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Sample records for secretin inhibits cholangiocarcinoma

  1. XIAP antagonist embelin inhibited proliferation of cholangiocarcinoma cells.

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    Cody J Wehrkamp

    Full Text Available Cholangiocarcinoma cells are dependent on antiapoptotic signaling for survival and resistance to death stimuli. Recent mechanistic studies have revealed that increased cellular expression of the E3 ubiquitin-protein ligase X-linked inhibitor of apoptosis (XIAP impairs TRAIL- and chemotherapy-induced cytotoxicity, promoting survival of cholangiocarcinoma cells. This study was undertaken to determine if pharmacologic antagonism of XIAP protein was sufficient to sensitize cholangiocarcinoma cells to cell death. We employed malignant cholangiocarcinoma cell lines and used embelin to antagonize XIAP protein. Embelin treatment resulted in decreased XIAP protein levels by 8 hours of treatment with maximal effect at 16 hours in KMCH and Mz-ChA-1 cells. Assessment of nuclear morphology demonstrated a concentration-dependent increase in nuclear staining. Interestingly, embelin induced nuclear morphology changes as a single agent, independent of the addition of TNF-related apoptosis inducing ligand (TRAIL. However, caspase activity assays revealed that increasing embelin concentrations resulted in slight inhibition of caspase activity, not activation. In addition, the use of a pan-caspase inhibitor did not prevent nuclear morphology changes. Finally, embelin treatment of cholangiocarcinoma cells did not induce DNA fragmentation or PARP cleavage. Apoptosis does not appear to contribute to the effects of embelin on cholangiocarcinoma cells. Instead, embelin caused inhibition of cell proliferation and cell cycle analysis indicated that embelin increased the number of cells in S and G2/M phase. Our results demonstrate that embelin decreased proliferation in cholangiocarcinoma cell lines. Embelin treatment resulted in decreased XIAP protein expression, but did not induce or enhance apoptosis. Thus, in cholangiocarcinoma cells the mechanism of action of embelin may not be dependent on apoptosis.

  2. Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Banales, Jesus M; Cardinale, Vincenzo; Carpino, Guido

    2016-01-01

    Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature....... In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim...... to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted....

  3. Inhibition by secretin of the gastric acid responses to meals and to pentagastrin in duodenal ulcer patients.

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    Konturek, S J; Biernat, J; Grzelec, T

    1973-11-01

    The inhibitory effects of intravenous secretion on the gastric acid responses to a meal and to pentagastrin were studied in seven duodenal ulcer patients.A test meal of 10% peptone adjusted to pH 5.0 was introduced into the stomach and the Fordtran and Walsh method was used to measure the gastric acid output by monitoring the rate at which a solution of 0.3 M sodium bicarbonate had to be added to keep the pH of the gastric content constant at the value of 5.0. A constant dose of secretin (1 U/kg-hr) significantly depressed the serum gastrin response to a meal and produced an inhibition of acid secretion by about 70% of the control level. Secretin inhibited the acid response induced by pentagastrin by about 60% and simultaneously provoked a pancreatic bicarbonate output sufficient to neutralize about 60% of the gastric acid output to pentagastrin. We conclude that secretin is a strong inhibitor of gastric secretion in duodenal ulcer patients induced by a meal and by pentagastrin.

  4. Suppression of p53 potentiates chemosensitivity in nutrient-deprived cholangiocarcinoma cells via inhibition of autophagy.

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    Hu, Fei; Guo, Xian-Ling; Zhang, Shan-Shan; Zhao, Qiu-Dong; Li, Rong; Xu, Qing; Wei, Li-Xin

    2017-08-01

    Tumor protein p53 has been intensively studied as a major tumor suppressor. The activation of p53 is associated with various anti-neoplastic functions, including cell senescence, cell cycle arrest, apoptosis and inhibition of angiogenesis. However, the role of p53 in cancer cell chemosensitivity remains unknown. Cholangiocarcinoma cell lines QBC939 and RBE were grown in full-nutrient and nutrient-deprived conditions. The cell lines were treated with 5-fluorouracil or cisplatin and the rate of cell death was determined in these and controls using Cell Counting Kit-8 and microscopy-based methods, including in the presence of autophagy inhibitor 3MA, p53 inhibitor PFT-α or siRNA against p53 or Beclin-1. The present study demonstrated that the inhibition of p53 enhanced the sensitivity to chemotherapeutic agents in nutrient-deprived cholangiocarcinoma cells. Nutrient deprivation-induced autophagy was revealed to be inhibited following inhibition of p53. These data indicate that p53 is important for the activation of autophagy in nutrient-deprived cholangiocarcinoma cells, and thus contributes to cell survival and chemoresistance.

  5. Hydroxytyrosol inhibits cholangiocarcinoma tumor growth: an in vivo and in vitro study.

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    Li, Shuai; Han, Zhiyang; Ma, Yong; Song, Ruipeng; Pei, Tiemin; Zheng, Tongsen; Wang, Jiabei; Xu, Dongsheng; Fang, Xiang; Jiang, Hongchi; Liu, Lianxin

    2014-01-01

    Cholangiocarcinoma (CCA) is a type of digestive tumor that is associated with a high rate of mortality due to the difficulty of early diagnosis and the resistance of this tumor type to chemotherapy. Hydroxytyrosol (HT), which is derived from virgin olive oil (VOO), has recently been reported to inhibit the proliferation of various types of human cancer cells. In the present study, we investigated the effect of HT on CCA. The antiproliferative and proapoptotic effects of HT on CCA were evaluated in the human CCA cell lines TFK-1 and KMBC and the human gallbladder cancer cell line GBS-SD. We also assessed this effect in vivo. We found that 75 µM HT inhibited the proliferation of the TFK-1, KMBC and GBS-SD cell lines. However, 200 µM HT treatment did not affect the proliferation of the human bile duct cell line HIBEpiC. More importantly, HT (250 and 500 mg/kg/day) markedly inhibited the growth of CCA xenografts in mice. G2/M phase cell cycle arrest and apoptosis were observed using flow cytometry and western blotting, and we also noted a time- and dose-dependent inhibition of phospho-ERK, with no changes in total-ERK, during treatment with HT. The present study showed that HT induces cell cycle arrest and apoptosis in vitro and in vivo. These data suggest that HT, which possesses excellent biocompatibility and few side-effects, could be developed as a novel agent against CCA.

  6. Down-regulation of Gab1 inhibits cell proliferation and migration in hilar cholangiocarcinoma.

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    Haiquan Sang

    Full Text Available Hilar cholangiocarcinoma is a highly aggressive malignancy originating from the hilar biliary duct epithelium. Due to few effective comprehensive treatments, the prognosis of hilar cholangiocarcinoma is poor. In this study, immunohistochemistry was first used to detect and analyze the expression of Gab1, VEGFR-2, and MMP-9 in hilar cholangiocarcinoma solid tumors and the relationships to the clinical pathological features. Furthermore, Gab1 and VEGFR-2 siRNA were used to interfere the hilar cholangiocarcinoma cell line ICBD-1 and then detect the PI3K/Akt signaling pathway, MMP-9 levels and malignant biological behaviors of tumor cells. The data showed that 1. Gab1, VEGFR-2, and MMP-9 were highly expressed and positively correlated with each other in hilar cholangiocarcinoma tissues, which were related to lymph node metastasis and differentiation. 2. After Gab1 or VEGFR-2 siRNA interference, PI3K/Akt pathway activity and MMP-9 levels were decreased in ICBD-1 cells. At the same time, cell proliferation decreased, cell cycle arrested in G1 phase, apoptosis increased and invasion decreased. These results suggest that the expression of Gab1, VEGFR-2, and MMP-9 are significantly related to the malignant biological behavior of hilar cholangiocarcinoma. Gab1 regulates growth, apoptosis and invasion through the VEGFR-2/Gab1/PI3K/Akt signaling pathway in hilar cholangiocarcinoma cells and influences the invasion of tumor cells via MMP-9.

  7. Sulfated Galactans from Red Seaweed Gracilaria fisheri Target EGFR and Inhibit Cholangiocarcinoma Cell Proliferation.

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    Sae-Lao, Thannicha; Tohtong, Rutaiwan; Bates, David O; Wongprasert, Kanokpan

    2017-01-01

    Cholangiocarcinoma (CCA) is increasing in incidence worldwide and is resistant to chemotherapeutic agents, making treatment of CCA a major challenge. Previous studies reported that natural sulfated polysaccharides (SPs) disrupted growth factor receptor activation in cancer cells. The present study, therefore, aimed at investigating the antiproliferation effect of sulfated galactans (SG) isolated from the red seaweed Gracilaria fisheri (G. fisheri) on CCA cell lines. Direct binding activity of SG to CCA cells, epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) were determined. The effect of SG on proliferation of CCA cells was investigated. Cell cycle analyses and expression of signaling molecules associated with proliferation were also determined. The results demonstrated that SG bound directly to EGFR. SG inhibited proliferation of various CCA cell lines by inhibiting EGFR and extracellular signal-regulated kinases (ERK) phosphorylation, and inhibited EGF-induced increased cell proliferation. Cell cycle analyses showed that SG induced cell cycle arrest at the G0/G1 phase, down-regulated cell cycle genes and proteins (cyclin-D, cyclin-E, cdk-4, cdk-2), and up-regulated the tumor suppressor protein P53 and the cyclin-dependent kinase inhibitor P21. Taken together, these data demonstrate that SG from G. fisheri inhibited proliferation of CCA cells, and its mechanism of inhibition is mediated, to some extent, by inhibitory effects on EGFR activation and EGFR/ERK signaling pathway. SG presents a potential EGFR targeted molecule, which may be further clinically developed in a combination therapy for CCA treatment.

  8. Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy.

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    Zai-Fa Hong

    Full Text Available Cholangiocarcinoma (CCA, a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K/protein kinase B (AKT/mammalian target of rapamycin (mTOR pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA.

  9. MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma

    DEFF Research Database (Denmark)

    Lampis, Andrea; Carotenuto, Pietro; Vlachogiannis, Georgios

    2017-01-01

    BACKGROUND & AIMS: Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA2...

  10. Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy

    NARCIS (Netherlands)

    Weijer, R.; Broekgaarden, M.; Krekorian, M.; Alles, L.K.; van Wijk, A.C; Mackaaij, C.; Verheij, J.; van der Wal, A.C.; van Gullik, T.M.; Storm, Gerrit; Heger, M.

    2016-01-01

    Background: Photodynamic therapy (PDT) induces tumor cell death by oxidative stress and hypoxia but also survival signaling through activation of hypoxia-inducible factor 1 (HIF-1). Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression

  11. Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy

    NARCIS (Netherlands)

    Weijer, Ruud; Broekgaarden, Mans; Krekorian, Massis; Alles, Lindy K.; van Wijk, Albert C.; Mackaaij, Claire; Verheij, Joanne; van der Wal, Allard C.; van Gulik, Thomas M.; Storm, Gert; Heger, Michal

    2016-01-01

    Photodynamic therapy (PDT) induces tumor cell death by oxidative stress and hypoxia but also survival signaling through activation of hypoxia-inducible factor 1 (HIF-1). Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression levels of

  12. Synthesis of biologically active porcine secretin and [ITyr10] porcine secretin

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    Kofod, Hans

    1991-01-01

    Porcine secretin, [Tyr10] secretin, and [Tyr13] secretin were synthesized by solid phase methodology and purified by stepwise gradient elution from a short reversed-phase column with ethanol and acetic acid as organic modifiers. [Tyr10] secretin and [Tyr13] secretin were iodinated by the chloramine-T...

  13. Effect of cholecystokinin and secretin on somatostatin release from cultured antral cells

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    Buchan, A M; Meloche, R M; Kwok, Y N

    1993-01-01

    Both secretin and cholecystokinin (CCK) inhibit gastric acid secretion. However, their mode of action has yet to be determined. A newly developed primary culture of human antral epithelial cells has been used to examine the effect of secretin and cholecystokinin on somatostatin release....

  14. Bcl-2 degradation is an additional pro-apoptotic effect of polo-like kinase inhibition in cholangiocarcinoma cells

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    Sydor, Svenja; Jafoui, Sami; Wingerter, Lena; Swoboda, Sandra; Mertens, Joachim C; Gerken, Guido; Canbay, Ali; Paul, Andreas; Fingas, Christian D

    2017-01-01

    AIM To examine the influence on apoptotic mechanisms following inhibition of polo-like kinases as therapeutically approach for cholangiocellular cancer treatment. METHODS As most cholangiocarcinomas are chemotherapy-resistant due to mechanisms preventing tumor cell death, we investigated the effect of Cisplatin on cholangiocellular carcinoma (CCA) cell lines KMCH-1 and Mz-Ch-1. Polo-like kinases (PLK) are important regulators of the cell cycle and their inhibition is discussed as a potential therapy while PLK inhibition can regulate apoptotic mediators. Here, cells were treated with PLK inhibitor BI6727 (Volasertib), Cisplatin, and in combination of both compounds. Cell viability was assessed by MTT; apoptosis was measured by DAPI staining and caspase-3/-7 assay. Western blot and qRT-PCR were used to measure expression levels of apoptosis-related molecules Bax and Bcl-2. RESULTS The cell viability in the CCA cell lines KMCH-1 and Mz-Ch-1 was reduced in all treatment conditions compared to vehicle-treated cells. Co-treatment with BI6727 and cisplatin could even enhance the cytotoxic effect of cisplatin single treatment. Thus, co-treatment of cisplatin with BI6727 could slightly enhance the cytotoxic effect of the cisplatin in both cell lines whereas there was evidence of increased apoptosis induction solely in Mz-Ch-1 as compared to KMCH-1. Moreover, PLK inhibition decreases protein levels of Bcl-2; an effect that can be reversed by the proteasomal degradation inhibitor MG-132. In contrast, protein levels of Bax were not found to be altered by PLK inhibition. These findings indicate that cytotoxic effects of Cisplatin in Mz-Ch-1 cells can be enhanced by cotreatment with BI6727. CONCLUSION In conclusion, BI6727 treatment can sensitize CCA cells to cisplatin-induced apoptosis with proteasomal Bcl-2 degradation as an additional pro-apoptotic effect. PMID:28652654

  15. Cerebellar Secretin Modulates Eyeblink Classical Conditioning

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    Fuchs, Jason R.; Robinson, Gain M.; Dean, Aaron M.; Schoenberg, Heidi E.; Williams, Michael R.; Morielli, Anthony D.; Green, John T.

    2014-01-01

    We have previously shown that intracerebellar infusion of the neuropeptide secretin enhances the acquisition phase of eyeblink conditioning (EBC). Here, we sought to test whether endogenous secretin also regulates EBC and to test whether the effect of exogenous and endogenous secretin is specific to acquisition. In Experiment 1, rats received…

  16. Bile Duct Cancer (Cholangiocarcinoma)

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

  17. MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma.

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    Lampis, Andrea; Carotenuto, Pietro; Vlachogiannis, Georgios; Cascione, Luciano; Hedayat, Somaieh; Burke, Rosemary; Clarke, Paul; Bosma, Else; Simbolo, Michele; Scarpa, Aldo; Yu, Sijia; Cole, Rebecca; Smyth, Elizabeth; Mateos, Javier Fernández; Begum, Ruwaida; Hezelova, Blanka; Eltahir, Zakaria; Wotherspoon, Andrew; Fotiadis, Nicos; Bali, Maria Antonietta; Nepal, Chirag; Khan, Khurum; Stubbs, Mark; Hahne, Jens C; Gasparini, Pierluigi; Guzzardo, Vincenza; Croce, Carlo M; Eccles, Suzanne; Fassan, Matteo; Cunningham, David; Andersen, Jesper B; Workman, Paul; Valeri, Nicola; Braconi, Chiara

    2017-11-04

    Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors. We performed a high-throughput screen of 484 small molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids, PDOs). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice. Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heatshockprotein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of PDOs to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21. miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for treatment of CCA and miRNA21 might be a marker of

  18. CRM-1 knockdown inhibits extrahepatic cholangiocarcinoma tumor growth by blocking the nuclear export of p27Kip1.

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    Luo, Jian; Chen, Yongjun; Li, Qiang; Wang, Bing; Zhou, Yanqiong; Lan, Hongzhen

    2016-08-01

    Cholangiocarcinoma is a deadly disease which responds poorly to surgery and conventional chemotherapy or radiotherapy. Early diagnosis is difficult due to the anatomical and biological characteristics of cholangiocarcinoma. Cyclin-dependent kinase inhibitor 1B (p27Kip1) is a cyclin‑dependent kinase inhibitor and in the present study, we found that p27Kip1 expression was suppressed in the nucleus and increased in the cytoplasm in 53 samples of cholangiocarcinoma from patients with highly malignant tumors (poorly-differentiated and tumor-node-metastsis (TNM) stage III-IV) compared with that in samples from 10 patients with chronic cholangitis. The expression of phosphorylated (p-)p27Kip1 (Ser10), one of the phosphorylated forms of p27Kip1, was increased in the patient samples with increasing malignancy and clinical stage. Coincidentally, chromosome region maintenance 1 (CRM-1; also referred to as exportin 1 or Xpo1), a critical protein responsible for protein translocation from the nucleus to the cytoplasm, was also overexpressed in the tumor samples which were poorly differentiated and of a higher clinical stage. Through specific short hairpin RNA (shRNA)-mediated knockdown of CRM-1 in the cholangiocarcinoma cell line QBC939, we identified an elevation of cytoplasmic p27Kip1 and a decrease of nuclear p27Kip1. Furthermore, the viability and colony formation ability of QBC939 cells was largely reduced with G1 arrest. Consistent with the findings of the in vitro experiments, in a xenograft mouse model, the tumors formed in the CRM-1 knockdown group were markedly smaller and weighed less than those in the control group in vivo. Taken together, these findings demonstrated that the interplay between CRM-1 and p27Kip1 may provide potentially potent biomarkers and functional targets for the development of future cholangiocarcinoma treatments.

  19. Imaging of perihilar cholangiocarcinoma.

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    Engelbrecht, Marc Rudi; Katz, Seth S; van Gulik, Thomas M; Laméris, Johan S; van Delden, Otto M

    2015-04-01

    The purpose of this article is to review imaging workup of perihilar cholangiocarcinoma, including MDCT and MRI protocols, imaging findings, differential diagnosis, and staging. A reporting template is included. Imaging plays a central role in the detection, differential diagnosis, and staging of perihilar cholangiocarcinoma.

