observed in 11 pHCC cases (50%) versus none of mICC cases (P = 0.002). Fibrous capsule was observed in 13 pHCC cases (59%) versus none of mICC cases (P < 0.001). On T2-weighted images a hypointense area was seen at the center of the tumor in 43% of mICC (6/14) and 9% of pHCC (2/22) cases (P = 0.018). Other parameters were not significantly different between the two types of nodules. CONCLUSION The absence of fat and fibrous capsule, and presence of enhancement at three minutes appear to be most characteristic for mICC and may help its differentiation from pHCC. PMID:25698097

  2. Differential Expression of Sonic Hedgehog Protein in Human Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.

    PubMed

    Al-Bahrani, Redha; Nagamori, Seishi; Leng, Roger; Petryk, Anna; Sergi, Consolato

    2015-09-01

    Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA) are the two most common primary liver malignancies in adult patients. The molecular mechanisms underlying the pathogenesis of HCC and CCA are still poorly understood. Sonic hedgehog (SHH) signaling plays an essential role during mammalian development, i.e., promoting organ growth, tissue differentiation, and cell polarity. The upregulation of SHH has been observed during carcinogenesis, including colorectal carcinoma. Our aim was to investigate the expression pattern of SHH in HCC and CCA. We investigated 40 malignant tumors of the liver, including 21 HCC and 19 of intrahepatic CCA cases by immunohistochemistry (IHC) using a polyclonal antibody against SHH and Avidin-Biotin Complex method. We also investigated the co-localization of SHH and Bone morphogenetic protein 4 (BMP4) in CCA using indirect double IHC. Moreover, we examined whether SHH is expressed in two HCC cell lines HepG2 and HuH-7 and three CCA cell lines OZ, HuCCT1 and HuH28. We found that SHH was expressed in 15 out of 21 cases (71.4 %) of HCC and 100 % of CCA cases by immunohistochemistry. SHH expression showed a positive trend in liver tumors (HCC, CCA) with high grade (G2-G3). SHH localized to the epithelial cells, while BMP4 was expressed in the stromal cells in CCA by double IHC. However, both HCC and CCA cell lines showed SHH expression by Western blot analysis. In conclusion, SHH seems to be an interesting marker of de-differentiation in liver tumors and the simultaneous epithelial-mesenchymal expression may be an intriguing prompt to investigate cross-talks between SHH and BMP4. PMID:25740074

  3. Down-Regulation of Nogo-B Expression as a Newly Identified Feature of Intrahepatic Cholangiocarcinoma.

    PubMed

    Nanashima, Atsushi; Hatachi, Go; Tominaga, Tetsurou; Murakami, Goushi; Takagi, Katsunori; Arai, Junichi; Wada, Hideo; Nagayasu, Takeshi; Sumida, Yorihisa

    2016-01-01

    Nogo-B, located in the endoplasmic reticulum, is an isoform belonging to the reticulon protein family, which is expressed specifically in cholangiocytes and non-parenchymal cells in the liver. Nogo-B expression is down-regulated with the progression of liver fibrosis, but its distinct function in liver malignancies has not been fully clarified. We have hypothesized that Nogo-B expression may be altered in intrahepatic cholangiocarcinoma (ICC), a relatively rare type of primary liver cancer with highly malignant behavior. The present study aimed to investigate the relationship between Nogo-B expression, assessed by immunohistochemical staining, and clinicopathological factors and prognosis in 34 ICC patients. Positive expression was observed in 19 (56%) of 34 ICC specimens: 6 patients (18%) with positivity levels of 1+ (positive cells in 10-50% of cancer cells) and 13 patients (38%) with 2+ (positive cells over 50%). Importantly, the remaining 15 patients (44%) were categorized as negative expression (Nogo-B-positive cells, less than 10%). Conversely, the mass-forming type of ICC tended to express Nogo-B with the degree of 2+ positivity, compared to the periductal infiltration type (p = 0.064), and the mass-forming type showed a better 5-year survival rate (66% vs. 5%) after hepatectomy (p < 0.05). However, the degree of positivity was not associated with tumor relapse rate, disease-free and overall survival, although each of the periductal infiltration type, intrahepatic metastasis, larger tumor size, and lower microvessel counts was associated with lower survival rates. We propose that Nogo-B expression is down-regulated in ICC, the implication of which, however, remains to be investigated. PMID:26656426

  4. 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

  5. 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

  6. Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: A systematic review and pooled analysis

    PubMed Central

    Al-Adra, D.P.; Gill, R.S.; Axford, S.J.; Shi, X.; Kneteman, N.; Liau, S.-S.

    2015-01-01

    Radioembolization with yttrium-90 microspheres offers an alternative treatment option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, the rarity and heterogeneity of ICC makes it difficult to draw firm conclusions about treatment efficacy. Therefore, the goal of the current study is to systematically review the existing literature surrounding treatment of unresectable ICCs with yttrium-90 microspheres and provide a comprehensive review of the current experience and clinical outcome of this treatment modality. We performed a comprehensive search of electronic databases for ICC treatment and identified 12 studies with relevant data regarding radioembolization therapy with yttrium-90 microspheres. Based on pooled analysis, the overall weighted median survival was 15.5 months. Tumour response based on radiological studies demonstrated a partial response in 28% and stable disease in 54% of patients at three months. Seven patients were able to be downstaged to surgical resection. The complication profile of radioembolization is similar to that of other intra-arterial treatment modalities. Overall survival of patients with ICC after treatment with yttrium-90 microspheres is higher than historical survival rates and shows similar survival to those patients treated with systemic chemotherapy and/or trans-arterial chemoembolization therapy. Therefore, the use of yttrium-90 microspheres should be considered in the list of available treatment options for ICC. However, future randomized trials comparing systemic chemotherapy, TACE and local radiation will be required to identify the optimal treatment modality for unresectable ICC. PMID:25449754

  7. 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.

  8. Clinical significance of nerve growth factor and tropomyosin-receptor-kinase signaling pathway in intrahepatic cholangiocarcinoma

    PubMed Central

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

    2014-01-01

    AIM: To investigate the correlation between nerve growth factor-tropomyosin-receptor-kinase (NGF-TrkA) signaling pathway and prognosis in intrahepatic cholangiocarcinoma (IHCC). METHODS: NGF and TrkA expression in 83 samples of IHCC was assessed by immunohistochemistry. Correlations between NGF-TrkA expression and clinicopathological features were analyzed by χ2 test. Moreover, we evaluated the association between NGF-TrkA and overall survival by univariate and multivariate analysis. With experiments in vitro, we investigated the crucial role of NGF-TrkA on proliferation and invasion of IHCC cells with recombinant NGF-β stimulation. RESULTS: We found that NGF and TrkA expression was significantly related with differentiation (P = 0.024) and intraneural invasion (P = 0.003), respectively. Additionally, double higher expression of NGF and TrkA was identified as an independent prognostic factor in IHCC (P = 0.003). Moreover, we demonstrated that NGF-TrkA signaling pathway can promote IHCC proliferation and invasion. CONCLUSION: NGF-TrkA double higher expression is an independent prognostic factor in IHCC. NGF-TrkA pathway can promote IHCC progression, indicating that NGF-TrkA may become a potential drug target. PMID:24744599

  9. Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis.

    PubMed

    Al-Adra, D P; Gill, R S; Axford, S J; Shi, X; Kneteman, N; Liau, S-S

    2015-01-01

    Radioembolization with yttrium-90 microspheres offers an alternative treatment option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, the rarity and heterogeneity of ICC makes it difficult to draw firm conclusions about treatment efficacy. Therefore, the goal of the current study is to systematically review the existing literature surrounding treatment of unresectable ICCs with yttrium-90 microspheres and provide a comprehensive review of the current experience and clinical outcome of this treatment modality. We performed a comprehensive search of electronic databases for ICC treatment and identified 12 studies with relevant data regarding radioembolization therapy with yttrium-90 microspheres. Based on pooled analysis, the overall weighted median survival was 15.5 months. Tumour response based on radiological studies demonstrated a partial response in 28% and stable disease in 54% of patients at three months. Seven patients were able to be downstaged to surgical resection. The complication profile of radioembolization is similar to that of other intra-arterial treatment modalities. Overall survival of patients with ICC after treatment with yttrium-90 microspheres is higher than historical survival rates and shows similar survival to those patients treated with systemic chemotherapy and/or trans-arterial chemoembolization therapy. Therefore, the use of yttrium-90 microspheres should be considered in the list of available treatment options for ICC. However, future randomized trials comparing systemic chemotherapy, TACE and local radiation will be required to identify the optimal treatment modality for unresectable ICC. PMID:25449754

  10. KrasG12D and p53 mutation cause primary intra-hepatic cholangiocarcinoma

    PubMed Central

    O’Dell, Michael R.; Huang, Jing-Li; Whitney-Miller, Christa L.; Deshpande, Vikram; Rothberg, Paul; Grose, Valerie; Rossi, Randall M.; Zhu, Andrew X.; Land, Hartmut; Bardeesy, Nabeel; Hezel, Aram F.

    2012-01-01

    Intrahepatic cholangiocarcinoma (IHCC) is a primary cancer of the liver with a rising incidence and poor prognosis. Preclinical studies of the etiology and treatment of this disease are hampered by the relatively small number of available IHCC cell lines or genetically faithful animal models. Here we report the development of a genetically engineered mouse model of IHCC that incorporates two of the most common mutations in human IHCC, activating mutations of Kras (KrasG12D) and deletion of p53. Tissue-specific activation of KrasG12D alone resulted in the development of invasive IHCC with low penetrance and long latency. Latency was shortened by combining KrasG12D activation with heterozygous or homozygous deletion of p53 (mean survival of 56 weeks versus 19 weeks, respectively), which also resulted in widespread local and distant metastasis. Serial analysis showed that the murine models closely recapitulated the multistage histopathologic progression of the human disease, including the development of stroma-rich tumors and the pre-malignant biliary lesions, intraductal papillary biliary neoplasms (IPBN) and Von Meyenburg complexes (VMC; also known as biliary hamartomas). These findings establish a new genetically and histopathologically faithful model of IHCC and lend experimental support to the hypothesis that IPBN and VMC are precursors to invasive cancers. PMID:22266220

  11. Comprehensive analysis of transcriptome and metabolome analysis in Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma

    PubMed Central

    Murakami, Yoshiki; Kubo, Shoji; Tamori, Akihiro; Itami, Saori; Kawamura, Etsushi; Iwaisako, Keiko; Ikeda, Kazuo; Kawada, Norifumi; Ochiya, Takahiro; Taguchi, Y-h

    2015-01-01

    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are liver originated malignant tumors. Of the two, ICC has the worse prognosis because it has no reliable diagnostic markers and its carcinogenic mechanism is not fully understood. The aim of this study was to integrate metabolomics and transcriptomics datasets to identify variances if any in the carcinogenic mechanism of ICC and HCC. Ten ICC and 6 HCC who were resected surgically, were enrolled. miRNA and mRNA expression analysis were performed by microarray on ICC and HCC and their corresponding non-tumor tissues (ICC_NT and HCC_NT). Compound analysis was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Principle component analysis (PCA) revealed that among the four sample groups (ICC, ICC_NT, HCC, and HCC_NT) there were 14 compounds, 62 mRNAs and 17 miRNAs with two distinct patterns: tumor and non-tumor, and ICC and non-ICC. We accurately (84.38%) distinguished ICC by the distinct pattern of its compounds. Pathway analysis using transcriptome and metabolome showed that several pathways varied between tumor and non-tumor samples. Based on the results of the PCA, we believe that ICC and HCC have different carcinogenic mechanism therefore knowing the specific profile of genes and compounds can be useful in diagnosing ICC. PMID:26538415

  12. Gene expression profiling of the tumor microenvironment in human intrahepatic cholangiocarcinoma

    PubMed Central

    Sulpice, Laurent; Desille, Mireille; Turlin, Bruno; Fautrel, Alain; Boudjema, Karim; Clément, Bruno; Coulouarn, Cédric

    2016-01-01

    Intrahepatic cholangiocarcinoma (ICC) is the second most common type of malignant primary tumors in the liver. ICC is an aggressive cancer with a poor survival and limited therapeutic options. At the histological level, ICC is characterized by an abundant stroma (i.e. the tumor microenvironment that notably includes components of the extracellular matrix, stromal cells and soluble factors). Tumor microenvironment is known to play a key role in tumor onset and progression but it is poorly characterized at the molecular level. Thus, this study was specifically designed to identify genes that are significantly deregulated in the tumor microenvironment of human ICC. Here we provide a detailed description of the experimental design and methods used to acquire the genomic data deposited into Gene Expression Omnibus (GEO) under the accession number GSE45001. Our genomic dataset provides insights on the molecular pathways altered in the microenvironment of ICC and allows the identification of novel ICC biomarkers, as exemplified previously in Hepatology (PMID: 23775819). PMID:26981414

  13. Gene expression profiling of the tumor microenvironment in human intrahepatic cholangiocarcinoma.

    PubMed

    Sulpice, Laurent; Desille, Mireille; Turlin, Bruno; Fautrel, Alain; Boudjema, Karim; Clément, Bruno; Coulouarn, Cédric

    2016-03-01

    Intrahepatic cholangiocarcinoma (ICC) is the second most common type of malignant primary tumors in the liver. ICC is an aggressive cancer with a poor survival and limited therapeutic options. At the histological level, ICC is characterized by an abundant stroma (i.e. the tumor microenvironment that notably includes components of the extracellular matrix, stromal cells and soluble factors). Tumor microenvironment is known to play a key role in tumor onset and progression but it is poorly characterized at the molecular level. Thus, this study was specifically designed to identify genes that are significantly deregulated in the tumor microenvironment of human ICC. Here we provide a detailed description of the experimental design and methods used to acquire the genomic data deposited into Gene Expression Omnibus (GEO) under the accession number GSE45001. Our genomic dataset provides insights on the molecular pathways altered in the microenvironment of ICC and allows the identification of novel ICC biomarkers, as exemplified previously in Hepatology (PMID: 23775819). PMID:26981414

  14. Double primary hepatic cancer (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) in a single patient: A case report

    PubMed Central

    ZHOU, RONGXING; ZHANG, MINJIA; CHENG, NANSHENG; ZHOU, YONG

    2016-01-01

    Double primary hepatic cancer, consisting of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) located separately within a single liver simultaneously, is extremely rare. The present study reports a case of double hepatic nodules, in which HCC and ICC occurred simultaneously in the right hepatic lobe. The 47-year-old male patient, who was a carrier of hepatitis B virus, was admitted to our hospital for physical examination, which revealed two liver masses. The results of initial laboratory tests, including liver function tests, were within normal limits, with the exception of mildly elevated aspartate aminotransferase and alanine aminotransferase, and decreased albumin levels. α-fetoprotein was in the normal range, while carbohydrate antigen 19-9 was marginally elevated. Abdominal ultrasonography and enhanced computed tomography revealed two tumors located in segments (S) VI and VII of the liver, respectively, with malignant behavior. Examination of the two masses following resection of S VI and VII confirmed a diagnosis of combined HCC and ICC. After 8 months of follow-up, no signs of recurrence have been observed with chemical therapy. PMID:26870202

  15. The diagnostic and prognostic value of MRP8/MRP14 in intrahepatic cholangiocarcinoma.

    PubMed

    Jin, Guang-Zhi; Dong, Wei; Dong, Hui; Yu, Hua; Chen, Jia; Yu, Wen-Long; Li, Ai-Jun; Cong, Wen-Ming; Wu, Meng-Chao

    2015-11-17

    Myeloid-related protein 8 (MRP8) and 14 (MRP14) are abundantly expressed in several kinds of benign and malignant tumors. However, little is known about their clinicopathological significance in intrahepatic cholangiocarcinoma (ICC), biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of bile duct (IPNB), or inflammatory hepatic biliary ducts epithelium (IHBD). This study aimed to investigate the diagnostic and prognostic values of MRP8 and MRP14 as new biomarkers for ICC. We examined MRP8 and MRP14 expression levels by immunohistochemistry in IHBD (n = 15), BilIN (BilIN1 = 24, BilIN2 = 9, BilIN3 = 5), IPNB (n = 18) and ICC (n = 416). The differential diagnostic and prognosis values were also evaluated. The results showed that the ratio of tumor-infiltrating MRP8 and MRP14 positive immune cells, relative to biliary epithelial cells, was significantly increased in ICC tissues compared with nonmalignant tissues, including IHBD, BilIN1, BilIN2, BilIN3, and IPNB (P value < 0.05). In addition, over-expression levels of MRP8 and MRP14 were correlated with overall survival (OS) and time to recurrence (TTR) by univariate analysis; MRP8/MRP14 combination was an independent prognostic factor for OS and TTR. MRP8 and MRP14 expression might help to identify the benign bile duct diseases from ICC, as high expression of MRP8 and MRP14 suggests a poor prognosis after surgical resection. PMID:26472105

  16. The diagnostic and prognostic value of MRP8/MRP14 in intrahepatic cholangiocarcinoma

    PubMed Central

    Chen, Jia; Yu, Wen-Long; li, Ai-Jun; Cong, Wen-Ming; Wu, Meng-Chao

    2015-01-01

    Myeloid-related protein 8 (MRP8) and 14 (MRP14) are abundantly expressed in several kinds of benign and malignant tumors. However, little is known about their clinicopathological significance in intrahepatic cholangiocarcinoma (ICC), biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of bile duct (IPNB), or inflammatory hepatic biliary ducts epithelium (IHBD). This study aimed to investigate the diagnostic and prognostic values of MRP8 and MRP14 as new biomarkers for ICC. We examined MRP8 and MRP14 expression levels by immunohistochemistry in IHBD (n = 15), BilIN (BilIN1 = 24, BilIN2 = 9, BilIN3 = 5), IPNB (n = 18) and ICC (n = 416). The differential diagnostic and prognosis values were also evaluated. The results showed that the ratio of tumor-infiltrating MRP8 and MRP14 positive immune cells, relative to biliary epithelial cells, was significantly increased in ICC tissues compared with nonmalignant tissues, including IHBD, BilIN1, BilIN2, BilIN3, and IPNB (P value < 0.05). In addition, over-expression levels of MRP8 and MRP14 were correlated with overall survival (OS) and time to recurrence (TTR) by univariate analysis; MRP8/MRP14 combination was an independent prognostic factor for OS and TTR. MRP8 and MRP14 expression might help to identify the benign bile duct diseases from ICC, as high expression of MRP8 and MRP14 suggests a poor prognosis after surgical resection. PMID:26472105

  17. Intrahepatic chemotherapy for unresectable cholangiocarcinoma: review of literature and personal experience.

    PubMed

    Massani, Marco; Nistri, Cristina; Ruffolo, Cesare; Bonariol, Roberta; Pauletti, Bruno; Bonariol, Luca; Caratozzolo, Ezio; Morana, Giovanni; Bassi, Nicolò

    2015-12-01

    Most patients with intrahepatic cholangiocarcinoma (IH-CCA) are unresectable and treatment options are limited. This study evaluates the efficacy of hepatic artery infusion (HAI) chemotherapy in patients whose disease is not initially treatable with resection. We selected patients with unresectable IH-CCA treated only with HAI chemotherapy at our centre between January 2008 and December 2012. We compared our outcome, using mRECIST, with published results of patients treated with systemic chemotherapy during the same period. Eleven patients underwent HAI chemotherapy with fluorouracil and oxaliplatin after placement of an HAI pump. A CT scan performed after the sixth cycle of therapy revealed that 5 of them had partial hepatic response (more than 45 %), 2 stable disease and 4 showed clear signs of disease progression. The average survival of the entire group was 17.6 months. Three of the patients with partial hepatic response underwent resection and 2 had more than 70 % tumour necrosis, both of whom are still alive and disease free. The median survival of patients with liver-only disease treated with systemic chemotherapy, who were not submitted for resection, was 15.3 months. HAI chemotherapy enables this small group of patients to have their unresectable IH-CCA disease converted into a resectable one, thus confirming its role in treatment of this disease. PMID:26468142

  18. Comprehensive analysis of transcriptome and metabolome analysis in Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma.

    PubMed

    Murakami, Yoshiki; Kubo, Shoji; Tamori, Akihiro; Itami, Saori; Kawamura, Etsushi; Iwaisako, Keiko; Ikeda, Kazuo; Kawada, Norifumi; Ochiya, Takahiro; Taguchi, Y-h

    2015-01-01

    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are liver originated malignant tumors. Of the two, ICC has the worse prognosis because it has no reliable diagnostic markers and its carcinogenic mechanism is not fully understood. The aim of this study was to integrate metabolomics and transcriptomics datasets to identify variances if any in the carcinogenic mechanism of ICC and HCC. Ten ICC and 6 HCC who were resected surgically, were enrolled. miRNA and mRNA expression analysis were performed by microarray on ICC and HCC and their corresponding non-tumor tissues (ICC_NT and HCC_NT). Compound analysis was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Principle component analysis (PCA) revealed that among the four sample groups (ICC, ICC_NT, HCC, and HCC_NT) there were 14 compounds, 62 mRNAs and 17 miRNAs with two distinct patterns: tumor and non-tumor, and ICC and non-ICC. We accurately (84.38%) distinguished ICC by the distinct pattern of its compounds. Pathway analysis using transcriptome and metabolome showed that several pathways varied between tumor and non-tumor samples. Based on the results of the PCA, we believe that ICC and HCC have different carcinogenic mechanism therefore knowing the specific profile of genes and compounds can be useful in diagnosing ICC. PMID:26538415

  19. Large Intrahepatic Cholangiocarcinoma with Tumor Infiltrative Lymphocytes and Autoimmune Hepatitis-Like Features

    PubMed Central

    Izumi, Sadanobu; Nakamura, Satoko; Mano, Shohei

    2010-01-01

    The development of a primary hepatic tumor associated with autoimmune hepatitis (AIH) has been rarely reported. This report describes a rare case of intrahepatic cholangiocarcinoma (ICC) that accompanied tumor infiltrative lymphocytes (TIL) and AIH-like features. Moreover, multiple early gastric cancers were recognized in synchrony. An 81-year-old male was admitted due to liver dysfunction. His laboratory data on admission showed an elevation of immunoglobulin G and a positive titer of antinuclear antibody. Biological tests for HBV and HCV were negative. Computed tomography showed a well-enhanced hepatic tumor and gastrointestinal fiberscopy revealed two early gastric cancers with mucosal invasion. Biopsies were obtained from the background liver and the hepatic tumor. Histologically, the tumor revealed adenocarcinoma and the liver showed piecemeal necrosis and interface hepatitis with lymphoplasmacytic infiltration. The patient underwent hepatectomy and distal gastrectomy. Finally, he was diagnosed to have a mass forming type ICC and early gastric cancers. Moreover, prominent TIL in the ICC was revealed. An analysis of the infiltrating lymphocytes by immunohistochemical staining suggested that there was a difference in the local immune response between the tumor and the background liver. Review of the literature showed that there are only three reports of ICC associated with AIH, if including the current case. PMID:21103227

  20. BSEP and MDR3: Useful Immunohistochemical Markers to Discriminate Hepatocellular Carcinomas From Intrahepatic Cholangiocarcinomas and Hepatoid Carcinomas.

    PubMed

    Fujikura, Kohei; Yamasaki, Takashi; Otani, Kyoko; Kanzawa, Maki; Fukumoto, Takumi; Ku, Yonson; Hirose, Takanori; Itoh, Tomoo; Zen, Yoh

    2016-05-01

    We herein examined the immunohistochemical expression of 2 hepatocyte-specific transporters (bile salt export pump [BSEP] and multidrug-resistance protein 3 [MDR3]) in hepatocellular carcinomas (HCCs, n=54), intrahepatic cholangiocarcinomas (n=34), combined hepatocellular and cholangiocarcinomas (n=23), and hepatoid carcinomas originated from extrahepatic organs (n=27) to compare their diagnostic values with those of arginase-1 (ARG1) and hepatocyte paraffin-1 (HepPar-1). BSEP was expressed in 91% of HCCs and MDR3 in 83%. Although their sensitivities were slightly lower than those of ARG1 (96%) and HepPar-1 (93%), the 2 transporters appeared to be more specific for HCCs. ARG1 and HepPar-1 were expressed in intrahepatic cholangiocarcinomas (9% and 6%) and hepatoid carcinomas (22% and 44%, respectively), whereas BSEP and MDR3 were entirely negative in these neoplasms, except for 1 case of BSEP-positive hepatoid carcinoma of the esophagus. The highly specific expression of BSEP and MDR3 in hepatocytes was recapitulated in additional examinations of combined hepatocellular and cholangiocarcinomas, in which the expression of the transporters was restricted to morphologically hepatocellular areas. In contrast, ARG1 and HepPar-1 were also variably positive in areas of biliary or indeterminate differentiation. We also applied BSEP and MDR3 immunohistochemistry to 8 biopsy cases of poorly differentiated primary liver cancer, in which the original diagnosis was not conclusive. The diagnosis of HCC was retrospectively suggested in 2 cases expressing both BSEP and MDR3. In conclusion, given the highly specific expression of BSEP and MDR3 in HCCs, immunohistochemistry for these transporters will be useful not only for determining hepatocellular differentiation in primary liver cancers but also for discriminating HCCs from hepatoid carcinomas. PMID:26735860

  1. High-mobility group box 1 expression and lymph node metastasis in intrahepatic cholangiocarcinoma

    PubMed Central

    Xu, Yun-Fei; Ge, Fu-Jun; Han, Bo; Yang, Xiao-Qing; Su, Hong; Zhao, An-Cheng; Zhao, Ming-Hong; Yang, Yu-Bao; Yang, Jie

    2015-01-01

    AIM: To evaluate the prognostic value of high-mobility group box 1 (HMGB1) expression in intrahepatic cholangiocarcinoma (IHCC) and the possible underlying mechanism. METHODS: Tissue microarray was constructed from 65 IHCC patients. Immunohistochemistry was performed to validate expression of HMGB1 and Vascular endothelial growth factor C (VEGF-C). Real-time PCR and Western blot analyses were used to study transcript and protein levels. The interaction between HMGB1 and VEGF-C was evaluated by siRNA, real-time PCR, and enzyme-linked immuno assays. The correlation between HMGB1 expression and other clinicopathologic parameters was analyzed by χ2 test, and the univariate as well as multivariate analyses were accomplished by Kaplan-Meier method and Cox-regression model, respectively. RESULTS: Overall, overexpression of HMGB1 was found in 38/65 (58.8%) IHCCs, whereas VEGF-C overexpression was present in 30/65 (46.2%) cases. Overexpression of HMGB1 was significantly correlated with lymphatic microvessel density (P = 0.031, r = 0.268) and VEGF-C expression (P = 0.041, r = 0.254). With univariate analysis, both HMGB1 (P = 0.001) and VEGF-C (P = 0.004) were identified to be significantly associated with overall survival rate. Multivariate analysis indicated that HMGB1 could be served as an unfavorable independent prognostic factor in IHCCs (P = 0.005). siRNA knockdown of HMGB1 inhibited transforming growth factor-β-induced epithelial-mesenchymal transition (EMT) by elevating E-Cadherin expression and reducing expression of N-Cadherin, Vimentin and Snail in RBE cells. Further in vitro study revealed that HMGB1 silencing significantly decreased the level of VEGF-C, whereas the recombinant HMGB1 increased the VEGF-C level in RBE cells (both P < 0.05), which suggested that HMGB1 could promote lymphatic microvessel density, and subsequently lymphatic invasion, via promoting VEGF-C expression. CONCLUSION: Our results define an important role of HMGB1 in the progression of

  2. 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

  3. 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.

  4. Trans-arterial embolisation therapies for unresectable intrahepatic cholangiocarcinoma: a systematic review

    PubMed Central

    Yang, Linda; Shan, Jocelyn; Shan, Leonard; Bester, Lourens; Morris, David L.

    2015-01-01

    Background Unresectable intrahepatic cholangiocarcinoma (ICC) portends a poor prognosis despite standard systemic treatments which confer minimal survival benefits and significant adverse effects. This study aimed to assess clinical outcomes, complications and prognostic factors of TAE therapies using chemotherapeutic agents or radiation. Methods A literature search and article acquisition was conducted on PubMed (MEDLINE), OVID (MEDLINE) and EBSCOhost (EMBASE). Original articles published after January 2000 on trans-arterial therapies for unresectable ICC were selected using strict eligibility criteria. Radiological response, overall survival, progression-free survival, safety profile, and prognostic factors for overall survival were assessed. Quality appraisal and data tabulation were performed using pre-determined forms. Results were synthesized by narrative review and quantitative analysis. Results Twenty articles were included (n=929 patients). Thirty three percent of patients presented with extrahepatic metastases. After treatment, the average rate of complete and partial radiological response was 10% and 22.2%, respectively. Overall median survival time was 12.4 months with a median 30-day mortality and 1-year survival rate of 0.6% and 53%, respectively. Acute treatment toxicity (within 30 days) was reported in 34.9% of patients, of which 64.3% were mild to moderate in severity. The most common clinical toxicities were abdominal pain, nausea and vomiting, and fatigue. Multiplicity, localization and vascularity of the tumor may predict worse overall survival. Conclusions Trans-arterial therapies are safe and effective treatment options which should be considered routinely for unresectable ICC. Consistent and standardized methodology and data collection is required to facilitate a meta-analysis. Randomized controlled trials will be valuable in the future. PMID:26487951

  5. 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

  6. Histone deacetylase inhibitor screening identifies HC toxin as the most effective in intrahepatic cholangiocarcinoma cells.

    PubMed

    Zhou, Wenjie; Chen, Xiaoxun; He, Ke; Xiao, Jinfeng; Duan, Xiaopeng; Huang, Rui; Xia, Zhenglin; He, Jingliang; Zhang, Jinqian; Xiang, Guoan

    2016-05-01

    Histone deacetylases (HDACs) are highly expressed in intrahepatic cholangiocarcinoma (ICC) and are associated with poor prognosis of these patients. The aim of the present study was to explore the inhibitory effects of HDAC inhibitors on ICC cells and identify effective and sensitive drugs for ICC. Effects of 34 HDAC inhibitors were screened through two rounds of cell viability assays, and HC toxin, a cyclic tetrapeptide first isolated from the secondary metabolite of Helminthosporium carbonum, exhibited an antitumor activity superior to that of the other HDAC inhibitors and gemcitabine. The mechanisms involved in the inhibitory effects of HC toxin on CCLP-1 cells were investigated by cell counting, colony formation assay, cell morphological observation, real-time PCR, western blotting and flow cytometry. It was demonstrated that HC toxin inhibited the cell proliferation and clone formation ability of the CCLP-1 cells. HC toxin increased the acetyl-histone H4 level and this was associated with the inhibitory effect of HC toxin on the CCLP-1 cells. We also found that HC toxin reduced the level of HDAC1 protein in a post-transcriptional manner. Morphological observation showed multiple morphological changes and indicated the possibility of cell differentiation owing to HC toxin. With increasing concentration of HC toxin, the cell cycle was gradually arrested at the G0/G1 stage and the percentage of apoptotic cells increased which was not mainly through the caspase-3-dependent ways. These results indicated that HC toxin was the most effective among the various HDAC inhibitors with multiple functions in the suppression of ICC in vitro. Thus, HC may be a potential chemotherapeutic for ICC. PMID:26935789

  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. 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.

  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. PMID:26391917

  10. Influence of surgical margins on overall survival after resection of intrahepatic cholangiocarcinoma

    PubMed Central

    Tang, Haowen; Lu, Wenping; Li, Bingmin; Meng, Xuan; Dong, Jiahong

    2016-01-01

    Abstract Background: Surgical resection is shown to present the best chance of cure in the treatment of intrahepatic cholangiocarcinoma (ICC). However, the appropriate length of the negative margin remains unclear. The aim of the present meta-analysis was to investigate whether a clear margin of 10 mm or more (≥10 mm) conferred any survival benefit over a margin of less than 10 mm (<10 mm) in patients with resected ICC. Methods: The meta-analysis was conducted in adherence with the PRISMA guidelines. PubMed, Web of Science, EMBASE, and the Cochrane Library were systematically searched to identify eligible studies published in English from the initiation of the databases to February 2016. Overall survival rates were pooled by using the hazard ratio and the corresponding 95% confidence interval (CI). Random-effect models were utilized because of between-study heterogeneity. Results: Six studies (eight cohorts) reporting on 712 patients were analyzed: 269 (37.80%) were in the 10 mm or more negative margin group, and 443 (62.20%) were in the less than 10 mm negative margin group. The pooled hazard ratio for the less than 10 mm group was found to be 1.59 (95% CI: 1.09–2.32) when this group was compared with the 10 mm or more group (reference), with moderate between-study heterogeneity (I2 = 45.30%, P = 0.07). Commensurate results were identified by sensitivity analysis. Conclusion: The result of this meta-analysis suggests a long-term survival (overall survival) advantage for negative margins of 10 mm or more in comparison with negative margins less than 10 mm for patients undergoing surgical resection of ICC. PMID:27583880

  11. Distinct Clinicopathologic and Genetic Features of 2 Histologic Subtypes of Intrahepatic Cholangiocarcinoma.

    PubMed

    Hayashi, Akimasa; Misumi, Kento; Shibahara, Junji; Arita, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Kokudo, Norihiro; Fukayama, Masashi

    2016-08-01

    Previous studies have identified 2 clinically significant morphologic subtypes of intrahepatic cholangiocarcinoma (ICC) on the basis of anatomic location and/or histologic appearances. Recognizing that these classification schemes are not always applicable practically, this study aimed to establish a novel classification system based on mucin productivity and immunophenotype and to determine the rationale of this classification by examining the clinicopathologic and genetic characteristics of the 2 subtypes defined by this method. We retrospectively investigated 102 consecutive ICC cases and classified them on the basis of mucin productivity and immunophenotype (S100P, N-cadherin, and NCAM). We found that 42 and 56 cases were classified as type 1 and type 2 ICCs, respectively, and only 4 cases were of indeterminate type. Type 1 ICC, generally characterized by mucin production and diffuse immunoreactivity to S100P, arose less frequently in chronic liver diseases and showed higher levels of serum CEA and CA 19-9 than did type 2 ICC, which generally showed little mucin production and exhibited immunoreactivity to N-cadherin and/or NCAM. Type 1 ICC was characterized by several pathologic features, including higher frequencies of perineural invasion and lymph node metastasis. Although the log-rank test demonstrated that type 1 ICC had significantly worse survival, the multivariate Cox regression analysis showed no prognostic significance of this histologic subtype. Genetic analyses revealed that KRAS mutation was significantly more frequent in type 1 ICC, whereas IDH mutation and FGFR2 translocation were restricted to type 2 ICC. In conclusion, the present classification of ICC based on mucin productivity and immunophenotype identified 2 subtypes with clinicopathologic significance. PMID:27259014

  12. Histone deacetylase inhibitor screening identifies HC toxin as the most effective in intrahepatic cholangiocarcinoma cells

    PubMed Central

    ZHOU, WENJIE; CHEN, XIAOXUN; HE, KE; XIAO, JINFENG; DUAN, XIAOPENG; HUANG, RUI; XIA, ZHENGLIN; HE, JINGLIANG; ZHANG, JINQIAN; XIANG, GUOAN

    2016-01-01

    Histone deacetylases (HDACs) are highly expressed in intrahepatic cholangiocarcinoma (ICC) and are associated with poor prognosis of these patients. The aim of the present study was to explore the inhibitory effects of HDAC inhibitors on ICC cells and identify effective and sensitive drugs for ICC. Effects of 34 HDAC inhibitors were screened through two rounds of cell viability assays, and HC toxin, a cyclic tetrapeptide first isolated from the secondary metabolite of Helminthosporium carbonum, exhibited an antitumor activity superior to that of the other HDAC inhibitors and gemcitabine. The mechanisms involved in the inhibitory effects of HC toxin on CCLP-1 cells were investigated by cell counting, colony formation assay, cell morphological observation, real-time PCR, western blotting and flow cytometry. It was demonstrated that HC toxin inhibited the cell proliferation and clone formation ability of the CCLP-1 cells. HC toxin increased the acetyl-histone H4 level and this was associated with the inhibitory effect of HC toxin on the CCLP-1 cells. We also found that HC toxin reduced the level of HDAC1 protein in a post-transcriptional manner. Morphological observation showed multiple morphological changes and indicated the possibility of cell differentiation owing to HC toxin. With increasing concentration of HC toxin, the cell cycle was gradually arrested at the G0/G1 stage and the percentage of apoptotic cells increased which was not mainly through the caspase-3-dependent ways. These results indicated that HC toxin was the most effective among the various HDAC inhibitors with multiple functions in the suppression of ICC in vitro. Thus, HC may be a potential chemotherapeutic for ICC. PMID:26935789

  13. Chemoembolization (TACE) of unresectable intrahepatic cholangiocarcinoma with slow-release doxorubicin-eluting beads: preliminary results.

    PubMed

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

    2008-01-01

    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. PMID:18478290

  14. Contrast-Enhanced Ultrasound for the Characterization of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

    PubMed Central

    Liu, Guang-Jian; Wang, Wei; Lu, Ming-De; Xie, Xiao-Yan; Xu, Hui-Xiong; Xu, Zuo-Feng; Chen, Li-Da; Wang, Zhu; Liang, Jin-Yu; Huang, Yang; Li, Wei; Liu, Jin-Ya

    2015-01-01

    Purpose and methods The ability of contrast-enhanced ultrasound (CEUS) to differentiate between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) is still controversial. We reviewed the CEUS imaging of 819 patients (HCC=546, ICC=273) with an established pathological diagnosis. The enhancement patterns of lesions and the diagnostic performance of CEUS were analyzed. Results Arterial hyperenhancement followed by washout was observed in 92.3% (504/546) of the HCC lesions and 85.7% (234/273) of the ICC lesions on CEUS (p<0.05). Additionally, the ICCs presented contrast washout much earlier than the HCCs, with an average time of 27.5 seconds after injecting the contrast agent compared with 70.1 seconds for the HCCs (p<0.05). Peripheral rim-like enhancement was observed in 68.5% (187/273) of the ICCs, which was significantly more common than that in the HCCs (2.0%, 11/546) (p<0.05). When using arterial hyperenhancement with a washout phase later than 43 seconds after injecting the contrast agent and with no peripheral rim-like enhancement as the diagnostic criteria for HCC ≤5 cm in diameter, the area under the curve was 0.808, with 64.1% sensitivity, 97.4% specificity and 73.6% accuracy. Conclusions Although ICC may show the typical enhancement pattern of HCC on CEUS, peripheral rim-like enhancement and quick contrast washout show high efficiency in the differentiation of HCC from ICC. PMID:26779444

  15. Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets

    PubMed Central

    Zhu, Andrew X.; Borger, Darrell R.; Kim, Yuhree; Cosgrove, David; Ejaz, Aslam; Alexandrescu, Sorin; Groeschl, Ryan Thomas; Deshpande, Vikram; Lindberg, James M.; Ferrone, Cristina; Sempoux, Christine; Yau, Thomas; Poon, Ronnie; Popescu, Irinel; Bauer, Todd W.; Gamblin, T. Clark; Gigot, Jean Francois; Anders, Robert A.; Pawlik, Timothy M.

    2014-01-01

    Background The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. Methods Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined. Results The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. Conclusions Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis. PMID:24889489

  16. Establishment and characterization of a human intrahepatic cholangiocarcinoma cell line derived from an Italian patient.

    PubMed

    Cavalloni, Giuliana; Peraldo-Neia, Caterina; Varamo, Chiara; Casorzo, Laura; Dell'Aglio, Carmine; Bernabei, Paola; Chiorino, Giovanna; Aglietta, Massimo; Leone, Francesco

    2016-03-01

    Biliary tract carcinoma is a rare malignancy with multiple causes, which underlie the different genetic and molecular profiles. Cancer cell lines are affordable models, reflecting the characteristics of the tumor of origin. They represent useful tools to identify molecular targets for treatment. Here, we established and characterized from biological, molecular, and genetic point of view, an Italian intrahepatic cholangiocarcinoma cell line (ICC), the MT-CHC01. MT-CHC01 cells were isolated from a tumor-derived xenograft. Immunophenotypical characterization was evaluated both at early and after stabilization passages. In vitro biological, genetic, and molecular features were also investigated. In vivo tumorigenicity was assessed in NOD/SCID mice. MT-CHC01cells retain epithelial cell markers, EPCAM, CK7, and CK19, and some stemness and pluripotency markers, i.e., SOX2, Nanog, CD49f/integrin-α6, CD24, PDX1, FOXA2, and CD133. They grow as a monolayer, with a population double time of about 40 h; they show a low migration and invasion potential. In low attachment conditions, they are able to form spheres and to growth in anchorage-independent manner. After subcutaneous injection, they retain in vivo tumorigenicity; the expression of biliary markers as CA19-9 and CEA were maintained from primary tumor. The karyotype is highly complex, with a hypotriploid to hypertriploid modal number (3n+/-) (52 to 77 chromosomes); low level of HER2 gene amplification, TP53 deletion, gain of AURKA were identified; K-RAS G12D mutation were maintained from primary tumor to MT-CHC01 cells. We established the first ICC cell line derived from an Italian patient. It will help to study either the biology of this tumor or to test drugs both in vitro and in vivo. PMID:26486326

  17. A simple and effective prognostic staging system based on clinicopathologic features of intrahepatic cholangiocarcinoma

    PubMed Central

    Zhou, Huabang; Jiang, Xiaolan; Li, Qiaomei; Hu, Jingyi; Zhong, Zhengrong; Wang, Hao; Wang, Hui; Yang, Bing; Hu, Heping

    2015-01-01

    Incidence and mortality of intrahepatic cholangiocarcinoma (ICC) are increasing. However, its prognostic predictive system associated with outcome after surgery remains poorly defined. In this study, we conducted retrospective survival analyses in a primary cohort of 370 patients who underwent partial hepatectomy for ICC (2005 and 2009). We found that seven variables were significantly independent predictors for overall survival (OS): serum prealbumin (hazard ratio [HR]: 1.447; p = 0.015), carbohydrate antigen 19-9 (HR: 1.438; p = 0.009), carcinoembryonic antigen (HR: 1.732; p = 0.002), tumor number (HR: 1.781; p < 0.001), vascular invasion (HR: 1.784; p < 0.001), regional lymphatic metastasis (HR: 2.003; p < 0.001) and local extrahepatic metastasis (HR: 1.506; p = 0.008). Using these independent predictors, we created a simple clinicopathologic prognostic staging system for predicting survival of ICC patients after resection. The validity of the prognostic staging system was prospectively assessed in 115 patients who underwent partial hepatectomy between January 2010 and December 2010 at the same institution. The prognostic power was quantified using likelihood ratio test and Akaike information criteria. Compared with the 6th and 7th AJCC staging systems, the new staging system in the primary cohort had a higher predictive accuracy for OS in terms of homogeneity and discriminatory ability. In the validation cohort, the homogeneity and discrimination of the new staging system were also superior to the two other staging systems. Conclusions: The new staging system based on clinicopathologic features may provide relatively higher accuracy in prognostic prediction for ICC patients after tumor resection. PMID:26175951

  18. Negative Impact of Preoperative Platelet-Lymphocyte Ratio on Outcome After Hepatic Resection for Intrahepatic Cholangiocarcinoma

    PubMed Central

    Chen, Qing; Dai, Zhi; Yin, Dan; Yang, Liu-Xiao; Wang, Zheng; Xiao, Yong-Sheng; Fan, Jia; Zhou, Jian

    2015-01-01

    Abstract The elevated platelet-to-lymphocyte ratio (PLR), determined using an easy blood test based on platelet and lymphocyte counts, is reported to be a predictor of poor survival in patients with several cancers. The prognostic role of preoperative PLR in patients with intrahepatic cholangiocarcinoma (ICC) has, until now, been rarely investigated. The purpose of our study was to evaluate the prognostic significance of PLR in a large cohort of ICC patients after hepatic resection. We obtained data from 322 consecutive nonmetastatic ICC patients who underwent hepatectomy without preoperative therapy between 2005 and 2011. Clinicopathological parameters, including PLR, were evaluated. Overall survival (OS) and recurrence-free survival (RFS) were assessed using the Kaplan–Meier method. Using multivariate Cox regression models, the independent prognostic value of preoperative PLR was determined. Our results showed that PLR represents an independent adverse prognostic factor for OS and RFS in ICC patients using univariate and multivariate analyses. The optimal PLR cutoff value was 123 using receiver operating curve analyses. The 5-year OS and RFS rates after hepatectomy were 30.3% and 28.9% for the group with PLR 123 greater, compared with 46.2% and 39.4% for the group with PLR less than 123 (P = 0.0058 and 0.0153, respectively). In addition, high PLR values were associated with tumor size (P = 0.020). Our results suggest that preoperative PLR might represent a novel independent prognostic factor for OS and RFS in ICC patients with hepatic resection. PMID:25837750

  19. Comprehensive Multiple Molecular Profile of Epithelial Mesenchymal Transition in Intrahepatic Cholangiocarcinoma Patients

    PubMed Central

    Ke, Ai-Wu; Dong, Zhao-Ru; Zhang, Peng-Fei; Fan, Jia; Peng, Bao-Gang; Zhou, Jian

    2014-01-01

    Background The aim of this study is to investigate the expression profile of multiple epithelial mesenchymal transition (EMT)-related molecules in intrahepatic cholangiocarcinoma (ICC) and the related prognostic significance. Methods Immunohistochemistry was performed to determine the expression of E-cadherin, Vimentin, Snail, slug and β-catenin in a tissue microarray consisting of tumor tissues of 140 ICC patients undergoing curative resection. The correlation between the expression of these molecules and the clinicopathological characteristics of ICC patients was analyzed, and their prognostic implication was evaluated. Results Reduced E-cadherin and increased Vimentin expression, the characteristic changes of EMT, identified in 55.0% and 55.7% of primary ICCs, respectively, were correlated with lymphatic metastasis and poorer overall survival (OS) and disease-free survival (DFS) of ICCs. The overexpression of snail and nonmembranous β-catenin, which are the major regulators of the EMT, were identified in 49.2% and 45.7% of primary ICCs, while little slug expression was detected in ICCs. Cytoplasmic/nuclear β-catenin did not significantly predict worse DFS and was not related with E-cadherin loss. The overexpression of snail predicted worse OS and DFS. Snail overexpression correlated with the down-regulation of E-cadherin and the up-regulation of Vimentin. Inhibition of snail in an ICC cell line decreased the expression of E-cadherin, enhanced the expression of Vimentin and impaired the invasion and migration ability of ICC cells. Conclusions These data support the hypothesis that EMT plays vital roles in ICC progression and suggest that snail but not slug and β-catenin plays a crucial role in the EMT induction of ICC. PMID:24816558

  20. Model to predict survival after surgical resection of intrahepatic cholangiocarcinoma: the Mayo Clinic experience

    PubMed Central

    Ali, Shahzad M; Clark, Clancy J; Mounajjed, Taofic; Wu, Tsung-Teh; Harmsen, William S; Reid-Lombardo, KMarie; Truty, Mark J; Kendrick, Michael L; Farnell, Michael B; Nagorney, David M; Que, Florencia G

    2015-01-01

    Background The 7th edition of the American Joint Committee on Cancer (AJCC) staging system has recently been validated and shown to predict survival in patients with intrahepatic cholangiocarcinoma (ICC). The present study attempted to investigate the validity of these findings. Methods A single-centre, retrospective cohort study was conducted. Histopathological restaging of disease subsequent to primary surgical resection was carried out in all consecutive ICC patients. Overall survival was compared using Kaplan–Meier estimates and log-rank tests. Results A total of 150 patients underwent surgery, 126 (84%) of whom met the present study's inclusion criteria. Of these 126 patients, 68 (54%) were female. The median length of follow-up was 4.5 years. The median patient age was 58 years (range: 24–79 years). Median body mass index was 27 kg/m2 (range: 17–46 kg/m2). Staging according to the AJCC 7th edition categorized 33 (26%) patients with stage I disease, 27 (21%) with stage II disease, five (4%) with stage III disease, and 61 (48%) with stage IVa disease. The AJCC 7th edition failed to accurately stratify survival in the current cohort; analysis revealed significantly worse survival in those with microvascular invasion, tumour size of >5 cm, grade 4 disease, multiple tumours and positive lymph nodes (P < 0.001). A negative resection margin was associated with improved survival (P < 0.001). Conclusions The AJCC 7th edition did not accurately predict survival in patients with ICC. A multivariable model including tumour size and differentiation in addition to the criteria used in the AJCC 7th edition may offer a more accurate method of predicting survival in patients with ICC. PMID:25410716

  1. A case of an alpha-fetoprotein-producing intrahepatic cholangiocarcinoma suggests probable cancer stem cell origin.

    PubMed

    Ishikawa, Kenji; Sasaki, Atsushi; Haraguchi, Naotsugu; Yoshikawa, Yasuji; Mori, Masaki

    2007-03-01

    Recent evidence suggests that some cancers may originate from cancer stem cells, which may derive from carcinogenesis of normal stem cells. A hepatic progenitor cell population, which gives rise to hepatocytes and cholangiocytes, has been suggested in humans, though whether these cells can give rise to malignant tumors has not been confirmed. We report here a case of an alpha-fetoprotein (AFP)-producing intrahepatic cholangiocarcinoma (ICC) in an 81-year-old woman with chronic hepatitis C viral infection, suggesting malignant transformation of hepatic stem cells as a mechanism for hepatic neoplasia. Abdominal computed tomography revealed a low-density mass with surrounding enhancement measuring 5 cm x 5 cm in segments IV and VIII of the liver. The preoperative serum levels of tumor markers were 1.7 ng/ml of carcinoembryonic antigen, 22 mAU/ml of protein induced by vitamin K absence or antagonist II, 43.4 U/ml of carbohydrate antigen 19-9, and 1,560 ng/ml of AFP. Following central bisegmentectomy of the liver, serum AFP levels decreased dramatically. Histologically, the tumor cells showed indistinct glandular structures with abundant fibrous stroma. Immunohistochemical analysis demonstrated that the neoplastic cells reacted strongly to antibodies against AFP and cytokeratin (CK) 7. In addition, cancer cells showed partially positive reaction to anti-CK14, a liver stem cell marker, and to anticluster designation (CD) 133, a hematopoietic stem cell marker, and negative reaction to antihepatocyte paraffin (HepPar) 1. These data may indicate that the tumor was derived from a normal liver stem cell that underwent oncogenic transformation. PMID:17405896

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

    PubMed

    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

  3. 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

  4. Synchronous development of intrahepatic cholangiocarcinoma and hepatocellular carcinoma in different sites of the liver with chronic B-viral hepatitis: two case reports

    PubMed Central

    2013-01-01

    Background Synchronous development of primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma has been reported rarely. In literature review, there have been only 35 reported cases of synchronous hepatocellular carcinoma and intrahepatic cholangiocarcinoma, and most of these tumors developed in patients with hepatitis C-related liver cirrhosis. Here, we present synchronous development of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in two patients with chronic B-viral hepatitis. Case presentation Two patients with chronic hepatitis B were referred to our hospital due to a hepatic mass. Patient 1 had a 6.4 cm multinodular hepatic mass in the left lobe and a small nodule in the right lobe. Patient 2 had a 4.3 cm hypervascular mass in the right lobe and a 1.1 cm nodule in the left lobe. The pre-operative diagnosis of both cases was hepatocellular carcinoma with metastatic nodule, however, surgical resection pathology revealed that hepatocellular carcinoma and intrahepatic cholangiocarcinoma existed independently in the other side of the liver in both cases. Additionally, the background liver histology of both cases was hepatitis B-related chronic hepatitis without cirrhotic change. Conclusion Our cases suggest that hepatitis B virus infection can also predispose to development of double liver cancers. PMID:24313990

  5. [A Case of Resected Gastric Cancer Occurring Simultaneously with Intrahepatic Cholangiocarcinoma after S-1 plus Cisplatin Chemotherapy].

