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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. 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

  8. 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

  9. 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

  10. 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

  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. 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

  19. 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

  20. 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

  1. 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

  2. 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

  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. 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

  6. 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.

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

    PubMed Central

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

    2016-01-01

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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  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. 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.

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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.

  11. 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

  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. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  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. 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.

  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. 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

  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. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. [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

  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. 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

  16. 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

  17. 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

  18. 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

  19. 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

  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. 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

  6. 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

  7. 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

  8. 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

  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