  20. Insulin release by glucagon and secretin

    DEFF Research Database (Denmark)

    Kofod, Hans; Andreu, D; Thams, P

    1988-01-01

    Secretin and glucagon potentiate glucose-induced insulin release. We have compared the effects of secretin and glucagon with that of four hybrid molecules of the two hormones on insulin release and formation of cyclic AMP (cAMP) in isolated mouse pancreatic islets. All six peptides potentiated...... the release of insulin at 10 mM D-glucose, and their effects were indistinguishable with respect to the dynamics of release, dose-response relationship, and glucose dependency. However, measurements of cAMP accumulation in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-4) M...... potentiating effects of secretin and glucagon on glucose-induced insulin release, their modes of action may be different....

  1. Intravenous secretin for autism spectrum disorders (ASD).

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    Williams, Katrina; Wray, John A; Wheeler, Danielle M

    2012-04-18

    In 1998 secretin, a gastrointestinal hormone, was suggested as an effective treatment for autism spectrum disorders (ASD) based on anecdotal evidence. To assess whether intravenous secretin improves the core features of ASD, other aspects of behaviour or function such as self-injurious behaviour, and the quality of life of affected individuals and their carers. We also assessed whether secretin causes harm. This is an updated version of our review of this topic originally published in 2005. We searched CENTRAL (2010 Issue 1), MEDLINE (1950 to January 2010) , EMBASE (1980 to 2010 Week 2), PsycINFO (1806 to 2010 Week 2), CINAHL (1938 to January 2010), ERIC (1966 to January 2010), Sociological Abstracts (1952 to January 2010). Sociofile and HealthStar were searched in March 2005 when this review was first published, but were not available for this update. Records were limited to studies published since 1998 as this is when secretin was first proposed as a possible treatment for ASD. We searched reference lists of trials and reviews; we also contacted experts and trialists to find unpublished studies. Randomised controlled trials of intravenous secretin compared to a placebo treatment in children or adults diagnosed with ASD, where at least one standardised outcome measure was reported. Sixteen studies met the inclusion criteria but for two of these, conducted by Repligen, the only available multisite data were reported in press releases. All outcome data from the other 14 trials were continuous. Where trials used cross-over designs, we conducted analysis on results from the first treatment phase. Where mean change from baseline was reported, we used this in preference to post-treatment scores for meta-analyses or forest plots. Meta-analysis was able to be attempted for only one outcome (Childhood Autism Rating Scale). Insufficient data were available to conduct sensitivity or subgroup analyses to assess the impact of study quality, clinical differences in the

  2. Origin of secretin receptor precedes the advent of tetrapoda: evidence on the separated origins of secretin and orexin.

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    Tam, Janice K V; Lau, Kwan-Wa; Lee, Leo T O; Chu, Jessica Y S; Ng, Kwong-Man; Fournier, Alain; Vaudry, Hubert; Chow, Billy K C

    2011-04-29

    At present, secretin and its receptor have only been identified in mammals, and the origin of this ligand-receptor pair in early vertebrates is unclear. In addition, the elusive similarities of secretin and orexin in terms of both structures and functions suggest a common ancestral origin early in the vertebrate lineage. In this article, with the cloning and functional characterization of secretin receptors from lungfish and X. laevis as well as frog (X. laevis and Rana rugulosa) secretins, we provide evidence that the secretin ligand-receptor pair has already diverged and become highly specific by the emergence of tetrapods. The secretin receptor-like sequence cloned from lungfish indicates that the secretin receptor was descended from a VPAC-like receptor prior the advent of sarcopterygians. To clarify the controversial relationship of secretin and orexin, orexin type-2 receptor was cloned from X. laevis. We demonstrated that, in frog, secretin and orexin could activate their mutual receptors, indicating their coordinated complementary role in mediating physiological processes in non-mammalian vertebrates. However, among the peptides in the secretin/glucagon superfamily, secretin was found to be the only peptide that could activate the orexin receptor. We therefore hypothesize that secretin and orexin are of different ancestral origins early in the vertebrate lineage.

  3. Origin of secretin receptor precedes the advent of tetrapoda: evidence on the separated origins of secretin and orexin.

    Directory of Open Access Journals (Sweden)

    Janice K V Tam

    Full Text Available At present, secretin and its receptor have only been identified in mammals, and the origin of this ligand-receptor pair in early vertebrates is unclear. In addition, the elusive similarities of secretin and orexin in terms of both structures and functions suggest a common ancestral origin early in the vertebrate lineage. In this article, with the cloning and functional characterization of secretin receptors from lungfish and X. laevis as well as frog (X. laevis and Rana rugulosa secretins, we provide evidence that the secretin ligand-receptor pair has already diverged and become highly specific by the emergence of tetrapods. The secretin receptor-like sequence cloned from lungfish indicates that the secretin receptor was descended from a VPAC-like receptor prior the advent of sarcopterygians. To clarify the controversial relationship of secretin and orexin, orexin type-2 receptor was cloned from X. laevis. We demonstrated that, in frog, secretin and orexin could activate their mutual receptors, indicating their coordinated complementary role in mediating physiological processes in non-mammalian vertebrates. However, among the peptides in the secretin/glucagon superfamily, secretin was found to be the only peptide that could activate the orexin receptor. We therefore hypothesize that secretin and orexin are of different ancestral origins early in the vertebrate lineage.

  4. Differential Effects of Secretin-fragments imply a dual Mechanism of Action for Secretin

    DEFF Research Database (Denmark)

    Kofod, Hans; Thams, P; Holst, J J

    1991-01-01

    on the insulin release. Glucagon release seen after intact secretin could not be shown for any of the smaller fragments. Accumulation of cAMP in the islets as seen with secretin, could at 10 mmol/L D-glucose only be demonstrated with S22-27 or S19-27 but not with S10-18 or S1-6. Our results indicate that full...

  5. Teaching the Role of Secretin in the Regulation of Gastric Acid Secretion Using a Classic Paper by Johnson and Grossman

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    Walton, Kristen L. W.

    2009-01-01

    The regulation of gastric acid secretion has been the subject of investigation for over a century. Inhibition of gastrin-induced acid secretion by the intestine-derived hormone secretin provides a classic physiological example of negative feedback in the gastrointestinal tract. A classic paper by Leonard R. Johnson and Morton I. Grossman clearly…

  6. Endoscopic tissue diagnosis of cholangiocarcinoma.

    LENUS (Irish Health Repository)

    Harewood, Gavin C

    2008-09-01

    The extremely poor outcome in patients with cholangiocarcinoma, in large part, reflects the late presentation of these tumors and the challenging nature of establishing a tissue diagnosis. Establishing a diagnosis of cholangiocarcinoma requires obtaining evidence of malignancy from sampling of the epithelium of the biliary tract, which has proven to be challenging. Although endoscopic ultrasound-guided fine needle aspiration performs slightly better than endoscopic retrograde cholangiopancreatography in diagnosing cholangiocarcinoma, both endoscopic approaches demonstrate disappointing performance characteristics.

  7. Epigenome dysregulation in cholangiocarcinoma

    DEFF Research Database (Denmark)

    O'Rourke, Colm J; Munoz-Garrido, Patricia; Aguayo, Esmeralda L

    2017-01-01

    Epigenomics is a fast-evolving field of research that has lately attracted considerable interest, mainly due to the reversibility of epigenetic marks. Clinically, among solid tumors, the field is still limited. In cholangiocarcinoma (CCA) it is well known that the epigenetic landscape is deregula...... on the role of non-coding RNA (ncRNA) interactions, DNA methylation, post-translational modifications (PTMs) of histones and chromatin remodeling complexes....

  8. Resection of Perihilar Cholangiocarcinoma.

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

    2016-04-01

    Perihilar cholangiocarcinoma presents at the biliary and vascular junction of the hepatic hilum with a tendency to extend longitudinally into segmental bile ducts. Most patients show metastatic or unresectable disease at time of presentation or surgical exploration. In patients eligible for surgical resection, challenges are to achieve negative bile duct margins, adequate liver remnant function, and adequate portal and arterial inflow to the liver remnant. Surgical treatment is characterized by high rates of postoperative morbidity and mortality. This article reviews the various strategies and techniques, the role of staging laparoscopy, intraoperative frozen section, caudate lobectomy, and vascular reconstruction. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. The serendipitous origin of chordate secretin peptide family members

    Directory of Open Access Journals (Sweden)

    Gomes Ana S

    2010-05-01

    Full Text Available Abstract Background The secretin family is a pleotropic group of brain-gut peptides with affinity for class 2 G-protein coupled receptors (secretin family GPCRs proposed to have emerged early in the metazoan radiation via gene or genome duplications. In human, 10 members exist and sequence and functional homologues and ligand-receptor pairs have been characterised in representatives of most vertebrate classes. Secretin-like family GPCR homologues have also been isolated in non-vertebrate genomes however their corresponding ligands have not been convincingly identified and their evolution remains enigmatic. Results In silico sequence comparisons failed to retrieve a non-vertebrate (porifera, cnidaria, protostome and early deuterostome secretin family homologue. In contrast, secretin family members were identified in lamprey, several teleosts and tetrapods and comparative studies revealed that sequence and structure is in general maintained. Sequence comparisons and phylogenetic analysis revealed that PACAP, VIP and GCG are the most highly conserved members and two major peptide subfamilies exist; i PACAP-like which includes PACAP, PRP, VIP, PH, GHRH, SCT and ii GCG-like which includes GCG, GLP1, GLP2 and GIP. Conserved regions flanking secretin family members were established by comparative analysis of the Takifugu, Xenopus, chicken and human genomes and gene homologues were identified in nematode, Drosophila and Ciona genomes but no gene linkage occurred. However, in Drosophila and nematode genes which flank vertebrate secretin family members were identified in the same chromosome. Conclusions Receptors of the secretin-like family GPCRs are present in protostomes but no sequence homologues of the vertebrate cognate ligands have been identified. It has not been possible to determine when the ligands evolved but it seems likely that it was after the protostome-deuterostome divergence from an exon that was part of an existing gene or gene fragment

  10. Glucagon- and secretin-related peptides differentially alter ocular growth and the development of form-deprivation myopia in chicks.

    Science.gov (United States)

    Vessey, Kirstan A; Rushforth, David A; Stell, William K

    2005-11-01

    Exogenous glucagon inhibits the induction of myopia in chicks, but the endogenous peptide and receptor that regulate eye growth are unknown. The purpose of this study was to determine which peptides and receptors in the glucagon-secretin family play a role in the control of ocular growth. The effect of intravitreally injected peptides on the development of form-deprivation (FD) myopia and on the growth of eyes with unrestricted vision was determined by refraction and A-scan ultrasonography. Chicks received three injections, one every 48 hours, of secretin-related peptides (porcine secretin, human peptide histidine-isoleucine-amide-27, vasoactive intestinal peptide [VIP], VIP fragment 6-28, or pituitary adenylate cyclase-activating polypeptide; 10(-8)-10(-4) M in 20 microL) or five injections of proglucagon-derived peptides (human glucagon, oxyntomodulin, miniglucagon, or glucagon-like peptide [GLP]-2 or chicken GLP-1). Immunohistochemistry was used to detect proglucagon-derived peptides in the eye. Secretin-related peptides had no effect on FD myopia, whereas some proglucagon-derived peptides did. Both glucagon and oxyntomodulin dose-dependently inhibited development of myopia, primarily by inhibition of vitreous chamber elongation (EC(50) = 10(-4) M and 10(-5.5) M, respectively). GLP-1 increased deprivation-induced myopic refractive error by altering anterior chamber development. None of the peptides significantly affected refractive error in eyes with unrestricted vision, although changes in anterior and posterior eye growth were observed in response to glucagon, oxyntomodulin, GLP-1, and miniglucagon. Immunoreactivity for miniglucagon and GLP-1 was colocalized in glucagon-immunoreactive amacrine cells. Prevention of experimental myopia by exogenous glucagon is mediated by receptors selective for glucagon and oxyntomodulin, indicating that glucagon-like peptides and receptors are probable endogenous retinal regulators of the development of myopia.

  11. Secretin, its discovery, and the introduction of the hormone concept

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; de Muckadell, O B

    2000-01-01

    The English physician E. H. Starling discovered in collaboration with the physiologist W. M. Bayliss secretin, the first hormone, in 1902. Three years later they introduced the hormone concept with recognition of chemical regulation, early regulatory physiology took a major step forward. The isol......The English physician E. H. Starling discovered in collaboration with the physiologist W. M. Bayliss secretin, the first hormone, in 1902. Three years later they introduced the hormone concept with recognition of chemical regulation, early regulatory physiology took a major step forward...

  12. Stathmin decreases cholangiocarcinoma cell line sensitivity to staurosporine-triggered apoptosis via the induction of ERK and Akt signaling

    Science.gov (United States)

    Bo, Xiaobo; Wang, Yaojie; Wang, Jiwen; Shen, Sheng; Liu, Han; Suo, Tao; Pan, Hongtao; Ai, Zhilong; Liu, Houbao

    2017-01-01

    Cholangiocarcinoma is a rare, but highly fatal malignancy. However, the intrinsic mechanism involved in its tumorigenesis remains obscure. An urgent need remains for a promising target for cholangiocarcinoma biological therapies. Based on comparative proteomical technologies, we found 253 and 231 different spots in gallbladder tumor cell lines and cholangiocarcinoma cell lines, respectively, relative to non-malignant cells. Using Mass Spectrometry (MS) and database searching, we chose seven differentially expressed proteins. High Stathmin expression was found in both cholangiocarcinoma and gallbladder carcinoma cells. Stathmin expression was validated using immunohistochemistry and western blot in cholangiocarcinoma tissue samples and peritumoral tissue. It was further revealed that high Stathmin expression was associated with the repression of staurosporine-induced apoptosis in the cholangiocarcinoma cell. Moreover, we found that Stathmin promoted cancer cell proliferation and inhibited its apoptosis through protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) signaling. Integrin, β1 appears to serve as a partner of Stathmin induction of ERK and Akt signaling by inhibiting apoptosis in the cholangiocarcinoma cell. Understanding the regulation of anti-apoptosis effect by Stathmin might provide new insight into how to overcome therapeutic resistance in cholangiocarcinoma. PMID:28178656

  13. Prolonged oxidative stress down-regulates Early B cell factor 1 with inhibition of its tumor suppressive function against cholangiocarcinoma genesis.

    Science.gov (United States)

    Armartmuntree, Napat; Murata, Mariko; Techasen, Anchalee; Yongvanit, Puangrat; Loilome, Watcharin; Namwat, Nisana; Pairojkul, Chawalit; Sakonsinsiri, Chadamas; Pinlaor, Somchai; Thanan, Raynoo

    2018-04-01

    Early B cell factor 1 (EBF1) is a transcription factor involved in the differentiation of several stem cell lineages and it is a negative regulator of estrogen receptors. EBF1 is down-regulated in many tumors, and is believed to play suppressive roles in cancer promotion and progression. However, the functional roles of EBF1 in carcinogenesis are unclear. Liver fluke-infection-associated cholangiocarcinoma (CCA) is an oxidative stress-driven cancer of bile duct epithelium. In this study, we investigated EBF1 expression in tissues from CCA patients, CCA cell lines (KKU-213, KKU-214 and KKU-156), cholangiocyte (MMNK1) and its oxidative stress-resistant (ox-MMNK1-L) cell lines. The formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) was used as an oxidative stress marker. Our results revealed that EBF1 expression was suppressed in cancer cells compared with the individual normal bile duct cells at tumor adjacent areas of CCA tissues. CCA patients with low EBF1 expression and high formation of 8-oxodG were shown to correlate with poor survival. Moreover, EBF1 was suppressed in the oxidative stress-resistant cell line and all of CCA cell lines compared to the cholangiocyte cell line. This suggests that prolonged oxidative stress suppressed EBF1 expression and the reduced EBF1 level may facilitate CCA genesis. To elucidate the significance of EBF1 suppression in CCA genesis, EBF1 expression of the MMNK1 cell line was down-regulated by siRNA technique, and its effects on stem cell properties (CD133 and Oct3/4 expressions), tumorigenic properties (cell proliferation, wound healing and cell migration), estrogen responsive gene (TFF1), estrogen-stimulated wound healing, and cell migration were examined. The results showed that CD133, Oct3/4 and TFF1 expression levels, wound healing, and cell migration of EBF1 knockdown-MMNK1 cells were significantly increased. Also, cell migration of EBF1-knockdown cells was significantly enhanced after 17β-estradiol treatment. Our

  14. Monolobar Caroli's Disease and Cholangiocarcinoma

    Science.gov (United States)

    Abdalla, Eddie K.; Forsmark, Christopher E.; Lauwers, Gregory Y.; Vauthey, J. Nicolas

    1999-01-01

    Caroli's Disease (CD) is a rare congenital disorder characterized by cystic dilatation of the intrahepatic bile ducts. This report describes a patient with cholangiocarcinoma arising in the setting of monolobar CD. In spite of detailed investigations including biliary enteric bypass and endoscopic retrograde cholangiography, the diagnosis of mucinous cholangiocarcinoma (CCA) was not made for almost one year. The presentation, diagnosis and treatment of monolobar CD and the association between monolobar CD and biliary tract cancer are discussed. Hepatic resection is the treatment of choice for monolobar CD. PMID:10468120

  15. Cancer review: Cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Yezaz Ahmed Ghouri

    2015-01-01

    Full Text Available 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.

  16. Molecular pathogenesis of intrahepatic cholangiocarcinoma

    DEFF Research Database (Denmark)

    Andersen, Jesper Bøje

    2014-01-01

    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...

  17. Molecular profiling of intrahepatic cholangiocarcinoma

    DEFF Research Database (Denmark)

    Oliveira, Douglas V N P; Zhang, Shanshan; Chen, Xin

    2017-01-01

    INTRODUCTION: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent primary tumor of the liver and a highly lethal disease. Therapeutic options for advanced iCCA are limited and ineffective due to the largely incomplete understanding of the molecular pathogenesis of this deadly tumor...

  18. Secretin and its C-terminal hexapeptide potentiates insulin release in mouse islets

    DEFF Research Database (Denmark)

    Kofod, Hans; Hansen, B; Lernmark, A

    1986-01-01

    [Val-NH2, S-(24-27)] or only marginally [S-(26-27), S-(23-27)] potentiating effects on insulin release in the presence of 10 mmol/l D-glucose. The effects of secretin and S-(22-27) were not influenced by 2 mmol/l glutamine. The intact hormone and the five synthetic peptides as well as Val-NH2 had...... no stimulatory effect on islet glutamate dehydrogenase activity. In fact, S-(23-27), S-(24-27), and S-(25-27) inhibited the islet glutamate dehydrogenase activity, the activation by which amino acids and amino acid derivatives are known to elicit a potentiation of insulin release. Our results suggest that the C...