    PubMed

    Nishimura, Masashige; Kawada, Junji; Matsuura, Norihiro; Kitagawa, Akihiro; Nomura, Masatoshi; Okumura, Yuichiro; Nakatsuka, Rie; Miyazaki, Susumu; Danno, Katsuki; Motoori, Masaaki; Kubota, Masaru; Matsuda, Chu; Fujitani, Kazumasa; Iwase, Kazuhiro

    2015-11-01

    It is sometimes difficult to differentiate between metastatic and primary liver tumors, when the liver tumor occurs simultaneously with a gastric cancer. We encountered a case of resected gastric cancer, which occurred concomitantly with intrahepatic cholangiocarcinoma after S-1 plus cisplatin chemotherapy, in a patient who was previously diagnosed with metastatic liver tumor before treatment. An 80-year-old man was admitted to our hospital because of epigastralgia. Endoscopic study of the upper gastrointestinal tract showed a type 3 tumor at the upper body of the stomach. A plain CT scan showed an irregular, low-density area, which was enhanced by contrast medium in the lateral segment of the liver. We performed an ultrasound- guided needle biopsy, because it was impossible to make a definitive diagnosis by dynamic CT, contrast-enhanced ultrasonography, and MRI. Immunohistochemical analysis for cytokeratin 7/20 resulted in 7 (+)/20 (-) for both the gastric cancer and the liver tumor. Therefore, we diagnosed the patient with gastric cancer, which occurred concomitantly with the metastatic liver tumor, and administered chemotherapy with S-1 plus cisplatin. After 3 courses of the regimen, a reduction in the size of mass was observed in the stomach and the liver. We subsequently performed left hepatectomy and total gastrectomy with lymph node dissection. Microscopic examination revealed the gastric cancer, which occurred simultaneously with the intrahepatic cholangiocarcinoma. The postoperative course was uneventful, and the patient remains well without recurrences. PMID:26805150

  6. 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

  7. [A Case of Intrahepatic Cholangiocarcinoma with Invasion to the Transverse Colon and Gallbladder, Forming an Intra-Tumor Abscess].

    PubMed

    Okada, Nami; Kametaka, Hisashi; Koyama, Takashi; Seike, Kazuhiro; Makino, Hironobu; Fukada, Tadaomi; Sato, Yutaka; Miyazaki, Masaru

    2015-11-01

    An 81-year-old man was referred to our institution for evaluation of high fever and a liver tumor that had been detected by ultrasonography. Computed tomography revealed a low-density mass with peripheral ring-like enhancement in S5 of the liver. The liver mass was in contact with the gallbladder, and the boundary between the mass and the gallbladder was unclear. On the suspicion of liver abscess, percutaneous transhepatic drainage was performed. The cavity of the abscess communicated with the gallbladder. Because the cavity had no tendency to reduce in size, we performed surgical resection under a preoperative diagnosis of liver abscess or primary liver carcinoma invading to the gallbladder. Intraoperative findings revealed a liver tumor invading the transverse colon and gallbladder. Subsegmentectomy of S4a and S5 of the liver combined with gallbladder and transverse colon resection was performed. Histopathological findings indicated the growth of a mass forming type intrahepatic cholangiocarcinoma with invasion to the transverse colon and gallbladder, and the pathological stage of the tumor was pT3N0M0, fStage Ⅲ. Thus far, the patient is alive without recurrence 9 months after surgery. Here, we report an extremely rare case of intrahepatic cholangiocarcinoma that invaded other organs and was associated with an intra-tumor abscess. PMID:26805160

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

    PubMed Central

    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

    2014-01-01

    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. PMID:25229838

  9. Computed Tomography-Guided Interstitial HDR Brachytherapy (CT-HDRBT) of the Liver in Patients with Irresectable Intrahepatic Cholangiocarcinoma

    SciTech Connect

    Schnapauff, Dirk Denecke, Timm; Grieser, Christian; Colletini, Federico; Seehofer, Daniel; Sinn, Marianne; Wust, Peter; Gebauer, Bernhard

    2012-06-15

    Purpose: 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.MethodFifteen 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. Results: 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. Conclusion: 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.

  10. 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

  11. Low expression of ARID1A correlates with poor prognosis in intrahepatic cholangiocarcinoma

    PubMed Central

    Yang, Song-Zhu; Wang, An-Qiang; Du, Juan; Wang, Jian-Tao; Yu, Wei-Wei; Liu, Qing; Wu, Yan-Fang; Chen, Shu-Guang

    2016-01-01

    AIM: To investigate the relationship between ARID1A expression and clinicopathologic parameters, as well as its prognostic value, for patients with intrahepatic cholangiocarcinoma (IHCC). METHODS: We assessed ARID1A protein and mRNA expression in IHCC tissues and paracarcinomatous (PC) tissues from 57 patients with IHCC using western blot and quantitative real-time reverse transcription polymerase chain reaction, respectively. We used Fisher’s exact and χ2 tests to analyze relationships between clinicopathological parameters and ARID1A expression. The Kaplan-Meier method and Cox regression were used to analyze survival. RESULTS: The mean ARID1A protein level in IHCC tissues was 1.16 ± 0.36 relative units (RU), which was significantly lower than that in PC tissues (1.26 ± 0.21 RU, P < 0.01) and NL tissues (1.11 ± 0.31, P < 0.001). The mean ARID1A mRNA level in IHCC tissues (1.20 ± 0.18) was also lower than that in PC tissues (1.27 ± 0.15, P < 0.001) and normal liver tissues (1.15 ± 0.34, P < 0.001). Low ARID1A expression was significantly associated with tumor nodules, vein invasion, and recurrence. Median overall survival (OS) and disease-free survival (DFS) for the low ARID1A expression group was 15.0 and 7.0 mo, respectively, which were significantly shorter than those for the high ARID1A expression group at 25.0 and 22.0 mo (OS: P < 0.01; DFS: P < 0.001), respectively. Low ARID1A expression was significantly associated with worse OS (HR = 3.967, 95%CI: 1.299-12.118, P = 0.016) in multivariate analyses. CONCLUSION: Low expression of ARID1A is associated with poor prognosis in patients with IHCC, and thus may be a potential prognostic biomarker candidate in IHCC. PMID:27433094

  12. 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.

  13. 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

  14. 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

  15. 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

    2016-01-01

    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

  16. Clinical diagnosis and staging of cholangiocarcinoma

    PubMed Central

    Blechacz, Boris; Komuta, Mina; Roskams, Tania; Gores, Gregory J.

    2012-01-01

    Cholangiocarcinoma is the most frequent biliary malignancy. It is difficult to diagnose owing to its anatomic location, growth patterns and lack of definite diagnostic criteria. Currently, cholangiocarcinoma is classified into the following types according to its anatomic location along the biliary tree: intrahepatic, perihilar or distal extrahepatic cholangiocarcinoma. These cholangiocarcinoma types differ in their biological behavior and management. The appropriate stratification of patients with regard to the anatomic location and stage of cholangiocarcinoma is a key determinate in their management. Staging systems can guide this stratification and provide prognostic information. In addition, staging systems are essential in order to compare and contrast the outcomes of different therapeutic approaches. A number of staging systems exist for cholangiocarcinoma—several early ones have been updated, and new ones are being developed. We discuss the emerging diagnostic criteria as well as the different staging systems for cholangiocarcinoma, and provide a critical appraisal regarding these advances in biliary tract malignancies. PMID:21808282

  17. Extensive Use of Interventional Therapies Improves Survival in Unresectable or Recurrent Intrahepatic Cholangiocarcinoma

    PubMed Central

    Seidensticker, Ricarda; Seidensticker, Max; Doegen, Kathleen; Mohnike, Konrad; Schütte, Kerstin; Stübs, Patrick; Kettner, Erika; Pech, Maciej; Amthauer, Holger; Ricke, Jens

    2016-01-01

    Aim. To assess the outcomes of patients with unresectable intrahepatic cholangiocellular carcinoma (ICC) treated by a tailored therapeutic approach, combining systemic with advanced image-guided local or locoregional therapies. Materials and Methods. Treatment followed an algorithm established by a multidisciplinary GI-tumor team. Treatment options comprised ablation (RFA, CT-guided brachytherapy) or locoregional techniques (TACE, radioembolization, i.a. chemotherapy). Results. Median survival was 33.1 months from time of diagnosis and 16.0 months from first therapy. UICC stage analysis showed a median survival of 15.9 months for stage I, 9 months for IIIa, 18.4 months for IIIc, and 13 months for IV. Only the number of lesions, baseline serum CEA and serum CA19-9, and objective response (RECIST) were independently associated with survival. Extrahepatic metastases had no influence. Conclusion. Patients with unresectable ICC may benefit from hepatic tumor control provided by local or locoregional therapies. Future prospective study formats should focus on supplementing systemic therapy by classes of interventions (“toolbox”) rather than specific techniques, that is, local ablation leading to complete tumor destruction (such as RFA) or locoregional treatment leading to partial remission (such as radioembolization). This trial is registered with German Clinical Trials Registry (Deutsche Register Klinischer Studien), DRKS-ID: DRKS00006237. PMID:26966431

  18. Extensive Use of Interventional Therapies Improves Survival in Unresectable or Recurrent Intrahepatic Cholangiocarcinoma.

    PubMed

    Seidensticker, Ricarda; Seidensticker, Max; Doegen, Kathleen; Mohnike, Konrad; Schütte, Kerstin; Stübs, Patrick; Kettner, Erika; Pech, Maciej; Amthauer, Holger; Ricke, Jens

    2016-01-01

    Aim. To assess the outcomes of patients with unresectable intrahepatic cholangiocellular carcinoma (ICC) treated by a tailored therapeutic approach, combining systemic with advanced image-guided local or locoregional therapies. Materials and Methods. Treatment followed an algorithm established by a multidisciplinary GI-tumor team. Treatment options comprised ablation (RFA, CT-guided brachytherapy) or locoregional techniques (TACE, radioembolization, i.a. chemotherapy). Results. Median survival was 33.1 months from time of diagnosis and 16.0 months from first therapy. UICC stage analysis showed a median survival of 15.9 months for stage I, 9 months for IIIa, 18.4 months for IIIc, and 13 months for IV. Only the number of lesions, baseline serum CEA and serum CA19-9, and objective response (RECIST) were independently associated with survival. Extrahepatic metastases had no influence. Conclusion. Patients with unresectable ICC may benefit from hepatic tumor control provided by local or locoregional therapies. Future prospective study formats should focus on supplementing systemic therapy by classes of interventions ("toolbox") rather than specific techniques, that is, local ablation leading to complete tumor destruction (such as RFA) or locoregional treatment leading to partial remission (such as radioembolization). This trial is registered with German Clinical Trials Registry (Deutsche Register Klinischer Studien), DRKS-ID: DRKS00006237. PMID:26966431

  19. Hepatitis B virus and hepatitis C virus play different prognostic roles in intrahepatic cholangiocarcinoma: A meta-analysis

    PubMed Central

    Wang, Zheng; Sheng, Yuan-Yuan; Dong, Qiong-Zhu; Qin, Lun-Xiu

    2016-01-01

    AIM: To identify the prognostic value of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in patients with intrahepatic cholangiocarcinoma. METHODS: A search was performed for relevant publications in PubMed, EMBASE and Web of Science databases. The pooled effects were calculated from the available information to identify the relationship between HBV or HCV infection and the prognosis and clinicopathological features. The χ2 and I2 tests were used to evaluate heterogeneity between studies. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated by a fixed-effects model, if no heterogeneity existed. If there was heterogeneity, a random-effects model was applied. RESULTS: In total, 14 studies involving 2842 cases were enrolled in this meta-analysis. The patients with HBV infection presented better overall and disease-free survival, and the pooled HRs were significant at 0.76 (95%CI: 0.70-0.83) and 0.78 (95%CI: 0.66-0.94), respectively. Additionally, our study revealed that HCV infection was correlated with shortened overall survival in comparison with the control group (HR = 2.64, 95%CI: 1.77-3.93). We also found that HBV infection occurred more frequently in male patients [odds ratio (OR) = 1.91, 95%CI: 1.06-3.44] and was correlated with higher levels of serum aspartate transaminase (AST) and alpha-fetoprotein (AFP) (OR = 1.93, 95%CI: 1.11-3.35; OR = 3.86, 95%CI: 2.58-5.78) and a lower level of serum carbohydrate antigen 19-9 (CA19-9) (OR = 0.47, 95%CI: 0.34-0.65). Moreover, HBV infection was associated with cirrhosis (OR = 6.44, 95%CI: 4.33-9.56), a higher proportion of capsule formation (OR = 6.04, 95%CI: 3.56-10.26), and a lower rate of lymph node metastasis (OR = 0.39, 95%CI: 0.25-0.58). No significant publication bias was seen in any of the enrolled studies. CONCLUSION: HBV infection may indicate a favorable prognosis in patients with intrahepatic cholangiocarcinoma, while HCV infection suggests a poor prognosis. PMID

  20. Ring finger protein 43 expression is associated with genetic alteration status and poor prognosis among patients with intrahepatic cholangiocarcinoma.

    PubMed

    Talabnin, Chutima; Janthavon, Patcharee; Thongsom, Sunisa; Suginta, Wipa; Talabnin, Krajang; Wongkham, Sopit

    2016-06-01

    Ring finger E3 ligases have roles in processes central to maintenance of genomic integrity and cellular homeostasis. Many ring finger E3 ligases are implicated in malignancy. Ring finger protein 43 (RNF43) is a ring finger E3 ligase that negatively regulates the Wnt/β-catenin signaling pathway. RNF43 is frequently mutated in several types of malignancy, including intrahepatic cholangiocarcinoma (ICC). The significance of its expression in ICC has not, however, been reported. We determined RNF43 expression and identified RNF43 polymorphisms in ICC tissues. We also investigated the correlation between RNF43 expression and RNF43 mutation status, RNF43 polymorphisms, clinicopathological features, and prognosis of ICC patients. RNF43 reduced expression in ICC, and the reduction of RNF43 messenger RNA expression was significantly correlated with the presence of rs2257205 and RNF43 somatic mutations, confirming that all RNF43 somatic mutations in ICC are inactivating. Overall survival was worst in patients with down-regulation of RNF43. Univariate and multivariate analyses revealed that RNF43 expression was an independent prognostic factor. There was no statistically significant association between RNF43 messenger RNA and protein expression nor any clinicopathological features or RNF43 polymorphisms. The results imply that RNF43 is down-regulated in ICC and may play a crucial role during development of ICC. PMID:26980022

  1. Contrast-Enhanced Ultrasound in the Diagnosis of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: Controversy over the ASSLD Guideline

    PubMed Central

    2015-01-01

    Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are both regarded as primary liver cancers, having different biological behaviors and prognoses. Correct differentiation between them is essential for surgical planning and prognosis assessment. In 2005, the American Association for the Study of Liver Diseases (AASLD) recommended that noninvasive diagnosis of HCC is achievable by a single dynamic technique (including contrast-enhanced ultrasound (CEUS)) showing intense arterial uptake followed by washout of contrast in the venous-delayed phases. However, CEUS has been dropped from the diagnostic techniques in the latest AASLD guideline according to the opinion of some authors from Europe that CEUS may offer false positive HCC diagnosis in patients with ICC. Since the update of AASLD guideline has been released, increased attention has been paid to this interesting topic. Remarkable controversy over this issue is present and this removal was not well received in Europe and Asia. This commentary summarized the opinions for the role of CUES in differentiation between HCC and ICC in recent years. It is concluded that prospective studies with strict design and large case series are mandatory to solve the controversies and stratification of ICC in terms of tumor size and liver background is also essential. PMID:26090401

  2. Sarcopenia as a prognostic factor in hepatolithiasis-associated intrahepatic cholangiocarcinoma patients following hepatectomy: a retrospective study

    PubMed Central

    Zhou, Gongting; Bao, Haili; Zeng, Qiqiang; Hu, Weijian; Zhang, Qiyu

    2015-01-01

    Background: Sarcopenia is closely associated with poor performance status and high mortality in cancer patients. The present study is to determine the correlation between sarcopenia and prognosis of hepatectomy for hepatolithiasis-associated intrahepatic cholangiocarcinoma (IHHCC). Methods: Sixty-seven eligible IHHCC patients who underwent hepatectomy, between January 2000 and August 2014 were retrospectively evaluated. Sarcopenia was determined from skeletal muscle index (SMI), assessed by skeletal muscle mass on axial computed tomography images. Factors contributing to overall survival (OS) and recurrence-free survival (RFS) were analyzed by univariate and multivariate analyses. Results: Sarcopenia occurred in 33 (49.3%) out of 67 patients. Median OS of the enrolled patients was 12 months. Sarcopenic patients had a shorter OS compared with non-sarcopenic patients (P < 0.001). On univariate analyses, sarcopenia was significantly associated with overall survival (OS) and recurrence-free survival (RFS; both P < 0.05). On multivariate analysis, sarcopenic patients suffered poor overall survival (P < 0.001) and recurrence-free survival (P = 0.011) compared with non-sarcopenic patients. Conclusions: Preoperative sarcopenia is an independent biomarker of poor prognosis in IHHCC patients following hepatectomy. The identification of sarcopenia may enhance a clinical consideration on decision making for IHHCC patients before surgery. PMID:26770426

  3. Dynamic enhancement patterns of intrahepatic cholangiocarcinoma in cirrhosis on contrast-enhanced computed tomography: risk of misdiagnosis as hepatocellular carcinoma

    PubMed Central

    Li, Rui; Cai, Ping; Ma, Kuan-sheng; Ding, Shi-Yi; Guo, De-Yu; Yan, Xiao-Chu

    2016-01-01

    This study aimed to assess the features of intrahepatic cholangiocarcinoma (ICC) at computerized tomography (CT) and verify the risk of misdiagnosis of ICC as hepatocellular carcinoma (HCC) in cirrhosis. CT appearances of 98 histologically confirmed ICC nodules from 84 cirrhotic patients were retrospectively reviewed, taking into consideration the pattern and dynamic contrast uptake during the arterial, portal venous and delayed phases. During the arterial phase, 53 nodules (54.1%) showed peripheral rim-like enhancement, 35 (35.7%) hyperenhancement, 9 (9.2%) hypoenhancement and 1 (1.0%) isoenhancement. The ICC nodules showed heterogeneous dynamic contrast patterns, being progressive enhancement in 35 nodules (35.7%), stable enhancement in 28 nodules (28.6%), wash-in and wash-out pattern in 15 nodules (15.3%) and all other enhancement patterns in 20 nodules (20.4%). There were no significant differences in the dynamic vascular patterns of ICC according to nodule size (p > 0.05). ICC in cirrhosis has varied enhancement patterns at contrast-enhanced multiphase multidetector CT. Though the majority of ICC did not display typical radiological hallmarks of HCC, if dynamic CT scan was used as the sole modality for the non-invasive diagnosis of nodules in cirrhosis, the risk of misdiagnosis of ICC for HCC is not negligible. PMID:27226026

  4. Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma

    PubMed Central

    Wang, Jinghan; Zhang, Keqiang; Wang, Jinhui; Wu, Xiwei; Liu, Xiyong; Li, Bin; Zhu, Yan; Yu, Yong; Cheng, Qingbao; Hu, Zhenli; Guo, Chao; Hu, Shuya; Mu, Bing; Tsai, Chun-Hao; Li, Jie; Smith, Lynne; Yang, Lu; Liu, Qi; Chu, Peiguo; Chang, Vincent; Zhang, Baihe; Wu, Mengchao; Jiang, Xiaoqing; Yen, Yun

    2015-01-01

    Intrahepatic cholangiocarcinoma (ICC) is a rare and highly aggressive malignancy. In this study, we identified the presence of gene deletion and missense mutation leading to inactivation or underexpression of liver kinase B1 (LKB1) tumor suppressor and excluded the involvement of LKB1 gene hypermethylation in ICC tissues. Immunohistochemical analysis showed that LKB1 was underexpressed in a portion of 326 ICC tissues compared to their adjacent normal tissues. By statistical analysis underexpression of LKB1 in ICC tissues significantly correlated with poor survival and malignant disease characteristics in ICC patients. Moreover, we showed that knockdown of LKB1 significantly enhanced growth, migration, and invasion of three LKB1-competent ICC cell lines. Global transcriptional profiling analysis identified multiple malignancy-promoting genes, such as HIF-1α, CD24, Talin1, Vinculin, Wnt5, and signaling pathways including Hedgehog, Wnt/β-catenin, and cell adhesion as novel targets of LKB1 underexpression in ICC cells. Furthermore, knockdown of LKB1 gene expression dramatically enhanced Wnt/β-catenin signaling in ICC cells, while an inverse correlation between LKB1 and nuclear β-catenin was observed in ICC tissues. Our findings suggest a novel mechanism for ICC carcinogenesis in which LKB1 underexpression enhances multiple signaling pathways including Wnt/β-catenin to promote disease progression. PMID:26056085

  5. Overexpression of PDZK1IP1, EEF1A2 and RPL41 genes in intrahepatic cholangiocarcinoma.

    PubMed

    Yang, Guanghua; Zong, Huajie

    2016-06-01

    Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy in the liver, which is associated with a poor prognosis. However, the molecular pathogenesis of iCCA remains unclear. RNA-Seq for tumor and para-tumor sample pairs enables the characterization of changes in the gene expression profiles of patients with iCCA. The present study analyzed RNA‑Seq data of seven iCCA para‑tumor and tumor sample pairs. Differential gene expression analysis demonstrated significant upregulation of PDZK1IP1, EEF1A2 and RPL41 (ENSG00000279483) genes in the iCCA samples when compared with the matched para‑tumor samples. Furthermore, genes associated with the immune system, metabolism and metabolic energy were significantly downregulated in the iCCA tumor tissues, indicating that this is involved in the pathogenesis of iCCA. The present study aimed to elucidate the gene expression patterns associated with the tumorigenesis of iCCA by comparing tumor and normal tissues, in order to isolate novel diagnostic factors for iCCA. PMID:27082702

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

    PubMed

    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

  7. The Degree of Contrast Washout on Contrast-Enhanced Ultrasound in Distinguishing Intrahepatic Cholangiocarcinoma from Hepatocellular Carcinoma.

    PubMed

    Han, Jing; Liu, Yubo; Han, Feng; Li, Qing; Yan, Cuiju; Zheng, Wei; Wang, Jianwei; Guo, Zhixing; Wang, Jun; Li, Anhua; Zhou, Jianhua

    2015-12-01

    We aim to assess the role and degree of contrast washout in the differential diagnosis of intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC) on contrast-enhanced ultrasound (CEUS). Fifty-six histopathology-confirmed ICC nodules and 184 HCC nodules were included in this study. The nodules' washout degree on CEUS at 1, 2 and 3 min was semi-quantitatively and qualitatively assessed using gray-scale video signal intensity. Semi-quantitative assessment showed that the washout degree of ICCs at 1, 2 and 3 min were significantly lower than those of HCCs (p < 0.001) and similar results were found in the same size range subgroups. There were no significant differences in the washout degree of ICCs between patients with chronic hepatitis and those without. The areas under receiver operating characteristic curves, using the nodules' washout degree at 1, 2 and 3 min to differentiate ICC from HCC, were 0.957, 0.979 and 0.982, respectively. The qualitative assessment showed the washout of ICCs was more rapid and obvious than that of HCCs. At 3 min, moderate and marked washout were observed in all ICCs, but in only 12.5% HCCs (p < 0.001). In conclusion, ICCs displayed much higher degree of contrast washout than HCCs on CEUS, which allowed for differentiation from HCCs. PMID:26386477

  8. Intrahepatic Cholangiocarcinoma With Lymphoepithelioma-like Carcinoma Components Not Associated With Epstein-Barr Virus: Report of a Case

    PubMed Central

    Aosasa, Suefumi; Maejima, Tadashi; Kimura, Akifumi; Nishiyama, Kiyoshi; Edo, Hiromi; Shinmoto, Hiroshi; Kaji, Tatsumi; Ogata, Sho; Hatsuse, Kazuo; Hase, Kazuo; Yamamoto, Junji

    2015-01-01

    A carcinoma displaying undifferentiated features with dense lymphoplasmacytic infiltration is defined as lymphoepithelioma-like carcinoma (LELC). Intrahepatic cholangiocarcinoma (ICC) with LELC components is rare, and most LELCs are associated with Epstein-Barr virus (EBV). We report here on a case of ICC with LELC components not associated with EBV. A 65-year-old woman was incidentally found to have a hepatic tumor in the caudate lobe. An extended right hepatectomy with lymphadenectomy was performed. Histologically, the tumor was mainly composed of large undifferentiated epithelial cells with vesicular nuclei, prominent nucleoli, indistinct cell borders, and heavy small lymphocytic infiltration, which are the characteristic features of LELC. Immunohistochemical studies revealed that the tumor cells were positive for cytokeratin 19 but were negative for glypican 3. In situ hybridization using EBV-encoded RNA was negative. Therefore, a diagnosis of ICC with LELC components not associated with EBV was made. Because there is limited information available regarding the prognosis and treatment of ICC with LELC components because of the limited number of reported cases, additional studies will be needed to clarify the clinicopathologic features of this disease. PMID:25875552

  9. Dynamic enhancement patterns of intrahepatic cholangiocarcinoma in cirrhosis on contrast-enhanced computed tomography: risk of misdiagnosis as hepatocellular carcinoma.

    PubMed

    Li, Rui; Cai, Ping; Ma, Kuan-Sheng; Ding, Shi-Yi; Guo, De-Yu; Yan, Xiao-Chu

    2016-01-01

    This study aimed to assess the features of intrahepatic cholangiocarcinoma (ICC) at computerized tomography (CT) and verify the risk of misdiagnosis of ICC as hepatocellular carcinoma (HCC) in cirrhosis. CT appearances of 98 histologically confirmed ICC nodules from 84 cirrhotic patients were retrospectively reviewed, taking into consideration the pattern and dynamic contrast uptake during the arterial, portal venous and delayed phases. During the arterial phase, 53 nodules (54.1%) showed peripheral rim-like enhancement, 35 (35.7%) hyperenhancement, 9 (9.2%) hypoenhancement and 1 (1.0%) isoenhancement. The ICC nodules showed heterogeneous dynamic contrast patterns, being progressive enhancement in 35 nodules (35.7%), stable enhancement in 28 nodules (28.6%), wash-in and wash-out pattern in 15 nodules (15.3%) and all other enhancement patterns in 20 nodules (20.4%). There were no significant differences in the dynamic vascular patterns of ICC according to nodule size (p > 0.05). ICC in cirrhosis has varied enhancement patterns at contrast-enhanced multiphase multidetector CT. Though the majority of ICC did not display typical radiological hallmarks of HCC, if dynamic CT scan was used as the sole modality for the non-invasive diagnosis of nodules in cirrhosis, the risk of misdiagnosis of ICC for HCC is not negligible. PMID:27226026

  10. [Two long-term survival cases of unresectable intrahepatic cholangiocarcinoma treated with hepatic arterial infusion chemotherapy and radiation therapy].

    PubMed

    Komatsu, Hisateru; Kanazawa, Akishige; Tsukamoto, Tadashi; Shimizu, Sadatoshi; Ishikawa, Akira; Mori, Yoshihiro; Nakajima, Takayoshi; Ohira, Go; Kodai, Shintaro; Morimoto, Junya; Yamazoe, Sadaaki; Yamamoto, Atsushi; Inoue, Toru; Yamashita, Yoshito; Nishiguchi, Yukio; Ikehara, Teruyuki; Taira, Koichi; Horii, Katsuhiko; Yamazaki, Osamu

    2012-11-01

    The prognosis for patients with unresectable intrahepatic cholangiocarcinoma(ICC) is extremely poor. Case 1 was a 65- year-old woman who had an ICC of 9 cm in diameter (mass-forming type) in the right lobe with portal trunk invasion. She was treated with hepatic arterial infusion chemotherapy[cisplatin(CDDP)/5-fluorouracil(5-FU)/l-leucovorin(l-LV)] and radiation therapy (total dose, 50 Gy). After 6 months, abdominal computed tomography (CT) revealed that the tumor had regressed. She survived for 7 years without recurrence of the ICC; subsequently, she died of peritoneal cancer. Case 2 was a 59-year-old woman who had an ICC of 8 cm in diameter (mass-forming type) in the left lobe with lymph node metastasis in the hepatoduodenal ligament; the right hepatic artery was involved by the metastatic lymph nodes. She was treated with hepatic arterial infusion chemotherapy(CDDP/5-FU/l-LV) and radiation therapy(total dose, 30 Gy). After 10 months, abdominal CT revealed that the tumor had disappeared, but paraaortic and mediastinal lymph node metastases were detected. She was therefore treated with systemic chemotherapy. Treatment with systematic chemotherapy enabled her to survive for over 5 years with a good performance status. PMID:23267958

  11. 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

  12. Synchronous double primary cancer - intrahepatic cholangiocarcinoma with bone metastases and thyroid carcinoma: A case report

    PubMed Central

    WANG, QING-LIANG; LI, XIAO-JIE; ZHAO, KUN; LIU, BO; YE, XIAO-MING

    2015-01-01

    There is a low incidence of multiple primary cancer, particularly when the cancer is synchronous. The present report presents a case of synchronous double primary malignancies. A 58-year-old woman was admitted to Ling Nan Hospital (Guangzhou, China) complaining of pain in the left hip. X-ray revealed an osteolytic lesion and further examination indicated the presence of double primary cancer, consisting of hepatic cholangiocarcinoma and thyroid carcinoma. Biopsy of the osteolytic lesion showed a metastatic adenocarcinoma of unknown origin. Subsequently, final diagnosis was confirmed by I-131 scan and liver lesion biopsy. The patient received positive multidisciplinary treatments and survived for 9 months following diagnosis. The results of the present case suggest that multiplicity of primary malignancy is not necessarily an indicator of poor prognosis, as long as effective diagnosis and adequate disease management are achieved. PMID:26788211

  13. 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

  14. Regional Chemotherapy for Unresectable Intrahepatic Cholangiocarcinoma: A Potential Role for Dynamic Magnetic Resonance Imaging as an Imaging Biomarker and a Survival Update from Two Prospective Clinical Trials

    PubMed Central

    Konstantinidis, Ioannis T.; Gultekin, David H.; Gönen, Mithat; Schwartz, Lawrence H.; Fong, Yuman; Allen, Peter J.; D'Angelica, Michael I.; DeMatteo, Ronald P.; Klimstra, David S.; Kemeny, Nancy E.; Jarnagin, William R.

    2015-01-01

    Background For patients with unresectable intrahepatic cholangiocarcinoma (ICC), treatment options are limited and survival is poor. This study summarizes the long-term outcome of two previously reported clinical trials using hepatic arterial infusion (HAI) with floxuridine and dexamethasone (with or without bevacizumab) in advanced ICC. Methods Prospectively collected clinicopathologic and survival data were retrospectively reviewed. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST). Pre-HAI dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) images were reviewed, and tumor perfusion data correlated with outcome. Results Forty-four patients were analyzed (floxuridine, 26; floxuridine/bevacizumab, 18). At a median follow-up of 29.3 months, 41 patients had died of disease. Partial response by RECIST was observed in 48 %, and 50 % had stable disease. Three patients underwent resection after response, and 82 % received additional HAI after removal from the trials. Median survival was similar in both trials (floxuridine 29.3 months vs. floxuridine/bevacizumab 28.5 months; p = 0.96). Ten (23 %) patients survived ≥3 years, including 5 (11 %) who survived ≥5 years. Tumor perfusion measured on pre-treatment DCE-MRI [area under the gadolinium concentration curve at 90 and 180 s (AUC90 and AUC180, respectively)] was significantly higher in ≥3-year survivors and was the only factor that distinguished this group from <3-year survivors (mean AUC90 22.6 vs. 15.9 mM s, p = 0.025, and mean AUC180 48.9 vs. 32.3 mM s, p = 0.003, respectively). Median hepatic progression-free survival was longer in ≥3-year survivors (12.9 vs. 9.3 months, respectively; p = 0.008). Conclusions HAI chemotherapy can result in prolonged survival in unresectable ICC. Pre-HAI DCE-MRI may predict treatment outcome. PMID:24664624

  15. Postoperative CA19-9 Change Is a Useful Predictor of Intrahepatic Cholangiocarcinoma Survival following Liver Resection

    PubMed Central

    Yoo, Tae; Park, Sang-Jae; Han, Sung-Sik; Kim, Seong Hoon; Lee, Seung Duk; Kim, Young-Kyu; Kim, Tae Hyun; Woo, Sang Myung; Lee, Woo Jin; Hong, Eun Kyung

    2015-01-01

    Background. To investigate the clinical significance of the perioperative CA19-9 change for predicting survival in intrahepatic cholangiocarcinoma (ICC) patients treated with surgical resection. Methods. We retrospectively reviewed the data from 74 ICC patients treated with surgical resection between April 2001 and July 2010. Perioperative CA19-9 (preoperative level, postoperative lowest level, and level at recurrence) levels were analyzed for patient distribution and survival. Results. Before surgery, there were 45 patients who had high preoperative CA19-9 levels (>37 U/mL) and 29 who had normal levels (≤37 U/mL). Of 45 patients with high CA19-9 levels, 34 had normalized CA19-9 levels after resection and 11 had persistently high levels. Of 34 patients with normalized CA19-9 levels, 18 showed recurrence. Of 29 patients with normal preoperative levels, 15 showed recurrence. Multivariate analysis presented that old age (hazard ratio [HR] = 3.881, p < 0.01), persistently high postoperative CA19-9 level (HR = 4.41, p < 0.001), perineural invasion (HR = 3.073, p = 0.01), narrow resection margin (HR = 3.152, p = 0.05), and lymph node metastasis (HR = 3.427, p = 0.02) were significant independent risk factors for survival. Conclusions. Patients who have normalized CA19-9 levels postoperatively have longer survival outcomes. Therefore, normalized postoperative CA19-9 may be a useful clinical marker for ICC survival. PMID:26839445

  16. Intensity-modulated radiotherapy following null-margin resection is associated with improved survival in the treatment of intrahepatic cholangiocarcinoma

    PubMed Central

    Jia, Angela Y.; Wu, Jian-Xiong; Zhao, Yu-Ting; Li, Ye-Xiong; Wang, Zhi; Rong, Wei-Qi; Wang, Li-Ming; Jin, Jing; Wang, Shu-Lian; Song, Yong-Wen; Liu, Yue-Ping; Ren, Hua; Fang, Hui; Wang, Wen-Qing; Liu, Xin-Fan; Yu, Zi-Hao

    2015-01-01

    Background The current study is the first to examine the effectiveness and toxicity of postoperative intensity-modulated radiotherapy (IMRT) in the treatment of intrahepatic cholangiocarcinoma (ICC) abutting the vasculature. Specifically, we aim to assess the role of IMRT in patients with ICC undergoing null-margin (no real resection margin) resection. Methods Thirty-eight patients with ICC adherent to major blood vessels were included in this retrospective study. Null-margin resection was performed on all patients; 14 patients were further treated with IMRT. The median radiation dose delivered was 56.8 Gy (range, 50-60 Gy). The primary endpoints were overall survival (OS) and disease-free survival (DFS). Results At a median follow-up of 24.6 months, the median OS and DFS of all patients (n=38) were 17.7 months (95% CI, 13.2-22.2) and 9.9 months (95% CI, 2.8-17.0), respectively. Median OS was 21.8 months (95% CI, 15.5-28.1) among the 14 patients in the postoperative IMRT group and 15.0 months (95% CI, 9.2-20.9) among the 24 patients in the surgery-only group (P=0.049). Median DFS was 12.5 months (95% CI, 6.8-18.2) in the postoperative IMRT group and 5.5 months (95% CI, 0.7-12.3) in the surgery-only group (P=0.081). IMRT was well-tolerated. Acute toxicity included one case of Grade 3 leukopenia; late toxicity included one case of asymptomatic duodenal ulcer discovered through endoscopy. Conclusions The study results suggest that postoperative IMRT is a safe and effective treatment option following null-margin resections of ICC. Larger prospective and randomized trials are necessary to establish postoperative IMRT as a standard practice for the treatment of ICC adherent to major hepatic vessels. PMID:25830032

  17. 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

  18. 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

  19. Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma

    PubMed Central

    Borger, Darrell R.; Goyal, Lipika; Yau, Thomas; Poon, Ronnie T.; Ancukiewicz, Marek; Deshpande, Vikram; Christiani, David C.; Liebman, Hannah M.; Yang, Hua; Kim, Hyeryun; Yen, Katharine; Faris, Jason E.; Iafrate, A. John; Kwak, Eunice L.; Clark, Jeffrey W.; Allen, Jill N.; Blaszkowsky, Lawrence S.; Murphy, Janet E.; Saha, Supriya K.; Hong, Theodore S.; Wo, Jennifer Y.; Ferrone, Cristina R.; Tanabe, Kenneth K.; Bardeesy, Nabeel; Straley, Kimberly S.; Agresta, Sam; Schenkein, David P.; Ellisen, Leif W.; Ryan, David P.; Zhu, Andrew X.