  19. Structure and Function of Cross-class Complexes of G Protein-coupled Secretin and Angiotensin 1a Receptors.

    Science.gov (United States)

    Harikumar, Kaleeckal G; Augustine, Mary Lou; Lee, Leo T O; Chow, Billy K C; Miller, Laurence J

    2016-08-12

    Complexes of secretin (SecR) and angiotensin 1a (Atr1a) receptors have been proposed to be functionally important in osmoregulation, providing an explanation for overlapping and interdependent functions of hormones that bind and activate different classes of GPCRs. However, the nature of these cross-class complexes has not been well characterized and their signaling properties have not been systematically explored. We now use competitive inhibition of receptor bioluminescence resonance energy transfer and bimolecular fluorescence complementation to establish the dominant functionally important state as a symmetrical homodimeric form of SecR decorated by monomeric Atr1a, interacting through lipid-exposed faces of Atr1a TM1 and TM4. Conditions increasing prevalence of this complex exhibited negative allosteric modulatory impact on secretin-stimulated cAMP responses at SecR. In contrast, activating Atr1a with full agonist in such a complex exhibited a positive allosteric modulatory impact on the same signaling event. This modulation was functionally biased, with secretin-stimulated calcium responses unaffected, whereas angiotensin-stimulated calcium responses through the complex were reduced or absent. Further supporting this interpretation, Atr1a with mutations of lipid-exposed faces of TM1 and TM4 that did not affect its ability to bind or signal, could be expressed in the same cell as SecR, yet not exhibit either the negative or positive allosteric impact on cAMP observed with the inactive or activated states of wild type Atr1a on function, and not interfere with angiotensin-stimulated calcium responses like complexes with Atr1a. This may provide a more selective means of exploring the physiologic functional impact of this cross-class receptor complex without interfering with the function of either component receptor. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Induction of biliary cholangiocarcinoma cell apoptosis by 103Pd cholangial radioactive stent gamma-rays.

    Science.gov (United States)

    He, Gui-jin; Sun, Dan-dan; Ji, Da-wei; Sui, Dong-ming; Yu, Fa-qiang; Gao, Qin-yi; Dai, Xian-wei; Gao, Hong; Jiang, Tao; Dai, Chao-liu

    2008-06-05

    In recent years, interventional tumor therapy, involving implantation of intra-cholangial metal stents through percutaneous trans-hepatic punctures, has provided a new method for treating cholangiocarcinoma. (103)Pd cholangial radioactive stents can concentrate high radioactive dosages into the malignant tumors and kill tumor cells effectively, in order to prevent re-stenosis of the lumen caused by a relapsed tumor. The aim of the present study was to investigate the efficacy of gamma-rays released by the (103)Pd biliary duct radioactive stent in treating cholangiocarcinoma via induction of biliary cholangiocarcinoma cell apoptosis. A group of biliary duct cancer cells was collectively treated with a dose of gamma-rays. Cells were then examined by the 3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl terazolium-bromide (MTT) technique for determining the inhibition rate of the biliary duct cancer cells, as well as with other methods including electron microscopy, DNA agarose gel electrophoresis, and flow cytometry were applied for the evaluation of their morphological and biochemical characteristics. The growth curve and the growth inhibition rate of the cells were determined, and the changes in the ultrastructure of the cholangiocarcinoma cells and the DNA electrophoresis bands were examined under a UV-lamp. The gamma-ray released by (103)Pd inhibited cholangiocarcinoma cell growth, as demonstrated when the growth rate of the cells was stunned by a gamma-ray with a dosage larger than 197.321 MBq. Typical features of cholangiocarcinoma cell apoptosis were observed in the 197.321 MBq dosage group, while cell necrosis was observed when irradiated by a dosage above 245.865 MBq. DNA agarose gel electrophoresis results were different between the 197.321 MBq irradiation dosage group, the 245.865 MBq irradiation dosage group, and the control group. (103)Pd radioactive stents which provide a radioactive dosage of 197.321 MBq are effective in the treatment of cholangiocarcinoma

  1. The Value of Secretin-Enhanced MRCP in Patients With Recurrent Acute Pancreatitis.

    Science.gov (United States)

    Sandrasegaran, Kumar; Tahir, Bilal; Barad, Udaykamal; Fogel, Evan; Akisik, Fatih; Tirkes, Temel; Sherman, Stuart

    2017-02-01

    The purpose of this study is to assess the additional value of secretin-enhanced MRCP over conventional (non-secretin-enhanced) MRCP in diagnosing disease in patients with recurrent acute pancreatitis. A retrospective review of a radiology database found 72 patients with recurrent acute pancreatitis who had secretin-enhanced MRCP and ERCP correlation within 3 months of each other between January 2007 and December 2011. Of these patients, 54 had no history of pancreatic tumor or surgery and underwent MRI more than 3 months after an episode of acute pancreatitis. In addition, 57 age- and sex-matched control subjects with secretin-enhanced MRCP and ERCP correlation and without a diagnosis of recurrent acute pancreatitis or chronic pancreatitis were enrolled as the control group. All studies were anonymized, and secretin-enhanced MRCP images (image set A) were separated from conventional 2D and 3D MRCP and T2-weighted images (image set B). Image sets A and B for each patient were assigned different and randomized case numbers. Two blinded reviewers independently assessed both image sets for ductal abnormalities and group A image sets for exocrine response to secretin. There were statistically significantly more patients with recurrent acute pancreatitis with reduced exocrine function compared with patients in the control group (32% vs 9%; p pancreatitis were more likely to have side branch dilation (p = 0.02; odds ratio, 3.6), but not divisum, compared with the control group. Secretin-enhanced images were superior to non-secretin-enhanced images for detecting ductal abnormalities in patients with recurrent acute pancreatitis, with higher sensitivity (76% vs 56%; p = 0.01) and AUC values (0.983 vs 0.760; p pancreatitis showed exocrine functional abnormalities. Secretin-enhanced MRCP had a significantly higher yield for ductal abnormalities than did conventional MRI and should be part of the MRCP protocol for investigation of patients with recurrent acute pancreatitis.

  2. Mandibular metastasis of cholangiocarcinoma: A case report

    Energy Technology Data Exchange (ETDEWEB)

    You, Tae Min [Dept. of Advanced General Dentistry, Dankook University, Cheonan (Korea, Republic of); Kim, Kee Dong; Jeong, Ho Gui; Park, Won Se [Advanced General Dentistry, Dankook University, Cheonan (Korea, Republic of)

    2015-12-15

    Tumors metastasizing from distant regions to the oral and maxillofacial region are uncommon, comprising only 1%-2% of all malignancies. Cholangiocarcinoma is a malignancy that arises from cholangiocytes, which are epithelial cells that line the bile ducts. These cancers are difficult to diagnose and have a poor prognosis. In this paper, we report a rare case of mandibular metastasis of cholangiocarcinoma diagnosed at the primary site and discuss the radiographic findings observed in this case.

  3. Cholangiocarcinoma: Has There been Any Progress?

    Directory of Open Access Journals (Sweden)

    Judith Meza-Junco

    2010-01-01

    Full Text Available Cholangiocarcinoma is the second most common primary hepatic tumour after hepatocellular carcinoma. Primary sclerosing cholangitis is one of the most commonly recognized risk factors for cholangiocarcinoma; however, approximately 90% of patients have no identifiable risk factors. Extrahepatic type is its most common presentation. Cholangiocarcinoma is considered to be a devastating disease, with a poor survival rate and few therapeutic options. Although surgical resection has been considered the best treatment option for localized cholangiocarcinoma, local recurrences of this cancer are very common, and imply persistent micrometastatic disease in lymph nodes or at surgical margins, even after extended surgical resection. Consequently, the five-year survival rate after attempted curative resection is only 20% to 40%. Early studies of liver transplantation for cholangiocarcinoma did not show a survival benefit and, currently, this tumour is considered to be an absolute contraindication for liver transplantation in most transplant centres worldwide. Recently, neoadjuvant chemoradiation in combination with liver transplantation for highly selected patients with cholangiocarcinoma has shown impressive results, with five-year survival rates at approximately 76% to 82% – similar to other standard indications for liver transplantation, such as hepatocellular carcinoma or hepatitis C-induced cirrhosis. However, this success of liver transplantation applies to only a subset of patients and most of the data originated from a single centre. Wider application of this strategy, especially for patients with potentially resectable disease, will require validation by other centres.

  4. The central mechanisms of secretin in regulating multiple behaviors

    Directory of Open Access Journals (Sweden)

    Li eZhang

    2014-05-01

    Full Text Available Secretin (SCT was firstly discovered as a gut peptide hormone in stimulating pancreatic secretion, while its novel neuropeptide role has drawn substantial research interests in recent years. SCT and its receptor (SCTR are widely expressed in different brain regions, where they exert multiple cellular functions including neurotransmission, gene expression regulation, neurogenesis and neural protection. As all these neural functions ultimately can affect behaviors, it is hypothesized that SCT controls multiple behavioral paradigms. Current findings support this hypothesis as SCT-SCTR axis participates in modulating social interaction, spatial learning, water and food intake, motor coordination and motor learning behaviors. This mini-review focuses on various aspects of SCT and SCTR in hippocampus, hypothalamus and cerebellum including distribution profiles, cellular functions and behavioral phenotypes to elucidate the link between cellular mechanisms and behavioral control.

  5. miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth.

    Science.gov (United States)

    Han, Yuyan; Meng, Fanyin; Venter, Julie; Wu, Nan; Wan, Ying; Standeford, Holly; Francis, Heather; Meininger, Cynthia; Greene, John; Trzeciakowski, Jerome P; Ehrlich, Laurent; Glaser, Shannon; Alpini, Gianfranco

    2016-06-01

    Disruption of circadian rhythm is associated with cancer development and progression. MicroRNAs (miRNAs) are a class of small non-coding RNAs that trigger mRNA translation inhibition. We aimed to evaluate the role of Per1 and related miRNAs in cholangiocarcinoma growth. The expression of clock genes was evaluated in human cholangiocarcinoma tissue arrays and cholangiocarcinoma lines. The rhythmic expression of clock genes was evaluated in cholangiocarcinoma cells and H69 (non-malignant cholangiocytes) by qPCR. We measured cell proliferation, cell cycle and apoptosis in Mz-ChA-1 cells after Per1 overexpression. We examined tumor growth in vivo after injection of Per1 overexpressing cells. We verified miRNAs that targets Per1. The circadian rhythm of miR-34a was evaluated in cholangiocarcinoma and H69 cells. We evaluated cell proliferation, apoptosis and invasion after inhibition of miR-34a in vitro, and the potential molecular mechanisms by mRNA profiling after overexpression of Per1. Expression of Per1 was decreased in cholangiocarcinoma. The circadian rhythm of Per1 expression was lost in cholangiocarcinoma cells. Decreased cell proliferation, lower G2/M arrest, and enhanced apoptosis were shown in Per1 overexpressing cells. An in vivo study revealed decreased tumor growth, decreased proliferation, angiogenesis and metastasis after overexpressing Per1. Per1 was verified as a target of miR-34a. miR-34a was rhythmically expressed in cholangiocarcinoma cells and H69. The inhibition of miR-34a decreased proliferation, migration and invasion in cholangiocarcinoma cells. mRNA profiling has shown that overexpression of Per1 inhibits cell growth through regulation of multiple cancer-related pathways, such as cell cycle, cell growth and apoptosis pathways. Disruption of circadian rhythms of clock genes contribute to the malignant phenotypes of human cholangiocarcinoma. The current study is about how biological clock and its regulators affect the bile duct tumor growth. The

  6. Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Banales, Jesus M; Cardinale, Vincenzo; Carpino, Guido

    2016-01-01

    to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted....

  7. Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS.

    Directory of Open Access Journals (Sweden)

    Xianzhi Qu

    Full Text Available The tumor cells have some metabolic characteristics of the original tissues, and the metabolism of the tumor cells is closely related to autophagy. However, the mechanism of autophagy and metabolism in chemotherapeutic drug resistance is still poorly understood. In this study, we investigated the role and mechanism of autophagy and glucose metabolism in chemotherapeutic drug resistance by using cholangiocarcinoma QBC939 cells with primary cisplatin resistance and hepatocellular carcinoma HepG2 cells. We found that QBC939 cells with cisplatin resistance had a higher capacity for glucose uptake, consumption, and lactic acid generation, and higher activity of the pentose phosphate pathway compared with HepG2 cells, and the activity of PPP was further increased after cisplatin treatment in QBC939 cells. It is suggested that there are some differences in the metabolism of glucose in hepatocellular carcinoma and cholangiocarcinoma cells, and the activation of PPP pathway may be related to the drug resistance. Through the detection of autophagy substrates p62 and LC3, found that QBC939 cells have a higher flow of autophagy, autophagy inhibitor chloroquine can significantly increase the sensitivity of cisplatin in cholangiocarcinoma cells compared with hepatocellular carcinoma HepG2 cells. The mechanism may be related to the inhibition of QBC939 cells with higher activity of the PPP, the key enzyme G6PDH, which reduces the antioxidant capacity of cells and increases intracellular ROS, especially mitochondrial ROS. Therefore, we hypothesized that autophagy and the oxidative stress resistance mediated by glucose metabolism may be one of the causes of cisplatin resistance in cholangiocarcinoma cells. It is suggested that according to the metabolism characteristics of tumor cells, inhibition of autophagy lysosome pathway with chloroquine may be a new route for therapeutic agents against cholangiocarcinoma.

  8. Surgical options for intrahepatic cholangiocarcinoma

    Science.gov (United States)

    Wang, Kui; Zhang, Han; Xia, Yong; Liu, Jian

    2017-01-01

    Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, accounting for 10–15% of primary hepatic malignancy. The incidence and cancer-related mortality of ICC continue to increase worldwide. At present, hepatectomy is still the most effective treatment for ICC patients to achieve long-term survival, although its overall efficacy may not be as good as that for patients with hepatocellular carcinoma (HCC) due to the unique pathogenesis and clinical-pathological profiles of ICC. Viral infection, lithiasis and metabolic factors may all be associated with the pathogenesis of ICC. Poor blood supply, cirrhosis (in rare cases), surrounding organ invasion, and lymph node/distal metastasis have significant impacts on the selection of surgical strategies, surgical resection rate, postoperative complications, recurrence and metastasis. Surgical treatment for ICC includes R0 resection, lymphadenectomy, total gross resection of the involved biliary tracts, blood vessels and surrounding tissues in adjacent organs, and reconstruction. Postoperative adjuvant therapy and local-regional therapy after recurrence may improve survival. Liver transplantation (LT) is reported to have a moderate treatment effect on early ICC although its efficacy remains controversial. In this article, we reviewed the epidemiology and staging of ICC and highlighted the selection of surgical modalities and postoperative outcomes of ICC patients via literature review. PMID:28503555

  9. Inhibitory Effect of Aspirin on Cholangiocarcinoma Cells

    Science.gov (United States)

    Boueroy, Parichart; Aukkanimart, Ratchadawan; Boonmars, Thidarut; Sriraj, Pranee; Ratanasuwan, Panaratana; Juasook, Amornrat; Wonkchalee, Nadchanan; Vaeteewoottacharn, Kulthida; Wongkham, Sopit

    2017-11-26

    Aspirin and other non-steroidal anti-inflammatory drugs reduce the risk of cancer due to their anti-proliferative and apoptotic effects, which are the important mechanisms for their anti-tumor activity. Here, the effect of aspirin on human cholangiocarcinoma cells (KKU-214) and the underlying mechanisms of its action were explored. Cell proliferation was measured by sulforhodamine B (SRB) assay, while cell cycle distribution and apoptosis were determined by flow cytometry. Western blotting was used to explore protein expression underlying molecular mechanisms of anti-cancer treatment of aspirin. Aspirin reduced cell proliferation in a dose- and time-dependent manner, and altered the cell cycle phase distribution of KKU-214 cells by increasing the proportion of cells in the G0/G1 phase and reducing the proportion in the S and G2/M phases. Consistent with its effect on the cell cycle, aspirin also reduced the expression of cyclin D1 and cyclin‑dependent kinase 4 (Cdk-4), which are important for G0/G1 cell cycle progression. Treatment with aspirin led to increased induction of apoptosis in a dose-dependent manner. Further analysis of the mechanism underlying the effect of this drug showed that aspirin induced the expression of the tumor-suppressor protein p53 while inhibiting the anti-apoptotic protein B‑cell lymphoma-2 (Bcl-2). Correspondingly, the activation of caspase-9 and -3 was also increased. These findings suggest that aspirin causes cell cycle arrest and apoptosis, both of which could contribute to its anti-proliferative effect. Creative Commons Attribution License

  10. Two offset printing workers with cholangiocarcinoma.

    Science.gov (United States)

    Kumagai, Shinji

    2014-01-01

    Previously, the author reported a cluster of 11 cholangiocarcinoma cases exposed to 1,2-dichloropropane (1,2-DCP) and/or dichloromethane (DCM) in an offset proof-printing company. Before that report, the association between the two chemicals and cholangiocarcinoma had not been known. The current study describes two cholangiocarcinoma patients exposed to 1,2-DCP or DCM in different offset printing companies. The author obtained medical records for the patients, and interviewed the surviving patient and a relative of the deceased patient about their occupational history. Case 1 was a man born in 1950. He worked in the printing section in a proof-printing company for 26 years. He was diagnosed as cholangiocarcinoma in 1998 and died in 2000. In proof-printing operations, he used gasoline for 14 years and 1,2-DCP for 11 years to remove ink from a rubber transcription roller (blanket). The exposure concentration of 1,2-DCP was estimated to be between 72 and 5,200 ppm. Case 2 was a man born in 1963. He worked in the printing section in a general offset printing company for 11 years. He was diagnosed with cholangiocarcinoma in 2007. In printing operations, he used both kerosene and a mixture of 50% DCM and 50% 1,1,1-trichloroethane (1,1,1-TCE) for 11 years to remove ink from a blanket. The exposure concentration of DCM was estimated to be between 240 and 6,100 ppm. He was simultaneously exposed to similar levels of 1,1,1-TCE. Because the offset printing process may cause cholangiocarcinoma, occupational history should be examined for patients with this cancer.

  11. Role of secretin-enhanced magnetic resonance cholangiopancreatography in the evaluation of patients following pancreatojejunostomy

    Directory of Open Access Journals (Sweden)

    Munazza Anis

    2013-01-01

    Full Text Available Objective: This study was conducted to assess the role of secretin-enhanced magnetic resonance cholangiopancreatography (S-MRCP in the evaluation of patients following pancreatico-jejunal anatomosis. Materials and Methods: S-MRCP studies ( n = 83 performed at Brigham and Women′s Hospital between 1/2005 and 7/2005 were retrospectively reviewed. Among these, there were 13 patients (10 females, 3 males; mean age = 45 years, range = 18-74 years who were evaluated with S-MRCP following pancreatojejunal anatomosis. Single-shot fast spin-echo T2-weighted thick slab dynamic MRCP images obtained before and every minute (for 10 min after IV injection of secretin (2 mcg/kg body weight of SecreFloTM IV over 1 min were reviewed retrospectively and independently by 3 readers. Image analysis included measurement of the main pancreatic duct (MPD diameter and subjective assessment of the grade of visualization of the MPD remnant. The amount of jejunal fluid and visualization of the pancreatico-jejunal anatomosis pre-and post-secretin were also documented. Direct correlation with endoscopic retrograde cholangiopancreatography (ERCP finding was available in six of the 13 cases. Results: The MPD diameter and MPD remnant visualization improved post-secretin for 1/3 readers. The number of pancreatico-jejunal anastomoses and the amount of jejunal fillings pre-and post-secretin was seen to improve significantly for 1 of the 3 readers. For Reader 1, the mean MPD diameter in the body of the pancreas, on the pre-and post-secretin image, was 3.2 ± 1.3 mm and 3.8 ± 1.9 mm, respectively. There was no statistical difference in the values pre- and post-secretin in the MPD diameter ( P = 0.07, MPD visualization ( P = 0.16 and the number of pancreatico-jejunal anastomoses seen ( P = 0.125 5/13 pre- and 9/13 post-secretin. Statistical significance was seen in the amount of jejunal filling ( P = 0.01 after secretin. For Reader 2, the MPD diameter pre-and post-secretin was 4

  12. Characterization of secretin release in response to food and intraduodenal administration of fat and hydrochloric acid.

    Science.gov (United States)

    Draviam, E J; Gomez, G; Hashimoto, T; Miyashita, T; Hill, F L; Uchida, T; Singh, P; Greeley, G H; Thompson, J C

    1991-04-01

    The development and validation of a radioimmunoassay that detects release of secretin in plasma in response to low doses of secretagogues [intraduodenal HCl (0.033 meq/min); intraduodenal sodium oleate (0.04 mmol/min)] or an oral mixed meal in conscious dogs is described. Plasma secretin levels increased significantly (P less than 0.05) in response to an oral mixed meal in conscious dogs from a basal level of 4.0 to a peak level of 12.3 pg/ml at 15 min. Infusion of graded doses of HCl (2, 4, 8, 16, meq/hr for 30 min) intraduodenally in six dogs resulted in significant elevation of plasma secretin levels in a dose-dependent manner. The pancreatic bicarbonate and volume outputs correlated with the dosage of HCl administered and with the elevations in plasma secretin concentrations. Intraduodenal infusion of increasing doses of sodium oleate (2.4, 4.8, 9.6, and 19.2 mmol in 15-min periods) resulted in a significant (P less than 0.05) elevation of plasma levels of secretin.

  13. Effect of secretin and somatostatin on secretion of epidermal growth factor from Brunner's glands in the rat

    DEFF Research Database (Denmark)

    Olsen, P S; Kirkegaard, P; Poulsen, Steen Seier

    1994-01-01

    The effect of secretin and somatostatin on secretion of epidermal growth factor (EGF) from Brunner's glands was investigated in rats. Secretin increased volume secretion and the median output of EGF rose from 720 fmol/5 hr (total range 460-1320) in controls to 2065 fmol/5 hr (total range 1560...

  14. Bile duct lymphoma disguised as cholangiocarcinoma.

    Science.gov (United States)

    Durham, Charis; Jaiswal, Deepna; Wong, Lucas

    2017-04-01

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

  15. Evolution of secretin family GPCR members in the metazoa

    Directory of Open Access Journals (Sweden)

    Clark Melody S

    2006-12-01

    Full Text Available Abstract Background Comparative approaches using protostome and deuterostome data have greatly contributed to understanding gene function and organismal complexity. The family 2 G-protein coupled receptors (GPCRs are one of the largest and best studied hormone and neuropeptide receptor families. They are suggested to have arisen from a single ancestral gene via duplication events. Despite the recent identification of receptor members in protostome and early deuterostome genomes, relatively little is known about their function or origin during metazoan divergence. In this study a comprehensive description of family 2 GPCR evolution is given based on in silico and expression analyses of the invertebrate receptor genes. Results Family 2 GPCR members were identified in the invertebrate genomes of the nematodes C. elegans and C. briggsae, the arthropods D. melanogaster and A. gambiae (mosquito and in the tunicate C. intestinalis. This suggests that they are of ancient origin and have evolved through gene/genome duplication events. Sequence comparisons and phylogenetic analyses have demonstrated that the immediate gene environment, with regard to gene content, is conserved between the protostome and deuterostome receptor genomic regions. Also that the protostome genes are more like the deuterostome Corticotrophin Releasing Factor (CRF and Calcitonin/Calcitonin Gene-Related Peptide (CAL/CGRP receptors members than the other family 2 GPCR members. The evolution of family 2 GPCRs in deuterostomes is characterised by acquisition of new family members, with SCT (Secretin receptors only present in tetrapods. Gene structure is characterised by an increase in intron number with organismal complexity with the exception of the vertebrate CAL/CGRP receptors. Conclusion The family 2 GPCR members provide a good example of gene duplication events occurring in tandem with increasing organismal complexity during metazoan evolution. The putative ancestral receptors

  16. Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice

    Science.gov (United States)

    Procino, Giuseppe; Milano, Serena; Carmosino, Monica; Barbieri, Claudia; Nicoletti, Maria C; H. Li, Jian; Wess, Jürgen; Svelto, Maria

    2014-01-01

    X-linked nephrogenic diabetes insipidus (X-NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. Loss of V2R function prevents plasma membrane expression of the AQP2 water channel in the kidney collecting duct cells and impairs the kidney concentration ability. In an attempt to develop strategies to bypass V2R signaling in X-NDI, we evaluated the effects of secretin and fluvastatin, either alone or in combination, on kidney function in a mouse model of X-NDI. The secretin receptor was found to be functionally expressed in the kidney collecting duct cells. Based on this, X-NDI mice were infused with secretin for 14 days but urinary parameters were not altered by the infusion. Interestingly, secretin significantly increased AQP2 levels in the collecting duct but the protein primarily accumulated in the cytosol. Since we previously reported that fluvastatin treatment increased AQP2 plasma membrane expression in wild-type mice, secretin-infused X-NDI mice received a single injection of fluvastatin. Interestingly, urine production by X-NDI mice treated with secretin plus fluvastatin was reduced by nearly 90% and the urine osmolality was doubled. Immunostaining showed that secretin increased intracellular stores of AQP2 and the addition of fluvastatin promoted AQP2 trafficking to the plasma membrane. Taken together, these findings open new perspectives for the pharmacological treatment of X-NDI. PMID:24522493

  17. Current research in perineural invasion of cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Deng Xi-Yun

    2010-03-01

    Full Text Available Abstract Background Perineural invasion is a common path for cholangiocarcinoma (CCA metastasis, and it is highly correlated with postoperative recurrence and poor prognosis. It is often an early event in a disease that is commonly diagnosed in advanced stages, and thus it could offer a timely therapeutic and diagnostic target if better understood. This article systematically reviews the progress of CCA neural invasion-related molecules. Methods Studies were identified by searching MEDLINE and PubMed databases for articles from January 1990 to December 2009, using the keywords "cholangiocarcinoma," "perineural invasion," "nerve growth factor"(NGF, "neural cell adhesion molecule" (NCAM, "matrix metalloproteinase"(MMP, "neurotransmitter," "acetylcholine" (Ach, and "transforming growth factor" (TGF." Additional papers and book chapters were identified by a manual search of references from the key articles. Results From above we found that the molecules NGF, NCAM, MMP, Ach and TGF may have prognostic significance in, and offer clues to the mechanism of CCA neural invasion. Conclusions Cholangiocarcinoma's increasing worldwide incidence is especially poignant in view of both the lacking effective therapies, and the fact that it is commonly diagnosed in advanced stages. As CCA neural invasion often appears early, more complete characterization of its molecular pathology could lead to the identification of targets for the diagnosis and therapy of this devastating malignancy.

  18. Autoimmune pancreatitis: imaging findings on contrast-enhanced MR, MRCP and dynamic secretin-enhanced MRCP.

    Science.gov (United States)

    Carbognin, G; Girardi, V; Biasiutti, C; Camera, L; Manfredi, R; Frulloni, L; Hermans, J J; Mucelli, R Pozzi

    2009-12-01

    This study retrospectively determined magnetic resonance (MR), MR cholangiopancreatography (MRCP) and secretin-MRCP findings in patients with autoimmune pancreatitis (AIP). The MR examinations of 28 patients with histopathologically proven AIP were reviewed. In 14 cases, secretin-enhanced MRCP was performed. The observers evaluated pancreatic parenchymal enlargement, signal intensity abnormalities, enhancement, vascular involvement, bile-duct diameter and main pancreatic duct (MPD) narrowing (diffuse/focal/segmental). After secretin administration, the presence of the "duct-penetrating" sign was evaluated. MR imaging showed diffuse pancreatic enlargement in 8/28(29%) cases, focal pancreatic enlargement in 16/28 (57%) cases and no enlargement in 4/28 (14%) cases. The alteration of pancreatic signal intensity was diffuse in 8/28 (29%) cases (eight diffuse AIP) and focal in 20/28 (71%) cases (20 focal AIP). Delayed pancreatic enhancement was present in all AIP, with peripheral rim of enhancement in 8/28 (29%) AIP (1/8 diffuse, 7/20 focal); vascular encasement was present in 7/28 (25%) AIP (1/8 diffuse, 6/20 focal); distal common bile duct narrowing was present in 12/28(43%) AIP (5/8 diffuse, 7/20 focal). MRCP showed MPD narrowing in 17/28 (61%) AIP (4/8 diffuse, 15/20 focal), MPD dilation in 8/28(29%) AIP (3/8 diffuse, 5/20 focal) and normal MPD in 1/8 diffuse AIP. Secretin-MRCP showed the duct-penetrating sign in 6/14(43%) AIP (one diffuse AIP with MPD segmental narrowing, five focal AIP with MPD focal narrowing), demonstrating integrity of the MPD. Delayed enhancement and MPD stenosis are suggestive for AIP on MR and MRCP imaging. Secretin-enhanced MRCP is a problem-solving tool in the differential diagnosis between focal AIP and ductal adenocarcinoma.

  19. Hilar cholangiocarcinoma with intratumoral calcification: A case report.

    Science.gov (United States)

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

    2015-10-14

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

  20. PBK/TOPK in the differential diagnosis of cholangiocarcinoma from hepatocellular carcinoma and its involvement in prognosis of human cholangiocarcinoma.

    Science.gov (United States)

    He, Furong; Yan, Qingguo; Fan, Linni; Liu, Yixiong; Cui, Jihong; Wang, Juanhong; Wang, Lu; Wang, Yingmei; Wang, Zhe; Guo, Ying; Huang, Gaosheng

    2010-03-01

    The increased expression of PDZ binding kinase/lymphokine-activated killer T-cell-originated protein kinase (PBK/TOPK) is associated with some human malignant tumors. In this study, we analyzed PBK/TOPK expression in hepatic primary tumor and explored its role in cholangiocarcinoma biology. Seventy-four cholangiocarcinomas, 33 hepatocellular carcinomas, and 10 normal liver tissues were prepared from paraffin-embedded specimens. PBK/TOPK protein was assessed by immunohistochemical staining, and the survival time was analyzed with the Kaplan-Meier method. The protein, mRNA of PBK/TOPK, and cell cycle of cholangiocarcinoma cell line after PBK/TOPK suppression with small interfere RNA were studied by Western blot, semiquantitative reverse transcriptase-polymerase chain reaction, and flow cytometry, respectively. PBK/TOPK was usually expressed in normal bile duct epithelial cells and much more frequently expressed in cholangiocarcinoma (68/74) but never expressed in hepatocytes and hepatocellular carcinomas (0/33). PBK/TOPK down-regulation was related to the poor prognosis of patients with cholangiocarcinoma (P = .013). Epidermal growth factor can enhance PBK/TOPK expression in cholangiocarcinoma QBC 939 cells, but suppression of PBK/TOPK in the cells did not affect their proliferation. PBK/TOPK protein could serve as a useful indicator for histopathologic differentiation between cholangiocarcinoma and hepatocellular carcinomas and the low expression of PBK/TOPK is predicative of poor survival in cholangiocarcinoma patients. Copyright 2010 Elsevier Inc. All rights reserved.

  1. Does secretin stimulation add to magnetic resonance cholangiopancreatography in characterising pancreatic cystic lesions as side-branch intraductal papillary mucinous neoplasm?

    Energy Technology Data Exchange (ETDEWEB)

    Purysko, Andrei S.; Gandhi, Namita S.; Veniero, Joseph C. [Cleveland Clinic, From the Abdominal Imaging Section, Imaging Institute, Cleveland, OH (United States); Walsh, R.M. [Cleveland Clinic, Department of General Surgery, Digestive Disease Institute, Cleveland, OH (United States); Obuchowski, Nancy A. [Cleveland Clinic, Department of Quantitative Health Sciences, Cleveland, OH (United States)

    2014-12-15

    To assess the value of secretin during magnetic resonance cholangiopancreatography (MRCP) in demonstrating communication between cystic lesions and the pancreatic duct to help determine the diagnosis of side-branch intraductal papillary mucinous neoplasm (SB-IPMN). This is an IRB-approved, HIPAA-compliant retrospective study of 29 SB-IPMN patients and 13 non-IPMN subjects (control) who underwent secretin-enhanced MRCP (s-MRCP). Two readers blinded to the final diagnosis reviewed three randomised image sets: (1) pre-secretin HASTE, (2) dynamic s-MRCP and (3) post-secretin HASTE. Logistic regression, generalised linear models and ROC analyses were used to compare pre- and post-secretin results. There was no significant difference in median scores for the pre-secretin [reader 1: 1; reader 2: 2 (range -2 to 2)] and post-secretin HASTE [reader 1: 1; reader 2: 1 (range -2 to 2)] in the SB-IPMN group (P = 0.14), while the scores were lower for s-MRCP [reader 1: 0.5 (range -2 to 2); reader 2: 0 (range -1 to 2); P = 0.016]. There was no significant difference in mean maximum diameter of SB-IPMN on pre- and post-secretin HASTE, and s-MRCP (P > 0.05). Secretin stimulation did not add to MRCP in characterising pancreatic cystic lesions as SB-IPMN. (orig.)

  2. Does the MMR vaccine and secretin or its receptor share an antigenic epitope?

    Science.gov (United States)

    Mehta, Bijal K; Munir, Kerim M

    2003-05-01

    In a subgroup of children with autism-spectrum like conditions symptoms seem to appear as a 'regression' (in normal development). It has been postulated that the onset of such autistic symptoms may involve an autoimmune response against the central nervous system and that the antigenic determinant could possibly be gastrointestinal in origin. It has been suggested that the presence of the measles virus and 'autistic enterocolitis' demonstrates the possibility that the MMR triple vaccine may be mediating the inflammation with possible production of antibodies against the virus containing vaccine. Such an antibody may share antigenic determinant to molecules found in the gut. We propose that this may be secretin or its receptor, found in the gut as well as in the central nervous system. The antibody response to the gut may also conceivably occur in the brain at a critical time in development. The modulation of development by secretin may be a static event possibly occurring at a specific time in early childhood development and if it involves an autoimmune response then a disruption in development may result. These hypothesized events can only occur if the MMR vaccine shares antigenic determinants that resemble secretin or any of its receptor types and remains to be studied.

  3. Santorinicele: secretin-enhanced magnetic resonance cholangiopancreatography findings before and after minor papilla sphincterotomy

    Energy Technology Data Exchange (ETDEWEB)

    Boninsegna, Enrico; Manfredi, Riccardo; Ventriglia, Anna; Negrelli, Riccardo; Pedrinolla, Beatrice; Mehrabi, Sara; Pozzi Mucelli, Roberto [University of Verona, Department of Radiology - Policlinico G.B. Rossi, Verona (Italy); Gabbrielli, Armando [University of Verona, Department of Medicine - Policlinico G.B. Rossi, Verona (Italy)

    2015-08-15

    To evaluate secretin-enhanced MRCP (S-MRCP) findings of patients with pancreas divisum and Santorinicele, before and after minor papilla sphincterotomy. S-MRCP examinations of 519 patients with suspected pancreatic disease were included. Size of the main pancreatic duct, presence and calibre of Santorinicele were evaluated. Duodenal filling was assessed on dynamic images. After sphincterotomy the same parameters and the clinical findings were re-evaluated. Pancreas divisum was depicted in 55/519 patients (11 %) by MRCP and an additional 26/519 by S-MRCP (total 81/519, 16 %). Santorinicele was detected in 7/81 patients (8.6 %) with pancreas divisum by MRCP and an additional 20/81 by S-MRCP (total 27/81, 33 %). Dorsal duct in patients with Santorinicele was significantly larger in the head compared with patients with only pancreas divisum (p < 0.01), in basal conditions (average 2.4 versus 1.9 mm) and after secretin administration (average 3.0 versus 2.4 mm). Duodenal filling was impaired in 11/27 patients (41 %) with Santorinicele. After sphincterotomy significant reduction in size of Santorinicele (-33 %) and dorsal duct (-17 %), increase of pancreatic juice and symptoms improvement were observed. Secretin administration increases the accuracy of MRCP in detecting Santorinicele and demonstrates the impaired duodenal filling. S-MRCP is useful to assess results of sphincterotomy. (orig.)

  4. Combining biological agents and chemotherapy in the treatment of cholangiocarcinoma

    DEFF Research Database (Denmark)

    Jensen, Lars Henrik; Jakobsen, Anders

    2011-01-01

    The nonsurgical treatment of cholangiocarcinoma has seen major changes within the last few years. A multidisciplinary approach is the cornerstone in planning optimal treatment, but despite several examinations the diagnosis is often based on a certain probability, and histopathological confirmation...

  5. Secretin empties bile duct cell cytoplasm of vesicles when it initiates ductular HCO3- secretion in the pig.

    Science.gov (United States)

    Buanes, T; Grotmol, T; Landsverk, T; Raeder, M G

    1988-08-01

    To determine whether secretin has any effect on bile duct cell ultrastructure, bile duct cells from liver biopsy specimens of pigs were analyzed morphometrically. During secretory rest, bile duct cell cytoplasmic vesicles totaled 96 (84-103) arbitrary units per cell volume (U). Secretin increased bile HCO3- secretion from 9 mumol/min (range 6-15) to 131 mumol/min (range 118-200) and lowered the bile duct cell vesicles to 5 U (range 3-9). Acute elevation of arterial PCO2 to 10.9 kPa (range 10.2-11.1) doubled vesicle number in resting duct cells and augmented the secretory response to secretin. At high arterial PCO2, secretin cleared the duct cell cytoplasm of vesicles and more than doubled the basolateral plasma membrane surface area. Taurocholate-induced canalicular choleresis, in contrast, did not alter duct cell morphology. It is concluded that secretin clears the bile duct cell cytoplasm of vesicles as it initiates ductular HCO3- secretion, possibly through causing exocytotic insertion of vesicle material into the basolateral plasma membrane.