    2014-01-01

    Purpose Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in ~20% of intrahepatic cholangiocarcinoma (ICC) and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in ICC. Experimental Design We initially measured serum 2HG concentration in blood samples collected from 31 ICC patients in a Screening cohort. Findings were validated across 38 resected ICC patients from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1/2 mutational status, tumor burden and a number of clinical variables. Results Circulating levels of 2HG in the Screening cohort were significantly elevated in patients with IDH1/2-mutant (median 478 ng/ml) versus IDH1/2-wild-type (median 118 ng/ml) tumors (p<0.001). This significance was maintained in the Validation cohort (343 ng/ml vs 55 ng/ml, p<0.0001) and levels of 2HG directly correlated with tumor burden in IDH1/2-mutant cases (p<0.05). Serum 2HG levels ≥170 ng/ml could predict the presence of an IDH1/2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regards to the levels of circulating 2HG. Conclusions This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in ICC and that circulating 2HG levels may correlate directly with tumor burden. PMID:24478380

  20. 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

  1. Osteopontin promoter polymorphisms at locus -443 are associated with metastasis and poor prognosis of human intrahepatic cholangiocarcinoma in Chinese population

    PubMed Central

    Zhao, Xiang-Qian; Ma, Huan-Xian; Su, Mao-Sheng; He, Lei

    2014-01-01

    Purpose: Osteopontin (OPN) is known to be a secreted adhesive glycoprotein. Role of OPN in human intrahepatic cholangiocarcinoma (ICC) has not been well understood. This study explored whether genetic variations in the osteopontin gene are associated with ICC risk, progression and metastasis. Material and methods: 260 patients with stages I to IV between 2008 and 2013 were recruited in this study and same number healthy persons were used as control. OPN-66 T/G, -156 G/GG and -443 C/T variants were genotyped using DNA from blood lymphocytes. Chi-square test and a Fisher’s exact test were used to analyze the genotype distribution between healthy subjects and patients, and further its distribution among TNM stages and incidence metastasis in patients. Results: For the variant at nt- 443 (CC), there was a significant difference between the number of patients with stage IV and those with all other stages of ICC (P < 0.01). Patients with -443 (CC) variant had significant higher incidence of lymph and distant metastasis development compared to other genotypes. For the variant at nt- 443 (CT), there was a significant difference between the number of ICC patients with stage III + IV and those with stage I + II (P < 0.01). The survival rates for ICC patients with the C/C genotype were significantly lower than for patients with the other two genotypes (C/T, T/T). Conclusion: OPN -443 C/T polymorphism is a potential predictive marker of metastasis and poor prognosis in ICC patients. PMID:25400775

  2. Detailed Analysis of Temporal Features on Contrast Enhanced Ultrasound May Help Differentiate Intrahepatic Cholangiocarcinoma from Hepatocellular Carcinoma in Cirrhosis

    PubMed Central

    Li, Rui; Yuan, Meng-Xia; Ma, Kuan-sheng; Li, Xiao-Wu; Tang, Chun-Lin; Zhang, Xiao-Hang; Guo, De-Yu; Yan, Xiao-Chu

    2014-01-01

    Aim To verify if detailed analysis of temporal enhancement patterns on contrast enhanced ultrasound (CEUS) may help differentiate intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC) in cirrhosis. Methods Thirty three ICC and fifty HCC in cirrhosis were enrolled in this study. The contrast kinetics of ICC and HCC was analyzed and compared. Results Statistical analysis did not reveal significant difference between ICC and HCC in the time of contrast first appearance and arterial peak maximum time. ICC displayed much earlier washout than that of HCC (47.93±26.45 seconds vs 90.86±31.26 seconds) in the portal phase, and most ICC (87.9%) showed washout before 60 seconds than HCC (16.0%). Much more ICC (78.8%) revealed marked washout than HCC (12.0%) while most HCC (88.0%) showed mild washout or no washout in late part of the portal phase (90–120 seconds). Twenty six out of thirty three ICC (78.8%) demonstrated both early washout(<60seconds) and marked washout in late part of the portal phase, whereas, only six of fifty HCC (12.0%)showed these temporal enhancement features (p = 0.000).When both early washout and marked washout in the portal phase are taken as diagnostic criterion for ICC, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 78.8%,88.0%,81.3%,86.3%,and 84.3% respectively by CEUS. Conclusions Analysis of detailed temporal enhancement features on CEUS is helpful differentiate ICC from HCC in cirrhosis.If a nodule in cirrhotic liver displays hyper-enhancement in the arterial phase followed by early and marked washout in the portal phase, the nodule is highly suspicious of ICC rather than HCC. PMID:24874413

  3. Significance of P-cadherin overexpression and possible mechanism of its regulation in intrahepatic cholangiocarcinoma and pancreatic cancer

    PubMed Central

    Sakamoto, Keita; Imai, Katsunori; Higashi, Takaaki; Taki, Katunobu; Nakagawa, Shigeki; Okabe, Hirohisa; Nitta, Hidetoshi; Hayashi, Hiromitsu; Chikamoto, Akira; Ishiko, Takatoshi; Beppu, Toru; Baba, Hideo

    2015-01-01

    It has become evident that P-cadherin, one of the classical cadherins, contributes to the malignant behavior of several types of cancer. In this study, we analyzed the expression of P-cadherin and its clinicopathological and prognostic values in intrahepatic cholangiocarcinoma (ICC) and pancreatic cancer. Furthermore, we investigated the functional role of P-cadherin in these cancer cells by knockdown and overexpression in vitro and by analyzing the correlation between the P-cadherin expression and its promoter methylation status. Thirty of 59 ICC cases (51%) and 36 of 73 pancreatic cancer cases (49%) stained positive for P-cadherin with mainly membranous distribution in tumor cells by immunohistochemistry. P-cadherin expression was significantly correlated with several clinicopathological factors, which reflect tumor behavior, and was identified as an independent adverse prognostic factor for disease-free survival in patients with ICC (relative risk [RR] 2.93, P = 0.04) and pancreatic cancer (RR 2.68, P = 0.005) via multivariate analyses. P-cadherin downregulation by siRNA suppressed migration and invasion, and P-cadherin overexpression induced the opposite effects in both ICC and pancreatic cancer cells, without any effects on cell proliferation. P-cadherin expression was related to its promoter methylation status in both cell lines and cancer tissues. In summary, P-cadherin overexpression may serve as a useful biomarker of invasive phenotype and poor prognosis; P-cadherin expression was found to be regulated by its promoter methylation. These results suggest that P-cadherin represents a novel therapeutic target for the treatment of ICC and pancreatic cancer. PMID:26132727

  4. 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

  5. Lymphovascular and perineural invasion as selection criteria for adjuvant therapy in intrahepatic cholangiocarcinoma: a multi-institution analysis

    PubMed Central

    Fisher, Sarah B; Patel, Sameer H; Kooby, David A; Weber, Sharon; Bloomston, Mark; Cho, Clifford; Hatzaras, Ioannis; Schmidt, Carl; Winslow, Emily; Staley III, Charles A; Maithel, Shishir K

    2012-01-01

    Objectives Criteria for the selection of patients for adjuvant chemotherapy in intrahepatic cholangiocarcinoma (IHCC) are lacking. Some authors advocate treating patients with lymph node (LN) involvement; however, nodal assessment is often inadequate or not performed. This study aimed to identify surrogate criteria based on characteristics of the primary tumour. Methods A total of 58 patients who underwent resection for IHCC between January 2000 and January 2010 at any of three institutions were identified. Primary outcome was overall survival (OS). Results Median OS was 23.0 months. Median tumour size was 6.5 cm and the median number of lesions was one. Overall, 16% of patients had positive margins, 38% had perineural invasion (PNI), 40% had lymphovascular invasion (LVI) and 22% had LN involvement. A median of two LNs were removed and a median of zero were positive. Lymph nodes were not sampled in 34% of patients. Lymphovascular and perineural invasion were associated with reduced OS [9.6 months vs. 32.7 months (P= 0.020) and 10.7 months vs. 32.7 months (P= 0.008), respectively]. Lymph node involvement indicated a trend towards reduced OS (10.7 months vs. 30.0 months; P= 0.063). The presence of either LVI or PNI in node-negative patients was associated with a reduction in OS similar to that in node-positive patients (12.1 months vs. 10.7 months; P= 0.541). After accounting for adverse tumour factors, only LVI and PNI remained associated with decreased OS on multivariate analysis (hazard ratio 4.07, 95% confidence interval 1.60–10.40; P= 0.003). Conclusions Lymphovascular and perineural invasion are separately associated with a reduction in OS similar to that in patients with LN-positive disease. As nodal dissection is often not performed and the number of nodes retrieved is frequently inadequate, these tumour-specific factors should be considered as criteria for selection for adjuvant chemotherapy. PMID:22762399

  6. Sensitivity of Human Intrahepatic Cholangiocarcinoma Subtypes to Chemotherapeutics and Molecular Targeted Agents: A Study on Primary Cell Cultures

    PubMed Central

    Fraveto, Alice; Cardinale, Vincenzo; Bragazzi, Maria Consiglia; Giuliante, Felice; De Rose, Agostino Maria; Grazi, Gian Luca; Napoletano, Chiara; Semeraro, Rossella; Lustri, Anna Maria; Costantini, Daniele; Nevi, Lorenzo; Di Matteo, Sabina; Renzi, Anastasia; Carpino, Guido; Gaudio, Eugenio; Alvaro, Domenico

    2015-01-01

    We investigated the sensitivity of intrahepatic cholangiocarcinoma (IHCCA) subtypes to chemotherapeutics and molecular targeted agents. Primary cultures of mucin- and mixed-IHCCA were prepared from surgical specimens (N. 18 IHCCA patients) and evaluated for cell proliferation (MTS assay) and apoptosis (Caspase 3) after incubation (72 hours) with increasing concentrations of different drugs. In vivo, subcutaneous human tumor xenografts were evaluated. Primary cultures of mucin- and mixed-IHCCA were characterized by a different pattern of expression of cancer stem cell markers, and by a different drug sensitivity. Gemcitabine and the Gemcitabine-Cisplatin combination were more active in inhibiting cell proliferation in mixed-IHCCA while Cisplatin or Abraxane were more effective against mucin-IHCCA, where Abraxane also enhances apoptosis. 5-Fluoracil showed a slight inhibitory effect on cell proliferation that was more significant in mixed- than mucin-IHCCA primary cultures and, induced apoptosis only in mucin-IHCCA. Among Hg inhibitors, LY2940680 and Vismodegib showed slight effects on proliferation of both IHCCA subtypes. The tyrosine kinase inhibitors, Imatinib Mesylate and Sorafenib showed significant inhibitory effects on proliferation of both mucin- and mixed-IHCCA. The MEK 1/2 inhibitor, Selumetinib, inhibited proliferation of only mucin-IHCCA while the aminopeptidase-N inhibitor, Bestatin was more active against mixed-IHCCA. The c-erbB2 blocking antibody was more active against mixed-IHCCA while, the Wnt inhibitor, LGK974, similarly inhibited proliferation of mucin- and mixed-IHCCA. Either mucin- or mixed-IHCCA showed high sensitivity to nanomolar concentrations of the dual PI3-kinase/mTOR inhibitor, NVP-BEZ235. In vivo, in subcutaneous xenografts, either NVP-BEZ235 or Abraxane, blocked tumor growth. In conclusion, mucin- and mixed-IHCCA are characterized by a different drug sensitivity. Cisplatin, Abraxane and the MEK 1/2 inhibitor, Selumetinib were more

  7. Is Hepatic Resection for Large or Multifocal Intrahepatic Cholangiocarcinoma Justified? Results from a Multi-Institutional Collaboration

    PubMed Central

    Spolverato, Gaya; Kim, Yuhree; Alexandrescu, Sorin; Popescu, Irinel; Marques, Hugo P.; Aldrighetti, Luca; Gamblin, T. Clark; Miura, John; Maithel, Shishir K.; Squires, Malcolm H.; Pulitano, Carlo; Sandroussi, Charbel; Mentha, Gilles; Bauer, Todd W.; Newhook, Timothy; Shen, Feng; Poultsides, George A.; Marsh, J. Wallis; Pawlik, Timothy M.

    2016-01-01

    Background The role of surgical resection for patients with large or multifocal intrahepatic cholangiocarcinoma (ICC) remains unclear. This study evaluated the long-term outcome of patients who underwent hepatic resection for large (≥7 cm) or multifocal (≥2) ICC. Methods Between 1990 and 2013, 557 patients who underwent liver resection for ICC were identified from a multi-institutional database. Clinicopathologic characteristics, operative details, and long-term survival data were evaluated. Results Of the 557 patients, 215 (38.6 %) had a small, solitary ICC (group A) and 342 (61.4 %) had a large or multifocal ICC (group B). The patients in group B underwent an extended hepatectomy more frequently (16.9 vs. 30.4 %; P < 0.001). At the final pathology exam, the patients in group B were more likely to show evidence of vascular invasion (22.5 vs. 38.5 %), direct invasion of contiguous organs (6.5 vs. 12.9 %), and nodal metastasis (13.3 vs. 21.0 %) (all P < 0.05). Interestingly, the incidences of postoperative complications (39.3 vs. 46.8 %) and hospital mortality (1.1 vs. 3.7 %) were similar between the two groups (both P > 0.05). The group A patients had better rates for 5-year overall survival (OS) (30.5 vs. 18.7 %; P < 0.05) and disease-free survival (DFS) (22.6 vs. 8.2 %; P < 0.05) than the group B patients. For the patients in group B, the factors associated with a worse OS included more than three tumor nodules [hazard ratio (HR), 1.56], nodal metastasis (HR, 1.47), and poor differentiation (HR, 1.48). Conclusions Liver resection can be performed safely for patients with large or multifocal ICC. The long-term outcome for these patients can be stratified on the basis of a prognostic score that includes tumor number, nodal metastasis, and poor differentiation. PMID:25354576

  8. Genome-wide single nucleotide polymorphism array analysis reveals recurrent genomic alterations associated with histopathologic features in intrahepatic cholangiocarcinoma

    PubMed Central

    Huang, Wan-Ting; Weng, Shao-Wen; Wei, Yu-Ching; You, Huey-Ling; Wang, Jui-Tzu; Eng, Hock-Liew

    2014-01-01

    Recent studies indicate that genomic alterations (GAs) are associated with many human malignancies. Genome-wide analysis of GAs involved in intrahepatic cholangiocarcinoma (ICC) and association with histopathologic features are limited. To help characterize this relatively rare neoplasm, we collected 32 frozen tissue samples of ICC to study GAs and molecular karyotypes by using single-nucleotide polymorphism array. Recurrent GAs occurring in at least 40% of the patients were further correlated with histopathologic features. Gain of 1q21.3-q23.1 and losses of 1p36.33-p35.3 and 3p26.3-p13 were significantly associated with larger tumor size more than 5 cm in diameter; and loss of 4q13.2-q35.2 with tumor multiplicity. Moreover, losses of 1p36.32-p35.3, 3p26.3-p22.2, 4q13.1-q21.23, 4q31.3-q34.3 and 4q34.3-35.2 were inclined to be associated with high histological grade. As to tumor vascular invasion, gain of 1q21.3-q23.1 and losses of 3p22.1-p12.3 and 4q13.2-q35.2 were significantly associated with tumor vascular invasion. Some regions were concurrently associated with multiple histopathologic characteristics, including loss of 4q13.2-q35.2 associated with larger tumor size, high histological grade and vascular invasion; losses of 1p36.33-p35.3 and 3p26.3-p22.2 with larger tumor size and high histological grade; and gain of 1q21.3-q23.1 with larger tumor size and vascular invasion. Our study indicates that complex chromosomal instability is characteristic of ICC. Detecting crucial GAs will enable risk stratification and development of personalized therapies. PMID:25400767

  9. Selecting molecular therapeutic drug targets based on the expression profiles of intrahepatic cholangiocarcinomas and miRNA-mRNA regulatory networks.

    PubMed

    Sun, Boshi; Xie, Changming; Zheng, Tongsen; Yin, Dalong; Wang, Jiabei; Liang, Yingjian; Li, Yuejin; Yang, Guangchao; Shi, Huawen; Pei, Tiemin; Han, Jihua; Liu, Lianxin

    2016-01-01

    The incidence of intrahepatic cholangiocarcinoma (ICC) is increasing yearly, making it the second most common carcinoma after hepatocellular carcinoma among primary malignant liver tumors. Integrated miRNA and mRNA analysis is becoming more frequently used in antitumor ICC treatment. However, this approach generates vast amounts of data, which leads to difficulties performing comprehensive analyses to identify specific therapeutic drug targets. In this study, we provide an in-depth analysis of ICC function, identifying potential highly potent antitumor drugs for antitumor therapy. Two sets of whole genome expression profiles were obtained from the Gene Expression Omnibus (GEO) database. Using modular bioinformatic analysis, six core functional modules were identified for ICC. Based on a Fisher's test of the Cmap small molecule drug database, 65 drug components were identified that regulated the genes of these six core modules. Literature mining was then used to identify 15 new potential antitumor drugs. PMID:26498995

  10. Advances in endoscopic retrograde cholangiopancreatography for the treatment of cholangiocarcinoma

    PubMed Central

    Uppal, Dushant S; Wang, Andrew Y

    2015-01-01

    Cholangiocarcinoma (CCA) is a malignancy of the bile ducts that carries high morbidity and mortality. Patients with CCA typically present with obstructive jaundice, and associated complications of CCA include cholangitis and biliary sepsis. Endoscopic retrograde cholangiopancreatography (ERCP) is a valuable treatment modality for patients with CCA, as it enables internal drainage of blocked bile ducts and hepatic segments by using plastic or metal stents. While there remains debate as to if bilateral (or multi-segmental) hepatic drainage is required and/or superior to unilateral drainage, the underlying tenant of draining any persistently opacified bile ducts is paramount to good ERCP practice and good clinical outcomes. Endoscopic therapy for malignant biliary strictures from CCA has advanced to include ablative therapies via ERCP-directed photodynamic therapy (PDT) or radiofrequency ablation (RFA). While ERCP techniques cannot cure CCA, advancements in the field of ERCP have enabled us to improve upon the quality of life of patients with inoperable and incurable disease. ERCP-directed PDT has been used in lieu of brachytherapy to provide neoadjuvant local tumor control in patients with CCA who are awaiting liver transplantation. Lastly, mounting evidence suggests that palliative ERCP-directed PDT, and probably ERCP-directed RFA as well, offer a survival advantage to patients with this difficult-to-treat malignancy. PMID:26140095

  11. Advances in the surgical treatment of hilar cholangiocarcinoma.

    PubMed

    Tsuchikawa, Takahiro; Hirano, Satoshi; Okamura, Keisuke; Matsumoto, Joe; Tamoto, Eiji; Murakami, Soichi; Nakamura, Toru; Ebihara, Yuma; Kurashima, Yo; Shichinohe, Toshiaki

    2015-03-01

    With the improvement of perioperative management and surgical techniques as well as the accumulation of knowledge on the oncobiological behavior of bile duct carcinoma, the long-term prognosis of hilar cholangiocarcinoma has been improving. In this article, the authors review the recent developments in surgical strategies for hilar cholangiocarcinoma, focusing on diagnosis for characteristic disease extension, perioperative management to reduce postoperative morbidity and mortality, surgical techniques for extended curative resection and postoperative adjuvant therapy. PMID:25256146

  12. 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

  13. Recurrent Amplification at 13q34 Targets at CUL4A, IRS2, and TFDP1 As an Independent Adverse Prognosticator in Intrahepatic Cholangiocarcinoma

    PubMed Central

    Weng, Shao-Wen; Wei, Yu-Ching; Eng, Hock-Liew; Huang, Wan-Ting

    2015-01-01

    Amplification of genes at 13q34 has been reported to be associated with tumor proliferation and progression in diverse types of cancers. However, its role in intrahepatic cholangiocarcinoma (iCCA) has yet to be explored. We examined two iCCA cell lines and 86 cases of intrahepatic cholangiocarcinoma to analyze copy number of three target genes, including cullin 4A (CUL4A), insulin receptor substrate 2 (IRS2), and transcription factor Dp-1 (TFDP1) at 13q34 by quantitative real-time polymerase chain reaction. The cell lines and all tumor samples were used to test the relationship between copy number (CN) alterations and protein expression by western blotting and immunohistochemical assays, respectively. IRS2 was introduced, and each target gene was silenced in cell lines. The mobility potential of cells was compared in the basal condition and after manipulation using cell migration and invasion assays. CN alterations correlated with protein expression levels. The SNU1079 cell line containing deletions of the target genes demonstrated decreased protein expression levels and significantly lower numbers of migratory and invasive cells, as opposed to the RBE cell line, which does not contain CN alterations. Overexpression of IRS2 by introducing IRS2 in SUN1079 cells increased the mobility potential. In contrast, silencing each target gene showed a trend or statistical significance toward inhibition of migratory and invasive capacities in RBE cells. In tumor samples, the amplification of each of these genes was associated with poor disease-free survival. Twelve cases (13.9%) demonstrated copy numbers > 4 for all three genes tested (CUL4A, IRS2, and TFDP1), and showed a significant difference in disease-free survival by both univariate and multivariate survival analyses (hazard ratio, 2.69; 95% confidence interval, 1.23 to 5.88; P = 0.013). Our data demonstrate that amplification of genes at 13q34 plays an oncogenic role in iCCA featuring adverse disease-free survival

  14. MicroRNA-101 inhibits the migration and invasion of intrahepatic cholangiocarcinoma cells via direct suppression of vascular endothelial growth factor-C.

    PubMed

    Deng, Gang; Teng, Yinglu; Huang, Feizhou; Nie, Wanpin; Zhu, Lei; Huang, Wei; Xu, Hongbo

    2015-11-01

    MicroRNAs (miRs) have important roles in the pathogenesis of human malignancy. It has previously been suggested that deregulation of miR‑101 is associated with the progression of intrahepatic cholangiocarcinoma (ICC); however, the exact role of miR‑101 in the regulation of ICC metastasis remains largely unknown. The present study demonstrated that the expression levels of miR‑101 were significantly decreased in ICC tissue, as compared with matched adjacent normal tissue. Furthermore, miR‑101 was downregulated in the ICC‑9810 human ICC cell line, as compared with in the normal human intrahepatic biliary epithelial cell (HIBEC) line. Vascular endothelial growth factor (VEGF)‑C was identified as a target gene of miR‑101 in ICC‑9810 cells. The expression of VEGF‑C was negatively regulated by miR‑101 at the post‑transcriptional level in ICC‑9810 cells. Further investigation demonstrated that overexpression of miR‑101 markedly suppressed the migration and invasion of ICC‑9810 cells, and these effects were similar to those observed following VEGF‑C knockdown. Conversely, restoration of VEGF‑C reversed the inhibitory effects of miR‑101 overexpression on ICC‑9810 cell migration and invasion, thus suggesting that miR‑101 may suppress ICC‑9810 cell migration and invasion, at least partly via inhibition of VEGF‑C. It was also demonstrated that the mRNA and protein expression levels of VEGF‑C were frequently upregulated in ICC tissue and cells, and its expression level was inversely correlated with that of miR‑101 in ICC tissue. In conclusion, the present study identified important roles for miR‑101 and VEGF‑C in ICC, suggesting that miR‑101/VEGF‑C signaling may be a promising diagnostic and/or therapeutic target for ICC. PMID:26299768

  15. 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

  16. 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

  17. Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database

    PubMed Central

    Jutric, Zeljka; Johnston, W. Cory; Hoen, Helena M.; Newell, Pippa H.; Cassera, Maria A.; Hammill, Chet W.; Wolf, Ronald F.; Hansen, Paul D.

    2016-01-01

    Introduction Routine lymphadenectomy in the surgical treatment of intrahepatic cholangiocarcinoma (ICC) is not routinely performed. We aim to define predictive indicators of survival in patients with positive lymph nodes. Methods The National Cancer Data Base (NCDB) was queried for patients who underwent major hepatectomy for ICC between 1998 and 2011. Clinical and pathologic data were assessed using uni- and multi-variate analyses. A sub-analysis was performed on the 160 patients with positive lymph nodes. Results Of 849 patients with lymph node data, 57% had at least one lymph node examined. Median survival for lymph node negative patients was 37 months versus 15 months for lymph node positive patients. In lymph node positive patients, poorer survival was associated with not receiving chemotherapy (HR 1.83, p = 0.003), tumor size > 5 cm (p = 0.029), and older age (p < 0.0001). Lymph node positive patients age less than 45 had a median survival of 27 months. Conclusions Overall survival in patients with lymph node metastases from ICC is poor. Adjuvant therapy was associated with a longer survival in lymph node positive patients, although prospective data are needed. Routine lymphadenectomy should be strongly considered to provide prognostic information and guidance for adjuvant therapy. PMID:26776855

  18. Intrahepatic cholangiocarcinoma detected by elevated levels of alpha-fetoprotein-L3 after hepatectomy for hepatocellular carcinoma in a patient with Budd-Chiari syndrome.

    PubMed

    Yamamoto, Masakazu; Otsubo, Takehito; Ariizumi, Shunichi; Nakano, Masayuki; Takasaki, Ken

    2005-01-01

    We report the case of a 57-year-old woman with Budd-Chiari syndrome, hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma (ICC). She underwent partial hepatectomy for HCC in April 2000. After surgery, alpha-fetoprotein (AFP) and protein induced by vitamin K absence II (PIVKA-II) returned to normal levels, but lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3) increased, and ultrasonography showed a nodule 2 cm in greatest dimension in the left lateral segment of the liver. We diagnosed this nodule as recurrence from HCC and performed a partial hepatectomy in October 2001. Microscopic examination showed that tubular adenocarcinoma and immunohistochemical staining was focally positive for AFP. AFP-L3 was 0% and AFP was 5 ng/ml 3 months after re-operation. This case was interesting in that ICC was detected by elevated levels of AFP-L3, and ICC produced AFP from the time it was minute in size. PMID:16119710

  19. Irinotecan drug eluting beads used as a treatment of advanced intra hepatic cholangiocarcinoma.

    PubMed

    Roch, Jean Amede; Palma-Gutierrez, John; Lapalus, Marie Georges; Paillet, Carole; Pilleul, Frank

    2008-01-01

    This report describes a 74-year-old male with unresectable intrahepatic cholangiocarcinoma (ICC). However surgical procedure is the only curative treatment, it often seems to be ineffective because of the aggressive behaviour of the disease. The role of systemic chemotherapy in the ICC is undefined with a median survival between 6.43 to 12.17 months obtained by using the combination chemotherapy of gemcitabine with cisplatin. In the present case, we performed a targeted treatment using drug eluting beads (DEB) with irinotecan (IRI) administered as transarterial-chemoembolization (TACE). After one session, the tumour vascularity decreased significantly at the one month evaluation on computed tomography (CT) scan of the liver. This case report suggested that minimally invasive transcatheter DEB embolization could be a promising, safe and effective treatment for selective patients with unresectable ICC. PMID:22470601

  20. Clinical outcomes and toxicity using Stereotactic Body Radiotherapy (SBRT) for advanced cholangiocarcinoma

    PubMed Central

    2012-01-01

    Background To report single-institutional clinical outcomes and toxicity with SBRT for cholangiocarcinoma. Methods From March 2009 to July 2011, 10 patients with 12 unresectable primary (n = 6) or recurrent (n = 6) cholangiocarcinoma lesions underwent abdominal SBRT. Sites treated included liver (n = 10), abdominal lymph nodes (n = 1), and adrenal gland (n = 1). SBRT was delivered in three (n = 2) or five (n = 10) consecutive daily fractions over one week. The median prescription dose was 55 Gy (range, 45–60). Treatment response was graded by RECIST v.1.1, and toxicities were scored by CTCAE v.4.0. Data was analyzed using the Kaplan-Meier method to determine rates of local control (LC), freedom from distant progression (FFDM) and overall survival (OS). Results The median follow-up was 14 months (range, 2–26 months). LC, defined as freedom from progression within the SBRT field, was 100%, but four patients treated to intrahepatic sites experienced progression elsewhere in the liver. Estimates for FFDM at 6 and 12 months were 73% and 31%, respectively. Sites of disease relapse included liver (n = 3), liver and lymph nodes (n = 1), liver and lungs (n = 1), lymph nodes (n = 1), and mesentery (n = 1). OS estimates for the cohort at 6 and 12 months were 83% and 73%, respectively. The most common Grade ≥2 early toxicities were Grade 2 nausea and vomiting (n = 5) and gastrointestinal pain (n = 2). Late ≥2 toxicities included Grade 2 gastrointestinal pain (n = 3), Grade 3 biliary stenosis (n = 1), and Grade 5 liver failure (n = 1). Conclusions SBRT shows promise as an effective local therapy for properly-selected patients with cholangiocarcinoma. Further follow-up is needed to better quantify the risk of late complications associated with SBRT. PMID:22553982

  1. Notch1 is overexpressed in human intrahepatic cholangiocarcinoma and is associated with its proliferation, invasiveness and sensitivity to 5-fluorouracil in vitro.

    PubMed

    Wu, Wen-Rui; Zhang, Rui; Shi, Xiang-De; Zhu, Man-Sheng; Xu, Lei-Bo; Zeng, Hong; Liu, Chao

    2014-06-01

    The Notch signaling pathway has been reported to play crucial roles in inhibiting hepatocyte differentiation and allowing formation of intrahepatic bile ducts. However, little is known about its significance in intrahepatic cholangiocarcinoma (ICC). The aim of the present study was to investigate the effects of Notch1 expression in ICC tissues and cells. The expression of Notch1 was examined in paraffin-embedded sections of ICC (n=44) by immunohistochemistry. Notch1 was knocked down by RNA interference (RNAi) in cultured ICC cells (RBE and HCCC-9810). The proliferation, invasiveness and sensitivity to 5-fluorouracil (5-FU) were detected by Cell Counting Kit-8 (CCK-8), colony formation assays, Transwell assays and flow cytometry, respectively. The expression levels of several multidrug resistance (MDR)-related genes, MDR1-P-glycoprotein (ABCB‑1), breast cancer resistance protein (ABCG‑2) and the multidrug resistance protein isoform 1 (MRP‑1), were examined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Notch1 was overexpressed in cell membranes and cytoplasm of ICC compared with the adjacent liver tissue (35/44, 79.5%) and this was more common in cases with tumor size≥5 cm (p=0.021) and HBs-Ag positive (p=0.018). By silencing Notch1, the proliferation and invasiveness of ICC cells were inhibited and the inhibition rate of 5-FU was markedly increased. In addition, IC50 values of 5-FU in RBE cells were decreased from 148.74±0.72 to 5.37±0.28 µg/ml and the corresponding values for HCCC-9810 cells were 326.92±0.87 to 42.60±0.35 µg/ml, respectively. Furthermore, Notch1 silencing clearly increased the percentage of apoptotic cells treated by 5-FU compared with the control. Notch1 knockdown led to diminished expression levels of ABCB‑1 and MRP‑1. Therefore, Notch may play important roles in the development of ICC. Silencing Notch1 can inhibit the proliferation and invasiveness of ICC cells and increase their

  2. Transcriptomic Profiling Reveals Hepatic Stem-like Gene Signatures and Interplay of miR-200c and EMT in Intrahepatic Cholangiocarcinoma

    PubMed Central

    Oishi, Naoki; Kumar, Mia R.; Roessler, Stephanie; Ji, Junfang; Forgues, Marshonna; Budhu, Anuradha; Zhao, Xuelian; Andersen, Jesper B.; Ye, Qing-Hai; Jia, Hu-Liang; Qin, Lun-Xiu; Yamashita, Taro; Woo, Hyun Goo; Kim, Yoon Jun; Kaneko, Shuichi; Tang, Zhao-You; Thorgeirsson, Snorri S.; Wang, Xin Wei

    2012-01-01

    Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its tumor heterogeneity and molecular characteristics are largely unknown. In this study, we conducted transcriptomic profiling of 23 ICC and combined hepatocellular cholangiocarcinoma tumor specimens from Asian patients using Affymetrix mRNA and Nanostring microRNA microarrays to search for unique gene signatures linked to tumor subtypes and patient prognosis. We validated the signatures in additional 68 ICC cases derived from Caucasian patients. We found that both mRNA and microRNA expression profiles could independently classify Asian ICC cases into two main subgroups, one of which shared gene expression signatures with previously identified hepatocellular carcinoma (HCC) with stem cell gene expression traits. ICC-specific gene signatures could predict survival in Asian HCC cases and independently in Caucasian ICC cases. Integrative analyses of the ICC-specific mRNA and microRNA expression profiles revealed that a common signaling pathway linking miR-200c signaling to epithelial-mesenchymal transition (EMT) was preferentially activated in ICC with stem cell gene expression traits. Inactivation of miR-200c resulted in an induction of EMT while activation of miR-200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells. We also found that miR-200c and NCAM1 expression were negatively correlated and their expression levels were predictive of survival in ICC samples. NCAM1, a known hepatic stem/progenitor cell marker, was experimentally demonstrated to be a direct target of miR-200c. Conclusion: Our results indicate that ICC and HCC share common stem-like molecular characteristics and poor prognosis. We suggest that the specific components of EMT may be exploited as critical biomarkers and clinically relevant therapeutic targets for an aggressive form of stem cell-like ICC. PMID:22707408

  3. 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

  4. Expression and activation of EGFR and STAT3 during the multistage carcinogenesis of intrahepatic cholangiocarcinoma induced by 3’-methyl-4 dimethylaminoazobenzene in rats

    PubMed Central

    Zhang, Fan; Li, Lianhong; Yang, Xingwu; Wang, Bo; Zhao, Jinyao; Lu, Shilun; Yu, Xiaotang

    2015-01-01

    The purpose of this study was to investigate whether the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription-3 (STAT3) signal pathway contributes to the carcinogenesis of intrahepatic cholangiocarcinoma (ICC) induced by 3’-methyl-4 dimethylaminoazobenzene (3’Me-DAB) in rats. EGFR, TGFα, STAT3 and p-STAT3 in different stages of carcinogenesis were detected by immunohistochemistry (IHC). In situ hybridization (ISH) was applied to investigate the expression of STAT3 mRNA. Oval cells were verified by the immunohistochemical staining of alpha-fetoprotein (AFP), CD133 and epithelial cell adhesion molecules (EpCAM). Sequential development of necrosis, oval cell proliferation, cholangiofibrosis (CF) and ICC was observed in the liver of rats administered 3’Me-DAB. Oval cells showed positive expression of AFP, CD133 and EpCAM. The expression of EGFR was significantly higher in the ICC than in oval cells, CF or normal bile ducts (p<0.05), but there was no difference in EGFR expression between the other groups. The highest expression of p-STAT3 and TGFα was observed in CF. The expression of these two molecules in the ICC and oval cells was significantly higher than in normal bile ducts (p<0.05). Elevation of STAT3 mRNA was detected during carcinogenesis as shown by ISH, strong intensity was observed in the ICC and moderate intensity was observed in oval cells and CF. These observations suggest that the EGFR and STAT3 signal pathway contributes to the carcinogenesis of ICC. High activity of STAT3 during the carcinogenesis of ICC may be the result of high activity of EGFR triggered by TGFα. PMID:26028817

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

    PubMed

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

    2016-01-01

    PET using fluorine-18 fluorocholine ((18)F-fluorocholine) may detect malignancies that involve altered choline metabolism. While (18)F-fluorocholine PET/CT has shown greater sensitivity for detecting hepatocellular carcinoma (HCC) than (18)F-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 (18)F-fluorocholine PET/CT imaging were analyzed to preliminarily evaluate (18)F-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 (18)F-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 (18)F-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 (18)F-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

  6. 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

  7. Benefit of pyloroplasty to prevent gastric stasis in intrahepatic cholangiocarcinoma patients undergoing extensive left-sided lymph node dissection

    PubMed Central

    Cho, Jae-Won; Lee, Hae-Won

    2016-01-01

    Backgrounds/Aims Intrahepatic cholangiocacinoma (IHCC) can result in spread of tumor cells to the lymph nodes (LNs) around the gastric lesser curvature. Extensive dissection of the gastric lesser curvature can induce injury to the extragastric vagus nerve branches that control motility of the pyloric sphincter and result in intractable gastric stasis. Herein, we presented our experience of preventive pyloroplasty added to resection of IHCC to address dissection-induced gastric stasis in 6 patients during 15-years. Methods We analyzed the survival outcomes of 54 IHCC patients presenting left-sided LN metastasis. Nine study patients who underwent extended left-sided LN dissection including lesser curvature LN dissection were selected and divided into 2 groups according to performance of preventive pyloroplasty and the incidence of gastric stasis was analyzed. Results All 54 patients were classified as stage IV due to T1-3N1M0 stage. The tumor recurrence rate were 56.4% at 1 year, 84.3% at 3 years and 84.3% at 5 years; and the overall patient survival rate were 51.9% at 1 year, 13.6% at 3 years and 6.8% at 5 years. In all 3 study patients who did not receive pyloroplasty, overt postoperative gastric stasis persisted for >10 days leading to prolonged hospital stay. In contrast, none of the 6 study patients who underwent pyloroplasty suffered from gastric stasis. Conclusions Pyloroplasty is a useful surgical option to prevent gastric stasis when extensive left-sided LN dissection is required in IHCC patients with LN metastasis who have very poor post-resection prognosis. PMID:26925148

  8. Diagnosis of cholangiocarcinoma.

    PubMed

    Van Beers, B E

    2008-01-01

    Cholangiocarcinoma is suspected based on signs of biliary obstruction, abnormal liver function tests, elevated tumor markers (carbohydrate antigen 19-9 and carcinoembryonic antigen), and ultrasonography showing a bile stricture or a mass, especially in intrahepatic cholangiocarcinoma. Magnetic resonance imaging (MRI) or computed tomography (CT) is performed for the diagnosis and staging of cholangiocarcinomas. However, differentiation of an intraductal cholangiocarcinoma from a hypovascular metastasis is limited at imaging. Therefore, reasonable exclusion of an extrahepatic primary tumor should be performed. Differentiating between benign and malignant bile duct stricture is also difficult, except when metastases are observed. The sensitivity of fluorodeoxyglucose positron emission tomography is limited in small, infiltrative, and mucinous cholangiocarcinomas. When the diagnosis of a biliary stenosis remains indeterminate at MRI or CT, endoscopic imaging (endoscopic or intraductal ultrasound, cholangioscopy, or optical coherence tomography) and tissue sampling should be carried out. Tissue sampling has a high specificity for diagnosing malignant biliary strictures, but sensitivity is low. The diagnosis of cholangiocarcinoma is particularly challenging in patients with primary sclerosing cholangitis. These patients should be followed with yearly tumor markers, CT, or MRI. In the case of dominant stricture, histological or cytological confirmation of cholangiocarcinoma should be obtained. More studies are needed to compare the accuracy of the various imaging methods, especially the new intraductal methods, and the imaging features of malignancy should be standardized. PMID:18773062

  9. What is the current state-of-the-art imaging for detection and staging of cholangiocarcinoma?

    PubMed

    Slattery, James M; Sahani, Dushyant V

    2006-09-01

    Cholangiocarcinoma is an adenocarcinoma that arises from the bile duct epithelium and is the second most common primary hepatobiliary cancer, after hepatocellular cancer, with approximately 2,500 cases annually in the U.S. However, cholangiocarcinoma remains a relatively rare disease, accounting for <2% of all human malignancies. Although the entire biliary tree is potentially at risk, tumors involving the biliary confluence or the right or left hepatic ducts (hilar cholangiocarcinoma) are most common and account for 40%-60% of all cases. Most patients present with advanced disease that is not amenable to surgical treatment. The median survival time for patients with intrahepatic cholangiocarcinoma without involvement of the hilum varies among centers from 18-30 months. The median survival time for patients with perihilar cholangiocarcinoma is slightly less, varying from 12-24 months. Despite the overall poor prognosis, survival after surgical treatment of hilar cholangiocarcinoma has improved during the past 10-15 years. This review highlights the imaging features of cholangiocarcinoma, with particular emphasis on the imaging techniques that can best assess tumor resectability and guide the surgeon regarding the potential extent of resection required in operable candidates. PMID:16951395

  10. Co-expression of the carbamoyl-phosphate synthase 1 gene and its long non-coding RNA correlates with poor prognosis of patients with intrahepatic cholangiocarcinoma

    PubMed Central

    MA, SEN-LIN; LI, AI-JUN; HU, ZHAO-YANG; SHANG, FU-SHENG; WU, MENG-CHAO

    2015-01-01

    The mechanisms leading to high rates of malignancy and recurrence of human intrahepatic cholangiocarcinoma (ICC) remain unclear. It is difficult to diagnose and assess the prognosis of patients with ICC in the clinic due to the lack of specific biomarkers. In addition, long non-coding RNAs (lncRNAs) have been reported to serve important roles in certain types of tumorigenesis however a role in ICC remains to be reported. The aim of the current study was to screen for genes and lncRNAs that are abnormally expressed in ICC and to investigate their biological and clinicopathological significance in ICC. The global gene and lncRNA expression profiles in ICC were measured using bioinformatics analysis. Carbamoyl-phosphate synthase 1 (CPS1) and its lncRNA CPS1 intronic transcript 1 (CPS1-IT1) were observed to be upregulated in ICC. The expression of CPS1 and CPS1-IT1 was measured in 31 tissue samples from patients with ICC and a number of cell lines. The effects of CPS1 and CPS1-IT1 on the proliferation and apoptosis of the ICC-9810 cell line were measured. In addition, the clinicopathological features and survival rates of patients with ICC with respect to the gene and lncRNA expression status were analyzed. CPS1 and CPS1-IT1 were co-upregulated in ICC tissues compared with non-cancerous tissues. Knockdown of CPS1 andor CPS1-IT1 reduced the proliferation and increased the apoptosis of ICC-9810 cells. Additionally, clinical analysis indicated that CPS1 and CPS1-IT1 were associated with poor liver function and reduced survival rates when the relative expression values were greater than 4 in cancer tissues. The comparisons between the high CPS1 expression group and the low expression group indicated significant differences in international normalized ratio (P=0.048), total protein (P=0.049), indirect bilirubin (P=0.025), alkaline phosphatase (P=0.003) and disease-free survival (P=0.034). In addition, there were differential trends in CA19-9 (P=0.068), globulin (P=0

  11. [Interdisciplinary diagnosis of and therapy for cholangiocarcinoma].

    PubMed

    Kolligs, F T; Zech, C J; Schönberg, S O; Schirra, J; Thasler, W; Graeb, C; Beuers, U; Wilkowski, R; Jacobs, T; Böck, S; Berster, J; Heinemann, V; Schäfer, C

    2008-01-01

    The diagnosis of and therapy for cholangiocarcinomas still remains an interdisciplinary challenge. For diagnostic and therapeutic purposes intra- and extrahepatic cholangiocarcinomas need to be distinguished. Multiple imaging tools such as sonography, multidetector computer tomography, magnetic resonance tomography as well as endoscopic ultrasound and endoscopic retrograde cholangiography for the diagnosis and localisation of these tumours are available. To date, surgical resection is the only curative treatment. At the time of diagnosis, most of the tumours are advanced. Therefore, only a small percentage of patients are suitable for curative surgery. Infiltration of the portal vein no longer constitutes a contraindication for surgery. Liver transplantation is not a reasonable option for intrahepatic cholangiocarcinomas but may be of advantage for perihilar Klatskin tumours. Severe cholangitis is the main cause of death of patients with obstructive cholangiocarcinomas. Drainage of the biliary tree system or surgery with construction of a biliary-digestive anastomosis is often necessary. If possible, a photodynamic therapy (PDT) should be performed in addition to biliary drainage. PDT has been shown to facilitate biliary drainage and to improve survival. The value of radiologist-assisted interventional procedures as well as percutaneous ablation and radiochemotherapy is not well established. In addition, so far, there is no standardised chemotherapy in a palliative situation established but there is some evidence for a benefit of gemcitabine-based chemotherapy. For the best care and treatment of patients with cholangiocarcinomas an interdisciplinary approach is required and to achieve progress in the therapy patients should be included in prospective clinical trials to test new approaches. PMID:18188818

  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. 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

  14. Update on the management of cholangiocarcinoma.

    PubMed

    Skipworth, J R A; Keane, M G; Pereira, S P

    2014-01-01

    Cholangiocarcinoma (CC) is a rare cancer arising from the epithelium of the biliary tree, anywhere from the small peripheral hepatic ducts to the distal common bile duct. Classification systems for CC typically group tumours by anatomical location into intrahepatic, hilar or extrahepatic subtypes. Surgical resection or liver transplantation remains the only curative therapy for CC, but up to 80% of patients present with advanced, irresectable disease. Unresectable CC remains resistant to many chemotherapeutic agents, although gemcitabine, particularly in combination with other agents, has been shown to improve overall survival. Ongoing investigation of biological agents has also yielded some promising results. Several novel interventional and endoscopic techniques for the diagnosis and management of non-operable CC have been developed: initial results show improvements in symptoms and progression-free survival, but further randomised studies are required to establish their role in the management of CC. PMID:25034290

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

    PubMed Central

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

    2015-01-01

    Background 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. Methods 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. Principal Findings 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. Conclusions/Significance The present findings suggest that oncogenes, PSMD10 and CDK4

  16. 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

  17. 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. PMID:26847022

  18. Role of the fibroblast growth factor receptor axis in cholangiocarcinoma.

    PubMed

    Ang, Celina

    2015-07-01

    Advanced cholangiocarcinoma (CCA) is a highly lethal disease with limited therapeutic options beyond cytotoxic chemotherapy. Molecular profiling of CCA has provided insights into the pathogenesis of this disease and identified potential therapeutic targets. The fibroblast growth factor receptor (FGFR) axis is important for maintaining tissue homeostasis. Aberrations in FGFR activity have been implicated in the development and progression of CCA and other malignancies, which has generated significant interest in exploring FGFR's therapeutic potential. FGFR2 fusion events are present in up to 17% of intrahepatic CCAs and appear to predict sensitivity to FGFR inhibitors even after progression on chemotherapy. These observations have led to a clinical trial evaluating FGFR inhibition in patients with CCA enriched for FGFR alterations. This review summarizes current knowledge about the role of the FGFR pathway in cholangiocarcinogenesis and ongoing work in developing FGFR-directed therapies as an antineoplastic strategy for CCA. PMID:25678238

  19. Co‑expression of the carbamoyl‑phosphate synthase 1 gene and its long non‑coding RNA correlates with poor prognosis of patients with intrahepatic cholangiocarcinoma.

    PubMed

    Ma, Sen-Lin; Li, Ai-Jun; Hu, Zhao-Yang; Shang, Fu-Sheng; Wu, Meng-Chao

    2015-12-01

    The mechanisms leading to high rates of malignancy and recurrence of human intrahepatic cholangiocarcinoma (ICC) remain unclear. It is difficult to diagnose and assess the prognosis of patients with ICC in the clinic due to the lack of specific biomarkers. In addition, long non‑coding RNAs (lncRNAs) have been reported to serve important roles in certain types of tumorigenesis however a role in ICC remains to be reported. The aim of the current study was to screen for genes and lncRNAs that are abnormally expressed in ICC and to investigate their biological and clinicopathological significance in ICC. The global gene and lncRNA expression profiles in ICC were measured using bioinformatics analysis. Carbamoyl‑phosphate synthase 1 (CPS1) and its lncRNA CPS1 intronic transcript 1 (CPS1‑IT1) were observed to be upregulated in ICC. The expression of CPS1 and CPS1‑IT1 was measured in 31 tissue samples from patients with ICC and a number of cell lines. The effects of CPS1 and CPS1‑IT1 on the proliferation and apoptosis of the ICC‑9810 cell line were measured. In addition, the clinicopathological features and survival rates of patients with ICC with respect to the gene and lncRNA expression status were analyzed. CPS1 and CPS1‑IT1 were co‑upregulated in ICC tissues compared with non‑cancerous tissues. Knockdown of CPS1 andor CPS1‑IT1 reduced the proliferation and increased the apoptosis of ICC‑9810 cells. Additionally, clinical analysis indicated that CPS1 and CPS1‑IT1 were associated with poor liver function and reduced survival rates when the relative expression values were greater than 4 in cancer tissues. The comparisons between the high CPS1 expression group and the low expression group indicated significant differences in international normalized ratio (P=0.048), total protein (P=0.049), indirect bilirubin (P=0.025), alkaline phosphatase (P=0.003) and disease‑free survival (P=0.034). In addition, there were differential trends in CA19‑9

  20. 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

  1. 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

  2. Perioperative Management of Hilar Cholangiocarcinoma

    PubMed Central

    Poruk, Katherine E.; Pawlik, Timothy M.

    2016-01-01

    Background Cholangiocarcinoma is the most common primary tumor of the biliary tract although it accounts for only 2 % of all human malignancies. We herein review hilar cholangiocarcinoma including its risk factors, the main classification systems for tumors, current surgical management of the disease, and the role chemotherapy and liver transplantation may play in selected patients. Methods We performed a comprehensive literature search using PubMed, Medline, and the Cochrane library for the period 1980–2015 using the following MeSH terms: “hilar cholangiocarcinoma”, “biliary cancer”, and “cholangiocarcinoma”. Only recent studies that were published in English and in peer reviewed journals were included. Findings Hilar cholangiocarcinoma is a disease of advanced age with an unclear etiology, most frequently found in Southeast Asia and relatively rare in Western countries. The best chance of long-term survival and potential cure is surgical resection with negative surgical margins, but many patients are unresectable due to locally advanced or metastatic disease at diagnosis. As a result of recent efforts, new methods of management have been identified for these patients, including preoperative portal vein embolism and biliary drainage, neoadjuvant chemotherapy with subsequent transplantation, and chemoradiation therapy. Conclusion Current management of hilar cholangiocarcinoma depends on extent of the tumor at presentation and includes surgical resection, liver transplantation, portal vein embolization, and chemoradiation therapy. Our understanding of hilar cholangiocarcinoma has improved in recent years and further research offers hope to improve the outcome in patients with these rare tumors. PMID:26022776

  3. 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

  4. [A case of huge intrahepatic cholangiocarcinosarcoma].

    PubMed

    Nakajima, Takahiro; Okamura, Akiharu

    2012-09-01

    A 77-year-old woman was referred to our hospital because of right-back pain. Dynamic computed tomography (CT) studies showed a huge tumor in the right lobe of the liver. After admission, transcatheter arterial embolization (TAE) was immediately performed because of the risk of rupture. The tumor, however, was hypovascular and we judged that the procedure had no effect on preventing rupture. Therefore, based on a diagnosis of cystadenocarcinoma or cholangiocarcinoma, we conducted right trisegmentectomy and caudate lobectomy in July 2010. The definitive pathological diagnosis was intrahepatic cholangiocarcinosarcoma. The postoperative course was uneventful, and the patient was discharged on postoperative day (POD) 17. Afterwards, despite chemotherapy treatment, a local recurrence on the right diaphragm was detected 2 months postoperatively, and she died 4 months postoperatively. Intrahepatic cholangiocarcinosarcoma is very rare. We report this case with a review of some relevant literature. PMID:22976229

  5. Cancer review: Cholangiocarcinoma

    PubMed Central

    Ghouri, Yezaz Ahmed; Mian, Idrees; Blechacz, Boris

    2015-01-01

    Cholangiocarcinoma (CCA) is the most common biliary tract malignancy. CCA is classified as intrahepatic, perihilar or distal extrahepatic; the individual subtypes differ in their biologic behavior, clinical presentation, and management. Throughout the last decades, CCA incidence rates had significantly increased. In addition to known established risk factors, novel possible risk factors (i.e. obesity, hepatitis C virus) have been identified that are of high importance in developed countries where CCA prevalence rates have been low. CCA tends to develop on the background of inflammation and cholestasis. In recent years, our understanding of the molecular mechanisms of cholangiocarcinogenesis has increased, thereby, providing the basis for molecularly targeted therapies. In its diagnostic evaluation, imaging techniques have improved, and the role of complementary techniques has been defined. There is a need for improved CCA biomarkers as currently used ones are suboptimal. Multiple staging systems have been developed, but none of these is optimal. The prognosis of CCA is considered dismal. However, treatment options have improved throughout the last two decades for carefully selected subgroups of CCA patients. Perihilar CCA can now be treated with orthotopic liver transplantation with neoadjuvant chemoradiation achieving 5-year survival rates of 68%. Classically considered chemotherapy-resistant, the ABC-02 trial has shown the therapeutic benefit of combination therapy with gemcitabine and cisplatin. The benefits of adjuvant treatments for resectable CCA, local ablative therapies and molecularly targeted therapies still need to be defined. In this article, we will provide the reader with an overview over CCA, and discuss the latest developments and controversies. PMID:25788866

  6. A review of the clinical diagnosis and therapy of cholangiocarcinoma.

    PubMed

    Yao, Denghua; Kunam, Vamsi Krishna; Li, Xiao

    2014-02-01

    Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy worldwide. The incidence of intrahepatic CCA is increasing, whereas that of extrahepatic CCA is decreasing. This review looks at the new advances that have been made in the management of CCA, based on a PubMed and Science Citation Index search of results from randomized controlled trials, reviews, and cohort, prospective and retrospective studies. Aggressive interventional approaches and new histopathological techniques have been developed to make a histological diagnosis in patients with high risk factors or suspected CCA. Resectability of the tumour can now be assessed using multiple radiological imaging studies; the main prognostic factor after surgery is a histologically negative resection margin. Biliary drainage and/or portal vein embolization may be performed before extended radical resection, or liver transplantation may be undertaken in combination with neoadjuvant chemotherapy or chemoradiotherapy. Though many advances have been made in the management of CCA, the standard modality of treatment has not yet been established. This review focuses on the clinical options for different stages of CCA. PMID:24366497

  7. Cholangiocarcinoma: A 7-year experience at a single center in Greece

    PubMed Central

    Alexopoulou, Alexandra; Soultati, Aspasia; Dourakis, Spyros P; Vasilieva, Larissa; Archimandritis, Athanasios J

    2008-01-01

    AIM: To evaluate survival rate and clinical outcome of cholangiocarcinoma. METHODS: The medical records of 34 patients with cholangiocarcinoma, seen at a single hospital between the years 1999-2006, were retrospectively reviewed. RESULTS: Thirty-four patients with a median age of 75 years were included. Seventeen (50%) had painless jaundice at presentation. Sixteen (47.1%) were perihilar, 15 (44.1%) extrahepatic and three (8.8%) intrahepatic. Endoscopic retrograde cholangiography (ERCP) and/or magnetic resonance cholangiography (MRCP) were used for the diagnosis. Pathologic confirmation was obtained in seven and positive cytological examination in three. Thirteen patients had co-morbidities (38.2%). Four cases were managed with complete surgical resection. All the rest of the cases (30) were characterized as non-resectable due to advanced stage of the disease. Palliative biliary drainage was performed in 26/30 (86.6%). The mean follow-up was 32 mo (95% CI, 20-43 mo). Overall median survival was 8.7 mo (95% CI, 2-16 mo). The probability of 1-year, 2-year and 3-year survival was 46%, 20% and 7%, respectively. The survival was slightly longer in patients who underwent resection compared to those who did not, but this difference failed to reach statistical significance. Patients who underwent biliary drainage had an advantage in survival compared to those who did not (probability of survival 53% vs 0% at 1 year, respectively, P = 0.038). CONCLUSION: Patients with cholangiocarcinoma were usually elderly with co-morbidities and/or advanced disease at presentation. Even though a slight amelioration in survival with palliative biliary drainage was observed, patients had dismal outcome without resection of the tumor. PMID:18985813

  8. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma.