  6. Autoimmune Hepatitis: A Risk Factor for Cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Rajat Garg

    2017-11-01

    Full Text Available Cholangiocarcinoma (CCA is a very aggressive and lethal tumor, which arises from the epithelial cells of bile ducts. CCA comprises about 3% of all gastrointestinal malignancies and its incidence is on the rise in the recent years. Anatomically, it is classified into intrahepatic, perihilar, or extrahepatic (distal CCA. There are a number of risk factors associated with CCA including primary sclerosing cholangitis, fibropolycystic liver disease, parasitic infection, viral hepatitis, chronic liver disease, and genetic disorders like Lynch syndrome. Autoimmune hepatitis is also recently reported to have an association with development of CCA. We report an interesting case of perihilar CCA in the setting of autoimmune hepatitis along with a literature review. This case highlights the importance of early treatment and close clinical follow-up of patients with autoimmune hepatitis for development of CCA.

  7. A perspective on molecular therapy in cholangiocarcinoma

    DEFF Research Database (Denmark)

    Andersen, Jesper Bøje; Thorgeirsson, Snorri S

    2014-01-01

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

  8. Colchicine blocks the effects of secretin on bile duct cell tubulovesicles and plasma membrane geometry and impairs ductular HCO3- secretion in the pig.

    Science.gov (United States)

    Veel, T; Buanes, T; Grotmol, T; Engeland, E; Raeder, M G

    1990-08-01

    Secretin causes the bile duct cells to secrete HCO3-. To examine whether the transformation of duct cell ultrastructure that follows secretin stimulation depends on microtubules and is important for ductular HCO3- secretion, we examined the effect of colchicine on ductular HCO3- secretion and on the morphology of cells lining bile ductules of anaesthetized pigs. Colchicine blocked secretin-dependent cytoplasmic clearance of tubulovesicles and prevented expansion of the basolateral plasma membrane in duct cells and reduced the ductular HCO3- secretory response from 132 +/- 25 mumol min-1 to 97 +/- 14 mumol min-1. In contrast, lumicolchicine did not affect secretin-dependent tubulovesicle clearance or plasma membrane geometry or ductular HCO3- secretion. Accordingly, secretin-dependent cytoplasmic clearance of tubulovesicles in bile duct cells appears to depend on microtubules and to be important for ductular HCO3- secretion.

  9. Incremental value of secretin-enhanced magnetic resonance cholangiopancreatography in detecting ductal communication in a population with high prevalence of small pancreatic cysts

    Energy Technology Data Exchange (ETDEWEB)

    Rastegar, Neda; Matteoni-Athayde, Luciana G.; Eng, John [Departments of Medicine (Gastroenterology) and Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions (United States); Takahashi, Naoki [Mayo Clinic (United States); Tamm, Eric P. [MD Anderson Cancer Center (United States); Mortele, Koenraad J. [Beth Israel Deaconess Medical Center (United States); Syngal, Sapna [Dana Farber Cancer Institute (United States); Margolis, Daniel [University of California, Los Angeles (United States); Lennon, Anne Marie; Wolfgang, Christopher L.; Fishman, Elliot K.; Hruban, Ralph H.; Goggins, Michael; Canto, Marcia I. [Departments of Medicine (Gastroenterology) and Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions (United States); Kamel, Ihab R., E-mail: ikamel@jhmi.edu [Departments of Medicine (Gastroenterology) and Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions (United States)

    2015-04-15

    Highlights: •Secretin improved visualization of ductal communication of a cystic pancreatic lesion. •No association between cysts and gender, ethnicity or type of high risk. •Incremental value of secretin could offset the added cost and time. -- Abstract: Purpose: We investigated the incremental diagnostic yield of S-MRCP in a population with high prevalence of small pancreatic cysts. Methods: Standard MRCP protocol was performed with and without secretin using 1.5 T units in subjects undergoing pancreatic screening because of a strong family history of pancreatic cancer as part of the multicenter Cancer of the Pancreas Screening-3 trial (CAPS 3). All studies were reviewed prospectively by two independent readers who recorded the presence and number of pancreatic cysts, the presence of visualized ductal communication before and after secretin, and the degree of confidence in the diagnoses. Result: Of 202 individuals enrolled (mean age 56 years, 46% males), 93 (46%) had pancreatic cysts detected by MRCP, and 64 of the 93 had pre-and post-secretin MRCP images available for comparison. Data from the 128 readings show that 6 (6/128 = 4.7%) had ductal communication visualized only on the secretin studies compared to pre-secretin studies (odds ratio 1.28, p = 0.04). In addition, there was a statistically significant increase in confidence in reporting ductal communication after secretin compared to before secretin (p < 0.0005). Conclusion: At 1.5 T MRI, the use of secretin can improve the visualization of ductal communication of cystic pancreatic lesions.

  10. Synergistic anticancer effects of cisplatin and histone deacetylase inhibitors (SAHA and TSA) on cholangiocarcinoma cell lines.

    Science.gov (United States)

    Asgar, Md Ali; Senawong, Gulsiri; Sripa, Banchob; Senawong, Thanaset

    2016-01-01

    Clinical application of cisplatin against cholangiocarcinoma is often associated with resistance and toxicity posing urgent demand for combination therapy. In this study, we evaluated the combined anticancer effect of cisplatin and histone deacetylase inhibitors (HDACIs), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), on the cholangiocarcinoma KKU-100 and KKU-M214 cell lines. Antiproliferative activity was evaluated using MTT assay. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. Cell cycle and apoptosis regulating proteins were evaluated by western blot analysis. MTT assay showed that cisplatin, SAHA and TSA dose-dependently reduced the viability of KKU-100 and KKU-M214 cells. The combination of cisplatin and HDACIs exerted significantly more cytotoxicity than the single drugs. Combination indices below 1.0 reflect synergism between cisplatin and HDACIs, leading to positive dose reductions of cisplatin and HDACIs. Cisplatin and HDACIs alone induced G0/G1 phase arrest in KKU-100 cells, but the drug combinations increased sub-G1 percent more than either drug. However, cisplatin and HDACIs alone or in combination increased only the sub-G1 percent in KKU-M214 cells. Annexin V-FITC staining revealed that cisplatin and HDACIs combinations induced more apoptotic cell death of both KKU-100 and KKU-M214 cells than the single drug. In KKU-100 cells, growth inhibition was accompanied by upregulation of p53 and p21 and downregulation of CDK4 and Bcl-2 due to exposure to cisplatin, SAHA and TSA alone or in combination. Moreover, combination of agents exerted higher impacts on protein expression. Single agents or combination did not affect p53 expression, however, combination of cisplatin and HDACIs increased the expression of p21 in KKU-M214 cells. Taken together, cisplatin and HDACIs combination may improve the therapeutic outcome in cholangiocarcinoma patients.

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

    Science.gov (United States)

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

    2016-02-21

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

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

    Science.gov (United States)

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

    2016-01-01

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

  13. Proteomic Studies of Cholangiocarcinoma and Hepatocellular Carcinoma Cell Secretomes

    Directory of Open Access Journals (Sweden)

    Chantragan Srisomsap

    2010-01-01

    Full Text Available Cholangiocarcinoma (CCA and hepatocellular carcinoma (HCC occur with relatively high incidence in Thailand. The secretome, proteins secreted from cancer cells, are potentially useful as biomarkers of the diseases. Proteomic analysis was performed on the secreted proteins of cholangiocarcinoma (HuCCA-1 and hepatocellular carcinoma (HCC-S102, HepG2, SK-Hep-1, and Alexander cell lines. The secretomes of the five cancer cell lines were analyzed by SDS-PAGE combined with LC/MS/MS. Sixty-eight proteins were found to be expressed only in HuCCA-1. Examples include neutrophil gelatinase-associated lipocalin (lipocalin 2, laminin 5 beta 3, cathepsin D precursor, desmoplakin, annexin IV variant, and annexin A5. Immunoblotting was used to confirm the presence of lipocalin 2 in conditioned media and cell lysate of 5 cell lines. The results showed that lipocalin 2 was a secreted protein which is expressed only in the conditioned media of the cholangiocarcinoma cell line. Study of lipocalin 2 expression in different types of cancer and normal tissues from cholangiocarcinoma patients showed that lipocalin 2 was expressed only in the cancer tissues. We suggest that lipocalin 2 may be a potential biomarker for cholangiocarcinoma.

  14. Synergistic Anticancer Effects of Vorinostat and Epigallocatechin-3-Gallate against HuCC-T1 Human Cholangiocarcinoma Cells

    Directory of Open Access Journals (Sweden)

    Tae Won Kwak

    2013-01-01

    Full Text Available The aim of this study was to investigate the effect of the combination of vorinostat and epigallocatechin-3-gallate against HuCC-T1 human cholangiocarcinoma cells. A novel chemotherapy strategy is required as cholangiocarcinomas rarely respond to conventional chemotherapeutic agents. Both vorinostat and EGCG induce apoptosis and suppress invasion, migration, and angiogenesis of tumor cells. The combination of vorinostat and EGCG showed synergistic growth inhibitory effects and induced apoptosis in tumor cells. The Bax/Bcl-2 expression ratio and caspase-3 and -7 activity increased, but poly (ADP-ribose polymerase expression decreased when compared to treatment with each agent alone. Furthermore, invasion, matrix metalloproteinase (MMP expression, and migration of tumor cells decreased following treatment with the vorinostat and EGCG combination compared to those of vorinostat or EGCG alone. Tube length and junction number of human umbilical vein endothelial cells (HUVECs decreased as well as vascular endothelial growth factor expression following vorinostat and EGCG combined treatment. These results indicate that the combination of vorinostat and EGCG had a synergistic effect on inhibiting tumor cell angiogenesis potential. We suggest that the combination of vorinostat and EGCG is a novel option for cholangiocarcinoma chemotherapy.

  15. Clinically acceptable colchicine concentrations have potential for the palliative treatment of human cholangiocarcinoma

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    Chun-Chieh Wu

    2015-05-01

    Full Text Available Microtubules are an ideal target for anticancer drugs because of their essential role in mitosis. Colchicine is a microtubule destabilizer. Whether the clinically acceptable colchicine concentrations had anticancer effects on human cholangiocarcinoma cells was investigated. Two human cholangiocarcinoma cell lines (C14/KMUH, C51/KMUH were investigated using clinically acceptable plasma colchicine concentrations (2 ng/mL and 6 ng/mL for the in vitro experiment, 0.07 mg colchicine/kg/d × 14 days for the nude mouse experiment. Our results showed that colchicine caused significantly dose-dependent antiproliferative effects on both cell lines (all p < 0.0001. Nude mouse (BALB/c-nu experiments showed that the increased tumor volume ratios in colchicine-treated mice were significantly lower than control mice started from the 11th day of treatment (p = 0.0167. The tumor growth rates in colchicine-treated mice after 14 days of treatment were significantly lower than in control mice (0.147 ± 0.004/d vs. 0.274 ± 0.003/d, p = 0.0015. In addition to the well-known direct colchicine–tubulin interaction as a common anticancer mechanism of colchicine, microarray and quantitative reverse transcriptase-polymerase chain reaction showed that the antiproliferative effects of both 2 ng/mL and 6 ng/mL colchicine on C14/KMUH cells could be partially explained by downregulations of both HSD11B2 and MT-COI. There was no effect of colchicine on MT-COI expression in C51/KMUH cells, however, 6 ng/mL colchicine also downregulated HSD11B2 in this cell line. In conclusion, clinically acceptable colchicine concentrations can inhibit the proliferation of human cholangiocarcinoma cells. This drug has good potential for the palliative treatment of cholangiocarcinoma due to its low cost and our long-standing prescription experience.

  16. The effects of omeprazole on interdigestive motility and early postprandial levels of gastrin and secretin

    Energy Technology Data Exchange (ETDEWEB)

    Rasmussen, L.; Oester-Joergensen, E.; Qvist, N. (and others) (Rigshospitalet, Copenhagen (Denmark))

    1992-01-01

    10 healthy men participated in a crossover study, and the experiments took place after 10 days of treatment (40 mg omeprazole every morning). Blood samples were drawn at fixed intervals during a complete migrating motor complex cycle. The manometric pressure tube was removed after passage of the second duodenal phase III, and an omelet tagged with {sup 99m}Tc was ingested, followed by 150 ml of water tagged with {sup 111}In-diethylenetriaminepentaacetic acid. Mean plasma gastrin in phases I, II, and III in the omeprazole group was 18.8, 23.3, 19.9, respectively. The corresponding figures for the placebo group were 9.3, 9.6, 9.5, respectively. It is concluded that 40 mg omeprazole elicits a phase-related increase in fasting plasma gastrin, a decrease in secretin in phases I and III, an augmented meal-stimulated gastrin response, and a secretin response characterized by a significantly lower mean in the immediate postprandial period. 12 refs., 4 figs.

  17. Trismus as the first manifestation of cholangiocarcinoma.

    Science.gov (United States)

    Patrocinio, Lucas G; Patrocinio, Tomas G; Pacheco, Leonardo F; Patrocinio, José A

    2008-09-01

    The initial presentation of a cholangiocarcinoma (CC) as trismus due to metastasis to the parotid gland is extremely rare and no previous reports have been found in the literature. A 29-year-old woman presented trismus that initiated 2 months before admission, just after superior left third molar extraction. Physical examination revealed severe trismus and a mass in the parotid gland. Computed tomography (CT) showed a heterogeneous mass in the left parotid gland. The next day she presented jaundice, bilirubinuria, and fever, followed by massive bleeding, intravascular disseminated coagulation, and respiratory insufficiency. Two days later she died. At autopsy, the parotid tumor was identified as a metastasis from a CC of the extrabiliary tract. To our knowledge, this is the first reported case of a metastatic CC that initially presented as trismus due to a mass in the parotid gland. This case represents a rare but important diagnosis that otolaryngologists and oral surgeons should add to the catalog of uncommon causes of trismus.

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

    Science.gov (United States)

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

    2012-10-01

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

  19. Hepatolithiasis and intrahepatic cholangiocarcinoma: A review.

    Science.gov (United States)

    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.

  20. Proteomic Studies of Cholangiocarcinoma and Hepatocellular Carcinoma Cell Secretomes

    OpenAIRE

    Srisomsap, Chantragan; Sawangareetrakul, Phannee; Subhasitanont, Pantipa; Chokchaichamnankit, Daranee; Chiablaem, Khajeelak; Bhudhisawasdi, Vaharabhongsa; Wongkham, Sopit; Svasti, Jisnuson

    2009-01-01

    Cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) occur with relatively high incidence in Thailand. The secretome, proteins secreted from cancer cells, are potentially useful as biomarkers of the diseases. Proteomic analysis was performed on the secreted proteins of cholangiocarcinoma (HuCCA-1) and hepatocellular carcinoma (HCC-S102, HepG2, SK-Hep-1, and Alexander) cell lines. The secretomes of the five cancer cell lines were analyzed by SDS-PAGE combined with LC/MS/MS. Sixty-eight...

  1. Cholangiocarcinoma with respect to IgG4 Reaction

    Directory of Open Access Journals (Sweden)

    Kenichi Harada

    2014-01-01

    Full Text Available IgG4 reactions marked by infiltration of IgG4-positive plasma cells in affected organs occur in cancer patients and in patients with IgG4-related diseases. Extrahepatic cholangiocarcinomas including gall bladder cancer are often accompanied by significant IgG4 reactions; these reactions show a negative correlation with CD8-positive cytotoxic T cells, suggesting that the evasion of immune surveillance is associated with cytotoxic T cells. The regulatory cytokine IL-10 may induce IgG4-positive plasma cell differentiation or promote B cell switching to IgG4 in the presence of IL-4. Cholangiocarcinoma cells may function as nonprofessional antigen presenting cells that indirectly induce IgG4 reactions via the IL-10-producing cells and/or these may act as Foxp3-positive and IL-10-producing cells that directly induce IgG4 reactions. Moreover, IgG4-related disease is a high-risk factor for cancer development; IgG4-related sclerosing cholangitis (IgG4-SC cases associated with cholangiocarcinoma or its precursor lesion biliary intraepithelial neoplasia (BilIN have been reported. IgG4-positive cell infiltration is an important finding of IgG4-SC but is not a histological hallmark of IgG4-SC. For the diagnosis of IgG4-SC, its differentiation from cholangiocarcinoma remains important.

  2. A study of mifepristone/IFN-γ-induced apoptosis of human cholangiocarcinoma cell line FRH-0201 in vitro

    Directory of Open Access Journals (Sweden)

    Sun QL

    2012-11-01

    Full Text Available Qi-Long Sun, Xu-Guang Zhang, Quan-Tai Xing, Peng Ding, Jin-Bo Feng, Xiao-Peng Wu, Zhan-Min WangDepartment of General Surgery, Qilu Hospital of Shandong University, Jinan, ChinaObjective: To investigate the effects of mifepristone, a progesterone receptor (PR antagonist, through the proliferation of human cholangiocarcinoma cell line FRH-0201 in vitro and the possible mechanisms involved.Methods: A two-step addition of poly-HRP anti-mouse immunoglobulin G detection system was used to detect the expression of PR in FRH-0201 cells. After treatments with various concentrations of mifepristone (10, 20, 40, 80, 160, and 320 µmol/L at various time intervals (24, 48, and 72 hours, the rate of cell inhibition, the rate of cell apoptosis, and the expression of bax/bcl-2/Fas were analyzed with tetrazolium blue (MTT assay, flow cytometry, reverse transcription polymerase chain reaction and Western blotting. The effect of mifepristone and mifepristone combined with interferon (IFN-γ-inducing apoptosis on the cells was observed.Results: Mifepristone remarkably inhibited the proliferation of FRH-0201 cells, which was revealed by MTT assay in a dose- and time-dependent manner. The inhibitory rate gradually increased following the increase of the dosage of mifepristone from a low dosage (10 µmol/L to a high dosage (320 µmol/L at different time intervals. Flow cytometry analysis showed mifepristone increased the rate of the FRH-0201 cell-line apoptosis. Notably, the rate of apoptosis increased markedly when the cells were pretreated with IFN-γ and then treated with mifepristone. In addition, mifepristone obviously upregulated bax and Fas expression and downregulated bcl-2 expression.Conclusion: Mifepristone effectively inhibited the growth of PR-positive human cholangiocarcinoma cell line FRH-0201 in vitro through multiple mechanisms. Mifepristone combined with IFN-γ might therefore induce the apoptosis of the cell line, which is possibly a beneficial

  3. Metastatic squamous cell carcinoma of the kidney from cholangiocarcinoma.

    Science.gov (United States)

    Choi, Hoon; Noh, Tae Il; Ham, Byeong Kuk; Park, Jae Young; Shim, Kang Soo; Bae, Jae Hyun

    2012-12-01

    We present a rare case of a metastatic renal tumor originating from adenosquamous carcinoma of the intrahepatic bile duct. A 64-year-old man treated with bisegmentectomy and extended cholecystectomy for cholangiocarcinoma had a left cystic renal mass, which had irregular wall thickening, heterogeneously low attenuation, and soft tissue infiltration as determined by a computed tomography scan. The first impression was renal abscess. Left nephrectomy was performed and the nonencapsulated mass was gray in color macroscopically. Histological examination of the specimen revealed alveolar proliferation of small cancer cells, which was consistent with the original tumor of the intrahepatic bile duct. The left renal tumor was misdiagnosed as a renal abscess but finally diagnosed as squamous cell carcinoma metastasized from the intrahepatic bile duct. The patient expired because of lung metastasis after 14 months following left nephrectomy. In our opinion, this case would be the first report of a renal metastasis from a cholangiocarcinoma clinically and was treated with nephrectomy.