    PubMed

    Kipp, Benjamin R; Voss, Jesse S; Kerr, Sarah E; Barr Fritcher, Emily G; Graham, Rondell P; Zhang, Lizhi; Highsmith, W Edward; Zhang, Jun; Roberts, Lewis R; Gores, Gregory J; Halling, Kevin C

    2012-10-01

    Somatic mutations in isocitrate dehydrogenase 1 and 2 genes are common in gliomas and help stratify patients with brain cancer into histologic and molecular subtypes. However, these mutations are considered rare in other solid tumors. The aims of this study were to determine the frequency of isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma and to assess histopathologic differences between specimens with and without an isocitrate dehydrogenase mutation. We sequenced 94 formalin-fixed, paraffin-embedded cholangiocarcinoma (67 intrahepatic and 27 extrahepatic) assessing for isocitrate dehydrogenase 1 (codon 132) and isocitrate dehydrogenase 2 (codons 140 and 172) mutations. Multiple histopathologic characteristics were also evaluated and compared with isocitrate dehydrogenase 1/2 mutation status. Of the 94 evaluated specimens, 21 (22%) had a mutation including 14 isocitrate dehydrogenase 1 and 7 isocitrate dehydrogenase 2 mutations. Isocitrate dehydrogenase mutations were more frequently observed in intrahepatic cholangiocarcinoma than in extrahepatic cholangiocarcinoma (28% versus 7%, respectively; P = .030). The 14 isocitrate dehydrogenase 1 mutations were R132C (n = 9), R132S (n = 2), R132G (n = 2), and R132L (n = 1). The 7 isocitrate dehydrogenase 2 mutations were R172K (n = 5), R172M (n = 1), and R172G (n = 1). Isocitrate dehydrogenase mutations were more frequently observed in tumors with clear cell change (P < .001) and poorly differentiated histology (P = .012). The results of this study show for the first time that isocitrate dehydrogenase 1 and 2 genes are mutated in cholangiocarcinoma. The results of this study are encouraging because it identifies a new potential target for genotype-directed therapeutic trials and may represent a potential biomarker for earlier detection of cholangiocarcinoma in a subset of cases. PMID:22503487

  9. [Medical management of cholangiocarcinomas in 2015].

    PubMed

    Marret, Grégoire; Neuzillet, Cindy; Rousseau, Benoît; Tournigand, Christophe

    2016-04-01

    Cholangiocarcinoma is a rare malignancy carrying a poor prognosis. Most patients are diagnosed with advanced-stage disease and are then ineligible for surgical resection, which is the only potentially curative therapeutic modality. The aim of this article is to provide an up-to-date review of medical management of patients with cholangiocarcinoma. The benefit of adjuvant therapy in patients undergoing curative-intent surgery is under evaluation. Combination chemotherapy with gemcitabine and platinum is the standard first-line treatment for patients with advanced cholangiocarcinoma. Targeted agents are not currently recommended due to limited data on use in this setting. The role of second-line chemotherapy is not established in advanced cholangiocarcinoma. Identification of predictive and prognostic markers to select patients who could benefit from second-line therapy is a major issue. A better understanding of the biological and molecular mechanisms underlying the carcinogenesis and the phenotypic heterogeneity of cholangiocarcinoma may path the way of new therapeutic strategies. PMID:26922666

  10. [Cases of advanced cholangiocarcinoma showing partial response by the combination chemotherapy including protracted continuous infusion of 5-FU combined with intravenous administration of low-dose leucovorin and intra-arterial administration of MMC and CQ].

    PubMed

    Tsushima, K; Sakata, Y; Shiratori, Y; Sakamoto, J; Koeda, J; Yamada, Y; Soma, N; Tamura, K; Yoshiwara, A; Soma, Y

    1991-12-01

    We treated a patient with advanced cholangiocarcinoma with a new combination chemotherapy (modified MQF). The regimen consisted of intra-arterial administration of MMC (20 mg/body) and CQ (4 mg/body), protracted continuous infusion of 5-FU (500 mg/body) and intravenous administration of low-dose leucovorin (30 mg/body). More than 50% reduction in the liver tumor for over 4 weeks was obtained by the therapy. As for toxicity, diarrhea and stomatitis were observed. PMID:1660702

  11. Hilar Cholangiocarcinoma: expert consensus statement

    PubMed Central

    Mansour, John C; Aloia, Thomas A; Crane, Christopher H; Heimbach, Julie K; Nagino, Masato; Vauthey, Jean-Nicolas

    2015-01-01

    An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists met on 15 January 2014 to review current evidence on the management of hilar cholangiocarcinoma in order to establish practice guidelines and to agree consensus statements. It was established that the treatment of patients with hilar cholangiocarcinoma requires a coordinated, multidisciplinary approach to optimize the chances for both durable survival and effective palliation. An adequate diagnostic and staging work-up includes high-quality cross-sectional imaging; however, pathologic confirmation is not required prior to resection or initiation of a liver transplant trimodal treatment protocol. The ideal treatment for suitable patients with resectable hilar malignancy is resection of the intra- and extrahepatic bile ducts, as well as resection of the involved ipsilateral liver. Preoperative biliary drainage is best achieved with percutaneous transhepatic approaches and may be indicated for patients with cholangitis, malnutrition or hepatic insufficiency. Portal vein embolization is a safe and effective strategy for increasing the future liver remnant (FLR) and is particularly useful for patients with an FLR of <30%. Selected patients with unresectable hilar cholangiocarcinoma should be evaluated for a standard trimodal protocol incorporating external beam and endoluminal radiation therapy, systemic chemotherapy and liver transplantation. Post-resection chemoradiation should be offered to patients who show high-risk features on surgical pathology. Chemoradiation is also recommended for patients with locally advanced, unresectable hilar cancers. For patients with locally recurrent or metastatic hilar cholangiocarcinoma, first-line chemotherapy with gemcitabine and cisplatin is recommended based on multiple Phase II trials and a large randomized controlled trial including a heterogeneous population of patients with biliary cancers. PMID:26172136

  12. Hilar cholangiocarcinoma: expert consensus statement.

    PubMed

    Mansour, John C; Aloia, Thomas A; Crane, Christopher H; Heimbach, Julie K; Nagino, Masato; Vauthey, Jean-Nicolas

    2015-08-01

    An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists met on 15 January 2014 to review current evidence on the management of hilar cholangiocarcinoma in order to establish practice guidelines and to agree consensus statements. It was established that the treatment of patients with hilar cholangiocarcinoma requires a coordinated, multidisciplinary approach to optimize the chances for both durable survival and effective palliation. An adequate diagnostic and staging work-up includes high-quality cross-sectional imaging; however, pathologic confirmation is not required prior to resection or initiation of a liver transplant trimodal treatment protocol. The ideal treatment for suitable patients with resectable hilar malignancy is resection of the intra- and extrahepatic bile ducts, as well as resection of the involved ipsilateral liver. Preoperative biliary drainage is best achieved with percutaneous transhepatic approaches and may be indicated for patients with cholangitis, malnutrition or hepatic insufficiency. Portal vein embolization is a safe and effective strategy for increasing the future liver remnant (FLR) and is particularly useful for patients with an FLR of <30%. Selected patients with unresectable hilar cholangiocarcinoma should be evaluated for a standard trimodal protocol incorporating external beam and endoluminal radiation therapy, systemic chemotherapy and liver transplantation. Post-resection chemoradiation should be offered to patients who show high-risk features on surgical pathology. Chemoradiation is also recommended for patients with locally advanced, unresectable hilar cancers. For patients with locally recurrent or metastatic hilar cholangiocarcinoma, first-line chemotherapy with gemcitabine and cisplatin is recommended based on multiple Phase II trials and a large randomized controlled trial including a heterogeneous population of patients with biliary cancers. PMID:26172136

  13. Trousseau’s Syndrome in Cholangiocarcinoma: The Risk of Making the Diagnosis

    PubMed Central

    Blum, Matthew F.; Ma, Vincent Y.; Betbadal, Anthony M.; Bonomo, Robert A.; Raju, Rajeeva R.; Packer, Clifford D.

    2016-01-01

    We report a case of Trousseau’s syndrome with cholangiocarcinoma complicated by a fatal pulmonary embolism after liver biopsy. A 69-year-old man who presented with right upper quadrant pain was found to have portal vein thrombosis and nonspecific liver hypodensities after imaging by computerized tomography. Following four days of anticoagulation, heparin was held for percutaneous liver biopsy. After the biopsy, he developed acute hepatic failure, acute kidney injury, lactic acidemia, and expired. Autopsy revealed intrahepatic cholangiocarcinoma and a pulmonary embolism. Trousseau’s syndrome with cholangiocarcinoma is rarely reported and has a poor prognosis. This case highlights a fundamental challenge in the diagnosis and early management of intrahepatic cholangiocarcinoma with hypercoagulability. Diagnostic biopsy creates an imperative to reduce post-operative bleeding risk, but this conflicts with the need to reduce thrombotic risk in a hypercoagulable state. Considering the risk of withholding anticoagulation in patients with proven or suspected cholangiocarcinoma complicated by portal vein thrombosis, physicians should consider biopsy procedures with lesser bleeding risks, such as transjugular liver biopsy or plugged percutaneous liver biopsy, to minimize interruption of anticoagulation. PMID:26847482

  14. 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

  15. Hilar cholangiocarcinoma. An evaluation of subtypes with CT and angiography.

    PubMed

    Yamashita, Y; Takahashi, M; Kanazawa, S; Charnsangavej, C; Wallace, S

    1992-07-01

    Sixty-seven patients had hilar cholangiocarcinomas which were divided into 3 types based on tumor morphology as observed on cholangiography and CT. The pathology, vascularity, and pattern of tumor spread of these types were compared. Most of the infiltrative tumors (n = 44) were scirrhous adenocarcinomas, which on CT showed poor or no contrast enhancement with frequent lymph node metastases and liver atrophy. At angiography, there was vascular encasement in 52%, in rare cases neovascularity, and tumor stain. The exophytic type (n = 19) was divided into 2 subgroups depending on the main location of the tumor. The nodular subtype (n = 16) was mainly inside the liver and somewhat hypervascular similar to peripheral cholangiocarcinoma, often with intrahepatic metastases. The periductal subtype (n = 3) was hypovascular, similar to the infiltrative cholangiocarcinoma, and had a tendency to spread along the portal vein. The intraductal type (n = 4) was observed as a filling defect on cholangiography. CT revealed an intraluminal low density mass. Histologically, they were papillary adenocarcinomas. The radiologic types of hilar cholangiocarcinoma showed different characteristics with regard to pathologic findings, vascularity, and pattern of spread. PMID:1321653

  16. Cutaneous metastasis of cholangiocarcinoma

    PubMed Central

    Liu, Min; Liu, Bai-Long; Liu, Bin; Guo, Liang; Wang, Qiang; Song, Yan-Qiu; Dong, Li-Hua

    2015-01-01

    AIM: To investigate the clinical characteristics and prognostic factors of cutaneous metastasis of cholangiocarcinoma by a retrospective analysis of published cases. METHODS: An extensive search was conducted in the English literature within the PubMed database using the following keywords: cutaneous metastasis or skin metastasis and cholangiocarcinoma or bile duct. The data of 30 patients from 21 articles from 1978 to 2014 were analyzed. Patient data retrieved from the articles included the following: age, gender, time cutaneous metastasis occurred, number of cutaneous metastases throughout life, sites of initial cutaneous metastasis, anatomic site, pathology and differentiation of cholangiocarcinoma, and immunohistochemical results of the cutaneous metastasis. The assessment of overall survival after cutaneous metastasis (OSCM) was the primary endpoint. RESULTS: The median age at diagnosis of cutaneous metastasis of cholangiocarcinoma was 60.0 years (range: 35-77). This metastasis showed a predilection towards males, with a male to female ratio of 3.29. In 8 cases (27.6%), skin metastasis was the first sign of cholangiocarcinoma. Additionally, 18 cases (60.0%) manifested single cutaneous metastasis, while 12 cases (40.0%) demonstrated multiple skin metastases. In 50.0% of patients, the metastasis occurred in the drainage region, while 50.0% of patients had distant cutaneous metastases. The scalp was the most frequently involved region of distant skin metastasis, occurring in 36.7% of patients. The median OSCM of cholangiocarcinoma was 4.0 mo. Patient age and cutaneous metastatic sites showed no significant relation with OSCM, while male gender and single metastasis of the skin were associated with a poorer OSCM (hazard ratio: 0.168; P = 0.005, and hazard ratio: 0.296; P = 0.011, respectively). CONCLUSION: The prognosis of cutaneous metastasis of cholangiocarcinoma is dismal. Both male gender and single skin metastasis are associated with a poorer OSCM. PMID

  17. 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

  18. Successful Parenchyma-Sparing Anatomical Surgery by 3-Dimensional Reconstruction of Hilar Cholangiocarcinoma Combined with Anatomic Variation.

    PubMed

    Ni, Qihong; Wang, Haolu; Liang, Xiaowen; Zhang, Yunhe; Chen, Wei; Wang, Jian

    2016-06-01

    The combination of hilar cholangiocarcinoma and anatomic variation constitutes a rare and complicated condition. Precise understanding of 3-dimensional position of tumor in the intrahepatic structure in such cases is important for operation planning and navigation. We report a case of a 61-year woman presenting with hilar cholangiocarcinoma. Anatomic variation and tumor location were well depicted on preoperative multidetector computed tomography (MDCT) combined with 3-dimensional reconstruction as the right posterior segmental duct drained to left hepatic duct. The common hepatic duct, biliary confluence, right anterior segmental duct, and right anterior branch of portal vein were involved by the tumor (Bismuth IIIa). After carefully operation planning, we successfully performed a radical parenchyma-sparing anatomical surgery of hilar cholangiocarcinoma: Liver segmentectomy (segments 5 and 8) and caudate lobectomy. MDCTcombined with 3-dimensional reconstruction is a reliable non-invasive modality for preoperative evaluation of hilar cholangiocarcinoma. PMID:27376205

  19. Is preoperative histological diagnosis necessary before referral to major surgery for cholangiocarcinoma?

    PubMed

    Buc, E; Lesurtel, M; Belghiti, J

    2008-01-01

    Major surgical resection is often the only curative treatment for cholangiocarcinoma. When imaging techniques fail to establish the accurate diagnosis, biopsy of the lesion is unavoidable. However, biopsy is not necessarily required for topography of the cholangiocarcinoma (intrahepatic or extrahepatic). 1) In extrahepatic cholangiocarcinoma (ECC), clinical features and radiological imaging relate to biliary obstruction. Provided that between 8% and 43% of bile duct strictures are not ECC, the lesions mimicking ECC that should be ruled out are gallbladder cancer, Mirizzi syndrome, primary sclerosing cholangitis (PSC), autoimmune pancreatitis and portal biliopathy. Systematic biopsy is usually difficult and has poor sensitivity, but a good knowledge of these mimicking ECC diseases, along with precise analysis of clinical and imaging semiology, may lead to a correct diagnosis without the need for biopsy. 2) Intrahepatic cholangiocarcinoma (ICC) developing in normal liver appears as a hypovascular tumour with fibrotic component and capsular retraction that can be confused with fibrous metastases such as breast and colorectal cancers. The lack of the primary site, a relatively large tumour size and ancillary findings such as bile duct dilatation may provide a clue to the diagnosis. If not, we advocate local resection with lymph node dissection, since ICC is the most likely diagnosis and surgery is the only curative treatment. In the event of adenocarcinoma from unknown primary, surgery is an effective treatment even if prognosis is poor. PMID:18773064

  20. Transjugular intrahepatic portosystemic shunt (TIPS)

    MedlinePlus

    ... gov/ency/article/007210.htm Transjugular intrahepatic portosystemic shunt (TIPS) To use the sharing features on this page, please enable JavaScript. Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure to create new connections ...

  1. BRCA-associated protein 1 mutant cholangiocarcinoma: an aggressive disease subtype

    PubMed Central

    Al-Shamsi, Humaid O.; Anand, Deepa; Shroff, Rachna T.; Jain, Apurva; Zuo, Mingxin; Conrad, Claudius; Vauthey, Jean-Nicolas

    2016-01-01

    Background BRCA-associated protein 1, an enzyme encoded by the BAP1 gene, is commonly mutated in uveal melanoma, mesothelioma, and renal cancers. Tumors with BAP1 mutation follow an aggressive course. BAP1 mutations have also been observed in cholangiocarcinoma (CCA). The clinical phenotype of BAP1 mutant CCA may yield useful prognostic and therapeutic information but has not been defined. Methods The records of CCA patients who underwent next-generation sequencing (NGS) were reviewed, and data on clinical, histopathological, genetic, and radiological features; response to therapy; time to progression; and survival were analyzed. Results Twenty-two cases of BAP1-mutation associated CCA were diagnosed from January 1, 2009, to February 1, 2015, at our center. Twenty patients had intrahepatic CCA and two had extrahepatic CCA. Tumor sizes (largest dimension) ranged from 2 to 16 cm (mean, 8.5 cm). Twelve patients had tumors that were poorly differentiated. Majority of the patients had advanced disease at presentation and 13 had bone metastases. Thirteen patients (59%) experienced rapidly progressive disease following primary therapy (chemotherapy or surgical resection). The mean time to tumor progression was 3.8 months after the first line chemotherapy. Conclusions BAP1 mutation in CCA may be associated with aggressive disease and poor response to standard therapies. Therefore, BAP1-targeted therapies need to be investigated. PMID:27563445

  2. Intrahepatic granulomatous arteriopathy

    PubMed Central

    Fox, H.; Gleeson, M. H.; Logan, W. F. W. E.

    1968-01-01

    The case history is detailed of a 55-year-old woman who was investigated for persistent pyrexia and anaemia. A liver biopsy specimen showed an unusual lesion of the small intrahepatic arteries. Many of these vessels showed circumferential replacement of their adventitial coat by a non-caseating granuloma whilst others showed localized granulomata focally interrupting the adventitial coat. The medial and intimal coats of the affected arteries were normal. This was an intrahepatic granulomatous arteriopathy of unknown origin. The patient responded promptly and completely to steroid therapy. ImagesFig. 1Fig. 2 PMID:5648674

  3. Hepatitis B virus infection, diabetes mellitus, and their synergism for cholangiocarcinoma development: A case-control study in Korea

    PubMed Central

    Lee, Ban Seok; Park, Eun-Cheol; Park, Seung Woo; Nam, Chung Mo; Roh, Jaehoon

    2015-01-01

    AIM: To identify possible risk factors and their synergism for cholangiocarcinoma development. METHODS: A hospital-based, case-control study in which we included 276 cholangiocarcinoma patients [193 extrahepatic cholangiocarcinoma (ECC) and 83 intrahepatic cholangiocarcinoma (ICC)], diagnosed at a training hospital in Korea between 2007 and 2013, and 552 healthy controls matched 2:1 for age, sex, and date of diagnosis. Risk factors for cholangiocarcinoma and possible synergism between those factors were evaluated using conditional logistic regression and synergism index, respectively. RESULTS: There was an association between cholangiocarcinoma and hepatitis B virus (HBV) infection, diabetes mellitus (DM), cholecystolithiasis, choledocholithiasis, and hepatolithiasis, with the adjusted odds ratios (AORs) of 4.1, 2.6, 1.7, 12.4, and 39.9, respectively. Synergistic interaction on the additive model was investigated between HBV infection and DM (AOR = 12.2; 95%CI: 1.9-80.1). In the subgroup analyses, cholecystolithiasis, choledocholithiasis, hepatolithiasis, and DM were significant risk factors for ECC (AOR = 2.0, 18.1, 14.9, and 2.0, respectively), whereas choledocholithiasis, hepatolithiasis, HBV infection, and DM were risk factors for ICC (AOR = 8.6, 157.4, 5.3 and 4.9, respectively). Synergistic interaction was also observed between HBV infection and DM (OR = 22.7; 95%CI: 2.4-214.1). However, there was no synergistic interaction between other significant risk factors for cholangiocarcinoma. CONCLUSION: In this Korean study, HBV infection and DM were found to exert independent and synergistic effects on the risk for cholangiocarcinoma, including ICC. Exploring the underlying mechanisms for such synergy may lead to the development of cholangiocarcinoma prevention strategies in high-risk individuals. PMID:25593465

  4. [Operation treatment method of Bismuth-Corlette Ⅲ, Ⅳ hilar cholangiocarcinoma].

    PubMed

    Lu, Z; Wang, D D

    2016-07-01

    Hilar cholangiocarcinoma (HCCA) is also known as cancer at the upper part of bile duct, perihilar cholangiocarcinoma or Klatskin tumor, etc.Bismuth-Corlette type Ⅲ hilar cholangiocarcinoma refers to tumor invading right hepatic duct (Ⅲa) or left hepatic duct (Ⅲb). While Bismuth-Corlette type Ⅳ hilar cholangiocarcinoma refers to both left and right intrahepatic bile ducts being invaded. Under the premise of strictly grasping the indications of surgery, if preoperative management is conducted carefully, extended hepatic resection is a safe and feasible surgery to remove Bismuth-Corlette type Ⅲ and type Ⅳ hilar cholangiocarcinoma. When conducting extended hepatic resection, right hepatectomy and combined caudate lobectomy should be conducted depending on the circumstances. Routine skeletization lymph node dissection of the hepatoduodenal ligament is performed, which could be expanded into celiac trunk, para-aortic area and the rear of pancreatic head. In the premise of radical resection, invaded vessels should be removed and then reconstructed depending on circumstances. PMID:27373472

  5. Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma

    PubMed Central

    Tamai, Keiichi; Nakamura, Mao; Mizuma, Masamichi; Mochizuki, Mai; Yokoyama, Misa; Endo, Hiroyuki; Yamaguchi, Kazunori; Nakagawa, Takayuki; Shiina, Masaaki; Unno, Michiaki; Muramoto, Koji; Sato, Ikuro; Satoh, Kennichi; Sugamura, Kazuo; Tanaka, Nobuyuki

    2014-01-01

    Cholangiocarcinoma is an aggressive malignant tumor originating from intrahepatic or extrahepatic bile ducts. Its malignant phenotypes may be assumed by cancer stem cells (CSC). Here, we demonstrate that CD274 (PD-L1), known as an immunomodulatory ligand, has suppressive effects on CSC-related phenotypes of cholangiocarcinoma. Using two human cholangiocarcinoma cell lines, RBE and HuCCT1, we attempted to isolate the CD274low and CD274high cells from each cell line, and xenografted them into immunodeficient NOD/scid/γcnull (NOG) mice. We found that the CD274low cells isolated from both RBE and HuCCT1 are highly tumorigenic in NOG mice compared with CD274high cells. Furthermore, the CD274low cells possess several CSC-related characteristics, such as high aldehyde dehydrogenase (ALDH) activity, reduced reactive oxygen species production and a dormant state in the cell cycle. Furthermore, depletion of CD274 expression by shRNA in RBE cells enhances their tumorigenicity and increases ALDH activity. These findings are compatible with our observation that clinical cholangiocarcinoma specimens are classified into low and high groups for CD274 expression, and the CD274 low group shows poorer prognosis when compared with the CD274 high group. These results strongly suggest that CD274 has a novel function in the negative regulation of CSC-related phenotypes in human cholangiocarcinoma, which is distinct from its immunomodulatory actions. PMID:24673799

  6. Intrahepatic splenosis mimicking hepatoma

    PubMed Central

    Yu, Haihua; Xia, Lijian; Li, Tao; Ju, Minjie; Liu, Liang; Wu, Zhiquan; Tang, Zhaoyou

    2009-01-01

    A 54-year-old man with a past history of splenectomy some 20 years previously presented with a hepatic mass. Subsequent histopathology revealed that the mass was due to intrahepatic splenosis. The presentation of this case is discussed together with a literature review of splenosis. PMID:21691391

  7. 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

  8. 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

  9. Benefits of Metformin Use for Cholangiocarcinoma.

    PubMed

    Kaewpitoon, Soraya J; Loyd, Ryan A; Rujirakul, Ratana; Panpimanmas, Sukij; Matrakool, Likit; Tongtawee, Taweesak; Kootanavanichpong, Nusorn; Kompor, Ponthip; Chavengkun, Wasugree; Kujapun, Jirawoot; Norkaew, Jun; Ponphimai, Sukanya; Padchasuwan, Natnapa; Pholsripradit, Poowadol; Eksanti, Thawatchai; Phatisena, Tanida; Kaewpitoon, Natthawut

    2015-01-01

    Metformin is an oral anti-hyperglycemic agent, which is the most commonly prescribed medication in the treatment of type-2 diabetes mellitus. It is purportedly associated with a reduced risk for various cancers, mainly exerting anti-proliferation effects on various human cancer cell types, such as pancreas, prostate, breast, stomach and liver. This mini-review highlights the risk and benefit of metformin used for cholangiocarcinoma (CCA) prevention and therapy. The results indicated metformin might be a quite promising strategy CCA prevention and treatment, one mechanism being inhibition of CCA tumor growth by cell cycle arrest in both in vitro and in vivo. The AMPK/mTORC1 pathway in intrahepatic CCA cells is targeted by metformin. Furthermore, metformin inhibited CCA tumor growth via the regulation of Drosha-mediated expression of multiple carcinogenic miRNAs. The use of metformin seems to be safe in patients with cirrhosis, and provides a survival benefit. Once hepatic malignancies are already established, metformin does not offer any therapeutic potential. Clinical trials and epidemiological studies of the benefit of metformin use for CCA should be conducted. To date, whether metformin as a prospective chemotherapeutic for CCA is still questionable and waits further atttention. PMID:26745042

  10. [A case of surgical resection of a combined hepatocellular and cholangiocarcinoma after transarterial chemoembolization].

    PubMed

    Yakoshi, Yuta; Toyoki, Yoshikazu; Ishido, Keinosuke; Kudo, Daisuke; Kimura, Norihisa; Wakiya, Taiichi; Hakamada, Kenichi

    2013-11-01

    A 48-year-old woman was admitted to our hospital for the treatment of a liver tumor (diameter, 10 cm), which was detected by abdominal contrast-enhanced computed tomography. The tumor occupied mainly the left medial segment and caudate lobe, invaded the left and right hepatic arteries, and obstructed the left portal vein. The tumor was diagnosed as an unresectable intrahepatic cholangiocarcinoma, and chemotherapy (a combination of gemcitabine and S-1) was initiated. Because the tumor continued to grow despite the chemotherapy, we performed transarterial chemoembolization(TACE)as a second-line treatment, which successfully reduced tumor size to 7 cm. Thereafter, surgical resection was performed. Histopathological examination indicated the presence of intrahepatic cholangiocarcinoma, which formed the main component, combined with hepatocellular carcinoma. This tumor was diagnosed as a combined hepatocellular and cholangiocarcinoma. Although adjuvant chemotherapy was not administered because of prolonged pancytopenia, currently, at 5 years after the operation, the patient is alive and has not experienced any recurrence. PMID:24393926

  11. 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

  12. Identification of SPHK1 as a therapeutic target and marker of poor prognosis in cholangiocarcinoma

    PubMed Central

    Chen, Ming-Huang; Yen, Chueh-Chuan; Cheng, Chi-Tung; Wu, Ren-Chin; Huang, Shih-Chiang; Yu, Chung-Shan; Chung, Yi-Hsiu; Liu, Chun-Yu; Chang, Peter Mu-Hsin; Chao, Yee; Chen, Ming-Han; Chen, Yu-Fen; Chiang, Kun-Chun; Yeh, Ta-Sen; Chen, Tzu Chi; Huang, Chi-Ying F.; Yeh, Chun-Nan

    2015-01-01

    Cholangiocarcinoma (CCA) is characterized by a uniquely aggressive behavior and lack of effective targeted therapies. After analyzing the gene expression profiles of seven paired intrahepatic CCA microarrays, a novel sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) pathway and a novel target gene, SPHK1, were identified. We hypothesized that therapeutic targeting of this pathway can be used to kill intrahepatic cholangiocarcinoma (CCA) cells. High levels of SPHK1 protein expression, which was evaluated by immunohistochemical staining of samples from 96 patients with intrahepatic CCA, correlated with poor overall survival. The SPHK1 inhibitor SK1-I demonstrated potent antiproliferative activity in vitro and in vivo. SK1-I modulated the balance of ceramide-sphinogosine-S1P and induced CCA apoptosis. Furthermore, SK1-I combined with JTE013, an antagonist of the predominant S1P receptor S1PR2, inhibited the AKT and ERK signaling pathways in CCA cells. Our preclinical data suggest SPHK1/S1P pathway targeting may be an effective treatment option for patients with CCA. PMID:26090720

  13. 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. PMID:25788760

  14. Peribiliary hepatic cysts presenting as hilar cholangiocarcinoma in a patient with end-stage liver disease

    PubMed Central

    Lim, Jane; Nissen, Nicholas N.; McPhaul, Christopher; Annamalai, Alagappan; Klein, Andrew S.; Sundaram, Vinay

    2016-01-01

    Peribiliary cysts are cystic dilatations of peribiliary glands in the liver. They are present in ~50% of cirrhotic patients, but are underrecognized because they are usually asymptomatic and rarely present as obstructive jaundice. A 63-year-old male with hepatitis C cirrhosis, awaiting liver transplantation, had a new finding of intrahepatic dilatation on magnetic resonance imaging. This was initially concerning for cholangiocarcinoma, but was ultimately diagnosed as peribiliary cysts. Peribiliary cysts can imitate cholangiocarcinoma on imaging. Therefore, awareness of this condition is essential because misdiagnosis may lead to inappropriate delay or denial for liver transplantation. The ideal imaging modalities to identify peribiliary cysts are magnetic resonance cholangiography and drip infusion cholangiographic computed tomography, though hepatic dysfunction may limit the usefulness of the latter. Peribiliary cysts should be considered in cirrhotic patients with cholestasis, biliary dilatations and negative biopsy of the biliary system for malignancy. PMID:27511912

  15. A Glasgow Tipple—transjugular intrahepatic portosystemic shunt insertion prior to Whipple resection

    PubMed Central

    Jabbar, Salman A.A.; Jamieson, Nigel B.; Morris, Andrew J.; Oien, Karin A.; Duthie, Fraser; McKay, Colin J.; Carter, Christopher R.; Dickson, Euan J.

    2016-01-01

    Abdominal surgery performed in patients with significant liver disease and portal hypertension is associated with high mortality rates, with even poorer outcomes associated with complex pancreaticobiliary operations. We report on a patient requiring portal decompression via transjugular intrahepatic portosystemic shunt (TIPS) prior to a pancreaticoduodenectomy. The 49-year-old patient presented with pain, jaundice and weight loss. At ERCP an edematous ampulla was biopsied, revealing high-grade dysplasia within a distal bile duct adenoma. Liver biopsy was performed to investigate portal hypertension, confirming congenital hepatic fibrosis (CHF). A TIPS was performed to enable a pancreaticoduodenectomy. Prophylactic TIPS can be performed for preoperative portal decompression for patients requiring pancreatic resection. A potentially curative resection was performed when abdominal surgery was initially thought impossible. Notably, CHF has been associated with the development of cholangiocarcinoma in only four previous instances, with this case being only the second reported distal bile duct cholangiocarcinoma. PMID:27177892

  16. 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

  17. Transjugular intrahepatic portosystemic shunt.

    PubMed

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

    2014-11-01

    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 polytetrafluoroethylene-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

  18. 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

  19. Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups.

    PubMed

    Simbolo, Michele; Fassan, Matteo; Ruzzenente, Andrea; 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

    2014-05-15

    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

  20. 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. PMID:27216979

  1. Resection of a cholangiocarcinoma via laparoscopic hepatopancreato- duodenectomy: A case report

    PubMed Central

    Zhang, Miao-Zun; Xu, Xiao-Wu; Mou, Yi-Ping; Yan, Jia-Fei; Zhu, Yi-Ping; Zhang, Ren-Chao; Zhou, Yu-Cheng; Chen, Ke; Jin, Wei-Wei; Matro, Erik; Ajoodhea, Harsha

    2014-01-01

    Some laterally advanced cholangiocarcinomas behave as ductal spread or local invasion, and hepatopancreatoduodenectomy (HPD) may be performed for R0 resection. To date, there have been no reports of laparoscopic HPD (LHPD) in the English literature. We report the first case of LHPD for the resection of a Bismuth IIIa cholangiocarcinoma invading the duodenum. The patient underwent laparoscopic pancreaticoduodenectomy and right hemihepatectomy. Child’s approach was used for the reconstruction. The patient recovered well with bile leakage from the 2nd postoperative day and was discharged on the 16th postoperative day with a drainage tube in place which was removed 2 wk after discharge. Postoperative pathology revealed a well-differentiated cholangiocarcinoma and the margin of liver parenchyma, pancreas and stomach was negative for metastases. The results suggest that LHPD is a feasible and safe procedure when performed in highly specialized centers and in suitable patients with cholangiocarcinoma. PMID:25493044

  2. 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

  3. [Transcatheter arterial chemo-embolization using degradable starch microspheres (DSM) markedly effective for post-hepatectomy intra-hepatic recurrence in a patient with cholangioma].

    PubMed

    Niinobu, T; Shibata, T; Fukushima, Y; Kitada, M; Tukahara, Y; Hata, S; Ikeda, K; Hayashida, H; Fuzita, J; Takahashi, Y; Nakamura, T; Suzuki, R; Shimano, T; Takami, M; Ishida, T

    2000-10-01

    Transcatheter arterial chemo-embolization (TACE) using degradable starch microspheres (DSM) was performed for multiple recurrence after hepatectomy in a patient with cholangiocarcinoma. The patient was a 68-year-man. He received treatment for hepatitis type C starting in 1996 at a nearby hospital. In November 1997, an increased AFP level was noted and a CT scan of the abdomen revealed an abnormal shadow in the liver. On May 21, 1998, imaging results led to the diagnosis of cholangiocarcinoma or a mixed type of hepatocellular carcinoma with cholangioma. Hepatic S7 sub-sequential resection was performed. The lesion was found to be a tumor-forming type, measuring 2.2 x 2.0 cm in diameter, diagnosed histopathologically as cholangiocarcinoma, tw (-), but Stage III since a nodule suggesting intrahepatic metastasis was noted in the cut surface of the resected liver. CT scan after a month revealed multiple metastatic lesions in the liver. TACE was performed by administering 450 mg of DSM, 10 mg of MMC and 30 mg of FARM, given in three divided doses on October 30, 1998, and February 9, 1999, according to Seldinger's method. A CT scan on January 31, 2000 revealed nearly complete remission of the hepatic SOL. Accordingly, TACE was considered to be useful therapy in combination with DSM, MMC and FARM for intrahepatic recurrence of cholangiocarcinoma. PMID:11086448

  4. Fascioliasis simulating an intrahepatic cholangiocarcinoma—Case report with imaging and pathology correlation

    PubMed Central

    Hirsch, Michael; Guzmán, Pablo; Fonseca, Flery; Hofmann, Edmundo; Alanís, Martín

    2015-01-01

    Human fascioliasis is a rare zoonosis in Chile. Clinically it presents with a highly polymorphous group of symptoms that evolve in two periods. The first, acute or a result of hepatic invasion, lasts 2 weeks to 4 months and is characterized essentially by pain in the right hypochondrium and/or epigastrium, continuous fever and painful hepatomegaly. This clinical picture, associated with eosinophilia and a history of raw watercress consumption, corresponds to the classic presentation of the disease in its initial stage. We report the case of a 57-year-old female patient with no risk factors for and no clinical signs of fascioliasis, with a lesion in the right hepatic lobe compatible with intrahepatic cholangiocarcinoma, studied with computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET-CT). With the clinical suspicion of intrahepatic cholangiocarcinoma, a regulated right hepatectomy was performed, the pathological study of which revealed cholangitis and granulomatous pericholangitis resulting from trematode eggs, compatible with Fasciola hepatica. PMID:25713810

  5. The role of liver transplantation in the treatment of hilar cholangiocarcinoma

    PubMed Central

    Sotiropoulos, Georgios C.; Kaiser, Gernot M.; Molmenti, Ernesto P.; Malagó, Massimo; Broelsch, Christoph E.

    2005-01-01

    Surgical resection or liver transplantation (LTx) are the only available treatments that offer a potential for long-term survival or cure in cases of hilar cholangiocarcinoma. Hilar resection in combination with partial hepatectomy and caudate lobectomy is regarded as the current treatment of choice. Overall 5-year survival rates range from 9% to 28%, and reach as high as 24–43% in R0 resections. Five-year survival rates in the very limited experience with LTx in hilar cholangiocarcinoma are not dramatically worse than those after resection. However, hilar cholangiocarcinoma is not at present an accepted indication for LTx given both the good results of LTx for benign diseases and the dramatic organ shortage. When compared with the prognosis of other gastrointestinal tumours, these survival rates are encouraging in the setting of an otherwise unresectable malignancy. As such, and considering the fact that it may represent the only possibility for cure, the general exclusion of patients with cholangiocarcinomas as candidates for LTx does not seem to be justified. Furthermore, recent advances in multimodal tumour therapy seem to be most promising in combination with LTx. Prospective studies are required to elucidate the influence of better patient selection and the role of multimodal treatments on the outcome of LTx in hilar cholangiocarcinoma. If the encouraging data achieved with neoadjuvant therapy prior to LTx are confirmed by further studies, we foresee that renewed interest in LTx for hilar cholangiocarcinoma could arise. PMID:18333205

  6. Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications

    PubMed Central

    Churi, Chaitanya R.; Shroff, Rachna; Wang, Ying; Rashid, Asif; Kang, HyunSeon C.; Weatherly, Jacqueline; Zuo, Mingxin; Zinner, Ralph; Hong, David; Meric-Bernstam, Funda; Janku, Filip; Crane, Christopher H.; Mishra, Lopa; Vauthey, Jean-Nicholas; Wolff, Robert A.; Mills, Gordon; Javle, Milind

    2014-01-01

    Background Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics. Methods We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials. Results There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors. Conclusion There are significant genetic differences between intra and extrahepatic CCA. NGS

  7. 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

  8. 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

  9. 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

  10. Cholangiocarcinoma: molecular pathways and therapeutic opportunities.

    PubMed

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

    2014-11-01

    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

  11. Primary intrahepatic malignant epithelioid mesothelioma

    PubMed Central

    Perysinakis, Iraklis; Nixon, Alexander M.; Spyridakis, Ioannis; Kakiopoulos, George; Zorzos, Charalampos; Margaris, Ilias

    2014-01-01

    INTRODUCTION Primary malignant hepatic mesotheliomas are extremely rare. We report the case of a patient with primary intrahepatic malignant mesothelioma who was treated in our department. PRESENTATION OF CASE A 66-year old male patient was admitted to our department for the evaluation of anemia. An abdominal computed tomography scan revealed a large space occupying lesion in the right liver lobe. DISCUSSION The tumor was subsequently resected and a diagnosis of primary intrahepatic malignant mesothelioma was made after pathologic examination. The patient did not receive adjuvant therapy and is currently alive and free of disease, 36 months after the resection. CONCLUSION To our knowledge this is the eighth adult case of primary intrahepatic malignant mesothelioma reported in the literature. These tumors are rarely diagnosed preoperatively. Absence of previous asbestos exposure does not exclude malignant mesothelioma from the differential diagnosis. Proper surgical treatment may offer prolonged survival to the patient, without adjuvant therapy. PMID:25460485

  12. Transjugular intrahepatic portosystemic shunt.

    PubMed

    Ochs, Andreas

    2005-01-01

    The transjugular intrahepatic portosystemic shunt (TIPS) is an interventional treatment resulting in decompression of the portal system by creation of a side-to-side portosystemic anastomosis. Since its introduction 16 years ago, more than 1,000 publications have appeared demonstrating broad acceptance and increasing clinical use. This review summarizes our present knowledge about technical aspects and complications, follow-up of patients and indications. A technical success rate near 100% and a low occurrence of complications clearly depend on the skills of the operator. The follow-up of the TIPS patient has to assess shunt patency, liver function, hepatic encephalopathy and the possible development of hepatocellular carcinoma. Shunt patency can best be monitored by duplex sonography and can avoid routine radiological revision. Short-term patency may be improved by anticoagulation, while such a treatment does not influence long-term patency. Stent grafts covered with expanded polytetrafluoroethylene show promising long-term patency comparable with that of surgical shunts. With respect to the indications of TIPS, much is known about treatment of variceal bleeding and refractory ascites. The thirteen randomized studies that are available to date show that survival is comparable in patients receiving TIPS or endoscopic treatment for acute or recurrent variceal bleeding. Another group comprises patients with refractory ascites and related complications, such as hepatorenal syndrome and hepatic hydrothorax. It has been demonstrated that TIPS improves these complications. Five randomized studies comparing TIPS with paracentesis and one study comparing TIPS with the peritoneo-venous shunt showed good response of ascites but controversial results on survival. In addition, TIPS has been successfully applied to patients with Budd-Chiari syndrome, portal vein thrombosis, before liver transplantation, and for the treatment of ectopic variceal bleeding. PMID:15920326

  13. Synchronous carcinoma of the gallbladder in a patient with intrahepatic bile duct carcinoma.

    PubMed

    Taniai, N; Onda, M; Tajiri, T; Yoshida, H; Naitou, Z

    2000-01-01

    An 83-year-old woman, diagnosed as having cholelithiasis, was admitted to the Department of Surgery, Nippon Medical School, with right hypochondrial pain. Ultrasonography and computed tomography revealed a mass in the gallbladder fundus and a hypovascular tumor in the anterior segment of the liver. Magnetic resonance imaging showed stenosis of the intrahepatic bile duct and dilatation of its proximal portion. She was diagnosed as having intrahepatic bile duct carcinoma combined with gallbladder carcinoma. At laparotomy, there was evidence of multiple peritoneal metastases and intraoperative histological examination of the gallbladder tumor revealed adenocarcinoma. Accordingly, only cholecystectomy and needle biopsy of the liver tumor was performed. Histological examination of the gallbladder revealed papillary adenocarcinoma invading the muscularis propria with medullary growth or intermediate stroma. There was no microvessel invasion, no perineural invasion and no lymph node involvement. On the other hand, the liver tumor was a cholangiocarcinoma with a well-differentiated tubular pattern. Therefore, this was a rare case of synchronous carcinoma of the gallbladder associated with intrahepatic bile duct carcinoma. PMID:10690592

  14. 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.

  15. Progressive familial intrahepatic cholestasis

    PubMed Central

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

    2009-01-01

    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

  16. The Role of Biliary Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 6 (CEACAM6) as a Biomarker in Cholangiocarcinoma

    PubMed Central

    Rose, J. Bart; Correa-Gallego, Camilo; Li, Yu; Nelson, James; Alseidi, Adnan; Helton, W. Scott; Allen, Peter J.; D’Angelica, Michael I.; DeMatteo, Ronald P.; Fong, Yuman; Kingham, T. Peter; Kowdley, Kris V.; Jarnagin, William R.; Rocha, Flavio G.

    2016-01-01

    Objective The aim of the present study is to determine if CEACAM6 can be detected in the bile of patients with biliary cancer and can serve as a diagnostic biomarker for cholangiocarcinoma. Summary Background Data Distinguishing bile duct carcinoma from other diagnoses is often difficult using endoscopic or percutaneous techniques. The cell surface protein CEACAM6 is over-expressed in many gastrointestinal cancers and may be selectively elevated in biliary adenocarcinoma. Methods Bile from patients with benign biliary disease and cholangiocarcinoma (hilar, intrahepatic and distal) was collected at the time of index operation. The concentration of CEACAM6 was quantified by sandwich enzyme-linked immunosorbent assay (ELISA) and correlated to pathologic diagnosis. Diagnostic capability of CEACAM6 was evaluated by Wilcoxon rank-sum, linear regression, multiple regression, and receiver operating characteristic (ROC) curve analysis. Results Bile from 83 patients was analyzed: 42 with benign disease and 41 with cholangiocarcinoma. Patients in the benign cohort were younger, predominantly female, and had lower median biliary CEACAM6 levels than patients in the malignant cohort (7.5 ng/ml vs. 40 ng/ml; p = <.001). ROC curve analysis determined CEACAM6 to be a positive predictor cholangiocarcinoma with a CEACAM6 level >14 ng/ml associated with 87.5% sensitivity, 69.1% specificity, and a likelihood ratio of 2.8 (AUC 0.74). Multiple regression analysis suggested elevated alkaline phosphatase and the presence of biliary endoprostheses may influence CEACAM6 levels. Conclusion Biliary CEACAM6 can identify patients with extrahepatic cholangiocarcinoma with a high degree of sensitivity and should be investigated further as a potential screening tool. PMID:26974538

  17. Outcome of curative resection for perihilar cholangiocarcinoma in Northeast Thailand

    PubMed Central

    Titapun, Attapol; Pugkhem, Ake; Luvira, Vor; Srisuk, Tharatip; Somintara, Ongart; Saeseow, O-tur; Sripanuskul, Anan; Nimboriboonporn, Anongporn; Thinkhamrop, Bandit; Khuntikeo, Narong

    2015-01-01

    AIM: To examine survival outcomes of perihilar cholangiocarcinoma (PCCA) resection including mortality, morbidity and prognostic factors. METHODS: Multivariate analyses were carried out based on the survival data of all patients with histologically confirmed PCCA who underwent curative resection at Srinagarind Hospital from January 2006 to December 2011. RESULTS: There were 29 (19%) cases of intrahepatic CCA that involved hilar and 124 (81%) with hilar bile-duct cancer. R0 resection was carried out on 66 (43.1%) patients of whom 50 (32.7%) also had lymph node metastasis. The other patients underwent R1 resection. The overall 5-year survival rate was 20.6% (95%CI: 13.8-28.4) and median survival time was 19.9 mo. Postoperative mortality was 2%, and 30% of patients had complications. Patients without lymph node metastasis were 60% less likely to die than those with metastasis. Achieving R0 led to a 58% reduction in the chance of mortality as compared to R1. CONCLUSION: To achieve a better survival outcome, focus should center on performing radical surgery and detection of patients with early stage cancer. PMID:26691730

  18. Penile metastasis from primary cholangiocarcinoma: the first case report

    PubMed Central

    2013-01-01

    Background Metastatic penile carcinoma derived from cholangiocarcinoma (CCA) has not been previously reported in the literature. Common metastatic sites for CCA include the regional lymph nodes and adjacent organs. CCAs are not highly vascularised tumours, making hematogenous metastases uncommon. Hematogenous CCA metastases commonly occur at distant organs such as the lungs, adrenal glands, and bones. Median survival for patients with metastatic disease is generally less than 1 year. Case presentation A 74-year-old Caucasian man consulted us after having undergone penile ultrasonography for pain and increased thickness at the base of the penis after self-examination. The patient presented with a history of hepatitis C-related cirrhosis and intrahepatic CCA, diagnosed 3 years previously. A biopsy of the corpora cavernosa on both sides revealed a carcinoma harbouring the same histological and immunophenotypical features as the primary hepatic lesion. Conclusions To date, there is no case of penile or urogenital system metastasis from CCA described in the literature. Therefore, this article represents the first case report of penile metastasis from CCA. PMID:24124668

  19. [Effectiveness of systemic chemotherapy of GEM+CBDCA+5-FU/LV and hepatic arterial infusion of CDDP in a case of advanced, combined hepatocellular-cholangiocarcinoma with multiple lung metastases].

    PubMed

    Tani, Satoshi; Murata, Shigemasa; Tamura, Miho; Fukunaga, Kaoru; Morita, Munetaka; Hirata, Yuzo; Iida, Hiroya; Kakuno, Ayako; Nishigami, Takashi; Yamanaka, Naoki

    2011-11-01

    This patient is a male in his 30's. He was diagnosed as hepatitis B virus-related huge primary liver cancer, 10cm in diameter, located in segment 4, accompanied with left portal thrombus and multiple lung metastases. Ten months after repeating systemic chemotherapy using gemcitabine (GEM)+carboplatin (CBDCA)+5-FU/leucovorin (LV) and hepatic arterial infusion chemotherapy with cisplatin (CDDP) 4 times, extended left lobectomy with caudate lobe could be successfully performed because of marked reducion of the huge tumor. The pathology revealed almost entirely necrotic changes of the main tumor, and the remaining, viable tumor nests showed combined hepatocellular and cholangiocarcinoma. Systemic chemotherapy was repeatedly given afterwards, which kept the pulmonary metastases stable without growth. The present case suggests that systemic chemotherapy using GEM+CBDCA+5-FU/LV may be useful in the multimodal treatment for the combined hepatocellular and cholangiocarcinoma with distant metastases. PMID:22056711

  20. [The rational diagnostic of cholangiocarcinoma].

    PubMed

    Rydlo, Martin; Dvořáčková, Jana; Kupka, Tomáš; Klvaňa, Pavel; Havelka, Jaroslav; Uvírová, Magdalena; Geryk, Edvard; Czerný, Daniel; Jonszta, Tomáš; Bojková, Martina; Hrabovský, Vladimír; Jelínková, Veronika; Martínek, Arnošt; Dítě, Petr

    2016-02-01

    Cholangiocarcinoma (CC) is a rare malignant tumour arising from cholangiocytes, and its prognosis is usually unfavourable, mostly as a result of late diagnosis of the tumour. The current incidence of cholangiocarcinoma in the Czech Republic is 1.4/100,000 inhabitants per year; in less than 30 % of patients with CC, one of the known risk factors can be identified, most frequently, primary sclerosing cholangitis. Only patients with early diagnosed and surgically amenable cholangiocarcinoma are likely to have a longer survival time; in their case, survival for more than five years has been achieved in 20 % to 40 %. From the perspective of the need for early diagnosis of CC, a significant part is played by imaging and histopathologic evaluation; the early diagnostic significance of oncomarkers is limited. The rational early diagnosis of CC consists in effective use of differentiated advantages of different imaging modalities - MRI with DSA appears to be the optimal method, endosonography is a sensitive method for the identification of malignancy in the hepatic hilum or distal common bile duct, MRCP (magnetic resonance cholangiopancreatography) is used to display pathological changes in the biliary tree, ERCP (endoscopic retrograde cholangiopancreatography) allows material removal for histopathological examination. Other new approaches are also beneficial, such as IDUS - intraductal ultrasonography of biliary tract or SPY-GLASS, enabling examination of the bile ducts by direct view with the possibility of taking targeted biopsies. Sensitivity and specificity of histology and cytology can be increased by using the molecular cytogenetic FISH method, i.e. fluorescence in situ by hybridization, with a specificity of 97 %. PMID:27172439

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

    PubMed Central

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

    2015-01-01

    Introduction 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. Presentation of case 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. Discussion 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. Conclusion 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. PMID:26413921

  2. Diagnosis and treatment update: cholangiocarcinoma.

    PubMed

    Wijaya, Indra; Abdullah, Murdani

    2011-07-01

    Cholangiocarcinoma is a rare and very aggressive neoplasm that arises from the biliary epithelium, constitutes approximately 2% of all reported cancer, and accounts for about 3% of all gastrointestinal malignancies. Up to date, there are many modalities to diagnosis and treat with a range of sensitivity and specificity, and also the advantage and disadvantage of its modality. As a physician, we should be able to assess and choose promptly which modality is best for our patient, even for paliative care. Treatment modalities are surgery and non-surgery like adjuvant chemotherapy, radiation, chemoradiation, radiotherapy, TACE, 5-FU chemoinfusion, intralesion PEI, photodynamic therapy, liver transplantation, and paliative therapy. The choice of treatment varies individually. Radical surgery remains the optimal therapy and offering a potential for cure. Overall prognosis in these patients is poor and survival is limited to a few months. PMID:21979289

  3. Anti-Tumor Effects of Second Generation β-Hydroxylase Inhibitors on Cholangiocarcinoma Development and Progression

    PubMed Central

    Chung, Waihong; de la Monte, Suzanne; Thomas, John-Michael; Olsen, Mark; Carlson, Rolf; Yu, Tunan; Dong, Xiaoqun; Wands, Jack

    2016-01-01

    Cholangiocarcinoma (CCA) has a poor prognosis due to widespread intrahepatic spread. Aspartate β-hydroxylase (ASPH) is a transmembrane protein and catalyzes the hydroxylation of aspartyl and asparaginyl residues in calcium binding epidermal growth factor (cbEGF)-like domains of various proteins, including Notch receptors and ligands. ASPH is highly overexpressed (>95%) in human CCA tumors. We explored the molecular mechanisms by which ASPH mediated the CCA malignant phenotype and evaluated the potential of ASPH as a therapeutic target for CCA. The importance of expression and enzymatic activity of ASPH for CCA growth and progression was examined using shRNA “knockdown” and a mutant construct that reduced its catalytic activity. Second generation small molecule inhibitors (SMIs) of β-hydroxylase activity were developed and used to target ASPH in vitro and in vivo. Subcutaneous and intrahepatic xenograft rodent models were employed to determine anti-tumor effects on CCA growth and development. It was found that the enzymatic activity of ASPH was critical for mediating CCA progression, as well as inhibiting apoptosis. Mechanistically, ASPH overexpression promoted Notch activation and modulated CCA progression through a Notch1-dependent cyclin D1 pathway. Targeting ASPH with shRNAs or a SMI significantly suppressed CCA growth in vivo. PMID:26954680

  4. Combined portal vein resection for hilar cholangiocarcinoma

    PubMed Central

    Bai, Tao; Chen, Jie; Xie, Zhi-Bo; Ma, Liang; Liu, Jun-Jie; Zhu, Shao-Liang; Wu, Fei-Xiang; Li, Le-Qun

    2015-01-01

    Background: Surgery is the only curative therapy for patients with hilar cholangiocarcinoma (HCCA). Combined portal vein resection (PVR) could achieve negative resection margins in HCCA patients with portal vein invasion. This systematic review aimed to analysis the efficiency of combined PVR for HCCA. Methods: MEDLINE, EMBASE, the Cochrane Library, the Chinese National Knowledge Infrastructure database, and clinical trial registries were searched through April 2015. Risk ratios (RRs), and 95% confidence intervals (CIs) were calculated. Results: The analysis included 21 retrospective studies, altogether involving 2403 patients (patients with PVR, n=637; patients without PVR, n=1766). Patients with PVR were likely to have more advanced HCCA (lymphatic invasion: RR=1.14, 95% CI 1.02 to 1.28; perineural invasion: RR=1.31, 95% CI 1.05 to 1.63) and suffered less curative resections (RR=0.89, 95% CI 0.75 to 0.99). Postoperative morbidity was similar between patients with or without PVR (RR=1.06, 95% CI 0.94 to 1.02). Patients with PVR suffered higher mortality rate (RR=1.52, 95% CI 1.06 to 2.18), and worse 5-year survival rate (RR=0.67, 95% CI 0.49 to 0.91). Conclusion: Combined PVR for HCCA patients would not increase postoperative morbidity rate. However, ascribed to PVR group concluded more advanced HCCA patients; patients with PVR had increased postoperative mortality rate and worse survival rate. The results still need further high quality trails for validation. PMID:26885035

  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. Cholangiocarcinoma

    MedlinePlus

    ... ducts. Both men and women are affected. Most patients are older than 65. Risks of this condition include: Bile duct (choledochal) cysts Chronic biliary and liver inflammation History of infection with the parasitic worm, liver flukes Primary sclerosing cholangitis Ulcerative colitis ...

  7. 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

  8. Molecular mechanism of cholangiocarcinoma carcinogenesis.

    PubMed

    Maemura, Kosei; Natsugoe, Shoji; Takao, Sonshin

    2014-10-01

    Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tract with a poor prognosis, which often arises from conditions causing long-term inflammation, injury, and reparative biliary epithelial cell proliferation. Several conditions are known to be major risk factors for cancer in the biliary tract or gallbladder, including primary sclerosing cholangitis, liver fluke infection, pancreaticobiliary maljunction, and chemical exposure in proof-printing workers. Abnormalities in various signaling cascades, molecules, and genetic mutations are involved in the pathogenesis of CCA. CCA is characterized by a series of highly recurrent mutations in genes, including KRAS, BRF, TP53, Smad, and p16(INK4a) . Cytokines that are affected by inflammatory environmental conditions, such as interleukin-6 (IL-6), transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and platelet-derived growth factor (PDGF), play an important role in cancer pathogenesis. Prominent signaling pathways important in carcinogenesis include TGF-β/Smad, IL-6/STAT-3, PI3K/AKT, Wnt, RAF/MEK/MAPK, and Notch. Additionally, some microRNAs regulate targets in critical pathways of CCA development and progression. This review article provides the understanding of the genetic and epigenetic mechanism(s) of carcinogenesis in CCA, which leads to the development of new therapeutic targets for the prevention and treatment of this devastating cancer. PMID:24895231

  9. 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

  10. [Prognosis factors of cholangiocarcinoma: contribution of recent molecular biology tools].

    PubMed

    Malouf, G; Dreyer, C; Guedj, N; Paradis, V; Degos, F; Belghiti, J; Le Tourneau, C; Faivre, S; Raymond, E

    2009-04-01

    Cholangiocarcinoma represents the second most common primary hepatobiliary cancer. Although few patients are candidates for surgery, surgical resection represents the only potential curative option. The prognosis for patients remains poor, despite advances in the understanding of mechanisms involved in carcinogenesis. This review aims to assess clinicopathological factors and biological markers for the ability to predict prognosis. Clinicopathologic factors most often cited are tumor size, lymph node involvement, resecability and surgical margins involvement. Molecular biomarkers have been examined and a number of these, including mdm2, p27, matrix metalloproteinases and vitamin D receptor appear to have prognostic utility. The advent of 'omic'-based profiling offers the potential to assess many different biomarkers at the same time. This 'protein/gene signature' could open the way for developing valid and reproducible predictors of survival based on protein or gene profiles. PMID:19357015

  11. Increased local dopamine secretion has growth promoting effects in cholangiocarcinoma

    PubMed Central

    Coufal, Monique; Invernizzi, Pietro; Gaudio, Eugenio; Bernuzzi, Francesca; Frampton, Gabriel A.; Onori, Paolo; Franchitto, Antonio; Carpino, Guido; Ramirez, Jonathan C.; Alvaro, Domenico; Marzioni, Marco; Battisti, Guido; Benedetti, Antonio; DeMorrow, Sharon

    2009-01-01

    Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. Symptoms are usually evident after blockage of the bile duct by the tumor, and at this late stage, they are relatively resistant to chemotherapy and radiation therapy. Therefore, it is imperative that alternative treatment options are explored. We have previously shown that serotonin metabolism is dysregulated in cholangiocarcinoma leading to an increased secretion of serotonin, which has growth-promoting effects. Because serotonin and dopamine share the degradation machinery, we evaluated the secretion of dopamine from cholangiocarcinoma and its effects on cell proliferation. Using 4 cholangiocarcinoma cell lines and human biopsy samples, we demonstrated that there was an increase in mRNA and protein expression of the dopamine synthesis enzymes tyrosine hydroxylase and dopa decarboxylase in cholangiocarcinoma. There was increased dopamine secretion from cholangiocarcinoma cell lines compared to H69 and HIBEC cholangiocytes and increased dopamine immunoreactivity in human biopsy samples. Furthermore, administration of dopamine to all cholangiocarcinoma cell lines studied increased proliferation by up to 30% which could be blocked by the pretreatment of the D2 and D4 dopamine receptor antagonists, whereas blocking dopamine production by α-methyldopa administration suppressed growth by up to 25%. Administration of α-methyldopa to nude mice also suppressed cholangiocarcinoma tumor growth. The data presented here represent the first evidence that dopamine metabolism is dysregulated in cholangiocarcinoma and that modulation of dopamine synthesis may represent an alternative target for the development of therapeutic strategies. PMID:19795457

  12. 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.

  13. Characterizing the Activation of the Wnt Signaling Pathway in Hilar Cholangiocarcinoma Using a Tissue Microarray Approach

    PubMed Central

    Chen, W.; Huang, L.; Liang, J.; Cai, J.; Lei, Y.; Lai, J.; Liang, L.; Zhang, K.

    2016-01-01

    Hilar cholangiocarcinoma (HCCA) is an invasive hepatic malignancy that is difficult to biopsy; therefore, novel markers of HCCA prognosis are needed. Here, the level of canonical Wnt activation in patients with HCCA, intrahepatic cholangiocarcinoma (IHCC), and congenital choledochal cysts (CCC) was compared to understand the role of Wnt signaling in HCCA. Pathology specimens from HCCA (n=129), IHCC (n=31), and CCC (n=45) patients were used to construct tissue microarrays. Wnt2, Wnt3, β-catenin, TCF4, c-Myc, and cyclin D1 were detected by immunohistochemistry. Parallel correlation analysis was used to analyze differences in protein levels between the HCCA, IHCC, and CCC groups. Univariate and multivariate analyses were used to determine independent predictors of successful resection and prognosis in the HCCA group. The protein levels of Wnt2, β-catenin, TCF4, c-Myc, and cyclin D1 were significantly higher in HCCA compared to IHHC or CCC. Wnt signaling activation (Wnt2+, Wnt3+, nuclear β-catenin+, nuclear TCF4+) was significantly greater in HCCA tissues than CCC tissues. Univariable analyses indicated that expression of cyclin D1 as well as Wnt signaling activation, and partial Wnt activation (Wnt2+ or Wnt3+ and nuclear β-catenin+ or nuclear TCF4+) predicted successful resection, but only cyclin D1 expression remained significant in multivariable analyses. Only partial Wnt activation was an independent predictor of survival time. Proteins in the canonical Wnt signaling pathway were present at higher levels in HCCA and correlated with tumor resecility and patient prognosis. These results suggest that Wnt pathway analysis may be a useful marker for clinical outcome in HCCA. PMID:26972709

  14. Late Intrahepatic Hematoma Complicating Transjugular Intrahepatic Portosystemic Shunt for Budd-Chiari Syndrome

    SciTech Connect

    Terreni, Natalia; Vangeli, Marcello; Raimondo, Maria Luisa; Tibballs, Jonathan M.; Patch, David; Burroughs, Andrew K.

    2007-09-15

    Late intrahepatic hematoma is a rare complication of the transjugular intrahepatic portosystemic shunt (TIPS) procedure. We describe a patient with Budd-Chiari syndrome (BCS), who presented with a large inrahepatic hematoma 13 days after TIPS. Review of the literature reveals only two previous cases, both occurring in patients with BCS and presenting after a similar time interval. This potentially serious complication appears to be specific for TIPS in BCS.

  15. Combined hepatocellular cholangiocarcinoma: Controversies to be addressed

    PubMed Central

    Wang, An-Qiang; Zheng, Yong-Chang; Du, Juan; Zhu, Cheng-Pei; Huang, Han-Chun; Wang, Shan-Shan; Wu, Liang-Cai; Wan, Xue-Shuai; Zhang, Hao-Hai; Miao, Ruo-Yu; Sang, Xin-Ting; Zhao, Hai-Tao

    2016-01-01

    Combined hepatocellular cholangiocarcinoma (CHC) accounts for 0.4%-14.2% of primary liver cancer cases and possesses pathological features of both hepatocellular carcinoma and cholangiocarcinoma. Since this disease was first described and classified in 1949, the classification of CHC has continuously evolved. The latest definition and classification of CHC by the World Health Organization is based on the speculation that CHC arises from hepatic progenitor cells. However, there is no evidence demonstrating the common origin of different components of CHC. Furthermore, the definition of CHC subtypes is still ambiguous and the identification of CHC subtype when a single tumor contains many components has remained unresolved. In addition, there is no summary on the newly recognized histopathology features or the contribution of CHC components to prognosis and outcome of this disease. Here we provide a review of the current literature to address these questions. PMID:27182157

  16. Carcinoma with shared pathologic characteristics of both hepatocellular carcinoma and cholangiocarcinoma

    PubMed Central

    Hiraoka, Atsushi; Kurose, Kiyotaka; Kumagi, Teru; Hirooka, Masashi; Yokota, Tomoyuki; Fujiwara, Toshiteru; Utsunomiya, Sachiko; Hirata, Mami; Ohtani, Hiromi; Michitaka, Kojiro; Horiike, Norio; Kobayashi, Nobuaki; Onji, Morikazu

    2005-01-01

    Background: α-Fetoprotein (AFP) is a useful marker of hepatocellular carcinoma (HCC), and protein induced by vitamin K absence or antagonist II (PIVKA-II) and fucosylated AFP (AFP-L3) are specific tumor markers. Objective: The aim of this article was to report a case of intrahepatic cholangiocarcinoma (CC) with high levels of expression of AFP, AFP-L3, and PIVKA-II. Methods: A 70-year-old man weighing 66 kg with a diagnosis of intrahepatic CC presented with a liver tumor 4.0 cm in diameter and elevated concentrations of carbohydrate antigen 19-9 (575 U/mL), PIVKA-II (379 mAU/mL), and AFP (497 ng/mL; AFP-L3, 88.1%). On extended medial hepatic segmentectomy, microscopy showed that the tumor was a CC without HCC. The patient subsequently underwent immunohistochemical assessments using cytokeratin-19, epithelial membrane antigen (EMA), hepatocyte paraffin-1 (HP-1), PIVKA-II, and AFP. Results: In all specimens, desmoplasia was observed. However, results of immunohistochemistry showed positive results for cytokeratin-19 and EMA; HP-1 results were negative. Results of PIVKA-II and AFP testing in the tumor were positive. Conclusions: The case presented here showed characteristics of CC and HCC, whereas the histologic expression of the tumor suggested CC. Based on the literature search, this is the first known report of a case of a CC expressing AFP and PIVKA-II confirmed on immunohistochemical staining. This case is interesting with regard to the ability of the progenitor cells to differentiate HCC and CC. PMID:24678077

  17. 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

  18. Endogenous cholecystokinin regulates growth of human cholangiocarcinoma.

    PubMed Central

    Evers, B M; Gomez, G; Townsend, C M; Rajaraman, S; Thompson, J C

    1989-01-01

    Exogenous administration of cholecystokinin (CCK) or caerulein inhibits growth of SLU-132, a human cholangiocarcinoma that we have shown to possess receptors for CCK. Chronic administration of cholestyramine, a resin that binds bile salts, increases release of CCK and growth of the pancreas in guinea pigs. Feeding the bile salt, taurocholate, inhibits meal-stimulated release of CCK. The purpose of this study was to determine whether endogenous CCK affects growth of the human cholangiocarcinoma, SLU-132. We implanted SLU-132 subcutaneously into athymic nude mice. The bile salt pool was depleted by feeding 4% cholestyramine for 40 days, either alone or enriched with 0.5% taurocholate for 32 days. When the mice were killed, tumors and pancreas were removed. Cholestyramine significantly inhibited the growth of SLU-132 and stimulated growth of the normal pancreas. Feeding of taurocholate acted to stimulate tumor growth. These results demonstrate that endogenous levels of CCK regulate growth of this human cholangiocarcinoma. Our findings suggest that manipulation of levels of endogenous gut hormones may, in the future, play a role in management of patients with certain gastrointestinal cancers. Images Fig. 1. PMID:2476084

  19. Neuropeptide Y inhibits cholangiocarcinoma cell growth and invasion

    PubMed Central

    DeMorrow, Sharon; Onori, Paolo; Venter, Julie; Invernizzi, Pietro; Frampton, Gabriel; White, Mellanie; Franchitto, Antonio; Kopriva, Shelley; Bernuzzi, Francesca; Francis, Heather; Coufal, Monique; Glaser, Shannon; Fava, Giammarco; Meng, Fanyin; Alvaro, Domenico; Carpino, Guido; Gaudio, Eugenio

    2011-01-01

    No information exists on the role of neuropeptide Y (NPY) in cholangiocarcinoma growth. Therefore, we evaluated the expression and secretion of NPY and its subsequent effects on cholangiocarcinoma growth and invasion. Cholangiocarcinoma cell lines and nonmalignant cholangiocytes were used to assess NPY mRNA expression and protein secretion. NPY expression was assessed by immunohistochemistry in human liver biopsies. Cell proliferation and migration were evaluated in vitro by MTS assays and matrigel invasion chambers, respectively, after treatment with NPY or a neutralizing NPY antibody. The effect of NPY or NPY depletion on tumor growth was assessed in vivo after treatment with NPY or the neutralizing NPY antibody in a xenograft model of cholangiocarcinoma. NPY secretion was upregulated in cholangiocarcinoma compared with normal cholangiocytes. Administration of exogenous NPY decreased proliferation and cell invasion in all cholangiocarcinoma cell lines studied and reduced tumor cell growth in vivo. In vitro, the effects of NPY on proliferation were blocked by specific inhibitors for NPY receptor Y2, but not Y1 or Y5, and were associated with an increase in intracellular d-myo-inositol 1,4,5-trisphosphate and PKCα activation. Blocking of NPY activity using a neutralizing antibody promoted cholangiocarcinoma growth in vitro and in vivo and increased the invasiveness of cholangiocarcinoma in vitro. Increased NPY immunoreactivity in human tumor tissue occurred predominantly in the center of the tumor, with less expression toward the invasion front of the tumor. We demonstrated that NPY expression is upregulated in cholangiocarcinoma, which exerts local control on tumor cell proliferation and invasion. Modulation of NPY secretion may be important for the management of cholangiocarcinoma. PMID:21270292

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

    PubMed Central

    Vabi, Benjamin W.; Carter, Jeffrey; Rong, Rong; Wang, Minhua; Corasanti, James G.

    2016-01-01

    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. PMID:27034804

  1. 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. PMID:27034804

  2. Defensive mechanism in cholangiocarcinoma cells against oxidative stress induced by chlorin e6-based photodynamic therapy

    PubMed Central

    Lee, Hye Myeong; Chung, Chung-Wook; Kim, Cy Hyun; Kim, Do Hyung; Kwak, Tae Won; Jeong, Young-Il; Kang, Dae Hwan

    2014-01-01

    In this study, the effect of chlorin e6-based photodynamic therapy (Ce6-PDT) was investigated in human intrahepatic (HuCC-T1) and extrahepatic (SNU1196) cholangiocarcinoma (CCA) cells. The amount of intracellular Ce6 increased with increasing Ce6 concentration administered, or with incubation time, in both cell lines. The ability to take up Ce6 and generate reactive oxygen species after irradiation at 1.0 J/cm2 did not significantly differ between the two CCA cell types. However, after irradiation, marked differences were observed for photodamage and apoptotic/necrotic signals. HuCC-T1 cells are more sensitive to Ce6-PDT than SNU1196 cells. Total glutathione (GSH) levels, glutathione peroxidase and glutathione reductase activities in SNU1196 cells were significantly higher than in HuCC-T1 cells. With inhibition of enzyme activity or addition of GSH, the phototoxic effect could be controlled in CCA cells. The intracellular level of GSH is the most important determining factor in the curative action of Ce6-PDT against tumor cells. PMID:25258513

  3. Anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma

    PubMed Central

    Kwak, Tae Won; Shin, Hee Jae; Jeong, Young-Il; Han, Myoung-Eun; Oh, Sae-Ock; Kim, Hyun-Jung; Kim, Do Hyung; Kang, Dae Hwan

    2015-01-01

    Background The aim of this study is to investigate the anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma. Methods The anticancer activity of streptochlorin was evaluated in vitro in various cholangiocarcinoma cell lines for apoptosis, proliferation, invasiveness, and expression of various protein levels. A liver metastasis model was prepared by splenic injection of HuCC-T1 cholangiocarcinoma cells using a BALB/c nude mouse model to study the systemic antimetastatic efficacy of streptochlorin 5 mg/kg at 8 weeks. The antitumor efficacy of subcutaneously injected streptochlorin was also assessed using a solid tumor xenograft model of SNU478 cells for 22 days in the BALB/c nude mouse. Results Streptochlorin inhibited growth and secretion of vascular endothelial growth factor by cholangiocarcinoma cells in a dose-dependent manner and induced apoptosis in vitro. In addition, streptochlorin effectively inhibited invasion and migration of cholangiocarcinoma cells. Secretion of vascular endothelial growth factor and activity of matrix metalloproteinase-9 in cholangiocarcinoma cells were also suppressed by treatment with streptochlorin. Streptochlorin effectively regulated metastasis of HuCC-T1 cells in a mouse model of liver metastasis. In a tumor xenograft study using SNU478 cells, streptochlorin significantly inhibited tumor growth without changes in body weight when compared with the control. Conclusion These results reveal that streptochlorin is a promising chemotherapeutic agent to the treatment of cholangiocarcinoma. PMID:25931814

  4. Non-canonical Hedgehog signaling contributes to chemotaxis in cholangiocarcinoma

    PubMed Central

    Razumilava, Nataliya; Gradilone, Sergio A.; Smoot, Rory L.; Mertens, Joachim C.; Bronk, Steven F.; Sirica, Alphonse E.; Gores, Gregory J.

    2014-01-01

    Background & Aims: The Hedgehog signaling pathway contributes to cholangiocarcinoma biology. However, canonical Hedgehog signaling requires cilia, and cholangiocarcinoma cells often do not express cilia. To resolve this paradox, we examined non-canonical (G-protein coupled, pertussis toxin sensitive) Hedgehog signaling in cholangiocarcinoma cells. Methods: Human [non-malignant (H69), malignant (HuCC-T1 and Mz-ChA-1)] and rat [non-malignant (BDE1 and NRC), and malignant (BDEneu)] cell lines were employed for this study. A BDEΔLoop2 cell line with the dominant-negative receptor Patched-1 was generated with the Sleeping Beauty transposon transfection system. Results: Cilia expression was readily identified in non-malignant, but not in malignant cholangiocarcinoma cell lines. Although the canonical Hh signaling pathway was markedly attenuated in cholangiocarcinoma cells, they were chemotactic to purmorphamine, a small-molecule direct Smoothened agonist. Purmorphamine also induced remodeling of the actin cytoskeleton with formation of filopodia and lamellipodia-like protrusions. All these biological features of cell migration were pertussis toxin sensitive, a feature of G-protein coupled (Gis) receptors. To further test the role of Hedgehog signaling in vivo, we employed a syngeneic orthotopic rat model of cholangiocarcinoma. In vivo, genetic inhibition of the Hedgehog signaling pathway employing BDEΔLoop2 cells or pharmacological inhibition with a small-molecule antagonist of Smoothened, vismodegib, was tumor and metastasis suppressive. Conclusions: Cholangiocarcinoma cells exhibit non-canonical Hedgehog signaling with chemotaxis despite impaired cilia expression. This non-canonical Hedgehog signaling pathway appears to contribute to cholangiocarcinoma progression, thereby, supporting a role for Hedgehog pathway inhibition in human cholangiocarcinoma. PMID:24239776

  5. 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.

  6. [Appropriate Biliary Drainage Methods for Unresectable Cholangiocarcinomas].

    PubMed

    Oishi, Tatsurou; Kanemoto, Yoshiaki; Yoshioka, Yuuta; Sawada, Ryuuichirou; Sekine, Sachi; Miyanaga, Hiroto; Sakahira, Hideki; Takahashi, Hironori; Miyamoto, Katsufumi; Koyama, Takashi

    2015-11-01

    We investigated the efficacy of different biliary drainage methods for the treatment of unresectable cholangiocarcinomas. We performed a retrospective study of 28 patients with unresectable cholangiocarcinomas who underwent biliary drainage at our hospital between January 2008 and June 2014 to compare the incidence of post-drainage stent dysfunction (SD) and reintervention (RI) for SD according to primary drainage method, lesion site, and complication status (the presence or absence of cholangitis). The duration of stent patency was compared between the different stent types. No significant differences in the incidence of SD and RI were found according to primary drainage methods, lesion site, or the presence or absence of cholangitis. The mean durations of stent patency for plastic and metal stents were 2.7 months and 7.4 months, respectively, suggesting that metal stents should be selected when the estimated prognosis is ≥2 months. Furthermore, metal stent placement, rather than the additional placement of plastic stents, should be considered a feasible option in cases of SD. PMID:26805093

  7. 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

  8. Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies.

    PubMed

    Brandi, Giovanni; Farioli, Andrea; Astolfi, Annalisa; Biasco, Guido; Tavolari, Simona

    2015-06-20

    Cholangiocarcinoma (CC) encompasses a group of related but distinct malignancies whose lack of a stereotyped genetic signature makes challenging the identification of genomic landscape and the development of effective targeted therapies. Accumulated evidences strongly suggest that the remarkable genetic heterogeneity of CC may be the result of a complex interplay among different causative factors, some shared by most human cancers while others typical of this malignancy. Currently, considerable efforts are ongoing worldwide for the genetic characterization of CC, also using advanced technologies such as next-generation sequencing (NGS). Undoubtedly this technology could offer an unique opportunity to broaden our understanding on CC molecular pathogenesis. Despite this great potential, however, the high complexity in terms of factors potentially contributing to genetic variability in CC calls for a more cautionary application of NGS to this malignancy, in order to avoid possible biases and criticisms in the identification of candidate actionable targets. This approach is further justified by the urgent need to develop effective targeted therapies in this disease. A multidisciplinary approach integrating genomic, functional and clinical studies is therefore mandatory to translate the results obtained by NGS into effective targeted therapies for this orphan disease. PMID:26142706

  9. Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies

    PubMed Central

    Brandi, Giovanni; Farioli, Andrea; Astolfi, Annalisa; Biasco, Guido; Tavolari, Simona

    2015-01-01

    Cholangiocarcinoma (CC) encompasses a group of related but distinct malignancies whose lack of a stereotyped genetic signature makes challenging the identification of genomic landscape and the development of effective targeted therapies. Accumulated evidences strongly suggest that the remarkable genetic heterogeneity of CC may be the result of a complex interplay among different causative factors, some shared by most human cancers while others typical of this malignancy. Currently, considerable efforts are ongoing worldwide for the genetic characterization of CC, also using advanced technologies such as next-generation sequencing (NGS). Undoubtedly this technology could offer an unique opportunity to broaden our understanding on CC molecular pathogenesis. Despite this great potential, however, the high complexity in terms of factors potentially contributing to genetic variability in CC calls for a more cautionary application of NGS to this malignancy, in order to avoid possible biases and criticisms in the identification of candidate actionable targets. This approach is further justified by the urgent need to develop effective targeted therapies in this disease. A multidisciplinary approach integrating genomic, functional and clinical studies is therefore mandatory to translate the results obtained by NGS into effective targeted therapies for this orphan disease. PMID:26142706

  10. 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

  11. 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. PMID:26593298

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

    ClinicalTrials.gov

    2015-12-28

    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

  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. Epidermal growth factor upregulates Skp2/Cks1 and p27kip1 in human extrahepatic cholangiocarcinoma cells

    PubMed Central

    Kim, Ja-yeon; Kim, Hong Joo; Park, Jung Ho; Park, Dong Il; Cho, Yong Kyun; Sohn, Chong Il; Jeon, Woo Kyu; Kim, Byung Ik; Kim, Dong Hoon; Chae, Seoung Wan; Sohn, Jin Hee

    2014-01-01

    AIM: To evaluate the expression status of S-phase kinase-associated protein 2 (Skp2)/cyclin-dependent kinases regulatory subunit 1 (Cks1) and p27kip1, and assess the prognostic significance of Skp2/Cks1 expression with p27kip1 in patients with extrahepatic cholangiocarcinoma. METHODS: Seventy-six patients who underwent curative resection for histologically confirmed extrahepatic cholangiocarcinoma at our institution from December 1994 to March 2008 were enrolled. Immunohistochemical staining for Skp2, Cks1, p27kip1, and Ki67, along with other relevant molecular biologic experiments, were performed. RESULTS: By Cox regression analyses, advanced age (> 65 years), advanced AJCC tumor stage, poorly differentiated histology, and higher immunostaining intensity of Skp2 were identified as independent prognostic factors in patients with extrahepatic cholangiocarcinoma. Exogenous epidermal growth factor (EGF, especially 0.1-10 ng/mL) significantly increased the proliferation indices by MTT assay and the mRNA levels of Skp2/Cks1 and p27kip1 in SNU-1196, SNU-1079, and SNU-245 cells. The protein levels of Skp2/Cks1 (from nuclear lysates) and p27kip1 (from cytosolic lysate) were also significantly increased in these cells. There were significant reductions in the protein levels of Skp2/Cks1 and p27kip1 (from nuclear lysate) after the treatment of LY294002. By chromatin immunoprecipitation assay, we found that E2F1 transcription factor directly binds to the promoter site of Skp2. CONCLUSION: Higher immunostaining intensity of Skp2/Cks1 was an independent prognostic factor for patients with extrahepatic cholangiocarcinoma. EGF upregulates the mRNA and protein levels of Skp2/Cks1 and p27kip1 via the PI3K/Akt pathway and direct binding of E2F1 transcription factor with the Skp2 promoter. PMID:24574749

  15. Semiquantitative analysis of intrahepatic CC-chemokine mRNas in chronic hepatitis C.

    PubMed Central

    Nischalke, Hans Dieter; Nattermann, Jacob; Fischer, Hans-Peter; Sauerbruch, Tilman; Spengler, Ulrich; Dumoulin, Franz Ludwig

    2004-01-01

    BACKGROUND: The mechanisms leading to hepatic injury in chronic hepatitis C virus (HCV) infection are only incompletely understood. Recent data propose a correlation of the intrahepatic expression of the CC chemokine RANTES and the degree of periportal and portal inflammatory liver damage. AIM: Here, we have studied the intrahepatic mRNA levels of CC chemokines RANTES together with that of other members of this chemokine family (MIP-1beta, MCP-1, and MCP-2) in chronic hepatitis C as compared with healthy controls. METHODS: Liver samples from 22 HCV-infected patients, nine individuals with primary biliary cirrhosis and from 12 normal controls were included into this study. Intrahepatic mRNA levels of CC chemokines RANTES, MIP-1beta, MCP-1, and MCP-2 were analyzed by a semi-quantitative reverse transcription/real-time polymerase chain reaction assay. RESULTS: In chronic HCV infection, intrahepatic RANTES mRNA levels were significantly higher than in non-infected controls (7.2-fold, p < 0.001) or in the disease control group (2.8-fold, p < 0.001) and higher levels of RANTES mRNA levels were observed in livers with an advanced stage of liver cell injury (histologic activity index > or = 6), although this difference was not statistically significant (p = 0.08). In contrast, mRNA levels of MIP-1beta (p = 0.021) and MCP-1 (p = 0.021) were significantly lower in HCV liver samples while MCP-2 expression was similar in all groups analyzed. CONCLUSION: The data support the concept of chemokines as mediators of liver cell injury in chronic hepatitis C. PMID:15770052

  16. Combined hepatocellular-cholangiocarcinoma: a case report.

    PubMed

    Toh, C H; Cheung, Y C; Ng, S H; Lin, C Y; Chan, S C; Ng, K K

    2004-12-01

    Combined hepatocellular-cholangiocarcinoma (HCC-CC) is a rare primary liver tumour. We report a carrier of both HBV and HCV presenting with intermittent abdominal pain, fever, chillness and elevated á-fetoprotein (AFP) of 1197 ng/ml. Computed tomography showed an irregular hypodense mass in the left lateral segment of the liver with vague contrast enhancement and multiple regional lymphadenopathy. Hepatic angiogram showed that the mass was hypovascular and the left portal vein was occluded with a tapered end. Percutaneous ultrasound-guided core needle biopsy of the liver yielded HCC-CC. We suggest that HCC-CC should be considered in hypovascular liver tumours with striking elevation of serum AFP and multiple regional lymphadenopathy. PMID:15646418

  17. Is There Any Evidence for a Role of Local Treatment in Cholangiocarcinoma?

    PubMed Central

    Vogel, Arndt; Dudeck, Oliver

    2014-01-01

    Summary Background Most cholangiocarcinomas (CCA) are locally advanced and unresectable at the time of diagnosis. Currently, chemotherapy combining gemcitabine with a platinum agent is the recommended first-line treatment regimen for advanced biliary tract cancer. However, median overall survival is only approximately 1 year. As the hepatic tumor burden is the limiting factor for the prognosis of these patients, local tumor control is essential. Methods We present and discuss the current evidence for such therapy options for patients with CCA. Results Local and locoregional therapies have been shown to be well tolerated and can contribute to tumor control in the context of a comprehensive oncologic treatment strategy, and may prolong survival of patients with advanced CCA. Unfortunately, only few high-quality clinical trials are available. Conclusion Randomized prospective clinical trials enrolling larger numbers of patients need to be carried out to elucidate the precise value of these treatments alone as well as in combination with systemic chemotherapy. PMID:26288598

  18. [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. PMID:24231699

  19. Cystic micropapillary neoplasm of peribiliary glands with concomitant perihilar cholangiocarcinoma.

    PubMed

    Uchida, Tsuneyuki; Yamamoto, Yusuke; Ito, Takaaki; Okamura, Yukiyasu; Sugiura, Teiichi; Uesaka, Katsuhiko; Nakanuma, Yasuni

    2016-02-21

    We report a case of a 75-year-old man with cystic micropapillary neoplasm of peribiliary glands detected preoperatively by radiologic examination. Enhanced computed tomography showed a low-density mass 2.2 cm in diameter in the right hepatic hilum and a cystic lesion around the common hepatic duct. Under a diagnosis of perihilar cholangiocarcinoma, right hepatectomy with caudate lobectomy and bile duct resection were performed. Pathological examination revealed perihilar cholangiocarcinoma mainly involving the right hepatic duct. The cystic lesion was multilocular and covered by columnar lining epithelia exhibiting increased proliferative activity and p53 nuclear expression; it also contained foci of micropapillary and glandular proliferation. Therefore, the lesion was diagnosed as a cystic micropapillary neoplasm of peribiliary glands and resembled flat branch-type intraductal papillary mucinous neoplasm of the pancreas. Histological examination showed the lesion was discontinuous with the perihilar cholangiocarcinoma. Immunohistochemistry showed the cystic neoplasm was strongly positive for MUC6 and that the cholangiocarcinoma was strongly positive for MUC5AC and S100P. These results suggest these two lesions have different origins. This case warrants further study on whether this type of neoplasm is associated with concomitant cholangiocarcinoma as observed in pancreatic intraductal papillary mucinous neoplasm with concomitant pancreatic duct adenocarcinoma. PMID:26900302

  20. Cystic micropapillary neoplasm of peribiliary glands with concomitant perihilar cholangiocarcinoma

    PubMed Central

    Uchida, Tsuneyuki; Yamamoto, Yusuke; Ito, Takaaki; Okamura, Yukiyasu; Sugiura, Teiichi; Uesaka, Katsuhiko; Nakanuma, Yasuni

    2016-01-01

    We report a case of a 75-year-old man with cystic micropapillary neoplasm of peribiliary glands detected preoperatively by radiologic examination. Enhanced computed tomography showed a low-density mass 2.2 cm in diameter in the right hepatic hilum and a cystic lesion around the common hepatic duct. Under a diagnosis of perihilar cholangiocarcinoma, right hepatectomy with caudate lobectomy and bile duct resection were performed. Pathological examination revealed perihilar cholangiocarcinoma mainly involving the right hepatic duct. The cystic lesion was multilocular and covered by columnar lining epithelia exhibiting increased proliferative activity and p53 nuclear expression; it also contained foci of micropapillary and glandular proliferation. Therefore, the lesion was diagnosed as a cystic micropapillary neoplasm of peribiliary glands and resembled flat branch-type intraductal papillary mucinous neoplasm of the pancreas. Histological examination showed the lesion was discontinuous with the perihilar cholangiocarcinoma. Immunohistochemistry showed the cystic neoplasm was strongly positive for MUC6 and that the cholangiocarcinoma was strongly positive for MUC5AC and S100P. These results suggest these two lesions have different origins. This case warrants further study on whether this type of neoplasm is associated with concomitant cholangiocarcinoma as observed in pancreatic intraductal papillary mucinous neoplasm with concomitant pancreatic duct adenocarcinoma. PMID:26900302

  1. FXYD6 is a new biomarker of cholangiocarcinoma.

    PubMed

    Chen, Xiongfei; Sun, Mingzhu; Hu, Yazhuo; Zhang, Honghong; Wang, Zhanbo; Zhou, Ningxin; Yan, Xinyun

    2014-02-01

    Members of the FXYD domain-containing ion transport regulator protein family, including FXYD3 and FXYD5, play an important role in the pathogenesis of numerous tumors. However, the correlation between the expression of FXYD6 and tumors remains poorly understood. In the current study, the expression of FXYD6 was examined immunohistochemically in 72 cholangiocarcinoma tissues and 30 distal normal bile duct tissues matched with the tumors. The results show that the positive expression rate of FXYD6 was significantly higher in cholangiocarcinoma than that in normal bile duct tissue (69 vs. 33.3%; P=0.002). Furthermore, the positive expression rate of FXYD6 in well- and moderately-differentiated cholangiocarcinoma was clearly higher than that in poorly-differentiated and mucinous cholangiocarcinoma (85.7 vs. 40%; P=0.000). However, there was no significant correlation between the expression of FXYD6 and gender (P=0.393), age (P=0.174), histological type (P=0.123), T stage (P=0.164), lymph node metastasis (P=0.343), perineural invasion (P=0.088) and tumor location (P=0.238). The results of this study indicate that FXYD6 may be a new biomarker for cholangiocarcinoma and may be associated with a favorable prognosis in this malignant disease. PMID:24396454

  2. Pathobiology of biliary epithelia and cholangiocarcinoma: proceedings of the Henry M. and Lillian Stratton Basic Research Single-Topic Conference.

    PubMed

    Sirica, Alphonse E; Nathanson, Michael H; Gores, Gregory J; Larusso, Nicholas F

    2008-12-01

    In June 2008, the American Association for the Study of Liver Diseases (AASLD) sponsored the Henry M. and Lillian Stratton Basic Research Single-Topic Conference on the Pathobiology of Biliary Epithelia and Cholangiocarcinoma, which was held in Atlanta, GA. Attendees from 12 different countries participated in this conference, making it a truly international scientific event. Both oral and poster presentations were given by multidisciplinary experts, who highlighted important areas of current basic and translational research on biliary epithelial cell biology and pathophysiology, and on the etiology, cellular and molecular pathogenesis, and target-based therapy of cholangiocarcinoma. The specific goals and objectives of the conference were: (1) to advance knowledge of basic and molecular mechanisms underlying developmental and proliferative disorders of the biliary tract; (2) to foster a better and more comprehensive understanding of mechanisms regulating biliary epithelial (cholangiocyte) growth and transport, signaling, cell survival, and abnormalities that result in disease; and (3) to understand basic mechanisms of cholangiocarcinoma development and progression, with the added goal of identifying and exploiting potentially critical molecular pathways that may be targeted therapeutically. A number of interrelated themes emerged from the oral and poster sessions that affected current understandings of the complex organization of transcriptional and signaling mechanisms that regulate bile duct development, hepatic progenitor cell expansion, cholangiocyte secretory functions and proliferation, and mechanisms of cholangiocarcinogenesis and malignant cholangiocyte progression. Most notable were the critical questions raised as to how best to exploit aberrant signaling pathways associated with biliary disease as potential targets for therapy. PMID:18855901

  3. 11C-Choline and FDG PET/CT Imaging of Primary Cholangiocarcinoma: A Comparative Analysis

    PubMed Central

    Chotipanich, Chanisa; Promteangtrong, Chetsadaporn; Kunawudhi, Anchisa; Chanwat, Rawisak; Sricharunrat, Thaniya; Suratako, Savitree; Wongsa, Paramest

    2015-01-01

    Objective(s): This study aimed to compare the diagnostic values of 11C-choline and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with cholangiocarcinoma (CCA). Methods: This prospective study was conducted on 10 patients (6 males and 4 females), aged 42-69 years, suspected of having CCA based on CT or magnetic resonance imaging (MRI) results. 11C-choline and 18F-FDG PET/CT studies were performed in all patients over 1 week. PET/CT results were visually analyzed by 2 independent nuclear medicine physicians and quantitatively by calculating the tumor-to-background ratio (T/B). Results: No 11C-choline PET/CT uptake was observed in primary extrahepatic or intrahepatic CCA cases. Intense 18F-FDG avidity was detected in the tumors of 8 patients (%80). Two patients, who were 18F-FDG negative, had primary extrahepatic CCA. Ki-67 measurements were positive in all patients (range; 14.2%-39.9%). The average T/B values of 11C-choline and 18F-FDG were 0.4±0.2 and 2.0±1.0 in all cases of primary CCA, respectively; these values were significantly lower for 11C-choline (P<0.005). Both FDG and 11C-choline PET/CT detected metastatic CCA foci in all 8 patients (two patients had no metastases). Conclusion: As the results suggested, primary CCA lesions showed a poor avidity for 11C-choline, whereas 18F-FDG PET/CT was of value for the detection of most primary CCA cases. In contrast to primary lesions, metastatic CCA lesions showed 11C-choline avidity.