  4. Expression of transforming growth factor β1 promotes cholangiocarcinoma development and progression.

    Science.gov (United States)

    Huang, Chiung-Kuei; Aihara, Arihiro; Iwagami, Yoshifumi; Yu, Tunan; Carlson, Rolf; Koga, Hironori; Kim, Miran; Zou, Jing; Casulli, Sarah; Wands, Jack R

    2016-09-28

    The role of transforming growth factor beta 1 (TGFβ1) in cholangiocarcinoma (CCA) initiation and growth requires further definition. We employed pharmacological and genetic approaches to inhibit or enhance TGFβ1 signaling, respectively, and determine the cellular mechanisms involved. It was observed that inhibiting TGFβ1 activity with short hairpin RNA (shRNA) or pharmaceutical agents suppressed CCA development and growth, whereas overexpression of TGFβ1 enhanced CCA tumor size and promoted intrahepatic metastasis in a rat model. Suppression of TGFβ1 activity inhibits downstream target gene expression mediated by miR-34a that includes cyclin D1, CDK6, and c-Met. In addition, "knockdown" of TGFβ1 expression revealed a miR-34a positive feedback mechanism for enhanced p21 expression in CCAs. A miR-34a inhibitor reversed the effects of "knocking down" TGFβ1 on cell growth, migration, cyclin D1, CDK6 and c-Met expression, suggesting that TGFβ1 mediated effects occur, in part, through this miR-34a signaling pathway. Overexpression of TGFβ1 was associated with CCA tumor progression. This study suggests that TGFβ1 is involved in CCA tumor progression and participates through miR-34a mediated downstream cascades, and is a target to inhibit CCA development and growth. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Bullous Pemphigoid as a Harbinger of Metastatic Cholangiocarcinoma - A Rarity.

    Science.gov (United States)

    Mirgh, Sumeet Prakash; Jobanputra, Yash B; Sharma, Purva; Mishra, Vikas A; Shah, Virti D; Sharma, Akhilesh

    2017-05-01

    Bullous pemphigoid (BP) is an autoimmune blistering disorder of the skin first described in 1953. A decade later, antibodies were described targeting the cutaneous basement membrane zone. The association of Bullous pemphigoid with malignancy is debatable1 but reported in many case reports.2-6 We report a 79 year old male with cholangiocarcinoma that presented with bullous pemphigoid as a paraneoplastic phenomenon. © Journal of the Association of Physicians of India 2011.

  6. Percutaneous Ultrasound-guided Radiofrequency Ablation of Intrahepatic Cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Yi-You Chiou

    2005-07-01

    Full Text Available This study evaluated the clinical applications, treatment effects, and complications of percutaneous ultrasound (US-guided radiofrequency ablation (RFA of intrahepatic cholangiocarcinoma. Ten patients (6 men and 4 women with histologically proven cholangiocarcinoma underwent US-guided percutaneous RFA. Tumor diameters ranged from 1.9 to 6.8 cm. There were 12 sessions of RFA for 10 solitary cholangiocarcinomas. Eight patients were treated at a single session and two patients had two treatment sessions. The efficacy of RFA was evaluated using contrast-enhanced dynamic computed tomography 1 month after treatment and then every 3 months. Complete necrosis was defined as lack of contrast enhancement of the treated region. There was complete necrosis in eight tumors. In two patients with large tumors (4.7 and 6.8 cm in diameter, enhancement of residual tissue was observed after RFA treatment, indicating residual tumor. Complete necrosis was seen in all five tumors (100% with diameters of 3.0 cm or less, two of three tumors (67% with diameters of 3.1-5.0 cm, and one of two tumors (50% with diameters of more than 5.0 cm. A large biloma was found in one patient after treatment. No serious complications occurred in the other nine patients. In conclusion, percutaneous RFA is effective and successful in the treatment of intrahepatic cholangiocarcinoma of 3 cm or less and satisfactory for tumors of 3-5 cm. The rate of serious complications after RFA is low. Further follow-up is necessary to determine long-term efficacy.

  7. Akt expression may predict favorable prognosis in cholangiocarcinoma.

    Science.gov (United States)

    Javle, Milind M; Yu, Jihnhee; Khoury, Thaer; Chadha, Krishdeep S; Chadha, Krishdeep C; Iyer, Renuka V; Foster, Jason; Kuvshinoff, Boris W; Gibbs, John F; Geradts, Joseph; Black, Jennifer D; Brattain, Michael G

    2006-11-01

    Overexpression of signaling proteins including epidermal growth factor receptor (EGFR), Akt, mitogen activated protein kinase (MAPK) and cyclooxygenase-2 (COX-2) occurs in cholangiocarcinoma cell lines. However, the prognostic value of these markers is unknown. No prior study correlated the expression of these signaling proteins with clinical outcome. Further, co-expression of these proteins has not been reported. Co-expression may reflect cross-talk between signaling pathways. The aim of this clinicopathological study was to investigate the overexpression and co-expression of EGFR and related signaling proteins in cholangiocarcinoma and explore their relationship to clinical outcome. Twenty-four consecutive cases of cholangiocarcinoma treated from 1996 to 2002 at Roswell Park Cancer Institute were included. Immunohistochemical staining of paraffin-embedded tissue sections was performed using antibodies against Akt, p-Akt, MAPK, p-MAPK, COX-2, EGFR and p-EGFR. Two pathologists independently scored the protein expression. Cyclooxygenase-2, Akt, and p-MAPK were commonly expressed in biliary cancers (100%, 96% and 87% of malignant cells, respectively). EGFR (60%) and p-EGFR (22%) overexpression was also detected. There was a significant association between EGFR and p-EGFR (P = 0.027) and between Akt and p-Akt (P = 0.017) expression in tumor tissue. A noteworthy association was shown between MAPK and p-Akt (P = 0.054). Multivariate analysis using the Cox proportional hazard model identified the use of chemotherapy (hazard ratio [HR] = 0.039, P = 0.0002), radiation (HR = 0.176, P = 0.0441) and Akt expression (HR = 0.139, P = 0.006) as the best predictors of overall prognosis. Epidermal growth factor receptor signaling intermediates are commonly expressed in cholangiocarcinoma. Expression of Akt and use of systemic chemotherapy or radiation may correlate with improved survival.

  8. Chemical exposure levels in printing workers with cholangiocarcinoma.

    Science.gov (United States)

    Yamada, Kenichi; Kumagai, Shinji; Nagoya, Toshio; Endo, Ginji

    2014-01-01

    This study aimed to identify chemicals used by printing workers with cholangiocarcinoma, as well as the levels of exposure to the chemicals. Information necessary to identify chemicals used by printing workers with cholangiocarcinoma and to estimate chemical exposure concentrations was obtained from the Ministry of Health, Labour and Welfare, Japan. Working environment concentrations of the chemicals in the printing rooms were estimated using a well-mixed model, and exposure concentrations during the ink removal operation were estimated using a near-field and far-field model. Shift time- weighted averages (TWA) of exposure concentrations were also calculated. Two workers from each of three small printing plants examined suffered from cholangiocarcinoma, and all six of these workers had been exposed to 1,2-dichloropropane (1,2-DCP) for 10-16 years. The estimated working environment concentrations of 1,2-DCP in the printing rooms were 17-180 ppm and estimated exposure concentrations during the ink removal operation were 150-620 ppm. Shift TWA values were estimated to be 62-240 ppm. Four of the six workers had also been exposed to dichloromethane (DCM) at estimated working environment concentrations of 0-98 ppm and estimated exposure concentrations during the ink removal operation of 0-560 ppm. Shift TWA values were estimated to be 0-180 ppm. Other chlorinated organic solvents (1,1,1-trichloroethane, 1,1-dichloro-1-fluoroethane) and petroleum solvents (gasoline, naphtha, mineral spirit, mineral oil, kerosene) were also used in the ink removal operation. All six printing workers with cholangiocarcinoma were exposed to very high levels of 1,2-DCP for a long term.

  9. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Chaisaingmongkol, Jittiporn; Budhu, Anuradha; Dang, Hien

    2017-01-01

    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We identified common molecular subtypes linked to similar prognosis among 199 Thai ICC and HCC patients through systems integratio...... metabolism. These molecular subtypes are found in 582 Asian, but less so in 265 Caucasian patients. Thus, Asian ICC and HCC, while clinically treated as separate entities, share common molecular subtypes with similar actionable drivers to improve precision therapy....

  10. [Resection as elective treatment of hilar cholangiocarcinoma (Klatskin tumor)].

    Science.gov (United States)

    Figueras, J; Lladó-Garriga, L; Lama, C; Pujol-Ràfols, J; Navarro, M; Martínez-Villacampa, M; Domínguez, J; Sancho, C; Rafecas, A; Fabregat, J; Torras, J; Ramos, E; Xiol, X; Baliellas, C; Casanovas, T; Jaurrieta, E

    1998-05-01

    A retrospective analysis of our experience in the treatment of hiliary cholangiocarcinoma or Klatskin tumor was performed with the aim of evaluating the morbi-mortality and prognosis of its treatment to thereby determine the usefulness of the different therapeutic options. From 1989 to 1997, 51 patients diagnosed with hiliary cholangiocarcinoma were treated in our hospital. Surgery was indicated in 16 with curative aims (group I) while palliative treatment with percutaneous biliary drainage was indicated in 35 (group II). Biliary resection was carried out in 8 patients being associated with hepatic resection in 4 (group IA) and in 8 patients undergoing liver transplantation (group IB). Clinico-epidemiologic data and hospital stay were similar in all the groups. The frequency of complications was similar in groups I and II although the frequency of cholangitis (49%) in group II was noticeable. The percentage of readmissions was also greater in group II (12 vs 46%, respectively; p = 0.03) with prosthesis obstruction being the most frequent cause. Accumulated survival at 1, 2, and 3 years in group I was 84, 64 and 48% with a median survival of 33 months, while in group II the median survival was of 6 months with no patient surviving more than 2 years (p = 0.0001). When groups IA and IB were compared, greater frequency of complications in groups IA (100 vs 37%; p = 0.002), similar frequency of readmissions (87 vs 75%; p = NS), median survival greater in group IB (12.5 months vs 48 months) and significantly higher actuarial survival in group IB (48% in 2 years vs 83% to 2 years; p = 0.02) was observed. In conclusion, surgery is the treatment of choice in hiliary cholangiocarcinoma whenever possible, given the greater survival without a significant increase in morbimortality. Likewise, we consider that liver transplantation is a useful option in the treatment of patients with cholangiocarcinoma type IV of Bismuth.

  11. Sonography-guided percutaneous microwave ablation of intrahepatic primary cholangiocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Yu Mingan [Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 (China); Liang Ping, E-mail: Liangping301@hotmail.com [Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 (China); Yu Xiaoling; Cheng Zhigang; Han Zhiyu; Liu Fangyi; Yu Jie [Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 (China)

    2011-11-15

    Objective: To evaluate the efficacy and safety of sonography-guided percutaneous microwave ablation of intrahepatic primary cholangiocarcinoma. Materials and methods: From May 2006 to March 2010, 15 patients (11 men, 4 women; mean age, 57.4 years) with 24 histologically proven intrahepatic primary cholangiocarcinoma lesions (mean tumor size, 3.2 {+-} 1.9 cm; range, 1.3-9.9 cm) were treated with microwave ablation. Results: Thirty-eight sessions were performed for 24 nodules in 15 patients. The follow-up period was 4-31 months (mean, 12.8 {+-} 8.0 months). The ablation success rate, the technique effectiveness rate, and the local tumor progression rate were 91.7% (22/24), 87.5% (21/24), and 25% (6/24) respectively according to the results of follow-up. The cumulative overall 6, 12, 24 month survival rates were 78.8%, 60.0%, and 60.0%, respectively. Major complication occurred including liver abscess in two patients (13.3%) and needle seeding in one patient (6.7%). Both complications were cured satisfied with antibiotic treatment combined to catheter drainage for abscess and resection for needle seeding. The minor complications and side effects were experienced by most patients which subsided with supportive treatment. Conclusion: Microwave ablation can be used as a safe and effective technique to treat intrahepatic primary cholangiocarcinoma.

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

    Directory of Open Access Journals (Sweden)

    Xu Lu

    2017-05-01

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

  13. S0514 Sorafenib in Treating Patients With Unresectable or Metastatic Gallbladder Cancer or Cholangiocarcinoma

    Science.gov (United States)

    2013-01-11

    Adenocarcinoma of the Extrahepatic Bile Duct; Adenocarcinoma of the Gallbladder; Adenocarcinoma With Squamous Metaplasia of the Gallbladder; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Squamous Cell Carcinoma of the Gallbladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  14. The effects of omeprazole on interdigestive motility and early postprandial levels of gastrin and secretin

    DEFF Research Database (Denmark)

    Rasmussen, L; Oster-Jørgensen, E; Qvist, N

    1992-01-01

    Ten healthy men participated in a crossover study, and the experiments took place after 10 days of treatment (40 mg omeprazole every morning). Blood samples were drawn at fixed intervals during a complete migrating motor complex (MMC) cycle. The manometric pressure tube was removed after passage...... of the second duodenal phase III, and an omelet (1400 KJ) tagged with 99mTc was ingested, followed by 150 ml of water tagged with 111In-diethylenetriaminepentaacetic acid. Mean plasma gastrin (pmol/l) in phases I, II, and III in the omeprazole group was 18.8, 23.3, 19.9, respectively. The corresponding figures...... for the placebo group were 9.3, 9.6, 9.5, respectively. All mean values for the omeprazole group were significantly higher (p less than 0.01). Mean plasma gastrin in the omeprazole group was significantly higher in phase II than in phase I (p less than 0.05). Mean plasma secretin (pmol/l) in phases I, II, and III...

  15. Secretin Modulates the Postnatal Development of Mouse Cerebellar Cortex Via PKA- and ERK-dependent Pathways

    Directory of Open Access Journals (Sweden)

    Lei Wang

    2017-11-01

    Full Text Available Postnatal development of the cerebellum is critical for its intact function such as motor coordination and has been implicated in the pathogenesis of psychiatric disorders. We previously reported that deprivation of secretin (SCT from cerebellar Purkinje neurons impaired motor coordination and motor learning function, while leaving the potential role of SCT in cerebellar development to be determined. SCT and its receptor (SCTR were constitutively expressed in the postnatal cerebellum in a temporal and cell-specific manner. Using a SCT knockout mouse model, we provided direct evidence showing altered developmental patterns of Purkinje cells (PCs and granular cells (GCs. SCT deprivation reduced the PC density, impaired the PC dendritic formation, induced accelerated GC migration and potentiated cerebellar apoptosis. Furthermore, our results indicated the involvement of protein kinase A (PKA and extracellular signal regulated kinase (ERK signaling pathways in SCT-mediated protective effects against neuronal apoptosis. Results of this study illustrated a novel function of SCT in the postnatal development of cerebellum, emphasizing the necessary role of SCT in cerebellar-related functions.

  16. The effects of morphine-neostigmine and secretin provocation on pancreaticobiliary morphology in healthy subjects: a randomized, double-blind crossover study using serial MRCP.

    Science.gov (United States)

    Chowdhury, Abeed H; Humes, David J; Pritchard, Susan E; Marciani, Luca; Gowland, Penny A; Simpson, John; Lobo, Dileep N

    2011-09-01

    Secretin-stimulated magnetic resonance cholangiopancreatography (MRCP) is used for the diagnosis of sphincter of Oddi dysfunction (SOD), but it does not correlate well with sphincter of Oddi manometry. Serial MRCP following morphine-neostigmine provocation may be of value in the assessment of SOD, but the effects of these pharmacological agents on pancreaticobiliary morphology in healthy subjects have not been studied. The aim of the present study was to use serial MRCP to characterize the effects of morphine-neostigmine and secretin provocation on serum pancreatic enzyme responses and pancreaticobiliary ductal morphology in healthy subjects. Following a baseline scan and serum lipase and amylase assays, 10 healthy subjects were randomized in a double-blind manner to receive morphine (10 mg intramuscularly [IM]), neostigmine (1 mg IM) and saline (intravenously [IV]); OR saline (IM), saline (IM) and secretin (1 U/kg IV). A MRCP study was performed at 5, 30, 60, 90, 120, 150, and 180 min thereafter, with blood samples taken every 60 min for 4 h. Pancreatic duct (PD) diameter, visible PD length, common bile duct (CBD) diameter, and gallbladder volume were recorded. Crossover studies were performed 10 days later. Serum pancreatic enzyme concentrations were significantly greater (amylase, P = 0.003; lipase, P = 0.04) after morphine-neostigmine than after secretin. Following morphine-neostigmine and secretin provocation, the mean (SEM) percentage increase in PD diameter was 28.7 (7.2) versus 12.9 (3.3); P < 0.0001, and visible PD length was 49.4 (11.5) versus 28.1 (8.2); P < 0.0001, respectively. The effects of morphine-neostigmine were more pronounced than those of secretin in healthy subjects. The diagnostic utility of morphine-neostigmine stimulated serial MRCP for SOD merits further evaluation.