  4. Association between cellular radiosensitivity and G1/G2 checkpoint proficiencies in human cholangiocarcinoma cell lines.

    PubMed

    Hematulin, Arunee; Sagan, Daniel; Sawanyawisuth, Kanlayanee; Seubwai, Wunchana; Wongkham, Sopit

    2014-09-01

    Cholangiocarcinoma is a destructive malignancy with a poor prognosis and lack of effective medical treatment. Radiotherapy is an alternative treatment for patients with unresectable cholangiocarcinoma. However, there are limited data on the radiation responsiveness of individual cholangiocarcinoma cells, which is a key factor that influences radiation treatment outcome. In this study, we found that cholangiocarcinoma cell lines differ remarkably in their radiosensitivity. The variation of radiosensitivity of cholangiocarcinoma cells correlates with their p53 status and existing G1 and/or G2 checkpoint defects. We also demonstrated the potential of checkpoint kinase Chk1/2 inhibition on the enhancement of the radiosensitivity of cholangiocarcinoma cells. Thus, this study provides useful information for predicting radiation response and provides evidence for the enchantment of radiotherapeutic efficiency by targeting checkpoint kinase Chk1/2 in some subpopulations of cholangiocarcinoma patients. PMID:24969815

  5. Current status of transjugular intrahepatic portosystemic shunts.

    PubMed Central

    Patel, N. H.; Chalasani, N.; Jindal, R. M.

    1998-01-01

    The use of the transjugular intrahepatic portosystemic shunt (TIPS) has emerged as an important nonoperative modality for variceal bleeding, intractable ascites, and for selected cases of hepatic venous obstruction. We believe that TIPS should be viewed as a 'bridge' to liver transplantation and should be carried out only in experienced centres. The adverse haemodynamic changes on the cardiopulmonary system after TIPS should be borne in mind. Prospective trials to evaluate the role of TIPS versus sclerotherapy in variceal bleeding will be watched with interest. There is, however, an urgent need to improve long-term results of TIPS as stent thrombosis and stenosis occur frequently. We advocate routine surveillance to detect these problems at an early stage. PMID:10320885

  6. 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. PMID:20052894

  7. Imaging and interventions in hilar cholangiocarcinoma: A review.

    PubMed

    Madhusudhan, Kumble Seetharama; Gamanagatti, Shivanand; Gupta, Arun Kumar

    2015-02-28

    Hilar cholangiocarcinoma is a common malignant tumor of the biliary tree. It has poor prognosis with very low 5-year survival rates. Various imaging modalities are available for detection and staging of the hilar cholangiocarcinoma. Although ultrasonography is the initial investigation of choice, imaging with contrast enhanced computed tomography scan or magnetic resonance imaging is needed prior to management. Surgery is curative wherever possible. Radiological interventions play a role in operable patients in the form of biliary drainage and/or portal vein embolization. In inoperable cases, palliative interventions include biliary drainage, biliary stenting and intra-biliary palliative treatment techniques. Complete knowledge of application of various imaging modalities available and about the possible radiological interventions is important for a radiologist to play a critical role in appropriate management of such patients.We review the various imaging techniques and appearances of hilar cholangiocarcinoma and the possible radiological interventions. PMID:25729485

  8. Resveratrol enhances the sensitivity of cholangiocarcinoma to chemotherapeutic agents

    PubMed Central

    Frampton, Gabriel; Lazcano, Eric; Li, Huang; Mohamad, Akimuddin; DeMorrow, Sharon

    2010-01-01

    Cholangiocarcinomas are devastating cancers that are resistant to chemotherapies. Resveratrol, a food-derived polyphenol with antitumorigenic properties can regulate the expression of Cytochrome p450 1b1 (Cyp1b1), which may confer chemoresistance in various cancers. Our aims were to assess the effects of resveratrol on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents and demonstrate an association between Cyp1b1 expression and chemosensitivity. Cholangiocarcinoma cell lines were treated with resveratrol prior to the addition of 5-fluorouracil (5-FU), gemcitabine or mitomycin C. Cell proliferation and apoptosis were assessed by MTS assays and Annexin staining. Resveratrol effects on cholangiocarcinoma tumor sensitivity to 5-FU was assessed in an in vivo xenograft model using Mz-ChA-1 cells. Following resveratrol treatment, Cyp1b1 expression was assessed by real time PCR and immunoblotting. Stable transfected cell lines with Cyp1b1 expression knocked down (Mz-Cyp1b1) were used to assess sensitivity to chemotherapeutic agents by MTS assays and Annexin staining and in a xenograft model using Mz-ChA-1 and Mz-Cyp1b1 cells, respectively. For each chemotherapeutic agent, co-treatment with resveratrol in vitro decreased cell proliferation and increased apoptosis to a greater extent than with the chemotherapeutic agent alone. In vivo, 5-FU+resveratrol decreased tumor size and increased TUNEL staining to a greater extent than 5-FU alone. In parallel, resveratrol decreased Cyp1b1 expression in Mz-ChA-1 cells and in cholangiocarcinoma tumors. Mz-Cyp1b1 cells were more sensitive to chemotherapeutic agents in vitro than mock-transfected cells, and Mz-Cyp1b1-induced tumors were more susceptible to 5-FU treatment. We suggest that resveratrol treatment may be a useful adjunct therapy to improve chemosensitivity in cholangiocarcinoma. PMID:20458282

  9. Chemopreventive and chemotherapeutic effects of dietary supplementation of vitamin D on cholangiocarcinoma in a Chemical-Induced animal model

    PubMed Central

    Lin, Kun-Ju; Su, Li-Jen; Yen, Tzu-Chen; Pang, Jong-Hwei S.; Kittaka, Atsushi; Sun, Chi-Chin; Chen, Miin-Fu; Jan, Yi-Yin; Chen, Tai C.; Juang, Horng-Heng; Yeh, Ta-Sen

    2014-01-01

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer. Vitamin D supplementation is getting popular due to its anti-tumor functions after conversion to its active form, 1α,25(OH)2D. Here, we show that dietary supplementation with 6 IU/g of vitamin D greatly suppressed ICC initiation and progression without apparent toxicity in a chemically induced rat model. Microarray analysis of rat ICC tissues showed vitamin D supplementation modulated the expressions of several unique genes, including lipocalin 2 (Lcn2), confirmed by RT-qPCR and immunohistochemical (IHC) staining. Further, 53 of 80 human ICC specimens (66%) exhibited high LCN2 expression and LCN2 knockdown in SNU308 cells decreased cell growth and migration, suggesting LCN2 be an oncogene in human ICC. As human ICC SNU1079 cells were treated by 1α,25(OH)2D3, LCN2 expression and cell proliferation were attenuated. The downregulation of LCN2 expression was blunted when vitamin D receptor (VDR) was knocked down, implicating that the in vivo Lcn2 downregulation is a direct consequence of vitamin D supplementation Our results support the prevailing concept that vitamin D status is negatively associated with cancer incidence and mortality and suggest LCN2 may be a potential target against ICC. Further studies of application of vitamin D or its analogs against ICC are warranted. PMID:24939880

  10. Chemopreventive and chemotherapeutic effect of dietary supplementation of vitamin D on cholangiocarcinoma in a Chemical-Induced animal model.

    PubMed

    Chiang, Kun-Chun; Yeh, Chun-Nan; Lin, Kun-Ju; Su, Li-Jen; Yen, Tzu-Chen; Pang, Jong-Hwei S; Kittaka, Atsushi; Sun, Chi-Chin; Chen, Miin-Fu; Jan, Yi-Yin; Chen, Tai C; Juang, Horng-Heng; Yeh, Ta-Sen

    2014-06-15

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer. Vitamin D, a pro-hormone, is getting popular due to its hormone-like functions after converted to its active form, 1α,25(OH)2D3. Here, we show that dietary supplementation with 6 IU/g of vitamin D greatly suppressed ICC initiation and progression without apparent toxicity in a chemically induced rat model. Microarray analysis of rat ICC tissues showed vitamin D supplementation modulated the expressions of several unique genes, including lipocalin 2 (Lcn2), confirmed by RT-qPCR and immunohistochemical (IHC) staining. Further, 53 of 80 human ICC specimens (66%) exhibited high LCN2 expression and LCN2 knockdown in SNU308 cells decreased cell growth and migration, suggesting LCN2 be an oncogene in human ICC. As human ICC SNU1079 cells were treated by 1α,25(OH)2D3, LCN2 expression and cell proliferation were attenuated. The downregulation of LCN2 expression was blunted when vitamin D receptor (VDR) was knocked down, implicating that the in vivo Lcn2 downregulation is a direct consequence of vitamin D supplementation Our results support the prevailing concept that vitamin D status is negatively associated with cancer incidence and mortality and suggest LCN2 may be a potential target against ICC. Further studies of application of vitamin D or its analog against ICC are warranted. PMID:24939880

  11. Neoadjuvant Down-Sizing of Hilar Cholangiocarcinoma with Photodynamic Therapy--Long-Term Outcome of a Phase II Pilot Study.

    PubMed

    Wagner, Andrej; Wiedmann, Marcus; Tannapfel, Andrea; Mayr, Christian; Kiesslich, Tobias; Wolkersdörfer, Gernot W; Berr, Frieder; Hauss, Johann; Witzigmann, Helmut

    2015-01-01

    Hilar cholangiocarcinoma (CC) is non-resectable in the majority of patients often due to intrahepatic extension along bile duct branches/segments, and even after complete resection (R0) recurrence can be as high as 70%. Photodynamic therapy (PDT) is an established palliative local tumor ablative treatment for non-resectable hilar CC. We report the long-term outcome of curative resection (R0) performed after neoadjuvant PDT for downsizing of tumor margins in seven patients (median age 59 years) with initially non-resectable hilar CC. Photofrin(®) was injected intravenously 24-48 h before laser light irradiation of the tumor stenoses and the adjacent bile duct segments. Major resective surgery was done with curative intention six weeks after PDT. All seven patients had been curatively (R0) resected and there were no undue early or late complications for the neoadjuvant PDT and surgery. Six of seven patients died from tumor recurrence at a median of 3.2 years after resection, the five-year survival rate was 43%. These results are comparable with published data for patients resected R0 without pre-treatment, indicating that neoadjuvant PDT is feasible and could improve overall survival of patients considered non-curatively resectable because of initial tumor extension in bile duct branches/segments--however, this concept needs to be validated in a larger trial. PMID:26561801

  12. Poorly Differentiated Gastric Adenocarcinoma Can Mimic Hilar Cholangiocarcinoma.

    PubMed

    Urasaki, Tetsuya; Kodaira, Makoto; Hibino, Masaki; Yamagata, Shingo; Watanabe, Yukihiro; Terazawa, Yasuyuki; Sano, Munetaka; Kuriki, Ken

    2016-01-01

    This report describes two cases with obstructive jaundice caused by poorly differentiated gastric adenocarcinoma. Computed tomography scans showed circumferential stenosis in the hilar bile ducts. Endoscopic retrograde cholangiopancreatography showed dilatation of the bilateral hepatic ducts and stenosis of the common hepatic ducts from the bifurcation of the bilateral hepatic ducts. The first diagnoses were hilar cholangiocarcinoma and biliary drainage decreased serum bilirubin; however, both patients died of cancer within a short period of time. Autopsies revealed lymphatic vessel invasion and possible subepithelial invasion by gastric adenocarcinoma into the hilar bile ducts. A differential diagnosis should thus be required in suspected cases of hilar cholangiocarcinoma. PMID:27301505

  13. Laparoscopic Management of Hilar Cholangiocarcinoma: a Case Report.

    PubMed

    Puntambekar, Shailesh; Sharma, Vikrant; Kumar, Sanjay; Mitkare, Sainath; Joshi, Geetanjali; Parikh, Hirav

    2016-02-01

    The only option for cure of Klatskin's tumour is surgical excision. The radicality of the procedure is determined by the extent of the tumour and functional parameters of the patient. Complete laparoscopic resection of hilar cholangiocarcinoma with biliary reconstruction is a challenging procedure. The main aim is to achieve pathological negative margins, complete lymph node retrieval and enterobiliary bypass. We present a case report of a patient with hilar cholangiocarcinoma managed laparoscopically. The nodal yield was nine. On 6-month follow-up, the patient was symptom free. The main aim is to study the feasibility of performing this complex procedure completely laparoscopically. PMID:27186042

  14. [Radiological diagnosis and intervention of cholangiocarcinomas (CC)].

    PubMed

    Vogl, T J; Zangos, S; Eichler, K; Gruber-Rouh, T; Hammerstingl, R M; Trojan, J; Weisser, P

    2012-10-01

    To present current data on diagnosis, indication and different therapy options in patients with cholangiocarcinoma (CC) based on an analysis of the current literature and clinical experience. The diagnostic routine includes laboratory investigations with parameters of cholestasis and also serum tumor markers CA19 - 9 and CEA. After ultrasound for clarifying a tumor and/or dilated bile ducts, contrast-enhanced magnetic resonance imaging (MRI) should be performed with magnetic resonance cholangiography (MRCP). The accuracy (positive predictive value) for diagnosing a CC is 37-84% (depending on the location) for ultrasound, 79-94% for computed tomography (CT), and 95% for MRI and MRCP. An endoscopic retrograde cholangiography (ERCP) can then be planned, especially if biliary drainage or cytological or histological specimen sampling is intended. A curative approach can be achieved by surgical resection, rarely by liver transplantation. However, many patients are not eligible for surgery. In addition to systemic chemotherapy, locoregional therapies such as transarterial chemoembolization (TACE), hepatic arterial infusion (HAI)--also known as chemoperfusion--, drug eluting beads-therapy (DEB) as well as thermoablative procedures, such as laser-induced thermotherapy (LITT), microwave ablation (MWA) and radiofrequency ablation (RFA) can be provided with a palliative intention. PMID:22711249

  15. Hepatocellular carcinoma and cholangiocarcinoma: an update.

    PubMed

    Yazici, Cemal; Niemeyer, David J; Iannitti, David A; Russo, Mark W

    2014-01-01

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer worldwide and is rising in incidence. Ultrasound is the preferred modality for screening high-risk patients for HCC because it detects clinically significant nodules, widespread availability and lower cost. HCC does not require a biopsy for diagnosis if specific imaging criteria are fulfilled. Transarterial chemoembolization (TACE) is the most common modality used to treat HCC followed by ablation. Cholangiocarcinoma (CCA) is increasing in incidence and the second most common primary malignancy of the liver. There is no effective screening strategy for CCA although magnetic resonance imaging and carbohydrate antigen 19-9 (CA 19-9) are commonly used without proven benefit. Therapy for CCA is challenging and resection, when possible, is the mainstay of therapy. Gemcitabine in combination with cisplatin or biologics may offer a modest survival benefit. Liver transplantation for CCA is associated with reasonable survival in select cases. Molecular diagnostics offer the potential to develop personalized approaches in the management of HCC and CCA. PMID:24245910

  16. 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. PMID:25701818

  17. Hepatitis C virus infection of cholangiocarcinoma cell lines

    PubMed Central

    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

    2015-01-01

    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. PMID:25701818

  18. Cholangiocarcinoma: new insights into disease pathogenesis and biology.

    PubMed

    Braconi, Chiara; Patel, Tushar

    2010-12-01

    Cholangiocarcinomas are rare malignant tumors whose incidence is increasing worldwide. Risk factors for this malignancy include both infectious and non-infectious diseases characterized by chronic inflammation of the bile duct epithelia. Diagnosis of these cancers remains difficult because of the lack of sensitive diagnostic tests. The prognosis is poor probably because of the lack of effective treatments for unresectable cancer. PMID:20937455

  19. Cholangiocarcinoma: New insights into disease pathogenesis and biology

    PubMed Central

    Braconi, Chiara; Patel, Tushar

    2010-01-01

    Synopsis Cholangiocarcinoma are rare malignant tumors whose incidence is increasing worldwide. Risk factors for this malignancy include biliary diseases characterized by chronic inflammation of the bile duct epithelia. Diagnosis of these cancers remains difficult due to the lack of sensitive diagnostic tests. The prognosis is poor likely due to the lack of effective treatments for unresectable cancer. PMID:20937455

  20. Expression levels of ROS1/ALK/c-MET and therapeutic efficacy of cetuximab plus chemotherapy in advanced biliary tract cancer

    PubMed Central

    Chiang, Nai-Jung; Hsu, Chiun; Chen, Jen-Shi; Tsou, Hsiao-Hui; Shen, Ying-Ying; Chao, Yee; Chen, Ming-Huang; Yeh, Ta-Sen; Shan, Yan-Shen; Huang, Shiu-Feng; Chen, Li-Tzong

    2016-01-01

    Aberrant expression of ROS1, ALK or c-MET (RAM) is implicated in carcinogenesis and cancer drug resistance. We retrospectively evaluated the effect of RAM expression on outcomes for advanced biliary tract cancer patients, who were treated with gemcitabine plus oxaliplatin (GEMOX), with or without cetuximab, in a randomized phase II trial. RAM expression levels on archived tissue sections were scored using immunohistochemistry (IHC). Of 110 tumors with IHC staining for all three markers, 18 were RAMhigh (IHC intensity 3+ for any markers). Ninety-two tumors were RAMlow (IHC intensity <3+ for all markers). All RAMhigh tumors were intra-hepatic cholangiocarcinomas (IHCC). Of the patients with IHCC (n = 80), median overall survival (OS) of RAMhigh group was inferior to that of the RAMlow group (5.7 vs. 11.7 months, p = 0.021). In multivariate analysis RAMhigh remained an independently adverse prognostic factor, with a hazard ratio of 2.01 (p = 0.039). In the RAMlow group, GEMOX treatment with cetuximab significantly improved the disease control rate (68% vs. 41%, p = 0.044), median progression-free survival (7.3 vs. 4.9 months, p = 0.026), and marginally prolonged median OS (14.1 vs 9.6 months, p = 0.056), compared to GEMOX treatment alone. Future trials of anti-EGFR inhibitors for IHCC may consider RAM expression as a patient stratification factor. PMID:27136744

  1. miR-17-92 Cluster Promotes Cholangiocarcinoma Growth

    PubMed Central

    Zhu, Hanqing; Han, Chang; Lu, Dongdong; Wu, Tong

    2015-01-01

    miR-17-92 is an oncogenic miRNA cluster implicated in the development of several cancers; however, it remains unknown whether the miR-17-92 cluster is able to regulate cholangiocarcinogenesis. This study was designed to investigate the biological functions and molecular mechanisms of the miR-17-92 cluster in cholangiocarcinoma. In situ hybridization and quantitative RT-PCR analysis showed that the miR-17-92 cluster is highly expressed in human cholangiocarcinoma cells compared with the nonneoplastic biliary epithelial cells. Forced overexpression of the miR-17-92 cluster or its members, miR-92a and miR-19a, in cultured human cholangiocarcinoma cells enhanced tumor cell proliferation, colony formation, and invasiveness, in vitro. Overexpression of the miR-17-92 cluster or miR-92a also enhanced cholangiocarcinoma growth in vivo in hairless outbred mice with severe combined immunodeficiency (SHO-PrkdcscidHrhr). The tumor-suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), was identified as a bona fide target of both miR-92a and miR-19a in cholangiocarcinoma cells via sequence prediction, 3′ untranslated region luciferase activity assay, and Western blot analysis. Accordingly, overexpression of the PTEN open reading frame protein (devoid of 3′ untranslated region) prevented miR-92a– or miR-19a–induced cholangiocarcinoma cell growth. Microarray analysis revealed additional targets of the miR-17-92 cluster in human cholangiocarcinoma cells, including APAF-1 and PRDM2. Moreover, we observed that the expression of the miR-17-92 cluster is regulated by IL-6/Stat3, a key oncogenic signaling pathway pivotal in cholangiocarcinogenesis. Taken together, our findings disclose a novel IL-6/Stat3–miR-17-92 cluster–PTEN signaling axis that is crucial for cholangiocarcinogenesis and tumor progression. PMID:25239565

  2. Hilar cholangiocarcinoma: diagnosis, treatment options, and management

    PubMed Central

    Soares, Kevin C.; Kamel, Ihab; Cosgrove, David P.; Herman, Joseph M.

    2014-01-01

    Hilar cholangiocarcinoma (HC) is a rare disease with a poor prognosis which typically presents in the 6th decade of life. Of the 3,000 cases seen annually in the United States, less than one half of these tumors are resectable. A variety of risk factors have been associated with HC, most notably primary sclerosing cholangitis (PSC), biliary stone disease and parasitic liver disease. Patients typically present with abdominal pain, pruritis, weight loss, and jaundice. Computed topography (CT), magnetic resonance imaging (MRI), and ultrasound (US) are used to characterize biliary lesions. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) assess local ductal extent of the tumor while allowing for therapeutic biliary drainage. MRCP has demonstrated similar efficacies to PTC and ERCP in identifying anatomic extension of tumors with less complications. Treatment consists of surgery, radiation, chemotherapy and photodynamic therapy. Biliary drainage of the future liver remnant should be performed to decrease bilirubin levels thereby facilitating future liver hypertrophy. Standard therapy consists of surgical margin-negative (R0) resection with extrahepatic bile duct resection, hepatectomy and en bloc lymphadenectomy. Local resection should not be undertaken. Lymph node invasion, tumor grade and negative margins are important prognostic indicators. In instances where curative resection is not possible, liver transplantation has demonstrated acceptable outcomes in highly selected patients. Despite the limited data, chemotherapy is indicated for patients with unresectable tumors and adequate functional status. Five-year survival after surgical resection of HC ranges from 10% to 40% however, recurrence can be as high as 50-70% even after R0 resection. Due to the complexity of this disease, a multi-disciplinary approach with multimodal treatment is recommended for this complex disease. PMID:24696835

  3. An Omics Perspective on Molecular Biomarkers for Diagnosis, Prognosis, and Therapeutics of Cholangiocarcinoma

    PubMed Central

    Seeree, Pattaya; Pearngam, Phorutai; Kumkate, Supeecha; Janvilisri, Tavan

    2015-01-01

    Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy arising from the epithelial bile duct. The lack of early diagnostic biomarkers as well as therapeutic measures results in severe outcomes and poor prognosis. Thus, effective early diagnostic, prognostic, and therapeutic biomarkers are required to improve the prognosis and prolong survival rates in CCA patients. Recent advancement in omics technologies combined with the integrative experimental and clinical validations has provided an insight into the underlying mechanism of CCA initiation and progression as well as clues towards novel biomarkers. This work highlights the discovery and validation of molecular markers in CCA identified through omics approaches. The possible roles of these molecules in various cellular pathways, which render CCA carcinogenesis and progression, will also be discussed. This paper can serve as a reference point for further investigations to yield deeper understanding in the complex feature of this disease, potentially leading to better approaches for diagnosis, prognosis, and therapeutics. PMID:26421274

  4. 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

  5. Transjugular intrahepatic portosystemic shunts and portal hypertension-related complications.

    PubMed

    Siramolpiwat, Sith

    2014-12-01

    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. Serotonin metabolism is dysregulated in cholangiocarcinoma, which has implications for tumor growth

    PubMed Central

    Alpini, Gianfranco; Invernizzi, Pietro; Gaudio, Eugenio; Venter, Julie; Kopriva, Shelley; Bernuzzi, Francesca; Onori, Paolo; Franchitto, Antonio; Stutes, Monique; Frampton, Gabriel; Alvaro, Domenico; Lee, Sum P.; Marzioni, Marco; Benedetti, Antonio; DeMorrow, Sharon

    2008-01-01

    Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. Symptoms are usually evident after blockage of the bile duct by the tumor and, at this late stage, they are relatively resistant to chemotherapy and radiation therapy. Therefore it is imperative that alternative treatment options are explored. We present novel data indicating that the metabolism of serotonin is dysregulated in cholangiocarcinoma cell lines compared to normal cholangiocytes and in tissue and bile from cholangiocarcinoma patients. Specifically there was an increased expression of tryptophan hydroxylase 1 and a suppression of monoamine oxidase A expression (enzymes responsible for the synthesis and degradation of serotonin respectively) in cholangiocarcinoma. This resulted in an increased secretion of serotonin from cholangiocarcinoma and increased serotonin in the bile from cholangiocarcinoma patients. Increased local serotonin release may have implications on cholangiocarcinoma cell growth. Serotonin administration increased cholangiocarcinoma cell growth in vitro, whereas inhibition of serotonin synthesis decreases tumor cell growth both in vitro and in vivo. The data presented here represents the first evidence that serotonin metabolism is dysregulated in cholangiocarcinoma and that modulation of serotonin synthesis may represent an alternative target for the development of therapeutic strategies. PMID:19010890

  7. 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

  8. Common Hepatic Duct Mixed Adenoneuroendocrine Carcinoma Masquerading as Cholangiocarcinoma.

    PubMed

    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

  9. 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

  10. 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

  11. Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response.

    PubMed

    Bonaccorsi-Riani, Eliano; Danger, Richard; Lozano, Juan José; Martinez-Picola, Marta; Kodela, Elisavet; Mas-Malavila, Roser; Bruguera, Miquel; Collins, Helen L; Hider, Robert C; Martinez-Llordella, Marc; Sanchez-Fueyo, Alberto

    2015-01-01

    Hepatic expression of iron homeostasis genes and serum iron parameters predict the success of immunosuppression withdrawal following clinical liver transplantation, a phenomenon known as spontaneous operational tolerance. In experimental animal models, spontaneous liver allograft tolerance is established through a process that requires intra-hepatic lymphocyte activation and deletion. Our aim was to determine if changes in systemic iron status regulate intra-hepatic lymphocyte responses. We used a murine model of lymphocyte-mediated acute liver inflammation induced by Concanavalin A (ConA) injection employing mice fed with an iron-deficient (IrDef) or an iron-balanced diet (IrRepl). While the mild iron deficiency induced by the IrDef diet did not significantly modify the steady state immune cell repertoire and systemic cytokine levels, it significantly dampened inflammatory liver damage after ConA challenge. These findings were associated with a marked decrease in T cell and NKT cell activation following ConA injection in IrDef mice. The decreased liver injury observed in IrDef mice was independent from changes in the gut microflora, and was replicated employing an iron specific chelator that did not modify intra-hepatic hepcidin secretion. Furthermore, low-dose iron chelation markedly impaired the activation of isolated T cells in vitro. All together, these results suggest that small changes in iron homeostasis can have a major effect in the regulation of intra-hepatic lymphocyte mediated responses. PMID:26287688

  12. Cancer of the Liver and Intrahepatic Bile Duct

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 39,230 % of All New Cancer Cases 2.3% Estimated Deaths in 2016 27,170 % of All Cancer ... of This Cancer : In 2013, there were an estimated 54,954 people living with liver and intrahepatic ...

  13. 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.

  14. Fetal Intrahepatic Cholestasis Secondary to BO Hemolytic Disease

    PubMed Central

    Raju, T. N. K.; Javed, Durr-I-Shahwar

    1981-01-01

    A rare occurrence of severe, direct hyperbilirubinemia in an infant with BO incompatibility was noted at four hours of age. Severe fetal hemolysis and markedly elevated indirect bilirubin levels might have caused induction of conjugating enzymes during fetal life in this case. Intrahepatic cholestasis was responsible for persistent conjugated hyperbilirubinemia after birth. This responded favorably to cholestyramine therapy. PMID:7196459

  15. Imaging approach to hepatocellular carcinoma, cholangiocarcinoma, and metastatic colorectal cancer.

    PubMed

    Fowler, Kathryn J; Saad, Nael E; Linehan, David

    2015-01-01

    Liver imaging is a highly evolving field with new imaging contrast agents and modalities. Knowledge of the different imaging options and what they have to offer in primary and metastatic liver disease is essential for appropriate diagnosis, staging, and prognosis in patients. This review summarizes the major imaging modalities in liver neoplasms and provides specific discussion of imaging hepatocellular carcinoma, cholangiocarcinoma, and colorectal liver metastases. The final sections provide an overview of presurgical imaging relevant to planning hepatectomies and ablative procedures. PMID:25444467

  16. Hilar cholangiocarcinoma: Cross sectional evaluation of disease spectrum

    PubMed Central

    Mahajan, Mangal S; Moorthy, Srikanth; Karumathil, Sreekumar P; Rajeshkannan, R; Pothera, Ramchandran

    2015-01-01

    Although hilar cholangiocarcinoma is relatively rare, it can be diagnosed on imaging by identifying its typical pattern. In most cases, the tumor appears to be centered on the right or left hepatic duct with involvement of the ipsilateral portal vein, atrophy of hepatic lobe on that side, and invasion of adjacent liver parenchyma. Multi-detector computed tomography (MDCT) and magnetic resonance cholangiopancreatography (MRCP) are commonly used imaging modalities to assess the longitudinal and horizontal spread of tumor. PMID:25969643

  17. 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

  18. miR-101 Inhibits Cholangiocarcinoma Angiogenesis through Targeting Vascular Endothelial Growth Factor (VEGF)

    PubMed Central

    Zhang, Jinqiang; Han, Chang; Zhu, Hanqing; Song, Kyoungsub; Wu, Tong

    2014-01-01

    Recent evidence has suggested an important role of miRNAs in liver biology and diseases, although the implication of miRNAs in cholangiocarcinoma remains to be defined further. This study was designed to examine the biological function and molecular mechanism of miR-101 in cholangiocarcinogenesis and tumor progression. In situ hybridization and quantitative RT-PCR were performed to determine the expression of miR-101 in human cholangiocarcinoma tissues and cell lines. Compared with noncancerous biliary epithelial cells, the expression of miR-101 is decreased in 43.5% of human cholangiocarcinoma specimens and in all three cholangiocarcinoma cell lines used in this study. Forced overexpression of miR-101 significantly inhibited cholangiocarcinoma growth in severe combined immunodeficiency mice. miR-101-overexpressed xenograft tumor tissues showed decreased capillary densities and decreased levels of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). The VEGF and COX-2 mRNAs were identified as the bona fide targets of miR-101 in cholangiocarcinoma cells by both computational analysis and experimental assays. miR-101 inhibits cholangiocarcinoma angiogenesis by direct targeting of VEGF mRNA 3′untranslated region and by repression of VEGF gene transcription through inhibition of COX-2. This study established a novel tumor-suppressor role of miR-101 in cholangiocarcinoma and it suggests the possibility of targeting miR-101 and related signaling pathways for future therapy. PMID:23608225

  19. 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.

  20. Neoadjuvant Down-Sizing of Hilar Cholangiocarcinoma with Photodynamic Therapy—Long-Term Outcome of a Phase II Pilot Study †

    PubMed Central

    Wagner, Andrej; Wiedmann, Marcus; Tannapfel, Andrea; Mayr, Christian; Kiesslich, Tobias; Wolkersdörfer, Gernot W.; Berr, Frieder; Hauss, Johann; Witzigmann, Helmut

    2015-01-01

    Hilar cholangiocarcinoma (CC) is non-resectable in the majority of patients often due to intrahepatic extension along bile duct branches/segments, and even after complete resection (R0) recurrence can be as high as 70%. Photodynamic therapy (PDT) is an established palliative local tumor ablative treatment for non-resectable hilar CC. We report the long-term outcome of curative resection (R0) performed after neoadjuvant PDT for downsizing of tumor margins in seven patients (median age 59 years) with initially non-resectable hilar CC. Photofrin® was injected intravenously 24–48 h before laser light irradiation of the tumor stenoses and the adjacent bile duct segments. Major resective surgery was done with curative intention six weeks after PDT. All seven patients had been curatively (R0) resected and there were no undue early or late complications for the neoadjuvant PDT and surgery. Six of seven patients died from tumor recurrence at a median of 3.2 years after resection, the five-year survival rate was 43%. These results are comparable with published data for patients resected R0 without pre-treatment, indicating that neoadjuvant PDT is feasible and could improve overall survival of patients considered non-curatively resectable because of initial tumor extension in bile duct branches/segments—however, this concept needs to be validated in a larger trial. PMID:26561801

  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. PMID:27015193

  2. Natural history of intrahepatic canine islet cell autografts.

    PubMed Central

    Alejandro, R; Cutfield, R G; Shienvold, F L; Polonsky, K S; Noel, J; Olson, L; Dillberger, J; Miller, J; Mintz, D H

    1986-01-01

    We have serially followed the function of intrahepatic canine islet autografts in 15 beagle dogs for up to 24 mo. Of these, only 20% sustained normal levels of fasting blood glucose for greater than 15 mo posttransplant. Failure of autograft function was accompanied by a preferential loss of well-granulated beta cells in the engrafted islets. The chronic stimulation of an initially marginal intrahepatic beta-cell mass ultimately resulted in metabolic deterioration and loss of beta cells below the minimal threshold required to maintain normal fasting blood glucose levels. It is possible that transplantation of a larger mass of islets would result in indefinite graft function in dogs. However, it remains to be demonstrated in larger mammals, including humans, whether an islet cell mass that is initially adequate in a heterotropic site such as the liver can remain functionally competent over a prolonged period. Images PMID:3095376

  3. MiR-21 Targets 15-PGDH and Promotes Cholangiocarcinoma Growth

    PubMed Central

    Lu, Lu; Byrnes, Kathleen; Han, Chang; Wang, Ying; Wu, Tong

    2014-01-01

    MicroRNAs (miRs) are a group of small, non-coding RNAs that modulate the translation of genes by binding to specific target sites in the target mRNA. This study investigated the biological function and molecular mechanism of microRNA-21 (miR-21) in human cholangiocarcinoma. In situ hybridization analysis of human cholangiocarcinoma specimens showed increased miR-21 in cholangiocarcinoma tissue compared to the non-cancerous biliary epithelium. Lentiviral transduction of miR-21 enhanced human cholangiocarcinoma cell growth and clonogenic efficiency in vitro, whereas inhibition of miR-21 decreased these parameters. Over-expression of miR-21 also promoted cholangiocarcinoma growth using an in vivo xenograft model system. The NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH/HPGD), a key enzyme that converts the protumorigenic prostaglandin E2 (PGE2) to its biologically inactive metabolite, was identified as a direct target of miR-21 in cholangiocarcinoma cells. In parallel, cyclooxygenase-2 (COX2) over-expression and PGE2 treatment increased miR-21 levels and enhanced miR-21 promoter activity in human cholangiocarcinoma cells. PMID:24699315

  4. Novel target genes and a valid biomarker panel identified for cholangiocarcinoma

    PubMed Central

    Andresen, Kim; Boberg, Kirsten Muri; Vedeld, Hege Marie; Honne, Hilde; Hektoen, Merete; Wadsworth, Chrisopher A.; Clausen, Ole Petter; Karlsen, Tom Hemming; Foss, Aksel; Mathisen, Øystein; Schrumpf, Erik; Lothe, Ragnhild A.; Lind, Guro E.

    2012-01-01

    Cholangiocarcinoma is notoriously difficult to diagnose, and the mortality rate is high due to late clinical presentation. CpG island promoter methylation is frequently seen in cancer development. In the present study, we aimed at identifying novel epigenetic biomarkers with the potential to improve the diagnostic accuracy of cholangiocarcinoma. Microarray data analyses of cholangiocarcinoma cell lines treated with epigenetic drugs and their untreated counterparts were compared with previously published gene expression profiles of primary tumors and with non-malignant controls. Genes responding to the epigenetic treatment that were simultaneously downregulated in primary cholangiocarcinoma compared with controls (n = 43) were investigated for their promoter methylation status in cancer cell lines from the gastrointestinal tract. Genes commonly methylated in cholangiocarcinoma cell lines were subjected to quantitative methylation-specific polymerase chain reaction in a total of 93 clinical samples (cholangiocarcinomas and non-malignant controls). CDO1, DCLK1, SFRP1 and ZSCAN18, displayed high methylation frequencies in primary tumors and were unmethylated in controls. At least one of these four biomarkers was positive in 87% of the tumor samples, with a specificity of 100%. In conclusion, the novel methylation-based biomarker panel showed high sensitivity and specificity for cholangiocarcinoma. The potential of these markers in early diagnosis of this cancer type should be further explored. PMID:22983262

  5. 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

  6. Congenital intrahepatic portosystemic shunts: Imaging findings and endovascular management.

    PubMed

    Chandrasekharan, Rajsekar; Pullara, Sreekumar K; Thomas, Tixon; Kader, Nazar Puthukudiyil; Moorthy, Srikanth

    2016-01-01

    We present two cases of congenital intrahepatic portosystemic shunts in which the right portal vein directly communicated with the inferior venacava (IVC) in one patient and with the hepatic vein in the other. Multiple hepatic nodules consistent with focal nodular hyperplasia (FNH) were seen in the first patient. The second patient presented with recurrent history of hepatic encephalopathy. Percutaneous transhepatic embolization was performed using coils and Amplatz device following which she completely recovered. PMID:27081230

  7. Congenital intrahepatic portosystemic shunts: Imaging findings and endovascular management

    PubMed Central

    Chandrasekharan, Rajsekar; Pullara, Sreekumar K; Thomas, Tixon; Kader, Nazar Puthukudiyil; Moorthy, Srikanth

    2016-01-01

    We present two cases of congenital intrahepatic portosystemic shunts in which the right portal vein directly communicated with the inferior venacava (IVC) in one patient and with the hepatic vein in the other. Multiple hepatic nodules consistent with focal nodular hyperplasia (FNH) were seen in the first patient. The second patient presented with recurrent history of hepatic encephalopathy. Percutaneous transhepatic embolization was performed using coils and Amplatz device following which she completely recovered. PMID:27081230

  8. Benign recurrent intrahepatic cholestasis--25 years of follow-up.

    PubMed Central

    Putterman, C.; Keidar, S.; Brook, J. G.

    1987-01-01

    Only 70 cases of recurrent intrahepatic cholestasis have been reported in the literature since the original description of this entity in 1959. The benign nature of the disease has been questioned, some authors suggesting progression to biliary cirrhosis. We report our follow-up of one such patient for over 25 years with no adverse physical consequences or histological deterioration. Sequential liver biopsies were obtained during this period. A conservative approach to diagnosis and treatment is therefore indicated. PMID:3684838

  9. Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes.

    PubMed

    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

    2016-08-01

    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

  10. 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

  11. Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma

    PubMed Central

    Francis, Heather; DeMorrow, Sharon; Venter, Julie; Onori, Paolo; White, Mellanie; Gaudio, Eugenio; Francis, Taylor; Greene, John F; Tran, Steve; Meininger, Cynthia J; Alpini, Gianfranco

    2011-01-01

    Background In several tumours the endogenous activity of histidine decarboxylase (HDC), the enzyme stimulating histamine synthesis, sustains the autocrine trophic effect of histamine on cancer progression. Cholangiocarcinoma is a biliary cancer with limited treatment options. Histamine interacts with four G-protein coupled receptors, H1–H4 histamine receptors (HRs). Objective To determine the effects of histamine stimulation and inhibition of histamine synthesis (by modulation of HDC) on cholangiocarcinoma growth. Methods In vitro studies were performed using multiple human cholangiocarcinoma lines. The expression levels of the histamine synthetic machinery and HRs were evaluated along with the effects of histamine stimulation and inhibition on cholangiocarcinoma proliferation. A xenograft tumour model was used to measure tumour volume after treatment with histamine or inhibition of histamine synthesis by manipulation of HDC. Vascular endothelial growth factor (VEGF) expression was measured in cholangiocarcinoma cells concomitant with the evaluation of the expression of CD31 in endothelial cells in the tumour microenvironment. Results Cholangiocarcinoma cells display (1) enhanced HDC and decreased monoamine oxidase B expression resulting in increased histamine secretion; and (2) increased expression of H1–H4 HRs. Inhibition of HDC and antagonising H1HR decreased histamine secretion in Mz-ChA-1 cells. Long-term treatment with histamine increased proliferation and VEGF expression in cholangiocarcinoma that was blocked by HDC inhibitor and the H1HR antagonist. In nude mice, histamine increased tumour growth (up to 25%) and VEGF expression whereas inhibition of histamine synthesis (by reduction of HDC) ablated the autocrine stimulation of histamine on tumour growth (~80%) and VEGF expression. No changes in angiogenesis (evaluated by changes in CD31 immunoreactivity) were detected in the in vivo treatment groups. Conclusion The novel concept that an autocrine loop

  12. Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism

    PubMed Central

    Frampton, Gabriel; Invernizzi, Pietro; Bernuzzi, Francesca; Pae, Hae Yong; Quinn, Matthew; Horvat, Darijana; Galindo, Cheryl; Huang, Li; McMillin, Matthew; Cooper, Brandon; Rimassa, Lorenza; DeMorrow, Sharon

    2015-01-01

    Background and objectives Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. The growth factor, progranulin, is overexpressed in a number of tumours. The study aims were to assess the expression of progranulin in cholangiocarcinoma and to determine its effects on tumour growth. Methods The expression and secretion of progranulin were evaluated in multiple cholangiocarcinoma cell lines and in clinical samples from patients with cholangiocarcinoma. The role of interleukin 6 (IL-6)-mediated signalling in the expression of progranulin was assessed using a combination of specific inhibitors and shRNA knockdown techniques. The effect of progranulin on proliferation and Akt activation and subsequent effects of FOXO1 phosphorylation were assessed in vitro. Progranulin knockdown cell lines were established, and the effects on cholangiocarcinoma growth were determined. Results Progranulin expression and secretion were upregulated in cholangiocarcinoma cell lines and tissue, which were in part via IL-6-mediated activation of the ERK1/2/RSK1/C/EBPβ pathway. Blocking any of these signalling molecules, by either pharmacological inhibitors or shRNA, prevented the IL-6-dependent activation of progranulin expression. Treatment of cholangiocarcinoma cells with recombinant progranulin increased cell proliferation in vitro by a mechanism involving Akt phosphorylation leading to phosphorylation and nuclear extrusion of FOXO1. Knockdown of progranulin expression in cholangiocarcinoma cells decreased the expression of proliferating cellular nuclear antigen, a marker of proliferative capacity, and slowed tumour growth in vivo. Conclusions Evidence is presented for a role for progranulin as a novel growth factor regulating cholangiocarcinoma growth. Specific targeting of progranulin may represent an alternative for the development of therapeutic strategies. PMID:22068162

  13. Wound healing and cancer progression in Opisthorchis viverrini associated cholangiocarcinoma.

    PubMed

    Botelho, Monica C; Alves, Helena; Richter, Joachim

    2016-07-01

    Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). It was shown previously that O. viverrini-secreted proteins accelerate wound resolution in human cholangiocytes. Recombinant Ov-GRN-1 (O. viverrini-derived gene encoding granulin-like growth factor) induced angiogenesis and accelerated mouse wound healing. Given the striking similarities of wound healing and cancer progression, here we discuss the major implications of this finding for an infection-induced cancer of major public health significance in the developing world. PMID:27130317

  14. 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

  15. Altered Expression of Oxidative Metabolism Related Genes in Cholangiocarcinomas.

    PubMed

    Aukkanimart, Ratchadawan; Boonmars, Thidarut; Juasook, Amornrat; Sriraj, Pranee; Boonjaraspinyo, Sirintip; Wu, Zhiliang; Laummuanwai, Porntip; Pairojkul, Chawalit; Khuntikeo, Narong; Rattanasuwan, Panaratana

    2015-01-01

    Cholangiocarcinoma (CCA) is a rare but highly fatal cancer for which the molecular mechanisms and diagnostic markers are obscure. We therefore investigated the kinetic expression of isocitrate dehydrogenase-1 (IDH1), isocitrate dehydrogenase-2 (IDH2) and homogentisate 1,2-dioxygenase (HGD) during the tumorigenesis of O. viverrini infection-associated CCA in an animal model, and confirmed down-regulation of expression in human cases of opisthorchiasis-associated CCA through real time PCR. Kinetic expression of HGD, IDH1 and IDH2 in the animal model of O. viverrini infection-induced CCA was correlated with human CCA cases. In the animal model, expression of HGD was decreased at all time points (p<0.01) and expression of both IDH1 and IDH2 was decreased in the CCA group. In human cases, expression of HGD, IDH1 and IDH2 was decreased more than 2 fold in 55 cases (70.5%), 25 cases (32.1%) and 24 cases (30.8%) respectively. The present study suggests that reduction of HGD, IDH1 and IDH2 may be involve in cholangiocarcinoma genesis and may be useful for molecular diagnosis. PMID:26320466

  16. Colon Mass as a Secondary Metastasis from Cholangiocarcinoma: A Diagnostic and Therapeutic Dilemma

    PubMed Central

    Niazi, Azfar

    2016-01-01

    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. PMID:27588228

  17. Colon Mass as a Secondary Metastasis from Cholangiocarcinoma: A Diagnostic and Therapeutic Dilemma.

    PubMed

    Niazi, Azfar; Saif, Muhammad W

    2016-01-01

    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. PMID:27588228

  18. Subtotal gastrectomy for diffused hemorrhagic gastritis induced by radiation, following liver resection for hilar cholangiocarcinoma. A case report

    PubMed Central

    Vasileios, Tatsis; Evaggelia, Peponi; Georgios, Papadopoulos; Periklis, Tsekeris; Michael, Fatouros; Georgios, Glantzounis

    2015-01-01

    Introduction A rare case of hemorrhagic gastritis induced by radiation is presented, which was resistant to conservative treatment and required subtotal gastrectomy. Presentation of case A 56-year-old male was initially undergone right hepatectomy, resection of the extrahepatic biliary tree, hilar lymph node dissection and hepatico-jejunostomy due to advanced hilar cholangiocarcinoma. Because of the extent of the disease, chemo-radiotherapy was administered. The patient received a total radiotherapy dose of 57.6 Gy in 32 sessions. Unfortunately, diffused hemorrhagic gastritis induced by radiation was developed, which was resistant to conservative treatment (endoscopic hemostasis, transfusion). A subtotal gastrectomy was performed. The patient is in good condition 45 months after the liver resection, but with local recurrence. Conclusion In resistant situations to conservative treatment and recurred bleeding of diffused hemorrhagic gastritis induced by radiation, surgical management may have a role. PMID:26686486

  19. JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression

    PubMed Central

    Smirnova, Olga V; Ostroukhova, Tatiana Yu; Bogorad, Roman L

    2007-01-01

    The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development. PMID:18161917

  20. 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

  1. 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.

  2. 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

  3. Intrahepatic Tissue Implantation Represents a Favorable Approach for Establishing Orthotopic Transplantation Hepatocellular Carcinoma Mouse Models.