  17. Expression of Her-2/neu in extrahepatic cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Shamekh R

    2017-02-01

    Full Text Available Rania Shamekh,1,* Marilin Rosa,2,* Zena Sayegh,2 Masoumeh Ghayouri,2 Richard Kim,3 Mokenge P Malafa,3 Domenico Coppola2 1Department of Pathology, University of South Florida, 2Department of Anatomic Pathology, 3Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA *These authors contributed equally to this work Background: Receptor tyrosine-protein kinase erbB-2, which is also frequently called human epidermal growth factor receptor-2 (Her-2 or Her-2/neu, has been found to be overexpressed in various human cancers.Hypothesis: The aim of this pilot study was to explore the frequency of Her-2/neu gene amplification and protein expression in extrahepatic cholangiocarcinoma (EHBC. We used the World Health Organization classification criteria for EHBC.Materials and methods: This was a retrospective study using 88 tissue samples, including 45 samples from non-neoplastic biliary tissue (NNB and 43 samples of extrahepatic cholangiocarcinoma (EHBC. A tissue microarray including NNB and EHBC was constructed and analyzed by immunohistochemistry (IHC and dual in situ hybridization for Her-2/neu protein expression and amplification, respectively. The Her-2/neu expression was scored following the guidelines used for the ToGA study.Results: All NNB samples and all but one EHBC samples showed no expression of Her-2/neu by IHC. The one EHBC case immunohistochemically positive for Her-2/neu had an IHC score of 3+. Her-2/neu gene amplification was present in two EHBC samples only and included the case found to be positive by IHC.Conclusion: Our findings are similar to those reported in the literature. Although Her-2/neu overexpression has been documented in many types of cancer, Her-2/neu protein overexpression tends to have no role in the development and/or progression of EHBC. Keywords: extrahepatic, cholangiocarcinoma, Her-2/neu, ToGA, immunohistochemistry

  18. The utility of secretin-enhanced MRCP in diagnosing congenital anomalies.

    Science.gov (United States)

    Sandrasegaran, Kumaresan; Cote, Gregory A; Tahir, Bilal; Ahmad, Iftikhar; Tann, Mark; Akisik, Fatih M; Lall, Chandana G; Sherman, Stuart

    2014-10-01

    To assess the additional value of secretin-enhanced MRCP (SMRCP) over conventional MRCP in diagnosing divisum. Retrospective HIPAA-compliant and IRB-approved review found 140 patients with SMRCP and ERCP correlation within 6 months of each other. All studies were anonymized and the SMRCP images (SMRCP image set) were separated from 2D and 3D MRCP and axial and coronal T2-weighted images (conventional MRI image set). Each image set on each patient was assigned different and randomized case numbers. Two reviewers (R1 and R2) independently reviewed the image sets for divisum vs. no divisum, complete divisum vs. incomplete divisum, and the certainty of diagnosis (1 = definitely certain, 2 = moderately certain, and 3 = unsure). ERCP findings were taken as gold standard. There was no difference in age and gender between the divisum (n = 97, with 13 incomplete divisum) and no divisum (n = 43) groups. In diagnosing divisum anatomy, the sensitivity was higher for SMRCP compared to conventional MRI for R1 (84.5 vs. 72.2, p = 0.02) but not R2 (89.7 vs. 84.4, p = 0.25). The specificity was higher in SMRCP image set compared to conventional MRI (R1: 88.1 vs. 76.2, p = 0.01; R2: 81.4 vs. 65.1, p MRCP.

  19. Autophagy may promote carcinoma cell invasion and correlate with poor prognosis in cholangiocarcinoma

    Science.gov (United States)

    Nitta, Takeo; Sato, Yasunori; Ren, Xiang Shan; Harada, Kenichi; Sasaki, Motoko; Hirano, Satoshi; Nakanuma, Yasuni

    2014-01-01

    The role of autophagy in cholangiocarcinoma is poorly understood. This study investigated its involvement in cholangiocarcinoma, focusing on carcinoma cell invasion and prognostic significance using cholangiocarcinoma cell lines, CCKS1 and HuCCT1, and human tissues of hilar and extrahepatic cholangiocarcinoma. Nutrient starvation induced the expression of LC3-II and the formation of LC3 puncta in both CCKS1 and HuCCT1, suggesting the occurrence of autophagy. The induction of autophagy was accompanied by the increased expression of an autophagy-related protein, Ambra1, in the cells. Under starvation conditions, the invasive activity of both cells was significantly increased, and a lysosomal inhibitor, chloroquine, attenuated this increased invasive activity. Transforming growth factor-β1 (TGF-β1), known as an inducer of epithelial-mesenchymal transition (EMT), increased the invasive activity of both cells, and chloroquine also significantly reduced TGF-β1-induced cell invasion. Immunohistochemical staining using cholangiocarcinoma tissues showed that the expression of Ambra1 positively correlated with the expression of Snail, one of the major transcriptional factors of EMT. In addition, overexpression of Ambra1 significantly correlated with lymph node metastasis and poor survival rate of the patients. These results suggest that the occurrence of autophagy may be associated with a malignant phenotype and poor prognosis in cholangiocarcinoma, and autophagy is possibly involved in EMT-related cholangiocarcinoma cell invasion. PMID:25197362

  20. Opisthorchiasis and cholangiocarcinoma in Southeast Asia: an unresolved problem

    Directory of Open Access Journals (Sweden)

    Hughes T

    2017-08-01

    Full Text Available Thomas Hughes,1,* Thomas O’Connor,1,* Anchalee Techasen,2,3 Nisana Namwat,2,3 Watcharin Loilome,2,3 Ross H Andrews,2–4 Narong Khuntikeo,3,5 Puangrat Yongvanit,3,6 Paiboon Sithithaworn,3,7 Simon D Taylor-Robinson1 1Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, London, UK; 2Department of Biochemistry, Faculty of Medicine, Liver Fluke and Cholangiocarcinoma Centre, 3Cholangiocarcinoma Screening and Care Program (CASCAP, Khon Kaen University, Khon Kaen, Thailand; 4Faculty of Medicine, St Mary’s Campus, Imperial College, London, UK; 5Department of Surgery, 6Department of Biochemistry, 7Department of Parasitology, Faculty of Medicine, Liver Fluke and Cholangiocarcinoma Centre, Khon Kaen University, Khon Kaen, Thailand *These authors contributed equally to this work Abstract: The prevalence of cholangiocarcinoma (CCA in Southeast Asia is much higher than other areas of the world. Eating raw, fermented, or undercooked cyprinid fish, infected with the liver fluke, Opisthorchis viverrini sensu lato (sl, results in chronic biliary inflammation, periductal fibrosis, and increased cancer risk. There may be associated glomerulonephritis. The process of infection is difficult to disrupt because eating practices have proven extremely difficult to change, and the life cycle of the fluke cannot be broken due to high prevalence in canine and feline reservoir hosts. Fecal analysis and enzyme-linked immunosorbent assay tests can be used to diagnose opisthorchiasis. Diagnosis of CCA is complex, partly due to the lack of definitive imaging characteristics but also due to the difficulty of obtaining samples for cytology or histology. This cancer has proven to be resistant to common chemotherapy treatments and so the two avenues of treatment available are surgical resection and liver transplantation, both requiring early detection of the tumor for the best chances of success. Late presentation of symptoms reduces the

  1. Impact of Microenvironment and Stem-Like Plasticity in Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Raggi, Chiara; Invernizzi, Pietro; Andersen, Jesper Bøje

    2014-01-01

    Clinical complexity, anatomic diversity and molecular heterogeneity of cholangiocarcinoma (CCA) represent a major challenge in the assessment of effective targeted therapies. Molecular and cellular mechanisms underlying diversity of CCA growth patterns remain a key issue and a clinical concern...... or tumor microenvironment (TME) likely promotes initiation and progression of this malignancy contributing to its heterogeneity. This review will emphasize the dynamic interplay between stem-like intrinsic and TME-extrinsic pathways, which may represent novel options for multi-targeted therapies in CCA....

  2. Peripheral cholangiocarcinoma : Radiologic significance of hypoechoic halo sign on sonography

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Young Eok; Moon, Haeng Jin; Lee, Eun Ja; Ahn, In Oak [Gyeong Sang National Univ., College of Medicine, Chinju (Korea, Republic of)

    2001-12-01

    To determine the prevalence and characteristics of the hypoechoic halo sign in peripheral cholangiocarcinoma. Seventeen sonograms of 17 patients with peripheral cholangiocarcinoma histologically proven by either percutaneous needle biopsy (n=16) or surgical biopsy (n=1) were retrospectively reviewed. The size, margin, homogeneity and internal echogenicity of the masses as well as their peritumoral ductal dilatation and intratumoral calcification were ascertained, and the presence of a hypoechoic halo, and if present, its thickness and type, were also determined. We arbitrarily defined a 'thin' and 'thick' halo respectively, as one with a thickness less than of less than 3 mm, and 3 mm or more, and classified halos as 'intratumoral', 'extratumoral', or 'mixed'. Tumor diameter ranged from 4 to 13.5 (mean,7.3)cm, and the margin was well-defined in 15 cases (smooth: n=2; lobulated: n=13) and irregular in two. Echogenicity was slightly heterogeneous in 11 cases, severely heterogeneous in three, and hemogeneous in three, while the central portion was hyperechoic in eight cases, isoechoic in seven, and hypoechoic in only two. A hypoechoic halo was detected in 10 of 15 tumors (67%) with isoechoic centers. In evaluating the halo, two cases in which the mass was hypoechoic were excluded. All ten hypoechoic halos were at least 3 (range, 4-13; mean, 8.3) mm thick; in two cases the presence of a halo was equivocal, and in three there was no halo. Eight of ten halos were the mixed type, two were intratumoral, and none were extratumoral. Peritumoral ductal dilatation was seen in four cases (24%), but no internal calcification was observed. US showed that the margins of peripheral cholangiocarcinomas were mostly well-defined and smooth (12%) or lobulated (76%), and that masses were mainly heterogeneous (64%) A hypoechoic halo, which in all cases was thick and in 80% of cases was mixed, was noted in 67% of tumors with a hyper (47

  3. Comparative study of antitumor effects of bromelain and papain in human cholangiocarcinoma cell lines.

    Science.gov (United States)

    Müller, Alena; Barat, Samarpita; Chen, Xi; Bui, Khac Cuong; Bozko, Przemyslaw; Malek, Nisar P; Plentz, Ruben R

    2016-05-01

    Cholangiocarcinoma (CC) worldwide is the most common biliary malignancy with poor prognostic value and new systemic treatments are desirable. Plant extracts like bromelain and papain, which are cysteine proteases from the fruit pineapple and papaya, are known to have antitumor activities. Therefore, in this study for the first time we investigated the anticancer effect of bromelain and papain in intra- and extrahepatic human CC cell lines. The effect of bromelain and papain on human CC cell growth, migration, invasion and epithelial plasticity was analyzed using cell proliferation, wound healing, invasion and apoptosis assay, as well as western blotting. Bromelain and papain lead to a decrease in the proliferation, invasion and migration of CC cells. Both plant extracts inhibited NFκB/AMPK signalling as well as their downstream signalling proteins such as p-AKT, p-ERK, p-Stat3. Additionally, MMP9 and other epithelial-mesenchymal-transition markers were partially found to be downregulated. Apoptosis was induced after bromelain and papain treatment. Interestingly, bromelain showed an overall more effective inhibition of CC as compared to papain. siRNA mediated silencing of NFκB on CC cells indicated that bromelain and papain have cytotoxic effects on human CC cell lines and bromelain and partially papain in comparison impair tumor growth by NFκB/AMPK signalling. Especially bromelain can evolve as promising, potential therapeutic option that might open new insights for the treatment of human CC.

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

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Xinkui; Sun, Daoyi; Chai, Hao; Shan, Wengang [Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province (China); Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province (China); Yu, Yue [Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province (China); Pu, Liyong [Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province (China); Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province (China); Cheng, Feng, E-mail: docchengfeng@njmu.edu.cn [Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province (China); Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province (China)

    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.

  5. Upregulation of transferrin receptor-1 induces cholangiocarcinoma progression via induction of labile iron pool.

    Science.gov (United States)

    Jamnongkan, Wassana; Thanan, Raynoo; Techasen, Anchalee; Namwat, Nisana; Loilome, Watcharin; Intarawichian, Piyapharom; Titapun, Attapol; Yongvanit, Puangrat

    2017-07-01

    Labile iron pool is a cellular source of ions available for Fenton reactions resulting in oxidative stress. Living organisms avoid an excess of free irons by a tight control of iron homeostasis. We investigated the altered expression of iron regulatory proteins and iron discrimination in the development of liver fluke-associated cholangiocarcinoma. Additionally, the levels of labile iron pool and the functions of transferrin receptor-1 on cholangiocarcinoma development were also identified. Iron deposition was determined using the Prussian blue staining method in human cholangiocarcinoma tissues. We investigated the alteration of iron regulatory proteins including transferrin, transferrin receptor-1, ferritin, ferroportin, hepcidin, and divalent metal transporter-1 in cholangiocarcinoma tissues using immunohistochemistry. The clinicopathological data of cholangiocarcinoma patients and the expressions of proteins were analyzed. Moreover, the level of intracellular labile iron pool in cholangiocarcinoma cell lines was identified by the RhoNox-1 staining method. We further demonstrated transferrin receptor-1 functions on cell proliferation and migration upon small interfering RNA for human transferrin receptor 1 transfection. Results show that Iron was strongly stained in tumor tissues, whereas negative staining was observed in normal bile ducts of healthy donors. Interestingly, high iron accumulation was significantly correlated with poor prognosis of cholangiocarcinoma patients. The expressions of iron regulatory proteins in human cholangiocarcinoma tissues and normal liver from cadaveric donors revealed that transferrin receptor-1 expression was increased in the cancer cells of cholangiocarcinoma tissues when compared with the adjacent normal bile ducts and was significantly correlated with cholangiocarcinoma metastasis. Labile iron pool level and transferrin receptor-1 expression were significantly increased in KKU-214 and KKU-213 when compared with cholangiocyte

  6. Cholangiocarcinoma with Lymphoepithelioma-like Component not Associated with Epstein-Barr Virus

    Directory of Open Access Journals (Sweden)

    Wen-Han Chang

    2015-12-01

    Full Text Available Lymphoepithelioma-like cholangiocarcinoma (LELCC is a rare variant of intrahepatic cholangiocarcinoma. We herein have reported an unusual case of LELCC in a 71-year-old Taiwanese women with cirrhotic liver disease and chronic hepatitis C. The patient's liver tumor was unexpectedly discovered during a regular abdominal ultrasound exam without obvious clinical symptoms and signs; she thereafter received surgical resection. Histologically, the liver tumor showed lymphoepithelial-like appearance and features of cholangiocarcinoma without association with Epstein-Barr virus (EBV. We maintained regular follow-up with the patient for 3 years, who at that time was alive without tumor recurrence.

  7. Construction, expression, purification and characterization of secretin domain of PilQ and triple PilA-related disulfide loop peptides fusion protein from Pseudomonas aeruginosa.

    Science.gov (United States)

    Faezi, Sobhan; Bahrmand, Ahmad Reza; Siadat, Seyed Davar; Nikokar, Iraj; Sardari, Soroush; Mahdavi, Mehdi

    2017-05-01

    Infection with Pseudomonas aeruginosa has been a long-standing obstacle for clinical therapy due to the complexity of the genetics and pathogenesis, as well for widespread resistance to antibiotics, thus attaching great importance to explore effective vaccines for prevention and treatment. This paper focuses on the introduction of novel Pseudomonas aeruginosa type IV pili (T4P)-based fusion protein containing the secretin domain of PilQ and tandem PilA-related peptides. We surveyed the expression of the PilQ380-705-PilA fusion protein in-frame with pET26b vector in which a rigid linker was used between two polypeptides and flexible linkers were inserted between the three tandem repeats and each pilA domains. The transformants were expressed in Escherichia coli BL21. The reactivity of specific antisera to the fusion protein was assessed by ELISA. The biological activities of this candidate vaccine were evaluated by western blotting, opsonophagocytosis, and twitching inhibition assays. The fusion protein was purified in high yield by osmotic shock method using HisTrap affinity column. The protein was confirmed by immunoblot analysis. The checkerboard titration showed that the optimal dilution of the antibody to react with antigen is 1:128. Results of opsonophagocytosis assay revealed that the antibodies elevated to the fusion protein promoted phagocytosis of the PAO1 and 6266E strains, so that the twitching immobilization test confirmed these results. Due to excellent killing activity mediated by opsonic antibodies and efficient immobilization of the strains, it seems that PilQ380-705-PilA fusion protein could be a reliable candidate vaccine against P. aeruginosa infection.

  8. Secretin-stimulated MR cholangio-pancreatography in the evaluation of asymptomatic patients with non-specific pancreatic hyperenzymemia

    Energy Technology Data Exchange (ETDEWEB)

    Donati, Francescamaria, E-mail: fra.donati@katamail.co [2nd Department of Radiology, Pisa University-Hospital, Via Paradisa 2, I-56124 Pisa (Italy); Boraschi, Piero; Gigoni, Roberto; Salemi, Simonetta [2nd Department of Radiology, Pisa University-Hospital, Via Paradisa 2, I-56124 Pisa (Italy); Faggioni, Lorenzo; Bertucci, Cristina; Cecchi, Claudia; Bartolozzi, Carlo [Diagnostic and Interventional Radiology, University of Pisa, Via Rome 67, I-56126 Pisa (Italy); Falaschi, Fabio [2nd Department of Radiology, Pisa University-Hospital, Via Paradisa 2, I-56124 Pisa (Italy)

    2010-08-15

    Purpose: To assess the diagnostic value of secretin-stimulated MRCP (SS-MRCP) compared with conventional MRCP in asymptomatic patients with mild elevations of pancreatic enzymes. Materials and methods: Eighty asymptomatic patients with pancreatic hyperenzymemia underwent MR imaging at 1.5 T-device (Signa EXCITE, GE Healthcare). After the acquisition of axial T1w,T2w sequences, and conventional MRCP, SS-MRCP was performed using a single-slice coronal breath-hold, thick-slab, SSFSE T2w sequence, repeated every 30 s up to 15 min following intravenous injection of secretin (Secrelux, Sanochemia). Results: On the basis of the standards of reference, our final diagnoses were: negative findings (n = 23), pancreas divisum (n = 22), mild chronic pancreatitis (n = 14), inflammatory ampullary stenosis (n = 3), juxtapapillary duodenal diverticulum (n = 1), small cystic lesions (<1 cm) (n = 22; 5/22 cases associated with pancreas divisum). The image quality of SS-MRCP was significantly higher than that of conventional MRCP (p < 0.0001). Standards of reference did not differ significantly from of SS-MRCP findings (p = 0.5), while was statistically different from those of conventional MRCP (p < 0.0001). A significant difference was found between conventional MRCP and SS-MRCP findings (p < 0.0001). Conclusion: In asymptomatic patients with non-specific pancreatic hyperenzymemia SS-MRCP may represent the best non-invasive diagnostic technique, since it gives morphological and functional information.

  9. Stent Placement With or Without Photodynamic Therapy Using Porfimer Sodium as Palliative Treatment in Treating Patients With Stage III or Stage IV Cholangiocarcinoma That Cannot Be Removed By Surgery

    Science.gov (United States)

    2013-04-02

    Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer

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

    DEFF Research Database (Denmark)

    Erice, O; Labiano, I; Arbelaiz, A

    2017-01-01

    BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangioc...