    PubMed

    Rao, Quan; You, Abin; Guo, Zhenglong; 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 0.5 cm (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

  4. Genetics of familial intrahepatic cholestasis syndromes

    PubMed Central

    van Mil, S W C; Houwen, R; Klomp, L

    2005-01-01

    Bile acids and bile salts have essential functions in the liver and in the small intestine. Their synthesis in the liver provides a metabolic pathway for the catabolism of cholesterol and their detergent properties promote the solubilisation of essential nutrients and vitamins in the small intestine. Inherited conditions that prevent the synthesis of bile acids or their excretion cause cholestasis, or impaired bile flow. These disorders generally lead to severe human liver disease, underscoring the essential role of bile acids in metabolism. Recent advances in the elucidation of gene defects underlying familial cholestasis syndromes has greatly increased knowledge about the process of bile flow. The expression of key proteins involved in bile flow is tightly regulated by transcription factors of the nuclear hormone receptor family, which function as sensors of bile acids and cholesterol. Here we review the genetics of familial cholestasis disorders, the functions of the affected genes in bile flow, and their regulation by bile acids and cholesterol. PMID:15937079

  5. 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. PMID:27095655

  6. 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

  7. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA.

    PubMed

    Kolykhalov, A A; Agapov, E V; Blight, K J; Mihalik, K; Feinstone, S M; Rice, C M

    1997-07-25

    More than 1% of the world's population is chronically infected with hepatitis C virus (HCV). HCV infection can result in acute hepatitis, chronic hepatitis, and cirrhosis, which is strongly associated with development of hepatocellular carcinoma. Genetic studies of HCV replication have been hampered by lack of a bona fide infectious molecular clone. Full-length functional clones of HCV complementary DNA were constructed. RNA transcripts from the clones were found to be infectious and to cause disease in chimpanzees after direct intrahepatic inoculation. This work defines the structure of a functional HCV genome RNA and proves that HCV alone is sufficient to cause disease. PMID:9228008

  8. The Transjugular Intrahepatic Portosystemic Shunt: Technique and Instruments.

    PubMed

    Keller, Frederick S; Farsad, Khashayar; Rösch, Josef

    2016-03-01

    Although transjugular intrahepatic portosystemic shunt (TIPS) was first described in 1971, it took 15 more years for technology, in the form of expandable metallic stents, to be developed to make TIPS a viable, widespread clinical procedure. Currently, expanded polytetrafluoroethylene-covered stent grafts that exhibit significantly greater long-term patency are used for TIPS creation by most interventionalists. TIPS creation requires specific interventional skills, tools, and devices for success. In the hands of skillful, experienced interventional radiologists, TIPS creation is performed safely and successfully in greater than 95% of cases. PMID:26997084

  9. Oncogenic potential of IDH1R132C mutant in cholangiocarcinoma development in mice

    PubMed Central

    Ding, Ning; Che, Li; Li, Xiao-Lei; Liu, Yan; Jiang, Li-Jie; Fan, Biao; Tao, Jun-Yan; Chen, Xin; Ji, Jia-Fu

    2016-01-01

    AIM: To investigate whether IDH1R132C mutant in combination with loss of p53 and activated Notch signaling promotes intrahepatic cholangiocarcinoma (ICC) development. METHODS: We applied hydrodynamic injection and sleeping beauty mediated somatic integration to induce loss of p53 (via shP53), activation of Notch [via intracellular domain of Notch1 (NICD)] and/or overexpression of IDH1R132C mutant together with the sleeping beauty transposase into the mouse liver. Specifically, we co-expressed shP53 and NICD (shP53/NICD, n = 4), shP53 and IDH1R132C (shP53/IDH1R132C, n = 3), NICD and IDH1R132C (NICD/IDH1R132C, n = 4), as well as NICD, shP53 and IDH1R132C (NICD/shP53/IDH1R132C, n = 9) in mice. Mice were monitored for liver tumor development and euthanized at various time points. Liver histology was analyzed by hematoxylin and eosin staining. Molecular features of NICD/shP53/IDH1R132C ICC tumor cells were characterized by Myc tag, Flag tag, Ki-67, p-Erk and p-AKT immunohistochemical staining. Desmoplastic reaction in tumor tissues was studied by Picro-Sirius red staining. RESULTS: We found that co-expression of shP53/NICD, shP53/IDH1R132C or NICD/IDH1R132C did not lead to liver tumor formation. In striking contrast, co-expression of NICD/shP53/IDH1R132C resulted in ICC development in mice (P < 0.01). The tumors could be identified as early as 12 wk post hydrodynamic injection. Tumors rapidly progressed, and by 18 wk post hydrodynamic injection, multiple cystic lesions could be identified on the liver surface. NICD/shP53/IDH1R132C liver tumors shared multiple histological features of human ICCs, including hyperplasia of irregular glands. Importantly, all tumor cells were positive for the biliary epithelial cell marker cytokeratin 19. Extensive collagen fibers could be visualized in tumor tissues using Sirus red staining, duplicating the desmoplastic reaction observed in human ICC. Tumors were highly proliferative and expressed ectopically injected genes. Together these

  10. EFFECT OF THE ANTIPARASITIC DRUG MEBENDAZOLE ON CHOLANGIOCARCINOMA GROWTH.

    PubMed

    Sawanyawisuth, Kanlayanee; Williamson, Tara; Wongkham, Sopit; Riggins, Gregory J

    2014-11-01

    Mebendazole (MBZ) is an anthelmintic drug which inhibits tubulin polymerization and eventually causes apoptosis in target organisms. Antitumor activity of MBZ has been reported in various cancers. The aim of this study was to investigate the effect of MBZ on cholangiocarcinoma (CCA) cells in vitro and in vivo. MBZ reduced cell proliferation in the KKU-M213 cell line associated with a remarkable enhancement of caspase-3 gene expression and enzyme activity. Oral administration of MBZ slightly reduced the growth rate of subcutaneously xeno-grafted KKU-M213 in nude mice. The TUNEL assay showed an increase of apoptotic cell numbers in the xenograft tumor tissue of MBZ-treated mice. The data obtained in this study suggested that MBZ can suppress CCA cell proliferation via caspase-3 activated apoptosis. Further investigation of the antitumor effects of MBZ might support the use of MBZ as an alternative drug for CCA treatment. PMID:26466412

  11. Diagnostic and prognostic serum marker of cholangiocarcinoma (Review)

    PubMed Central

    ZENG, XIAOJUN; TAO, HUALIN

    2015-01-01

    Cholangiocarcinoma (CCA) is a fatal disease that is typically diagnosed late and treated ineffectively. As the morbidity and mortality rates for CCA rise markedly, patietns with CCA currently have a poor prognosis. However, if it were possible to diagnose CCA early while effective treat methods are available, CCA patients would achieve a better quality of life. Therefore, preventing the process of CCA in the early stages is an urgent problem to solve. An accurate, quick and safe method to diagnose early-stage CCA is required. The present review discusses the risk factors, status of research and certain serum markers of CCA. The sensitivity and specificity of these markers differ from each other. To explore the more accurate serum markers may be a novel direction and method for the diagnosis of CCA in laboratory medicine in the future. PMID:25435926

  12. Resectable Cholangiocarcinoma: Reviewing the Role of Adjuvant Strategies

    PubMed Central

    Cidon, E. Una

    2016-01-01

    Cholangiocarcinoma is a very heterogeneous and rare group of neoplasms originating from the perihilar, intra-, or extrahepatic bile duct epithelium. It represents only 3% of gastrointestinal cancers, although their incidence is increasing as its mortality increases. Surgical resection is the only potentially curative option, but unfortunately the resectability rate is low. Overall, these malignancies have got a very poor prognosis with a five-year survival rate of 5–10%. Although the five-year survival rate increases to 25–30% in the cases amenable to surgery, only 10–40% of patients present with resectable disease. Therefore, it is necessary to optimize the benefit of adjuvant strategies after surgery to increase the rate of curability. This study reviewed the role of adjuvant chemotherapy in resectable bile duct cancers. PMID:27199577

  13. Liver transplantation in a patient with cholangiocarcinoma and ulcerative colitis.

    PubMed Central

    Abouna, G. M.; Preshaw, R. M.; Silva, J. L.; Hollingsworth, W. J.; Hershfield, N. B.; Novak, W.; Shaw, D. T.; Vetters, J. M.

    1976-01-01

    A 39 year-old patient with cholangiocarcinoma and pre-existing ulcerative colitis was successfully treated by orthotopic liver transplantation. He was given low doses of prednisone and azathioprine and survived for more than 9 months, dying with tumour metastases, thrombosis of the inferior vena cava and an intra-abdominal abscess. At autopsy the homograft showed little evidence of rejection. Preoperatively the patient had septicemia. Removal of his liver was difficult. The discrepancy between donor and recipient in size of blood vessels and the presence of two hepatic arteries in the donor caused problems during the vascular anastomoses. During the operation cardiac arrest occurred. Postoperatively there were several medical and surgical problems, including intraperitoneal and gastrointestinal hemorrhage, paralysis of the right dome of the diaphragm, sinus bradycardia, massive diuresis, peroneal nerve palsy, and one major and three minor episodes of rejection, which were reversed by giving pulse doses of methylprednisolone intravenously. Images FIG. 1 FIG. 2 FIG. 5 PMID:184908

  14. 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

  15. 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

  16. Expression levels of ROS1/ALK/c-MET and therapeutic efficacy of cetuximab plus chemotherapy in advanced biliary tract cancer.

    PubMed

    Chiang, Nai-Jung; Hsu, Chiun; Chen, Jen-Shi; Tsou, Hsiao-Hui; Shen, Ying-Ying; Chao, Yee; Chen, Ming-Huang; Yeh, Ta-Sen; Shan, Yan-Shen; Huang, Shiu-Feng; Chen, Li-Tzong

    2016-01-01

    Aberrant expression of ROS1, ALK or c-MET (RAM) is implicated in carcinogenesis and cancer drug resistance. We retrospectively evaluated the effect of RAM expression on outcomes for advanced biliary tract cancer patients, who were treated with gemcitabine plus oxaliplatin (GEMOX), with or without cetuximab, in a randomized phase II trial. RAM expression levels on archived tissue sections were scored using immunohistochemistry (IHC). Of 110 tumors with IHC staining for all three markers, 18 were RAM(high) (IHC intensity 3+ for any markers). Ninety-two tumors were RAM(low) (IHC intensity <3+ for all markers). All RAM(high) tumors were intra-hepatic cholangiocarcinomas (IHCC). Of the patients with IHCC (n = 80), median overall survival (OS) of RAM(high) group was inferior to that of the RAM(low) group (5.7 vs. 11.7 months, p = 0.021). In multivariate analysis RAM(high) remained an independently adverse prognostic factor, with a hazard ratio of 2.01 (p = 0.039). In the RAM(low) group, GEMOX treatment with cetuximab significantly improved the disease control rate (68% vs. 41%, p = 0.044), median progression-free survival (7.3 vs. 4.9 months, p = 0.026), and marginally prolonged median OS (14.1 vs 9.6 months, p = 0.056), compared to GEMOX treatment alone. Future trials of anti-EGFR inhibitors for IHCC may consider RAM expression as a patient stratification factor. PMID:27136744

  17. 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

  18. MicroRNA-26a Promotes Cholangiocarcinoma Growth by Activating β-catenin

    PubMed Central

    Zhang, Jinqiang; Han, Chang; Wu, Tong

    2013-01-01

    Background & Aims MicroRNAs (miRNAs) have been implicated in the development and progression of human cancers. We investigated the roles and mechanisms of miR-26a in human cholangiocarcinoma. Methods We used in situ hybridization and quantitative reverse transcriptase polymerase chain reaction to measure expression of miR-26a in human cholangiocarcinoma tissues and cell lines (eg, CCLP1, SG231, HuCCT1, TFK1). Human cholangiocarcinoma cell lines were transduced with lentiviruses that expressed miR-26a1 or a scrambled sequence (control); proliferation and colony formation were analyzed. We analyzed growth of human cholangiocarcinoma cells that overexpress miR-26a or its inhibitor in severe combined immune-deficient mice. Immunoblot, immunoprecipitation, DNA pull-down, immunofluorescence, and luciferase reporter assays were used to measure expression and activity of glycogen synthase kinase (GSK)-3β, β-catenin, and related signaling molecules. Results Human cholangiocarcinoma tissues and cell lines had increased levels of miR-26a compared with the noncancerous biliary epithelial cells. Overexpression of miR-26a increased proliferation of cholangiocarcinoma cells and colony formation in vitro, whereas miR-26 depletion reduced these parameters. In severe combined immune-deficient mice, overexpression of miR-26a by cholangiocarcinoma cells increased tumor growth and overexpression of the miR-26a inhibitor reduced it. GSK-3β messenger RNA was identified as a direct target of miR-26a by computational analysis and experimental assays. miR-26a–mediated reduction of GSK-3β resulted in activation of β-catenin and induction of several downstream genes including c-Myc, cyclinD1, and peroxisome proliferator-activated receptor δ. Depletion of β-catenin partially prevented miR-26a-induced tumor cell proliferation and colony formation. Conclusions miR-26a promotes cholangiocarcinoma growth by inhibition of GSK-3β and subsequent activation of β-catenin. These signaling

  19. Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor

    PubMed Central

    Huang, Li; Ramirez, Jonathan; Frampton, Gabriel A; Golden, Lessie E; Quinn, Matthew A; Pae, Hae Yong; Horvat, Darijana; Liang, Li-jian; DeMorrow, Sharon

    2011-01-01

    Cholangiocarcinomas are devastating cancers of biliary origin with limited treatment options. It has previously been shown that the endocannabinoid anandamide exerts antiproliferative effects on cholangiocarcinoma independent of any known cannabinoid receptors, and via the stabilization of lipid rafts, thereby allowing the recruitment and activation of the Fas death receptor complex. Recently, GPR55 was identified as a putative cannabinoid receptor; therefore, the role of GPR55 in the antiproliferative effects of anandamide was evaluated. GPR55 is expressed in all cholangiocarcinoma cells and liver biopsy samples to a similar level as in non-malignant cholangiocytes. Treatment with either anandamide or the GPR55 agonist, O-1602 reduced cholangiocarcinoma cell proliferation in vitro and in vivo. Furthermore, knocking down the expression of GPR55 prevented the antiproliferative effects of anandamide. Coupled to these effects was an increase in JNK activity. The antiproliferative effects of anandamide could be blocked by pretreatment with a JNK inhibitor and the lipid raft disruptors β-methylcyclodextrin and fillipin III. Activation of GPR55 by anandamide or O-1602 increased the amount of Fas in the lipid raft fractions, which could be blocked by pretreatment with the JNK inhibitor. This data represent the first evidence that GPR55 activation by anandamide can lead to the recruitment and activation of the Fas death receptor complex and that targeting GPR55 activation may be a viable option for the development of therapeutic strategies to treat cholangiocarcinoma. PMID:21464819

  20. Epigallocatechin-gallate modulates chemotherapy-induced apoptosis in human cholangiocarcinoma cells

    PubMed Central

    Lang, Molly; Henson, Roger; Braconi, Chiara; Patel, Tushar

    2014-01-01

    Green tea polyphenols are chemopreventive in several cancer models but their use as adjunctive therapeutic agents for cancer is unknown. Cholangiocarcinomas respond poorly to chemotherapeutic agents, and our aims were to assess the utility of green tea polyphenols as adjuncts to chemotherapy for cholangiocarcinoma. We assessed the effect of purified green tea catechins on chemotherapy-induced apoptosis in KMCH, CC-LP-1 and Mz-ChA-1 human cholangiocarcinoma cells. Epigallocatechin-gallate (EGCG), but not the structurally related catechin epigallocatechin, sensitized cells to apoptosis induced by gemcitabine, mitomycin C, or 5-fluorouracil in vitro. Mitochondrial membrane depolarization, cytosolic cytochrome C expression and apoptosis were increased in cells incubated with EGCG and gemcitabine compared to either agent alone. Furthermore, EGCG decreased in vivo growth and increased the sensitivity to gemcitabine of Mz-ChA-1 cells xenografts in nude mice. In conclusion, the green tea polyphenol EGCG sensitizes human cholangiocarcinoma cells to chemotherapy-induced apoptosis and warrants evaluation as an adjunct to chemotherapy for the treatment of human cholangiocarcinoma. PMID:19226332

  1. Arterial Perfusion Imaging–Defined Subvolume of Intrahepatic Cancer

    SciTech Connect

    Wang, Hesheng; Farjam, Reza; Feng, Mary; Hussain, Hero; Ten Haken, Randall K.; Lawrence, Theodore S.; Cao, Yue

    2014-05-01

    Purpose: To assess whether an increase in a subvolume of intrahepatic tumor with elevated arterial perfusion during radiation therapy (RT) predicts tumor progression after RT. Methods and Materials: Twenty patients with unresectable intrahepatic cancers undergoing RT were enrolled in a prospective, institutional review board–approved study. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed before RT (pre-RT), after delivering ∼60% of the planned dose (mid-RT) and 1 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 to 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 compared with the responsive tumors (P=.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% to 65%), whereas the progressive tumors had an increase of the subvolumes (median, 57%; range, −7% to 165%) (P=.003). Receiver operating characteristic analysis of the percentage change in the subvolume for predicting tumor progression post-RT had an area under the curve 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

  2. 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

  3. 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

  4. Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts.

    PubMed

    Barshes, Neal R; Wyllie, Samuel; Goss, John A

    2005-05-01

    Recent advances in clinical protocols have improved the outcomes of pancreatic islet transplantation (PIT), yet PIT recipients typically require pancreatic islet grafts derived from multiple donors to achieve insulin independence. This along with experimental models of syngeneic PIT, showing that up to 60% of pancreatic islet tissue undergoes apoptosis within the first several days post-transplantation, strongly suggest the involvement of nonalloantigen-specific, inflammatory events in partial destruction of the graft following PIT. Interleukin-1beta appears to be among the most important inflammatory mediators, causing pancreatic islet dysfunction and apoptosis through the up-regulation of inducible nitric oxide (NO) synthase and cyclooxygenase-2. Kupffer cells secrete many molecules, including cytokines, NO, and free radicals, which are known to be directly toxic to the pancreatic islets, and depletion or inhibition of Kupffer cells improves outcomes following experimental PIT. Immediately after transplantation, the pancreatic islets are perfused only by portal vein blood until the process of angiogenesis restores arterial blood flow some 7-10 days later. This delayed vascularization may have implications for the expression of leukocyte adhesion molecules, the effects of free radicals, and the role of ischemia-reperfusion injury. Finally, in the immediate post-transplant period, hepatocytes may contribute to pancreatic islet injury through the production of NO. This paper reviews literature regarding the inflammatory events that follow PIT as well as the pathogenesis of diabetes and the pathophysiology of hepatic ischemia-reperfusion and their relation to the survival and function of intrahepatic pancreatic islet grafts. PMID:15728243

  5. Benign Recurrent Intrahepatic Cholestasis in a Young Adult

    PubMed Central

    Charaniya, Riyaz; Ahuja, Arvind; Mittal, Sakshi; Sahoo, Ratnakar

    2016-01-01

    Benign Recurrent Intrahepatic Cholestasis (BRIC) is a rare genetic disorder characterized by recurrent episodes of cholestatic jaundice. The initial episode of jaundice generally occurs before second decade of life and can persist for several weeks to months before resolving spontaneously. It is a benign disease and even after repeated episodes of jaundice, fibrosis of liver cell does not occur. We had a young adult patient who was having recurrent episodes of cholestatic jaundice with intervening symptom free period for last 20 years. He had first episode of jaundice at the age of eight and since then had several similar episodes. Diagnosis was made by classical clinical presentation and histopathological findings. We intend to report this case due to rarity of this disease in India. PMID:27504332

  6. A large spontaneous intrahepatic portosystemic shunt in a cirrhotic patient

    PubMed Central

    Qi, Xingshun; Ye, Chun; Hou, Yue; Guo, Xiaozhong

    2016-01-01

    Summary A spontaneous portosystemic shunt is a rare malformation of the vessels supplying the liver. This condition often leads to the development of hepatic encephalopathy due to excessive shunting of blood from the portal vein to the inferior vena cava. Some studies have suggested that the presence of spontaneous portosystemic shunts is inversely associated with the appearance of large esophageal varices. Spontaneous intrahepatic portosystemic shunts (SIPSS) are far less frequently observed than extrahepatic portosystemic shunts, which include spleno-gastric-renal shunts, mesenteric-caval shunts, and a large patent umbilical vein. Reported here is a case of decompensated liver cirrhosis with a large SIPSS without any incidence of overt hepatic encephalopathy. PMID:26989653

  7. 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. PMID:22678661

  8. Transjugular Intrahepatic Portosystemic Shunt before and after Liver Transplantation.

    PubMed

    Saad, Wael E

    2014-09-01

    The transjugular intrahepatic portosystemic shunt (TIPS) has long been referred to as a procedure performed as "a bridge to transplantation" since, like many other portosystemic shunts, it decompresses the portal circulation and stabilizes patients but does not definitively treat portal hypertension. One of the major advantages of TIPS over surgically placed portosystemic shunts in the transplant era is that the TIPS is intrahepatic and is removed in situ with the native liver, and usually does not need additional surgery (unlike takedown/ligation of surgical shunts). There are several studies that evaluate TIPS before transplantation-not as a bridge/temporizing measure, but as a prelude to the transplant to decompress the portal circulation and reduce portosystemic engorgement and collaterals and thus, in theory, reduce intraoperative bleeding during liver transplantation. However, these studies, mostly in the transplant literature, have been equivocal from an intraoperative and posttransplant clinical outcome standpoint. TIPS creation in liver transplant recipients is another interesting aspect of TIPS. There has been a debate about whether or not liver transplantation adds additional technical difficulty to the TIPS procedure. Initially, many theories were proposed as to the technical difficulty of TIPS in a transplanted liver. However, recent opinions and published studies demonstrate that whole-graft liver transplantation does not pose a significant technical difficulty to TIPS. Moreover, there are several recent studies evaluating the outcomes of TIPS in liver transplant recipients, showing that outcomes are less favorable when compared with TIPS in nontransplanted patients. This article discusses the results of TIPS as a preoperative prelude to liver transplantation. In addition, it discusses the technical and clinical outcomes of TIPS in liver transplant recipients. PMID:25177084

  9. Measurement of Intrahepatic Pressure during Microwave Ablation in an Ex Vivo Bovine Liver Model

    PubMed Central

    Kim, Hae Jin; Rhim, Hyunchul; Lee, Min Woo; Jeong, Woo Kyoung

    2015-01-01

    Background/Aims We experimented with different ablation methods and two types of microwave antennas to determine whether microwave ablation (MWA) increases intrahepatic pressure and to identify an MWA protocol that avoids increasing intrahepatic pressure. Methods MWA was performed using either a single-step standard ablation or a stepwise increment ablation paired with either a 16-gauge (G) 2-cm antenna or a 14G 4-cm antenna. We compared the maximum pressures and total ablation volumes. Results The mean maximum intrahepatic pressures and ablation volumes were as follows: 16G single-step: 37±33.4 mm Hg and 4.63 cm3; 16G multistep: 31±18.7 mm Hg and 3.75 cm3; 14G single-step: 114±45.4 mm Hg and 15.33 cm3; and 14G multistep: 106±43.8 mm Hg and 10.98 cm3. The intrahepatic pressure rose during MWA, but there were no statistically significant differences between the single and multistep methods when the same gauge antennae were used. The total ablation volume was different only in the 14G groups (p<0.05). Conclusions We demonstrated an increase in intrahepatic pressure during MWA. The multistep method may be used to prevent increased intrahepatic pressure after applying the proper power. PMID:25963083

  10. Lymphoepithelioma-like cholangiocarcinoma: a mimic of hepatocellular carcinoma on imaging features.

    PubMed

    Liao, Tsan-Chieh; Liu, Chien-An; Chiu, Nai-Chi; Yeh, Yi-Chen; Chiou, Yi-You

    2015-04-01

    Primary lymphoepithelioma-like carcinoma in the liver is extremely rare. A few cases of lymphoepithelioma-like cholangiocarcinoma have been reported, but few radiologic features were described. We reviewed 23 cases of lymphoepithelioma-like cholangiocarcinoma reported between 1996 and 2014 and describe a rare case of a 35-year-old woman in our hospital who was diagnosed with lymphoepithelioma-like cholangiocarcinoma of the liver and was a hepatitis B carrier. The tumor (1.6 cm) in our patient appeared to be hypoechoic in sonographic images and hypodense in computed tomography (CT) images. In addition, it was homogeneous hypointense in T1-weighted magnetic resonance (MR) images (MRI) and hyperintense in T2-weighted MRI. Dynamic gadolinium-enhanced MRI showed typical image pattern of hepatocellular carcinoma (HCC). The patient underwent a laparoscopic left hepatic lobectomy, and the resected tumor consisted of well-differentiated glandular cells with extensive lymphocytic infiltration that were immunoreactive to CK (AE1/AE3), CD3, and CD20. In addition, the tumor was positive for Epstein-Barr virus-encoded RNA in situ hybridization. Finally, lymphoepithelioma-like cholangiocarcinoma was diagnosed. In previous studies, the incidence is highest among middle-aged people. Most tumors appeared to be hypodense with either hypovascular or hypervascular patterns in CT images. This case report is the first study to address sonography, CT, and MRI observations and delineate pathologic correlations. We suggest that the imaging pattern of lymphoepithelioma-like cholangiocarcinoma, either the typical cholangiocarcinoma pattern or a mimic of HCC, should be considered in the differential lists for HCC. PMID:25852298

  11. Lymphoepithelioma-like cholangiocarcinoma: A mimic of hepatocellular carcinoma on imaging features

    PubMed Central

    Liao, Tsan-Chieh; Liu, Chien-An; Chiu, Nai-Chi; Yeh, Yi-Chen; Chiou, Yi-You

    2015-01-01

    Primary lymphoepithelioma-like carcinoma in the liver is extremely rare. A few cases of lymphoepithelioma-like cholangiocarcinoma have been reported, but few radiologic features were described. We reviewed 23 cases of lymphoepithelioma-like cholangiocarcinoma reported between 1996 and 2014 and describe a rare case of a 35-year-old woman in our hospital who was diagnosed with lymphoepithelioma-like cholangiocarcinoma of the liver and was a hepatitis B carrier. The tumor (1.6 cm) in our patient appeared to be hypoechoic in sonographic images and hypodense in computed tomography (CT) images. In addition, it was homogeneous hypointense in T1-weighted magnetic resonance (MR) images (MRI) and hyperintense in T2-weighted MRI. Dynamic gadolinium-enhanced MRI showed typical image pattern of hepatocellular carcinoma (HCC). The patient underwent a laparoscopic left hepatic lobectomy, and the resected tumor consisted of well-differentiated glandular cells with extensive lymphocytic infiltration that were immunoreactive to CK (AE1/AE3), CD3, and CD20. In addition, the tumor was positive for Epstein-Barr virus-encoded RNA in situ hybridization. Finally, lymphoepithelioma-like cholangiocarcinoma was diagnosed. In previous studies, the incidence is highest among middle-aged people. Most tumors appeared to be hypodense with either hypovascular or hypervascular patterns in CT images. This case report is the first study to address sonography, CT, and MRI observations and delineate pathologic correlations. We suggest that the imaging pattern of lymphoepithelioma-like cholangiocarcinoma, either the typical cholangiocarcinoma pattern or a mimic of HCC, should be considered in the differential lists for HCC. PMID:25852298

  12. Targeting the IL-6 Dependent Phenotype Can Identify Novel Therapies for Cholangiocarcinoma

    PubMed Central

    Kogure, Takayuki; Huang, Nianyuan; Patel, Tushar

    2010-01-01

    Background The need for new therapies for cholangiocarcinoma is highlighted by their poor prognosis and refractoriness to chemotherapy. Increased production of Interleukin-6 promotes cholangiocarcinoma growth and contributes to chemoresistance by activating cell survival mechanisms. We sought to identify biologically active compounds capable of ameliorating the phenotypic effects of IL-6 expression and to explore their potential therapeutic use for cholangiocarcinoma. Methodology A genomic signature associated with Interleukin-6 expression in Mz-ChA-1 human malignant cholangiocytes was derived. Computational bioinformatics analysis was performed to identify compounds that induced inverse gene changes to the signature. The effect of these compounds on cholangiocarcinoma growth was then experimentally verified in vitro and in vivo. Interactions with other therapeutic agents were evaluated using median effects analysis. Principal Findings A group of structurally related compounds, nitrendipine, nifedipine and felodipine was identified. All three compounds were cytotoxic to Mz-ChA-1 cells with an IC50 for felodipine of 26 µM, nitrendipine, 44 µM and nifedipine, 15 µM. Similar results were observed in KMCH-1, CC-LP-1 and TFK-1 cholangiocarcinoma cell lines. At a fractional effect of 0.5, all three agents were synergistic with either camptothecin or gemcitabine in Mz-ChA-1 cells in vitro. Co-administration of felodipine and gemcitabine decreased the growth of Mz-ChA-1 cell xenografts in nude athymic mice. Conclusions Computational bioinformatics analysis of phenotype-based genomic expression can be used to identify therapeutic agents. Using this drug discovery approach based on targeting a defined tumor associated phenotype, we identified compounds with the potential for therapeutic use in cholangiocarcinoma. PMID:21179572

  13. Upregulated LASP-1 correlates with a malignant phenotype and its potential therapeutic role in human cholangiocarcinoma.

    PubMed

    Zhang, Hongchen; Li, Zhizhen; Chu, Bingfeng; Zhang, Fei; Zhang, Yijian; Ke, Fayong; Chen, Yuanyuan; Xu, Yi; Liu, Shibo; Zhao, Shuai; Liang, Haibin; Weng, Mingzhe; Wu, Xiangsong; Li, Maolan; Wu, Wenguang; Quan, Zhiwei; Liu, Yingbin; Zhang, Yong; Gong, Wei

    2016-06-01

    LIM and SH3 protein 1 (LASP-1) is demonstrated to play a key role in occurrence and development of tumors. However, the expression and function of LASP-1 in cholangiocarcinoma (CCA) remain largely unexplored. This study aimed to investigate the effect of regulated LASP-1 expression on migration, invasion, proliferation, and apoptosis of CCA cells and on tumorigenesis in vivo, and to examine clinico-oncological correlates of LASP-1 expression. Expression of LASP-1 by immunohistochemistry was evaluated in CCA tissue samples. HCCC-9810 and RBE cells were transfected with the LASP-1 small interfering RNA (siRNA), and the effect of knocking down LASP-1 gene expression on cell migration, invasion, proliferation, and apoptosis were examined by wound healing, transwell assays, CCK-8 assays, colony formation, and flow cytometry assays, respectively. Xenograft tumor model was used to validate the effect of downregulated LASP-1 in vivo. Our results demonstrated that LASP-1 was over-expressed in CCA tissues, positively correlating with larger tumors, poor histological differentiation, lymph node metastasis, advanced TNM stage, and poor prognosis in CCA patients (P < 0.05). Downregulation of LASP-1 in HCCC-9810 and RBE cell lines significantly increased cell apoptosis and suppressed cell migration, invasion, and proliferation in vitro and tumorigenesis in vivo. Our results indicate that LASP-1 may essentially involve in the metastasis and growth of CCA and clinical significance of LASP-1 may reside in function as a biomarker to predict prognosis and as a promising therapeutic strategy for CCA patients by the inhibition of LASP-1 expression. PMID:26729195

  14. A Novel Armed Oncolytic Measles Vaccine Virus for the Treatment of Cholangiocarcinoma

    PubMed Central

    Lange, Sebastian; Lampe, Johanna; Bossow, Sascha; Zimmermann, Martina; Neubert, Wolfgang; Bitzer, Michael

    2013-01-01

    Abstract Cholangiocarcinoma (CC) is curable only in early stages by complete surgical resection. Thus, in advanced disease stages in which a complete removal of the tumor mass is no longer possible and palliative chemotherapy achieves only modest success, therapeutics employing new methods of action are desperately needed. Oncolytic viruses employed in clinical studies have been shown to spread preferentially in cancer cells. Beyond that, virotherapeutic cell killing can be enhanced by virus-based expression of suicide genes. We engineered a measles vaccine virus (MeV) vector expressing super cytosine deaminase (SCD), a fusion protein of yeast cytosine deaminase and uracil phosphoribosyltransferase, which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) and subsequently to 5-fluorouridine-monophosphate. This novel vector was evaluated using three different human-derived CC cell lines. In vitro, all CC cell lines were found to be permissive to MeV infection. Partial blocking of MeV-mediated oncolysis could be overcome by employment of the SCD transgene together with administration of 5-FC. In vivo, intratumoral application of SCD-armed MeV together with a systemic 5-FC treatment showed a significant reduction in tumor size in a TFK-1 xenograft mouse model when compared with virus-only treatment. In a second animal experiment employing a HuCCT1 xenograft tumor model, an enhanced SCD-armed MeV vector, in which the SCD transgene was expressed from a different genomic position, led not only to reduced tumor volumes, but also to a significant survival benefit. On the basis of these encouraging preclinical data on employment of SCD-armed MeV for the virotherapeutic treatment of chemotherapy-resistant CC, a clinical virotherapy trial is set up currently. PMID:23550539

  15. A novel armed oncolytic measles vaccine virus for the treatment of cholangiocarcinoma.

    PubMed

    Lange, Sebastian; Lampe, Johanna; Bossow, Sascha; Zimmermann, Martina; Neubert, Wolfgang; Bitzer, Michael; Lauer, Ulrich M

    2013-05-01

    Cholangiocarcinoma (CC) is curable only in early stages by complete surgical resection. Thus, in advanced disease stages in which a complete removal of the tumor mass is no longer possible and palliative chemotherapy achieves only modest success, therapeutics employing new methods of action are desperately needed. Oncolytic viruses employed in clinical studies have been shown to spread preferentially in cancer cells. Beyond that, virotherapeutic cell killing can be enhanced by virus-based expression of suicide genes. We engineered a measles vaccine virus (MeV) vector expressing super cytosine deaminase (SCD), a fusion protein of yeast cytosine deaminase and uracil phosphoribosyltransferase, which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) and subsequently to 5-fluorouridine-monophosphate. This novel vector was evaluated using three different human-derived CC cell lines. In vitro, all CC cell lines were found to be permissive to MeV infection. Partial blocking of MeV-mediated oncolysis could be overcome by employment of the SCD transgene together with administration of 5-FC. In vivo, intratumoral application of SCD-armed MeV together with a systemic 5-FC treatment showed a significant reduction in tumor size in a TFK-1 xenograft mouse model when compared with virus-only treatment. In a second animal experiment employing a HuCCT1 xenograft tumor model, an enhanced SCD-armed MeV vector, in which the SCD transgene was expressed from a different genomic position, led not only to reduced tumor volumes, but also to a significant survival benefit. On the basis of these encouraging preclinical data on employment of SCD-armed MeV for the virotherapeutic treatment of chemotherapy-resistant CC, a clinical virotherapy trial is set up currently. PMID:23550539

  16. The current management of cholangiocarcinoma: A comparison of current guidelines.

    PubMed

    Cai, Yulong; Cheng, Nansheng; Ye, Hui; Li, Fuyu; Song, Peipei; Tang, Wei

    2016-05-23

    Cholangiocarcinoma (CC) accounts for about 3% of all gastrointestinal tumors and is the second most common primary liver tumor. Quality guidelines on CC are needed to guide hepatobiliary surgeons. Here, current guidelines on CC were reviewed to provide useful information and suggestions to help institutes and organizations all around the world to draft better guidelines on CC. Literature databases were electronically searched to identify guidelines or consensus statements regarding CC published from 2002-2016. Nine guidelines were included in this review. Comparison of the current guidelines revealed several inconsistencies. Signs of conflicting views indicated a lack of high level evidence. More studies need to be conducted in areas of contention to help update the guidelines. Organizations and medical societies need to be encouraged to use standard evaluation measures, to restrict tumors to CC or iCC, pCC, or dCC specifically, to give recommendations in accordance with the equipment that is available for diagnosis and treatment in different counties, and to use an appropriate and consistent structure when establishing and drafting guidelines for CC. PMID:27026485

  17. Identifying survival-associated ceRNA clusters in cholangiocarcinoma.

    PubMed

    Wan, Ming; Zhang, Fu-Min; Li, Zheng-Long; Kang, Peng-Cheng; Jiang, Ping-Ming; Wang, Yi-Min; Wang, Zhi-Dong; Zhong, Xiang-Yu; Li, Chun-Long; Wang, Hao; Zhao, Shi-Yong; Cui, Yun-Fu

    2016-09-01

    Competing endogenous RNAs (ceRNAs) represent a novel layer regulations of long non-coding RNAs (lncRNAs) and genes that play important roles in cancer pathogenesis by binding microRNAs (miRNAs). However, the competition mechanism of ceRNAs in cholangiocarcinoma (CHOL) is not fully understood. In this study, we constructed a dysregulated ceRNA competitive network (CCEN) to globally characterize the competing difference between CHOL and normal tissues. Then, we integrated affinity propagation and Kaplan‑Meier (K-M) methods to identify functional clusters associated with survival. A total of 7 key ceRNA clusters were identified. Further functional annotation analyses found that Cluster23 and Cluster32 involved cell based functions, and the loss of ceRNA competitive relations in clusters may contribute to CHOL, by disturbing important biological processes, such as 'Pathway in cancer', MAPK and Neurotrophin signaling pathway. This study provides further insights into understanding the competitive mechanism of ceRNAs in CHOL. PMID:27432084

  18. Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinoma.

    PubMed

    Kawahara, N; Ono, M; Taguchi, K; Okamoto, M; Shimada, M; Takenaka, K; Hayashi, K; Mosher, D F; Sugimachi, K; Tsuneyoshi, M; Kuwano, M

    1998-12-01

    Cholangiocarcinoma (CCC) is relatively hypovascular, in contrast to hepatocellular carcinoma (HCC), which is often highly vascular. We investigated if the diminished vascularity of CCC is related to altered expression of thrombospondin-1 (TSP-1), an antiangiogenic factor, and/or vascular endothelial growth factor (VEGF), a potent angiogenic factor, comparing the relationships with those of high- and low-vascular HCC. We also investigated the relationship between the mutation of the p53 gene and TSP-1 expression or VEGF expression. Northern blot analysis and immunohistochemical staining were performed on surgically resected human CCC and HCC. The ratios of TSP-1 mRNA level in cancer cells versus adjacent noncancerous cells (T/N ratios) were significantly higher in CCC (n = 11) than in HCC with high vascularity (n = 15). In contrast, T/N ratios of VEGF mRNA level in CCC (n = 11) were comparable with those in HCC with low vascularity (n = 5). In CCC, the cancer cells and fibroblasts were positively stained with anti-TSP-1 antibody. We observed that T/N ratios of VEGF mRNA level, but not those of the TSP-1 mRNA level, were significantly correlated with vascularity in HCC. The relative increase in TSP-1 and the relative decrease in VEGF in tumors compared with normal tissue may underlie the limited angiogenesis of CCC. The p53 gene did not affect the expression of TSP-1 in CCC or VEGF in HCC. PMID:9828214

  19. Utilizing signature-score to identify oncogenic pathways of cholangiocarcinoma

    PubMed Central

    Hsiao, Tzu-Hung; Chen, Hung-I Harry; Lu, Jo-Yang; Lin, Pei-Ying; Keller, Charles; Comerford, Sarah; Tomlinson, Gail E.; Chen, Yidong

    2013-01-01

    Extracting maximal information from gene signature sets (GSSs) via microarray-based transcriptional profiling involves assigning function to up and down regulated genes. Here we present a novel sample scoring method called Signature-score (S-score) which can be used to quantify the expression pattern of tumor samples from previously identified gene signature sets. A simulation result demonstrated an improved accuracy and robustness by S-score method comparing with other scoring methods. By applying the S-score method to cholangiocarcinoma (CAC), an aggressive hepatic cancer that arises from bile ducts cells, we identified enriched oncogenic pathways in two large CAC data sets. Thirteen pathways were enriched in CAC compared with normal liver and bile duct. Moreover, using S-score, we were able to dissect correlations between CAC-associated oncogenic pathways and Gene Ontology function. Two major oncogenic clusters and associated functions were identified. Cluster 1, which included beta-catenin and Ras, showed a positive correlation with the cell cycle, while cluster 2, which included TGF-beta, cytokeratin 19 and EpCAM was inversely correlated with immune function. We also used S-score to identify pathways that are differentially expressed in CAC and hepatocellular carcinoma (HCC), the more common subtype of liver cancer. Our results demonstrate the utility and effectiveness of S-score in assigning functional roles to tumor-associated gene signature sets and in identifying potential therapeutic targets for specific liver cancer subtypes. PMID:23905013

  20. Can thymidine phosphorylase be a predictive marker for gemcitabine and doxifluridine combination chemotherapy in cholangiocarcinoma?: case series.

    PubMed

    Kang, Myoung Hee; Lee, Won Sup; Go, Se-Il; Kim, Moon Jin; Lee, Un Seok; Choi, Hye Jung; Kim, Dong Chul; Lee, Jeong-Hee; Kim, Hoon-Gu; Bae, Kyung Soo; Cho, Jae Min

    2014-12-01

    Unresectable cholangiocarcinoma is poorly responded to chemotherapy, especially for the case refractory to gemcitabine and cisplatin. Here, we tested whether high expression of thymidine phosphorylase (TP) can be a predictive biomarker for the indicator for gemcitabine and doxifluridine combination chemotherapy in the cholangiocarcinoma refractory to gemcitabine and cisplatin. Immunohistochemical staining for TP was performed with a biopsy specimen. We accepted the result as positive when more than 10% of cancer cells were stained with moderate intensity. Here, we report 2 cases of TP-positive cholangiocarcinoma well controlled with gemcitabine and doxifluridine combination chemotherapy, which had been refractory to the first line treatment with gemcitabine and cisplatin combination chemotherapy. PMID:25526478

  1. miR-25 Targets TRAIL Death Receptor-4 and Promotes Apoptosis Resistance in Cholangiocarcinoma

    PubMed Central

    Razumilava, Nataliya; Bronk, Steve F.; Smoot, Rory L.; Fingas, Christian D.; Werneburg, Nathan W.; Roberts, Lewis R.; Mott, Justin L.

    2011-01-01

    It has been established that microRNA expression and function contribute to phenotypic features of malignant cells, including resistance to apoptosis. While targets and functional roles for a number of microRNAs have been described in cholangiocarcinoma, many additional microRNAs dysregulated in this tumor have not been assigned functional roles. In this study, we identify elevated miR-25 expression in malignant cholangiocarcinoma cell lines as well as patient samples. In cultured cells, treatment with the Smoothened inhibitor, cyclopamine, reduced miR-25 expression, suggesting Hedgehog signaling stimulates miR-25 production. Functionally, miR-25 was shown to protect cells against TNF-Related Apoptosis-Inducing Ligand (TRAIL)-induced apoptosis. Correspondingly, antagonism of miR-25 in culture sensitized cells to apoptotic death. Computational analysis identified the TRAIL Death Receptor-4 (DR4) as a potential novel miR-25 target, and this prediction was confirmed by immunoblot, cell staining, and reporter assays. Conclusion These data implicate elevated miR-25 levels in the control of tumor cell apoptosis in cholangiocarcinoma. The identification of the novel miR-25 target DR4 provides a mechanism by which miR-25 contributes to evasion of TRIAL-induced cholangiocarcinoma apoptosis. PMID:21953056

  2. Vitamin D3 regulates cell viability in gastric cancer and cholangiocarcinoma.

    PubMed

    Baek, Sungmin; Lee, Young-Suk; Shim, Hye-Eun; Yoon, Sik; Baek, Sun-Yong; Kim, Bong-Seon; Oh, Sae-Ock

    2011-09-01

    A low serum level of vitamin D has been associated with an increased incidence of gastrointestinal tract cancers. However, the effects of vitamin D3 have not been investigated in gastric cancer and cholangiocarcinoma. In the present study, we found that vitamin D3 treatment significantly suppressed the viability of gastric cancer and cholangiocarcinoma cells. Moreover, vitamin D3 had a synergistic effect with other anti-cancer drugs, such as paclitaxel, adriamycin, and vinblastine, for suppressing cell viability. To determine the underlying mechanism involved in the regulation of viability by vitamin D3, we examined the effects of vitamin D3 on expression of hedgehog signaling target genes, which has been associated with gastric cancer and cholangiocarcinoma. Vitamin D3 treatment decreased the level of mRNA expression of patched1, Gli1, cyclin D1, and Bcl2, suggesting the possibility that vitamin D3 may act through regulation of hedgehog signaling. From the above results, we conclude that vitamin D3 regulates cell viability in gastric cancer and cholangiocarcinoma. PMID:22025972

  3. 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. PMID:27356708

  4. 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.

  5. 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

  6. Genetic and environmental determinants of risk for cholangiocarcinoma in Thailand

    PubMed Central

    Miwa, Masanao; Honjo, Satoshi; You, Gyokukou; Tanaka, Masakazu; Uchida, Kazuhiko; Srivatanakul, Petcharin; Khuhaprema, Thiravud; Loilome, Watcharin; Techasen, Anchalee; Wongkham, Chaisiri; Limpaiboon, Temduang; Yongvanit, Puangrat; Wongkham, Sopit

    2014-01-01

    Cholangiocarcinoma (CCA) is a difficult cancer to diagnose in the early stage and to treat by curative resection. The incidence of CCA in the northeast of Thailand is the highest in the world. To make progress in detecting a high risk group and in the prevention and detection of CCA, we have been analyzing the risk factors for CCA. Although liver fluke infection is known to be a risk factor, there are patients who are not infected with the liver fluke and not all people infected with the liver fluke will suffer from the disease. Therefore, it is of the utmost importance to analyze the risk factors and the mechanism to prevent the disease and also to detect the disease in its early stage to save patients’ lives. Through collaboration among Thai and Japanese researchers, we analyzed the genetic and environmental determinants of risks for CCA. Also, we have been trying to develop methods to detect the disease in a non-invasive way. Without repeating findings reported in various reviews on CCA, we will first discuss the environmental and genetic determinants of the risks for CCA. Second, we will discuss the properties of CCA, including the etiological agents and the mechanism of cholangiocarcinogenesis, and finally, we will discuss future approaches to prevent and cure CCA from the standpoint of evidence-based medicine. We will discuss these points by including the data from our laboratories. We would like to emphasize the importance of the genetic data, especially whole genome approaches, to understand the properties of CCA, to find a high risk population for CCA and to develop effective preventative methods to stop the carcinogenic steps toward CCA in the near future. In addition, it is of the upmost importance to develop a non-invasive, specific and sensitive method to detect CCA in its early stage for the application of modern medical approaches to help patients with CCA. PMID:25401000

  7. Anatomy of the Portal Vein Bifurcation: Implication for Transjugular Intrahepatic Portal Systemic Shunts

    SciTech Connect

    Kwok, Philip Chong-hei Ng, Wai Fu; Lam, Christine Suk-yee; Tsui, Polly Po; Faruqi, Asma

    2003-06-15

    Purpose: The relationship of the portalvein bifurcation to the liver capsule in Asians, which is an important landmark for transjugular intrahepatic portosystemic shunt, has not previously been described. Methods: The anatomy of the portal vein bifurcation was studied in 70 adult Chinese cadavers; it was characterized as intrahepatic or extrahepatic. The length of the exposed portion of the right and left portal veins was measured when the bifurcation was extrahepatic. Results: The portal vein bifurcation was intrahepatic in 37 cadavers (53%) and extrahepatic in 33 cadavers (47%). The mean length of the right and left extrahepatic portal veins was 0.96 cm and 0.85 cm respectively.Both were less than or equal to 2 cm in 94% of the cadavers with extrahepatic bifurcation. There was no correlation between the presence of cirrhosis and the location of the portal vein bifurcation(p 1.0). There was no statistically significant difference in liver mass in cadavers with either extrahepatic or intrahepatic bifurcation (p =0.40). Conclusions: These findings suggest that fortransjugular intrahepatic portosystemic shunt placement, a portal vein puncture 2 cm from the bifurcation will be safe in most cases.

  8. Alanine aminotransferase as a predictor of adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy

    PubMed Central

    Ekiz, Ali; Kaya, Basak; Avci, Muhittin Eftal; Polat, Ibrahim; Dikmen, Selin; Yildirim, Gokhan

    2016-01-01

    Objective: To evaluate the associations between adverse perinatal outcomes and serum transaminase levels at the time of diagnosis in patients with intrahepatic cholestasis of pregnancy. Methods: We performed a retrospective analysis of patients hospitalized for evaluation of intrahepatic cholestasis of pregnancy from January 2013 to June 2014 in a tertiary center. Seventy-one patients were divided into two groups according to the presence (Group I) or absence of adverse perinatal outcomes (Group II). Results: The mean aminotransferase levels and conjugated bilirubin levels at the time of diagnosis were significantly higher in Group I than in Group II. Receiver operating characteristic curve analysis revealed that the alanine aminotransferase level could predict adverse perinatal outcomes with 76.47% sensitivity and 78.38% specificity, and the cut-off value was 95 IU/L. Among patients with intrahepatic cholestasis of pregnancy, those with adverse perinatal outcomes were significantly older, had an earlier diagnosis, and had higher alanine aminotransferase levels. Using the 95-IU/L cut-off value, patients with intrahepatic cholestasis of pregnancy had a 3.54-fold increased risk for adverse perinatal outcomes. Conclusions: Patients with intrahepatic cholestasis of pregnancy and high alanineaminotransferase levels should be followed up for possible adverse perinatal outcomes.

  9. The Evolution of Transjugular Intrahepatic Portosystemic Shunt: Tips

    PubMed Central

    Fanelli, Fabrizio

    2014-01-01

    Since Richter's description in the literature in 1989 of the first procedure on human patients, transjugular intrahepatic portosystemic shunt (TIPS) has been worldwide considered as a noninvasive technique to manage portal hypertension complications. TIPS succeeds in lowering the hepatic sinusoidal pressure and in increasing the circulatory flow, thus reducing sodium retention, ascites recurrence, and variceal bleeding. Required several revisions of the shunt TIPS can be performed in case of different conditions such as hepatorenal syndrome, hepatichydrothorax, portal vein thrombosis, and Budd-Chiari syndrome. Most of the previous studies on TIPS procedure were based on the use of bare stents and most patients chose TIPS 2-3 years after traditional treatment, thus making TIPS appear to be not superior to endoscopy in survival rates. Bare stents were associated with higher incidence of shunt failure and consequently patients required several revisions during the follow-up. With the introduction of a dedicated e-PTFE covered stent-graft, these problems were completely solved, No more reinterventions are required with a tremendous improvement of patient's quality of life. One of the main drawbacks of the use of e-PTFE covered stent-graft is higher incidence of hepatic encephalopathy. In those cases refractory to the conventional medical therapy, a shunt reduction must be performed. PMID:27335841

  10. Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Korean Infants

    PubMed Central

    Ko, Jae Sung; Song, Jung Han; Park, Sung Sup

    2007-01-01

    Citrin is a liver-type mitochondrial aspartate-glutamate carrier encoded by the SLC25A13 gene, and its deficiency causes adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Here, the authors investigated clinical findings in Korean infants with NICCD and performed mutation analysis on the SLC25A13 gene. Of 47 patients with neonatal cholestasis, three infants had multiple aminoacidemia (involving citrulline, methionine, and arginine) and galactosemia, and thus were diagnosed as having NICCD. Two of these three showed failure to thrive. The laboratory findings showed hypoproteinemia and hyperammonemia, and liver biopsies revealed micro-macrovesicular fatty liver and cholestasis. The three patients each harbored compound heterozygous 1,638-1,660 dup/ S225X mutation, compound heterozygous 851del4/S225X mutation, and heterozygous 1,638-1,660 dup mutation, respectively. With nutritional manipulation, liver functions were normalized and catch-up growth was achieved. NICCD should be considered in the differential diagnosis of cholestatic jaundice in Korean infants. PMID:18162705

  11. Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy

    PubMed Central

    Ozkan, Sebiha; Ceylan, Yasin; Ozkan, Orhan Veli; Yildirim, Sule

    2015-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is a reversible pregnancy-specific cholestatic condition characterized by pruritus, elevated liver enzymes, and increased serum bile acids. It commences usually in the late second or third trimester, and quickly resolves after delivery. The incidence is higher in South American and Scandinavian countries (9.2%-15.6% and 1.5%, respectively) than in Europe (0.1%-0.2%). The etiology is multifactorial where genetic, endocrine, and environmental factors interact. Maternal outcome is usually benign, whereas fetal complications such as preterm labor, meconium staining, fetal distress, and sudden intrauterine fetal demise not infrequently lead to considerable perinatal morbidity and mortality. Ursodeoxycholic acid is shown to be the most efficient therapeutic agent with proven safety and efficacy. Management of ICP consists of careful monitoring of maternal hepatic function tests and serum bile acid levels in addition to the assessment of fetal well-being and timely delivery after completion of fetal pulmonary maturity. This review focuses on the current concepts about ICP based on recent literature data and presents an update regarding the diagnosis and management of this challenging issue. PMID:26109799

  12. The Evolution of Transjugular Intrahepatic Portosystemic Shunt: Tips.

    PubMed

    Fanelli, Fabrizio

    2014-01-01

    Since Richter's description in the literature in 1989 of the first procedure on human patients, transjugular intrahepatic portosystemic shunt (TIPS) has been worldwide considered as a noninvasive technique to manage portal hypertension complications. TIPS succeeds in lowering the hepatic sinusoidal pressure and in increasing the circulatory flow, thus reducing sodium retention, ascites recurrence, and variceal bleeding. Required several revisions of the shunt TIPS can be performed in case of different conditions such as hepatorenal syndrome, hepatichydrothorax, portal vein thrombosis, and Budd-Chiari syndrome. Most of the previous studies on TIPS procedure were based on the use of bare stents and most patients chose TIPS 2-3 years after traditional treatment, thus making TIPS appear to be not superior to endoscopy in survival rates. Bare stents were associated with higher incidence of shunt failure and consequently patients required several revisions during the follow-up. With the introduction of a dedicated e-PTFE covered stent-graft, these problems were completely solved, No more reinterventions are required with a tremendous improvement of patient's quality of life. One of the main drawbacks of the use of e-PTFE covered stent-graft is higher incidence of hepatic encephalopathy. In those cases refractory to the conventional medical therapy, a shunt reduction must be performed. PMID:27335841

  13. Adaptive trial of personalized radiotherapy for intrahepatic cancer

    PubMed Central

    Pan, Charlie; Ben-Josef, Edgar; Lawrence, Theodore

    2010-01-01

    Primary liver cancer is a major health problem worldwide, with more than 500,000 new cases diagnosed yearly. Preliminary results suggest excellent local control rates of intrahepatic malignancies treated with stereotactic body radiation therapy (SBRT), but some patients have experienced life-threatening toxicity because the current approaches cannot accurately estimate residual liver function after treatment. An early-phase trial of SBRT in hepatocellular carcinoma patients, including those with compromised liver function, is described. Patients are treated with three fractions of SBRT, then treatment is paused for 4 weeks and liver function is evaluated by means of an indocyanine green assay. The size of the final two fractions of SBRT is determined based on the patient’s indocyanine green assay after the first three fractions, so that the therapy is personalized to each patient’s sensitivity to radiation. The sensitivity to the liver of the final two fractions of SBRT, compared with the first three fractions, is re-estimated using a Bayesian model throughout the trial, so this is an adaptive trial. The operating characteristics of the trial are described by Monte Carlo simulations. PMID:20448804

  14. Coincidental Occurrence of Hepatocellular Carcinoma and Cholangiocarcinoma (Collision Tumors) After Liver Transplantation: A Case Report

    PubMed Central

    Al Hamoudi, Waleed; Khalaf, Hatem; Allam, Naglaa; Al Sebayel, Mohammed

    2012-01-01

    Coincidental occurrence of hepatocellular carcinoma (HCC) and cholangiocarcinoma, known as “collision tumors”, within a cirrhotic liver is rare. Herein, we report a case of liver transplantation (LT) in a patient with such collision tumors. Our patient was a 56-year-old woman with hepatitis C virus-related cirrhosis and 2 focal hepatic lesions, measuring 1.5 and 3 cm, in the liver segments 8 and 5, respectively. The lesion on segment 8 showed the typical radiological characteristics of HCC; however, the lesion in segment 5 showed an atypical vascular pattern and was closely associated with the inferior vena cava. Serum alpha-fetoprotein level was normal and serum carbohydrate antigen 19-9 (CA19-9) level was slightly elevated (63 U/mL); the extrahepatic spread of HCC was ruled out. The patient underwent an uneventful deceased-donor LT. Histopathological examination of the explant confirmed that the lesion on segment 8 was an HCC, but surprisingly, the lesion on segment 5 was found to be a cholangiocarcinoma. Six months after LT, the serum CA19-9 level was markedly elevated (255 U/mL), and the patient began experiencing abdominal pain. Magnetic resonance imaging showed enlarged hilar and paraaortic lymph nodes that were suggestive of metastases; histopathological analysis using ultrasound (US)-guided biopsy confirmed recurrent cholangiocarcinoma. Unfortunately, the patient died because of tumor recurrence 9 months after LT. Collision tumor resulting from the co-existence HCC and cholangiocarcinoma in a cirrhotic liver is rare and has a negative impact on the outcome of LT. Atypical vascular pattern and elevated serum CA19-9 levels are suggestive of such tumors; patients with these findings should undergo a targeted biopsy to rule out the coincidental occurrence of HCC and cholangiocarcinoma. PMID:23162598

  15. Lower incidence of complications in endoscopic nasobiliary drainage for hilar cholangiocarcinoma

    PubMed Central

    Kawakubo, Kazumichi; Kawakami, Hiroshi; Kuwatani, Masaki; Haba, Shin; Kudo, Taiki; Taya, Yoko A; Kawahata, Shuhei; Kubota, Yoshimasa; Kubo, Kimitoshi; Eto, Kazunori; Ehira, Nobuyuki; Yamato, Hiroaki; Onodera, Manabu; Sakamoto, Naoya

    2016-01-01

    AIM: To identify the most effective endoscopic biliary drainage technique for patients with hilar cholangiocarcinoma. METHODS: In total, 118 patients with hilar cholangiocarcinoma underwent endoscopic management [endoscopic nasobiliary drainage (ENBD) or endoscopic biliary stenting] as a temporary drainage in our institution between 2009 and 2014. We retrospectively evaluated all complications from initial endoscopic drainage to surgery or palliative treatment. The risk factors for biliary reintervention, post-endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis, and percutaneous transhepatic biliary drainage (PTBD) were also analyzed using patient- and procedure-related characteristics. The risk factors for bilateral drainage were examined in a subgroup analysis of patients who underwent initial unilateral drainage. RESULTS: In total, 137 complications were observed in 92 (78%) patients. Biliary reintervention was required in 83 (70%) patients. ENBD was significantly associated with a low risk of biliary reintervention [odds ratio (OR) = 0.26, 95%CI: 0.08-0.76, P = 0.012]. Post-ERCP pancreatitis was observed in 19 (16%) patients. An absence of endoscopic sphincterotomy was significantly associated with post-ERCP pancreatitis (OR = 3.46, 95%CI: 1.19-10.87, P = 0.023). PTBD was required in 16 (14%) patients, and Bismuth type III or IV cholangiocarcinoma was a significant risk factor (OR = 7.88, 95%CI: 1.33-155.0, P = 0.010). Of 102 patients with initial unilateral drainage, 49 (48%) required bilateral drainage. Endoscopic sphincterotomy (OR = 3.24, 95%CI: 1.27-8.78, P = 0.004) and Bismuth II, III, or IV cholangiocarcinoma (OR = 34.69, 95%CI: 4.88-736.7, P < 0.001) were significant risk factors for bilateral drainage. CONCLUSION: The endoscopic management of hilar cholangiocarcinoma is challenging. ENBD should be selected as a temporary drainage method because of its low risk of complications. PMID:27170839

  16. Transjugular intrahepatic portosystemic shunt with covered stents for hepatocellular carcinoma with portal vein tumor thrombosis

    PubMed Central

    Zhao, Jian-Bo; Feng, Chao; Zhu, Qiao-Hua; He, Xiao-Feng; Li, Yan-Hao; Chen, Yong

    2014-01-01

    AIM: To evaluate transjugular intrahepatic portosystemic shunt (TIPS) with covered stents for hepatocellular carcinoma (HCC) with main portal vein tumor thrombus (PVTT). METHODS: Eleven advanced HCC patients (all male, aged 37-78 years, mean: 54.3 ± 12.7 years) presented with acute massive upper gastrointestinal bleeding (n = 9) or refractory ascites (n = 2) due to tumor thrombus in the main portal vein. The diagnosis of PVTT was based on contrast-enhanced computed tomography and color Doppler sonography. The patients underwent TIPS with covered stents. Clinical characteristics and average survival time of 11 patients were analyzed. Portal vein pressure was assessed before and after TIPS. The follow-up period was 2-18 mo. RESULTS: TIPS with covered stents was successfully completed in all 11 patients. The mean portal vein pressure was reduced from 32.0 to 11.8 mmHg (t = 10.756, P = 0.000). Gastrointestinal bleeding was stopped in nine patients. Refractory ascites completely disappeared in one patient and was alleviated in another. Hepatic encephalopathy was observed in six patients and was resolved with drug therapy. During the follow-up, ultrasound indicated the patency of the shunt and there was no recurrence of symptoms. Death occurred 2-14 mo (mean: 5.67 mo) after TIPS in nine cases, which were all due to multiple organ failure. In the remaining two cases, the patients were still alive at the 16- and 18-mo follow-up, respectively. CONCLUSION: TIPS with covered stents for HCC patients with tumor thrombus in the main portal vein is technically feasible, and short-term efficacy is favorable. PMID:24587637

  17. Transjugular intrahepatic porto-systemic shunt in the elderly: Palliation for complications of portal hypertension

    PubMed Central

    Syed, Mubin I; Karsan, Hetal; Ferral, Hector; Shaikh, Azim; Waheed, Uzma; Akhter, Talal; Gabbard, Alan; Morar, Kamal; Tyrrell, Robert

    2012-01-01

    AIM: To present a dedicated series of transjugular intrahepatic porto-systemic shunts (TIPS) in the elderly since data is sparse on this population group. METHODS: A retrospective review was performed of patients at least 65 years of age who underwent TIPS at our institutions between 1997 and 2010. Twenty-five patients were referred for TIPS. We deemed that 2 patients were not considered appropriate candidates due to their markedly advanced liver disease. Of the 23 patients suitable for TIPS, the indications for TIPS placement was portal hypertension complicated by refractory ascites alone (n = 9), hepatic hydrothorax alone (n = 2), refractory ascites and hydrothorax (n = 1), gastrointestinal bleeding alone (n = 8), gastrointestinal bleeding and ascites (n = 3). RESULTS: Of these 23 attempted TIPS procedure patients, 21 patients had technically successful TIPS procedures. A total of 29 out of 32 TIPS procedures including revisions were successful in 21 patients with a mean age of 72.1 years (range 65-82 years). Three of the procedures were unsuccessful attempts at TIPS and 8 procedures were successful revisions of our existing TIPS. Sixteen of 21 patients who underwent successful TIPS (excluding 5 patients lost to follow-up) were followed for a mean of 14.7 mo. Ascites and/or hydrothorax was controlled following technically successful procedures in 12 of 13 patients. Bleeding was controlled following technically successful procedures in 10 out of 11 patients. CONCLUSION: We have demonstrated that TIPS is an effective procedure to control refractory complications of portal hypertension in elderly patients. PMID:22400084

  18. Bile acid profiles in intrahepatic cholestasis of pregnancy: is this the solution to the enigma of intrahepatic cholestasis of pregnancy?

    PubMed

    Sinakos, Emmanouil; Lindor, Keith D

    2010-03-01

    Intrahepatic cholestasis of pregnancy (ICP) is a rare pregnancy-related liver disease characterized by pruritus, abnormal liver function tests, and an increased risk of fetal complications. An increase in the levels of bile acids is considered to be the diagnostic hallmark of the disease. Ursodeoxycholic acid (UDCA) is currently the most effective therapy. Tribe et al. (this issue) hypothesized that measuring the longitudinal profiles of individual bile acids would provide further insight into the mechanisms of disease. They used a novel chromatography method, which allowed the simultaneous measurement of 15 serum bile acids between 16 weeks of pregnancy and 4 weeks post-partum. ICP was associated with a predominant rise in cholic acid conjugated with taurine and glycine from 24 weeks of pregnancy. UDCA treatment significantly reduced serum taurocholic and taurodeoxycholic acid concentrations. Finally, bile acid profiles were similar in normal pregnancy and pregnancy associated with pruritus gravidarum. The study by Tribe et al. (this issue) presents a significant contribution to the solution of this enigmatic disease by expanding our knowledge on the pathophysiology of ICP and proposing a convenient method for diagnosis and monitoring of this disorder. PMID:20203641

  19. Intrahepatic versus extrahepatic cholestasis. Discrimination with biliary scintigraphy combined with ultrasound

    SciTech Connect

    Lieberman, D.A.; Krishnamurthy, G.T.

    1986-03-01

    Biliary scintigraphy and ultrasound imaging were performed in 52 patients with suspected biliary tract pathology. Results were correlated with the findings of direct cholangiography. Several new innovations in scintigraphic technique were used. The combination of ultrasound imaging and scintigraphy correctly identified biliary tract obstruction in 17 of 19 patients, 12 of whom had dilated bile ducts on ultrasonography. Intrahepatic cholestasis was correctly diagnosed in 11 of 13 patients. Accurate discrimination between intrahepatic and extrahepatic cholestasis was achieved in 28 of 32 patients (88%) with the combined studies. Scintigraphy also provided a correct diagnosis of acute cholecystitis in all 9 patients with surgically confirmed disease. Eleven additional patients with gallbladder or pancreatic disease had normal bile ducts at scintigraphy, which was confirmed with cholangiography. When combined with ultrasound imaging, modern biliary scintigraphy can (a) provide excellent discrimination between intrahepatic and extrahepatic cholestasis and (b) help determine the need for subsequent invasive diagnostic studies in selected patients.

  20. Integrin β6 serves as an immunohistochemical marker for lymph node metastasis and promotes cell invasiveness in cholangiocarcinoma

    PubMed Central

    Li, Zequn; Biswas, Siddhartha; Liang, Benjia; Zou, Xueqing; Shan, Liqun; Li, Yang; Fang, Ruliang; Niu, Jun

    2016-01-01

    Cholangiocarcinoma is a devastating malignancy that is notoriously difficult to diagnose and is associated with a high mortality. Despite extensive efforts to improve the diagnosis and treatment of this neoplasm, limited progress has been made. Integrin β6 is a subtype of integrin that is expressed exclusively on the surfaces of epithelial cells and is associated with a variety of tumors. In the present study, we investigated the expression and roles of integrin β6 in cholangiocarcinoma. β6 upregulation in cholangiocarcinoma was correlated with lymph node metastasis and distant metastasis. Moreover, integrin β6 was identified as a biomarker for the diagnosis of cholangiocarcinoma and an indicator of lymph node metastasis. Integrin β6 significantly promoted the proliferation, migration and invasion of cholangiocarcinoma cells. Furthermore, integrin β6 increased Rac1-GTPase, resulting in the upregulation of metalloproteinase-9 (MMP9) and F-actin polymerization. Taken together, our results indicate that integrin β6 promotes tumor invasiveness in a Rac1-dependent manner and is a potential biomarker for tumor metastasis. Integrin β6 may help to improve the diagnostic accuracy, and targeting β6 may be a novel strategy for the treatment of cholangiocarcinoma. PMID:27440504

  1. Apoptosis of human cholangiocarcinoma cell lines induced by β-escin through mitochondrial caspase-dependent pathway.

    PubMed

    Shen, Dong-Yan; Kang, Jin-He; Song, Wei; Zhang, Wen-Qing; Li, Wen-Gang; Zhao, Yan; Chen, Qing-Xi

    2011-10-01

    The study aimed to evaluate the effects of β-escin on human cholangiocarcinoma cell lines (QBC939, Sk-ChA-1 and MZ-ChA-1) and to explore its mechanisms. Cell growth, cell cycle and apoptosis were investigated, respectively, by MTT assay, single PI and FITC/PI double-staining flow cytometry, and fluorescence microscopy. The protein expression was determined by western blotting. The study revealed that β-escin inhibited cholangiocarcinoma cell growth in a dose- and time-dependent manner, and the cell cycle of QBC939 and Sk-ChA-1 cells was arrested in the G2/M phase, and MZ-ChA-1 cells in G1 phase. Apoptosis of the three cholangiocarcinoma cell lines induced by β-escin was associated with the collapse of the mitochondrial membrane potential and the activation of caspase-3. The apoptotic effect of β-escin was suppressed by pancaspase inhibitor z-VAD-fmk. Molecular dissection revealed that the antiapoptotic protein bcl-2 was down-regulated after cholangiocarcinoma cell lines were treated with β-escin, while the protein levels of bax and p53 were unchanged. Apoptosis was accompanied by an increase in reactive oxygen species (ROS). These results suggest that β-escin induces apoptosis of cholangiocarcinoma cells through an intrinsic mitochondrial caspase-dependent pathway, and the increase in the bax/bcl-2 ratio and ROS may play important roles in β-escin-induced apoptosis of cholangiocarcinoma cells. PMID:21394804

  2. Recombinant vaccinia virus GLV-1h68 is a promising oncolytic vector in the treatment of cholangiocarcinoma.

    PubMed

    Pugalenthi, Amudhan; Mojica, Kelly; Ady, Justin W; Johnsen, Clark; Love, Damon; Chen, Nanhai G; Aguilar, Richard J; Szalay, Aladar A; Fong, Yuman

    2015-12-01

    Although early stage cholangiocarcinoma (CC) can be cured by surgical extirpation, the options for treatment of advanced stage CC are very few and suboptimal. Oncolytic virotherapy using replication-competent vaccinia virus (VACV) is a promising new strategy to treat human cancers. The ability of oncolytic VACV GLV-1h68 to infect, replicate in, and lyse three human CC cell lines was assayed in vitro and in subcutaneous flank xenografts in athymic nude mice. In this study, we have demonstrated that GLV-1h68 effectively infects and lyses three CC cell lines (KMC-1, KMBC, and KMCH-1) in vitro. Expression of the viral marker gene ruc-gfp facilitated real-time monitoring of infection and replication. Furthermore in athymic nude mice, a single dose of GLV-1h68 significantly suppressed tumor growth. The treatment was well tolerated in all animals. Recombinant VACV GLV-1h68 has significant oncolytic ability against CC both in vitro and in vivo. GLV-1h68 has the potential to be used clinically as a therapeutic agent against CC. PMID:26584530

  3. Differential Intrahepatic Phospholipid Zonation in Simple Steatosis and Nonalcoholic Steatohepatitis

    PubMed Central

    Wattacheril, Julia; Seeley, Erin H.; Angel, Peggi; Chen, Heidi; Bowen, Benjamin P.; Lanciault, Christian; M.Caprioli, Richard; Abumrad, Naji; Flynn, Charles Robb

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) occurs frequently in a setting of obesity, dyslipidemia and insulin resistance, but the etiology of the disease, particularly the events favoring progression to nonalcoholic steatohepatitis (NASH) as opposed to simple steatosis (SS), are not fully understood. Based on known zonation patterns in protein, glucose and lipid metabolism, coupled with evidence that phosphatidylcholine may play a role in NASH pathogenesis, we hypothesized that phospholipid zonation exists in liver and that specific phospholipid abundance and distribution may be associated with histologic disease. A survey of normal hepatic protein expression profiles in the Human Protein Atlas revealed pronounced zonation of enzymes involved in lipid utilization and storage, particularly those facilitating phosphatidylcholine (PC) metabolism. Immunohistochemistry of obese normal, SS and NASH liver specimens with anti-phosphatidylethanomine N-methyltransferase (PEMT) antibodies showed a progressive decrease in the zonal distribution of this PC biosynthetic enzyme. Phospholipid quantitation by liquid chromatography mass spectrometry (LC-MS) in hepatic extracts of Class III obese patients with increasing NAFLD severity revealed that most PC species with 32, 34 and 36 carbons as well as total PC abundance was decreased with SS and NASH. Matrix assisted laser desorption ionization - imaging mass spectrometry (MALDI-IMS) imaging revealed strong zonal distributions for 32, 34 and 36 carbon PCs in controls (minimal histologic findings) and SS that was lost in NASH specimens. Specific lipid species such as PC 34∶1 and PC 36∶2 best illustrated this phenomenon. These findings suggest that phospholipid zonation may be associated with the presence of an intrahepatic proinflammatory phenotype and thus have broad implications in the etiopathogenesis of NASH. PMID:23451176

  4. The Influence of Liver Resection on Intrahepatic Tumor Growth.

    PubMed

    Brandt, Hannes H; Nißler, Valérie; Croner, Roland S

    2016-01-01

    The high incidence of tumor recurrence after resection of metastatic liver lesions remains an unsolved problem. Small tumor cell deposits, which are not detectable by routine clinical imaging, may be stimulated by hepatic regeneration factors after liver resection. It is not entirely clear, however, which factors are crucial for tumor recurrence. The presented mouse model may be useful to explore the mechanisms that play a role in the development of recurrent malignant lesions after liver resection. The model combines the easy-to-perform and reproducible techniques of defined amounts of liver tissue removal and tumor induction (by injection) in mice. The animals were treated with either a single laparotomy, a 30% liver resection, or a 70% liver resection. All animals subsequently received a tumor cell injection into the remaining liver tissue. After two weeks of observation, the livers and tumors were evaluated for size and weight and examined by immunohistochemistry. After a 70% liver resection, the tumor volume and weight were significantly increased compared to a laparotomy alone (p <0.05). In addition, immunohistochemistry (Ki67) showed an increased tumor proliferation rate in the resection group (p <0.05). These findings demonstrate the influence of hepatic regeneration mechanisms on intrahepatic tumor growth. Combined with methods like histological workup or RNA analysis, the described mouse model could serve as foundation for a close examination of different factors involved in tumor growth and metastatic disease recurrence within the liver. A considerable number of variables like the length of postoperative observation, the cell line used for injection or the timing of injection and liver resection offer multiple angles when exploring a specific question in the context of post-hepatectomy metastases. The limitations of this procedure are the authorization to perform the procedure on animals, access to an appropriate animal testing facility and acquisition

  5. [Repeat endovascular interventions after transjugular intrahepatic portosystemic shunt (tips) procedures].

    PubMed

    Shipovskiĭ, V N; Tsitsiashvili, M Sh; Saakian, A M; Monakhov, D V; Khuan, Ch; Nechaev, A I

    2010-01-01

    The authors share their experience with transjugular intrahepatic portosystemic shunt (TIPS) procedures preformed in a total of fifty-nine patients diagnosed with and hence operated on for class B and C hepatocirrhosis (according to the Child-Turcotte-Pugh classification), portal hypertension, grade 3 varicosely dilated oesophageal veins, or ascites. Of these, there were 12 women and 47 men (average age 56.3 years). Three types of stents were used: matrix stents (PERICO), self-expanding (ZA-stents, OptiMedsinus-SuperFlex- Visualstents, Zilverstents, SMART), and coated self-expanding stents (Gore Viatorr TIPS Endoprosthesis). Six (11 %) TIPS procedures ended in failure. Of the remaining 53 successful TIPS attempts, thirteen patients developed an in-stent thrombosis at various terms postoperatively, with one patient having experienced it twice Within four postoperative days, thrombosis occurred in three patients, at terms varying from one month to three months in five patients, and from 6 to 12 months in a further five patients. More often thromboses were encountered with the matrix stents (n = 3) 23.0% (PERICO) and self-expanding stents (n = 8) in 61.0% (OptiMed sinus-SuperFlex-Visual). Thromboses were clinically manifested by oesophageal variceal haemorrhage. An in-stent thrombosis was confirmed by means of ultrasonographic duplex scanning (lack of arterial blood flow). The primary stent patency rate following TIPS procedures amounted to 67%. with the secondary assisted graft patency rate equalling 89%. Restoration of the stent's lumen after TIPS procedures by means of endovascular recanalization, rheolytic thrombectomy, balloon angioplasty, and a stent-in-stent technique appears to be a minimally invasive, rather efficient method and virtually the only way to preserve the stent's patency. This technique makes it possible to decrease the rate of recurrent oesophageal variceal haemorrhage. PMID:21032871

  6. Calciphylaxis associated with cholangiocarcinoma treated with low-molecular-weight heparin and vitamin K.

    PubMed

    Riegert-Johnson, D L; Kaur, J S; Pfeifer, E A

    2001-07-01

    Calciphylaxis is a rare disorder of small-vessel calcification and cutaneous infarction associated with chronic renal failure. Rare cases of calciphylaxis not associated with chronic renal failure have been reported with breast cancer, hyperparathyroidism, and alcoholic cirrhosis. To our knowledge, we report the first case of calciphylaxis without chronic renal failure associated with cholangiocarcinoma and the first attempt to treat calciphylaxis with vitamin K. A 56-year-old woman presented with necrotic leg ulceration. She was treated initially with low-molecular-weight heparin, with no effect. A coagulation work-up showed vitamin K deficiency. During vitamin K therapy, the patient had fulminant progression of the calciphylaxis. She died, and an autopsy showed metastatic cholangiocarcinoma. Thrombosis and protein C deficiency have been implicated in the pathophysiology of calciphylaxis. Functional protein C deficiency may be one of several factors contributing to the development of calciphylaxis. Vitamin K therapy was ineffective in our patient and may have been detrimental. PMID:11444409

  7. Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center

    PubMed Central

    Giovannoni, Isabella; Callea, Francesco; Bellacchio, Emanuele; Torre, Giuliano; De Ville De Goyet, Jean; Francalanci, Paola

    2015-01-01

    Familial intrahepatic cholestases (FICs) are a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Three distinct forms are described: FIC1 and FIC2, associated with low/normal GGT level in serum, which are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and defects in ABCB11 encoding bile salt export pump protein, respectively; FIC3, linked to high GGT level, involves impaired biliary phospholipid secretion due to defects in ABCB4, encoding multidrug resistance 3 protein. Different mutations in these genes may cause either a progressive familial intrahepatic cholestasis (PFIC) or a benign recurrent intrahepatic cholestasis (BRIC). For the purposes of the present study we genotyped 27 children with intrahepatic cholestasis, diagnosed on either a clinical or histological basis. Two BRIC, 23 PFIC and 2 BRIC/PFIC were identified. Thirty-four different mutations were found of which 11 were novel. One was a 2Mb deletion (5’UTR- exon 18) in ATP8B1. In another case microsatellite analysis of chromosome 2, including ABCB11, showed uniparental disomy. Two cases were compound heterozygous for BRIC/PFIC2 mutations. Our results highlight the importance of the pathogenic role of novel mutations in the three genes and unusual modes of their transmission. PMID:26678486

  8. Percutaneous rheolytic mechanical thrombectomy in thrombosed direct intrahepatic portosystemic shunt: Report of two cases

    PubMed Central

    Tsetis, Dimitrios; Kehagias, Elias; Samonakis, Dimitrios; Kouroumalis, Elias; Hatzidakis, Adam

    2015-01-01

    We report two patients with Budd–Chiari syndrome, who underwent direct intrahepatic portosystemic shunt complicated by shunt thrombosis. Percutaneous AngioJet mechanical thrombectomy in combination with manual catheter aspiration and balloon disruption of the residual clot was successful, restoring patency of the thrombosed shunt. PMID:26767124

  9. Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center.

    PubMed

    Giovannoni, Isabella; Callea, Francesco; Bellacchio, Emanuele; Torre, Giuliano; De Ville De Goyet, Jean; Francalanci, Paola

    2015-01-01

    Familial intrahepatic cholestases (FICs) are a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Three distinct forms are described: FIC1 and FIC2, associated with low/normal GGT level in serum, which are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and defects in ABCB11 encoding bile salt export pump protein, respectively; FIC3, linked to high GGT level, involves impaired biliary phospholipid secretion due to defects in ABCB4, encoding multidrug resistance 3 protein. Different mutations in these genes may cause either a progressive familial intrahepatic cholestasis (PFIC) or a benign recurrent intrahepatic cholestasis (BRIC). For the purposes of the present study we genotyped 27 children with intrahepatic cholestasis, diagnosed on either a clinical or histological basis. Two BRIC, 23 PFIC and 2 BRIC/PFIC were identified. Thirty-four different mutations were found of which 11 were novel. One was a 2Mb deletion (5'UTR- exon 18) in ATP8B1. In another case microsatellite analysis of chromosome 2, including ABCB11, showed uniparental disomy. Two cases were compound heterozygous for BRIC/PFIC2 mutations. Our results highlight the importance of the pathogenic role of novel mutations in the three genes and unusual modes of their transmission. PMID:26678486

  10. HELLP syndrome preceded by intrahepatic cholestasis of pregnancy: one serious itch

    PubMed Central

    Jebbink, Jiska; Tabbers, Merit; Afink, Gijs; Beuers, Ulrich; Elferink, Ronald Oude; Ris-Stalpers, Carrie; van der Post, Joris

    2014-01-01

    We present four women with seven ongoing pregnancies. Five pregnancies were complicated by intrahepatic cholestasis of pregnancy (ICP) and severe haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome with uncommon maternal morbidity. The combination of ICP and HELLP syndrome has not previously been reported. Awareness is warranted to accurately identify this combination of pregnancy-specific diseases with severe maternal morbidity. PMID:24711473

  11. Minimally invasive management of intrahepatic type II gallbladder perforation: a case report

    PubMed Central

    Alshammari, Dheidan; Tzedakis, Stylianos; Hargat, Julie; Mutter, Didier; Marescaux, Jacques; Pessaux, Patrick

    2016-01-01

    Intrahepatic gallbladder perforation (GBP) is a rare medical entity, which creates a cholecystohepatic communication. We describe the case of a 70-year-old patient who presented with abdominal pain and a Niemeier type II GBP. This case report illustrates the minimally invasive management of a rare and life-threatening pathology. PMID:26904560

  12. Endothelin inhibits cholangiocarcinoma growth by a decrease in the vascular endothelial growth factor expression

    PubMed Central

    Fava, Giammarco; DeMorrow, Sharon; Gaudio, Eugenio; Franchitto, Antonio; Onori, Paolo; Carpino, Guido; Glaser, Shannon; Francis, Heather; Coufal, Monique; Marucci, Luca; Alvaro, Domenico; Marzioni, Marco; Horst, Trenton; Mancinelli, Romina; Benedetti, Antonio; Alpini, Gianfranco

    2009-01-01

    Background: Endothelins (ET-1, ET-2, ET-3) are peptides with vasoactive properties interacting with ETA and ETB receptors. ET-1 inhibits secretin-stimulated ductal secretion (hallmark of cholangiocyte growth) of cholestatic rats by interaction with ET receptors. Aim: The aims of the studies were to evaluate (i) the effect of ET-1 on cholangiocarcinoma growth in Mz-ChA-1 cells and nude mice and (ii) whether ET-1 regulation of cholangiocarcinoma growth is associated with changes in the expression of vascular endothelial growth factor-A (VEGF-A), VEGF-C, VEGF receptor-2 (VEGFR-2) and VEGFR-3. Methods: We determined the expression of ETA and ETB receptors on normal and malignant (Mz-ChA-1) cholangiocytes and human cholangiocarcinoma tissue and the effect of ET-1 on the proliferation and expression of VEGF-A, VEGF-C (regulators of tumour angiogenesis) and its receptors, VEGFR-2 and VEGFR-3, in Mz-ChA-1 cells. In vivo, Mz-ChA-1 cells were injected into the flanks of athymic mice and injections of ET-1 or saline into the tumours were performed daily. The effect of ET-1 on tumour size, cell proliferation, apoptosis, collagen quantity and the expression of VEGF-A and VEGF-C and VEGFR-2 and VEGFR-3 were measured after 73 days. Results: Higher expression of ETA and ETB was observed in malignant compared with normal cholangiocytes. ET-1 inhibited proliferation and VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression of Mz-ChA-1 cells. Chronic ET-1 treatment decreased tumour volume, tumour cell proliferation and VEGF-A and VEGF-C expression but increased apoptosis and collagen tissue deposition compared with controls. Conclusions: Modulation of VEGF-A and VEGF-C (by ET-1) may be important for managing cholangiocarcinoma growth. PMID:19291182

  13. Percutaneous biliary stenting combined with radiotherapy as a treatment for unresectable hilar cholangiocarcinoma

    PubMed Central

    TAN, YONG; ZHU, JIAN-YONG; QIU, BAO-AN; XIA, NIAN-XIN; WANG, JING-HAN

    2015-01-01

    Hilar cholangiocarcinoma is often unresectable at the time of the initial diagnosis, and the provision of a definite palliative benefit is important in patients with unresectable hilar cholangiocarcinoma. The aim of the present study was to evaluate the safety of percutaneous biliary stenting and to analyze whether percutaneous biliary stenting combined with radiotherapy (RT) prolonged the stent patency and survival time of patients. In total, the cases of 38 patients with unresectable hilar cholangiocarcinoma that underwent percutaneous biliary stenting at the Navy General Hospital were retrospectively reviewed in the present study. Uncovered metallic stenting (UMS) combined with RT was administered to 25 patients, and UMS alone was administered to 13 patients. The records of early complications subsequent to percutaneous biliary stenting were collected, and the stent patency and survival times of patients were analyzed and compared between the two groups. The technical success rate of the procedure was 100% and the successful drainage rate was 86.8%. The overall early complication rate was 15.8% and the procedure-associated mortality rate was 2.6%. The median stent patency was 326 days in the UMS+RT group and 196 days in the UMS group (P=0.022). The UMS+RT group (median, 367 days) demonstrated a longer survival time compared with the UMS group (median, 267 days; P=0.025). Percutaneous biliary stenting offers a safe and effective method for the palliative treatment of patients with unresectable hilar cholangiocarcinoma, and percutaneous biliary stenting combined with RT may prolong stent patency and patient survival time. PMID:26622885

  14. Portal vein occlusion after biliary metal stent placement in hilar cholangiocarcinoma.

    PubMed

    Woo, Kyung Hee; Kim, Jin Bae; Chang, Yoon Jung; Kim, Hyo Jung; Baek, Il Hyun; Ko, Jin Seok; Woo, Ji Young; Kim, Hong Dae; Lee, Myung Seok

    2008-06-01

    Acute symptomatic portal vein obstruction related to biliary stenting is an extremely rare but life-threatening complication. This usually occurs in patients with either tumor invasion into the portal vein or pre-existing portal vein thrombus. Therefore, the portal vein should be carefully evaluated before placing a biliary metallic stent in such patients. We describe a case of acute portal vein obstruction after placing metallic biliary stents in a patient with a periductal-infiltrating type of hilar cholangiocarcinoma. PMID:20485610

  15. Effects of thymidine phosphorylase on tumor aggressiveness and 5-fluorouracil sensitivity in cholangiocarcinoma

    PubMed Central

    Thanasai, Jongkonnee; Limpaiboon, Temduang; Jearanaikoon, Patcharee; Sripa, Banchob; Pairojkul, Chawalit; Tantimavanich, Srisurang; Miwa, Masanao

    2010-01-01

    AIM: To evaluate the role of thymidine phosphorylase (TP) in cholangiocarcinoma using small interfering RNA (siRNA). METHODS: A human cholangiocarcinoma-derived cell line KKU-M139, which has a naturally high level of endogenous TP, had TP expression transiently knocked down using siRNA. Cell growth, migration, in vitro angiogenesis, apoptosis, and cytotoxicity were assayed in TP knockdown and wild-type cell lines. RESULTS: TP mRNA and protein expression were decreased by 87.1% ± 0.49% and 72.5% ± 3.2%, respectively, compared with control cells. Inhibition of TP significantly decreased migration of KKU-M139, and suppressed migration and tube formation of human umbilical vein endothelial cells. siRNA also reduced the ability of TP to resist hypoxia-induced apoptosis, while suppression of TP reduced the sensitivity of KKU-M139 to 5-fluorouracil. CONCLUSION: Inhibition of TP may be beneficial in decreasing angiogenesis-dependent growth and migration of cholangiocarcinoma but may diminish the response to 5-fluorouracil chemotherapy. PMID:20355241

  16. 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

  17. 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

  18. Gadoxetate Disodium enhanced spectral dual-energy CT for evaluation of cholangiocarcinoma: Preliminary data

    PubMed Central

    Thomas, John V.; Bolus, David N.; Jackson, Bradford E.; Berland, Lincoln L.; Yester, Michael; Morgan, Desiree E.

    2016-01-01

    Purpose Evaluate Gadoxetate Disodium enhanced dual-energy CT for visualization of perihilar cholangiocarcinoma by exploiting the hepatobiliary uptake of Gadoxetate Disodium and viewing images at the k-edge of gadolinium on the spectrum of simulated monoenergetic energies available with Dual Energy CT. Material and methods In this prospective, IRB-approved study in patients with suspected cholangiocarcinoma, subjects who underwent a clinically indicated Gadoxetate Disodium liver MRI were immediately scanned without further IV contrast administration using rapid kVp-switching dual energy CT (rsDECT). Initial Gadoxetate Disodium dose was the FDA approved clinical dose, 0.025 mmol/kg; after additional IRB/FDA approval, 10 subjects were scanned with 0.05 mmol/kg. Both 50 keV and 70 keV simulated monoenergetic images as well as gadolinium(-water) material density images were viewed qualitatively and measured quantitatively for gadolinium uptake in the hepatic parenchyma and any focal lesions identified. Results Of 18 subjects (mean age 55 years, 10M, 8F, weight 84 kg), eight were scanned with 0.025 mmol/kg (Group 1) and 10 with 0.05 mmol/kg Gadoxetate Disodium (Group 2). Five patients had cholangiocarcinoma (all in Group 1). On synthetic monoenergetic images using standard and double Gadoxetate Disodium dose, the liver parenchyma did not appear enhanced qualitatively. Comparison of mean hepatic parenchymal HU at 50 and 70 keV showed a measurable increase in attenuation at the lower viewing energy, which corresponded to the k-edge of gadolinium. No statistically significant difference was observed on quantitative gadolinium measurement of hepatic parenchyma for single versus double Gadoxetate Disodium dose using rsDECT gadolinium material density images. Of the five cholangiocarcinomas, the tumor to nontumoral hepatic tissue HU differences were 51.1 (32.2) (mean and std dev) and 49.0(26.5) at 50 and 70 keV, respectively. Conclusion In this small pilot population

  19. Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-07-29

    Adult Cholangiocarcinoma; Advanced Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma; BCLC Stage D Adult Hepatocellular Carcinoma; Hilar Cholangiocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Recurrent Adult Liver Carcinoma; Recurrent Childhood Liver Cancer; Recurrent Extrahepatic Bile Duct Carcinoma; Recurrent Gallbladder Carcinoma; Stage II Gallbladder Cancer; Stage III Childhood Hepatocellular Carcinoma; Stage IIIA Gallbladder Cancer; Stage IIIB Gallbladder Cancer; Stage IV Childhood Hepatocellular Carcinoma; Stage IV Distal Bile Duct Cancer; Stage IVA Gallbladder Cancer; Stage IVB Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Carcinoma

  20. Idiopathic Non-Cirrhotic Intrahepatic Portal Hypertension (NCIPH)—Newer Insights into Pathogenesis and Emerging Newer Treatment Options

    PubMed Central

    Goel, Ashish; Elias, Joshua E.; Eapen, Chundamannil E.; Ramakrishna, Banumathi; Elias, Elwyn

    2014-01-01

    Chronic microangiopathy of portal venules results in idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH). Recent data suggest a role for vasoactive factors of portal venous origin in the pathogenesis of this ‘pure’ vasculopathy of the liver. Enteropathies (often silent), are an important ‘driver’ of this disease. NCIPH is under-recognized and often mis-labeled as cryptogenic cirrhosis. Liver biopsy is needed to prove the diagnosis of NCIPH. In these patients, with advancing disease and increased porto-systemic shunting, the portal venous vasoactive factors bypass the liver filter and contribute to the development of pulmonary vascular endothelial disorders—porto-pulmonary hypertension and hepato-pulmonary syndrome as well as mesangiocapillary glomerulonephritis. Prognosis in NCIPH patients is determined by presence, recognition and management of associated disorders. With better understanding of the pathogenesis of NCIPH, newer treatment options are being explored. Imbalance in ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13): vWF (von-Willebrand factor) ratio is documented in NCIPH patients and may have a pathogenic role. Therapeutic interventions to correct this imbalance may prove to be important in the management of NCIPH. PMID:25755567

  1. Placement of multiple metal stents for malignant intrahepatic biliary obstruction via an endoscopic ultrasound-guided choledochoduodenostomy fistula.

    PubMed

    Akiyama, Dai; Hamada, Tsuyoshi; Nakai, Yousuke; Isayama, Hiroyuki; Takagi, Kaoru; Mizuno, Suguru; Koike, Kazuhiko

    2015-01-01

    Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) using a fully-covered self-expandable metal stent (SEMS) is increasingly used as an alternative to failed endoscopic retrograde cholangiopancreatography. An EUS-CDS fistula can provide endoscopists with a new approach route for intrahepatic bile ducts. Here, we present successful placement of multiple SEMS for intrahepatic biliary obstruction via an EUS-CDS fistula. PMID:26462843

  2. Intrahepatic distribution of hepatitis B virus antigens in patients with and without hepatocellular carcinoma

    PubMed Central

    Safaie, Parham; Poongkunran, Mugilan; Kuang, Ping-Ping; Javaid, Asad; Jacobs, Carl; Pohlmann, Rebecca; Nasser, Imad; Lau, Daryl TY

    2016-01-01

    AIM: To study the intrahepatic expression of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) in chronic hepatitis B patients with and without hepatocellular carcinoma. METHODS: A total of 33 chronic hepatitis B patients (mean age of 40.3 ± 2.5 years), comprising of 14 HBeAg positive and 19 HBeAg negative patients; and 13 patients with hepatitis B virus related hepatocellular carcinoma (mean age of 49.6 ± 4.7 years), were included in our study. Immunohistochemical staining for HBcAg and HBsAg was done using standard streptavidin-biotin-immunoperoxidase technique on paraffin-embedded liver biopsies. The HBcAg and HBsAg staining distributions and patterns were described according to a modified classification system. RESULTS: Compared to the HBeAg negative patients, the HBeAg positive patients were younger, had higher mean HBV DNA and alanine transaminases levels. All the HBeAg positive patients had intrahepatic