  11. Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages

    DEFF Research Database (Denmark)

    Raggi, Chiara; Correnti, Margherita; Sica, Antonio

    2017-01-01

    BACKGROUND AND AIMS: Therapeutically challenging subset, termed cancer stem cells (CSCs) are responsible for cholangiocarcinoma (CCA) clinical severity. Presence of tumor-associated macrophages (TAMs) has prognostic significance in CCA and other malignancies. Thus, we hypothesized that CSCs may a...

  12. Transcriptomic and histopathological analysis of cholangiolocellular differentiation trait in intrahepatic cholangiocarcinoma

    DEFF Research Database (Denmark)

    Rhee, Hyungjin; Ko, Jung Eun; Chung, Taek

    2018-01-01

    BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous entity with diverse etiologies, morphologies, and clinical outcomes. Recently, histopathological distinction of cholangiolocellular differentiation (CD) of iCCA has been suggested. However, its genome-wide molecular feat...

  13. Multidisciplinary management of hilar cholangiocarcinoma (Klatskin tumor): Extended resection is associated with improved survival

    NARCIS (Netherlands)

    van Gulik, T. M.; Kloek, J. J.; Ruys, A. T.; Busch, O. R. C.; van Tienhoven, G. J.; Lameris, J. S.; Rauws, E. A. J.; Gouma, D. J.

    2011-01-01

    Background: Effective diagnosis and treatment of patients with hilar cholangiocarcinoma (HCCA) is based on the synergy of endoscopists, interventional radiologists, radiotherapists and surgeons. This report summarizes the multidisciplinary experience in management of HCCA over a period of two

  14. Alterations in Peptidoglycan Cross-Linking Suppress the Secretin Assembly Defect Caused by Mutation of GspA in the Type II Secretion System.

    Science.gov (United States)

    Vanderlinde, Elizabeth M; Strozen, Timothy G; Hernández, Sara B; Cava, Felipe; Howard, S Peter

    2017-04-15

    In Gram-negative bacteria, the peptidoglycan (PG) cell wall is a significant structural barrier for outer membrane protein assembly. In Aeromonas hydrophila, outer membrane multimerization of the type II secretion system (T2SS) secretin ExeD requires the function of the inner membrane assembly factor complex ExeAB. The putative mechanism of the complex involves the reorganization of PG and localization of ExeD, whereby ExeA functions by interacting with PG to form a site for secretin assembly and ExeB forms an interaction with ExeD. This mechanism led us to hypothesize that increasing the pore size of PG would circumvent the requirement for ExeA in the assembly of the ExeD secretin. Growth of A. hydrophila in 270 mM Gly reduced PG cross-links by approximately 30% and led to the suppression of secretin assembly defects in exeA strains and in those expressing ExeA mutants by enabling localization of the secretin in the outer membrane. We also established a heterologous ExeD assembly system in Escherichia coli and showed that ExeAB and ExeC are the only A. hydrophila proteins required for the assembly of the ExeD secretin in E. coli and that ExeAB-independent assembly of ExeD can occur upon overexpression of the d,d-carboxypeptidase PBP 5. These results support an assembly model in which, upon binding to PG, ExeA induces multimerization and pore formation in the sacculus, which enables ExeD monomers to interact with ExeB and assemble into a secretin that both is inserted in the outer membrane and crosses the PG layer to interact with the inner membrane platform of the T2SS.IMPORTANCE The PG layer imposes a strict structural impediment for the assembly of macromolecular structures that span the cell envelope and serve as virulence factors in Gram-negative species. This work revealed that by decreasing PG cross-linking by growth in Gly, the absolute requirement for the PG-binding activity of ExeA in the assembly of the ExeD secretin was alleviated in A. hydrophila In a

  15. Identification of bile survivin and carbohydrate antigen 199 in distinguishing cholangiocarcinoma from benign obstructive jaundice.

    Science.gov (United States)

    Liu, Yanfeng; Sun, Jingxian; Zhang, Qiangbo; Jin, Bin; Zhu, Min; Zhang, Zongli

    2017-01-01

    To investigate whether bile survivin and carbohydrate antigen 199 (CA199) can be helpful in distinguishing cholangiocarcinoma (malignant obstructive jaundice) from benign obstructive jaundice. Receiver operating characteristic curve was used to evaluate the feasibility of bile survivin and CA199 in differentiating cholangiocarcinoma from benign obstructive jaundice. The area under the curve for survivin and CA199 in bile and serum were 0.780 (p jaundice.

  16. Effect of the GLP-1 Analog Exendin-4 and Oxaliplatin on Intrahepatic Cholangiocarcinoma Cell Line and Mouse Model

    Directory of Open Access Journals (Sweden)

    Ben-Dong Chen

    2013-12-01

    Full Text Available The influence of Glucagon-like peptide-1 (GLP-1 and Exendin-4 on development of intrahepatic cholangiocarcinoma (ICC is evaluated in the study. In vitro tests, including acute toxicity test, cell colony formation assays, cells proliferation and apoptosis, transwell assay, were performed. An ICC in situ tumor animal model was established. Then, animals were randomly divided into four groups (n = 6: control, Exendin-4 treatment, oxaliplatin treatment and Exendin-4-oxaliplatin treatment. Animals in the Exendin-4 treatment and Exendin-4-oxaliplatin treatment groups received a subcutaneous injection of Exendin-4 (100 μg/kg/day for 1 week, and then received oxaliplatin (10 mg/kg/week by tail vein injection. Animals in the control group received PBS. Immunohistochemistry tests were used for PCNA, Ki67, Caspase 3 expression in tumor tissue. Results show that that, after incubation of human cholangiocarcinoma cell lines, HuCCTI and GLP-1, or HuCCTI and Exendin-4, colony formation number was sharply decreased. However, GLP-1, HuCCTI or Exendin-4 did not affect the colony of normal cells. Combination treatment with oxaliplatin and Exendin-4 can significantly inhibit tumor cells’ proliferation and promote apoptosis. The combined effect is stronger than that of oxaliplatin or Exendin-4. Combination treatment with oxaliplatin and Exendin4 can significantly decrease Ki67 and PCNA proteins’ expression in subcutaneous tumors of nude mice. The inhibitory effect of Combination treatment with oxaliplatin and Exendin4 is clearly stronger than that of oxaliplatin. In addition, Combination treatment with oxaliplatin and Exendin4 can significantly increase Caspase3 protein positive expression. In short, these results show that combination treatment with oxaliplatin and Exendin4 can inhibit tumor cells’ proliferation, and promote apoptosis.

  17. Disruption of endocytic trafficking protein Rab7 impairs invasiveness of cholangiocarcinoma cells.

    Science.gov (United States)

    Suwandittakul, Nantana; Reamtong, Onrapak; Molee, Pattamaporn; Maneewatchararangsri, Santi; Sutherat, Maleerat; Chaisri, Urai; Wongkham, Sopit; Adisakwattana, Poom

    2017-09-07

    Alterations and mutations of endo-lysosomal trafficking proteins have been associated with cancer progression. Identification and characterization of endo-lysosomal trafficking proteins in invasive cholangiocarcinoma (CCA) cells may benefit prognosis and drug design for CCA. To identify and characterize endo-lysosomal trafficking proteins in invasive CCA. A lysosomal-enriched fraction was isolated from a TNF-α induced invasive CCA cell line (KKU-100) and uninduced control cells and protein identification was performed with nano-LC MS/MS. Novel lysosomal proteins that were upregulated in invasive CCA cells were validated by real-time RT-PCR. We selected Rab7 for further studies of protein level using western blotting and subcellular localization using immunofluorescence. The role of Rab7 in CCA invasion was determined by siRNA gene knockdown and matrigel transwell assay. Rab7 mRNA and protein were upregulated in invasive CCA cells compared with non-treated controls. Immunofluorescence studies demonstrated that Rab7 was expressed predominantly in invasive CCA cells and was localized in the cytoplasm and lysosomes. Suppression of Rab7 translation significantly inhibited TNF-α-induced cell invasion compared to non-treated control (p= 0.044). Overexpression of Rab7 in CCA cells was associated with cell invasion, supporting Rab7 as a novel candidate for the development of diagnostic and therapeutic strategies for CCA.

  18. Effect of blocking Rac1 expression in cholangiocarcinoma QBC939 cells

    Directory of Open Access Journals (Sweden)

    Liu Xudong

    2011-05-01

    Full Text Available Cholangiocarcinomas (CCs are malignant tumors that originate from epithelial cells lining the biliary tree and gallbladder. Ras correlative C3 creotoxin substrate 1 (Rac1, a small guanosine triphosphatase, is a critical mediator of various aspects of endothelial cell functions. The objective of the present investigation was to study the effect of blocking Rac1 expression in CCs. Seventy-four extrahepatic CC (ECC specimens and matched adjacent normal mucosa were obtained from the Department of Pathology, Inner Mongolia Medicine Hospital, between 2007 and 2009. Our results showed that the expression of Rac1 was significantly higher (53.12% in tumor tissues than in normal tissues. Western blotting data indicated a significant reduction in Rac1-miRNA cell protein levels. Rac1-miRNA cell growth rate was significantly different at 24, 48, and 72 h after transfection. Flow cytometry analysis showed that Rac1-miRNA cells undergo apoptosis more effectively than control QBC939 cells. Blocking Rac1 expression by RNAi effectively inhibits the growth of CCs. miRNA silencing of the Rac1 gene suppresses proliferation and induces apoptosis of QBC939 cells. These results suggest that Rac1 may be a new gene therapy target for CC. Blocking Rac1 expression in CC cells induces apoptosis of these tumor cells and may thus represent a new therapeutic approach.

  19. miRNA and lncRNA as biomarkers in cholangiocarcinoma(CCA).

    Science.gov (United States)

    Zheng, Bo; Jeong, Seogsong; Zhu, Yanjing; Chen, Lei; Xia, Qiang

    2017-11-21

    The microRNAs are a group of 20 nucleotides-long non-coding RNAs. By binding to the 3'UTR region of target mRNA, microRNAs can perform extensive actions mediating gene expression at post-trancriptional stages. It makes microRNAs serve as very crucial regulators in various biological progress including carcinogenesis. Long non-coding RNAs, however, are a subgroup of RNA with the length of 200 nucleotides. Unlike microRNAs, long non-coding RNAs can form secondary of tertiary domain based on their length. With the ability of directly interacting with DNA, RNA, protein, long non-coding RNAs have promoting or inhibitive functions in gene expression regulation. Furthermore, the abnormal expression of certain long non-coding RNAs has roused people's interest in the role of long non-coding RNAs in tumorigenesis. Although the connection between microRNA/long non-coding RNA and CCA has been a hot field to researchers, the link between molecular mechanism and clinical outcome has been barely built. This review takes a retrospect at the latest researches on the link between microRNA/long non-coding RNA and cholangiocarcinoma and the potential of microRNA/long non-coding RNA serving as distinctive biomarkers for CCA in clinical practice.

  20. ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics

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    Fan, Zhongqi [Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021 (China); Yu, Huimei [Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021 (China); Cui, Ni [Bethune Medical College, Jilin University, Changchun, Jilin 130021 (China); Kong, Xianggui; Liu, Xiaomin; Chang, Yulei [State Key Laboratory of Luminescence and Applications, Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences, Changchun, Jilin 130033 (China); Wu, Yao [Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021 (China); Sun, Liankun, E-mail: sunlk@jlu.edu.cn [Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021 (China); Wang, Guangyi, E-mail: wgymd@sina.com [Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021 (China)

    2015-07-01

    Cholangiocarcinoma responses weakly to cisplatin. Mitochondrial dynamics participate in the response to various stresses, and mainly involve mitophagy and mitochondrial fusion and fission. Bcl-2 family proteins play critical roles in orchestrating mitochondrial dynamics, and are involved in the resistance to cisplatin. Here we reported that ABT737, combined with cisplatin, can promote cholangiocarcinoma cells to undergo apoptosis. We found that the combined treatment decreased the Mcl-1 pro-survival form and increased Bak. Cells undergoing cisplatin treatment showed hyperfused mitochondria, whereas fragmentation was dominant in the mitochondria of cells exposed to the combined treatment, with higher Fis1 levels, decreased Mfn2 and OPA1 levels, increased ratio of Drp1 60 kD to 80 kD form, and more Drp1 located on mitochondria. More p62 aggregates were observed in cells with fragmented mitochondria, and they gradually translocated to mitochondria. Mitophagy was induced by the combined treatment. Knockdown p62 decreased the Drp1 ratio, increased Tom20, and increased cell viability. Our data indicated that mitochondrial dynamics play an important role in the response of cholangiocarcinoma to cisplatin. ABT737 might enhance cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics and the balance within Bcl-2 family proteins. Furthermore, p62 seems to be critical in the regulation of mitochondrial dynamics. - Highlights: • Cholangiocarcinoma may adapt to cisplatin through mitochondrial fusion. • ABT737 sensitizes cholangiocarcinoma to cisplatin by promoting fission and mitophagy. • p62 might participate in the regulation of mitochondrial fission and mitophagy.

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

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    Hariraj Radhakrishnan

    2010-05-01

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

  2. Morphological study of the TK cholangiocarcinoma cell line with three-dimensional cell culture.

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    Akiyoshi, Kohei; Kamada, Minori; Akiyama, Nobutake; Suzuki, Masafumi; Watanabe, Michiko; Fujioka, Kouki; Ikeda, Keiichi; Mizuno, Shuichi; Manome, Yoshinobu

    2014-04-01

    Cholangiocarcinoma is an intractable carcinoma originating from the bile duct epithelium. To gain an understanding of the cell biology of cholangiocarcinoma, in vitro cell culture is valuable. However, well‑characterized cell lines are limited. In the present study, the morphology of the TK cholangiocarcinoma cell line was analyzed by three‑dimensional culture. Dispersed TK cells were injected into a gelatin mesh scaffold and cultivated for 3‑20 days. The morphology of the TK cells was investigated by phase‑contrast microscopy, optical microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). TK cells were observed to proliferate three-dimensionally in the scaffold. The cells exhibited a globoid structure and attached to the scaffold. The SEM observation demonstrated typical microvilli and plicae on the surface of the structure. Light microscopy and TEM confirmed intercellular and cell‑to‑scaffold attachment in the three‑dimensional mesh. The culture also exhibited the formation of a duct-like structure covered by structured microvilli. In conclusion, three‑dimensional culture of TK cells demonstrated the morphological characteristics of cholangiocarcinoma in vitro. Production of high levels of carbohydrate antigen (CA)19‑9, CA50 and carcinoembryonic antigen was previously confirmed in the TK cell line. As a characteristic morphology was demonstrated in the present study, the TK cholangiocarcinoma cell line may be useful as an experimental model for further study of cholangiocarcinoma.

  3. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA).

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    Banales, Jesus M; Cardinale, Vincenzo; Carpino, Guido; Marzioni, Marco; Andersen, Jesper B; Invernizzi, Pietro; Lind, Guro E; Folseraas, Trine; Forbes, Stuart J; Fouassier, Laura; Geier, Andreas; Calvisi, Diego F; Mertens, Joachim C; Trauner, Michael; Benedetti, Antonio; Maroni, Luca; Vaquero, Javier; Macias, Rocio I R; Raggi, Chiara; Perugorria, Maria J; Gaudio, Eugenio; Boberg, Kirsten M; Marin, Jose J G; Alvaro, Domenico

    2016-05-01

    Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.

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

    Science.gov (United States)

    2018-02-05

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

  5. Autocrine and Paracrine Mechanisms Promoting Chemoresistance in Cholangiocarcinoma

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    Massimiliano Cadamuro

    2017-01-01

    Full Text Available Resistance to conventional chemotherapeutic agents, a typical feature of cholangiocarcinoma, prevents the efficacy of the therapeutic arsenal usually used to combat malignancy in humans. Mechanisms of chemoresistance by neoplastic cholangiocytes include evasion of drug-induced apoptosis mediated by autocrine and paracrine cues released in the tumor microenvironment. Here, recent evidence regarding molecular mechanisms of chemoresistance is reviewed, as well as associations between well-developed chemoresistance and activation of the cancer stem cell compartment. It is concluded that improved understanding of the complex interplay between apoptosis signaling and the promotion of cell survival represent potentially productive areas for active investigation, with the ultimate aim of encouraging future studies to unveil new, effective strategies able to overcome current limitations on treatment.

  6. The miRNAome of Opisthorchis viverrini induced intrahepatic cholangiocarcinoma

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    Jin Peng

    2014-12-01

    Full Text Available 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.

  7. Diagnosis and Surgical Treatment of Intrahepatic Hepatolithiasis Associated Cholangiocarcinoma

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    Shao-Liang Han

    2009-01-01

    Full Text Available Liver malignancy is known to be associated with hepatolithiasis. The present report summarises the results and our experience for management of 23 patients with intrahepatic hepatolithiasis associated cholangiocarcinoma (IHHCC. The correct diagnosis rates of US (ultrasonography, CT (computed tomography, and MRCP (magnetic resonance cholangiopancreatography were 82.6% (19/23, 95.7% (22/23, and 91.7% (11/12, respectively. Carbohydrate antigen 19-9 (CA 19-9 was helpful in the diagnosis of IHHCC. All 23 patients with IHHCC underwent laparotomy. The surgical procedure consisted hepatectomy with a bile duct exploration in 16 patients (69.6%, a hepatectomy and drainage procedure such as sphincteroplasty and choledo-jejunostomy in three patients (13.0%, a bile duct exploration with biopsy in two patients (8.7%, and simple laparotomy and biopsy in two patients (8.7%. All the IHHCC patients who underwent a palliative procedure or laparotomy died within 1 year, and the overall cumulative survival rates at 1, 3, and 5 years were 43.8% (10/23, 13.0% (3/23, and 4.3% (1/23, respectively, and those patients who underwent curative resection were 88.9% (8/9, 33.3% (3/9, and 11.1% (1/9, respectively, which significantly longer than those (20.0%, 2/10; 0.0%, 0/10; and 0.0%, 0/10 patients who underwent palliative resection, respectively (p < 0.05. A suspicion of malignancy is necessary when managing patients with long-term hepatolithiasis. Hepatic resection with postoperative treatment is the treatment of choice for cholangiocarcinoma when it is resectable.

  8. Progranulin modulates cholangiocarcinoma cell proliferation, apoptosis, and motility via the PI3K/pAkt pathway

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    Daya M

    2018-01-01

    conclusion, our findings imply that PGRN modulates cell proliferation by dysregulating the G1 phase, inhibiting apoptosis, and that it plays a role in the EMT affecting CCA cell motility, possibly via the PI3K/pAkt pathway. Keywords: progranulin, cholangiocarcinoma, proliferation, migration, invasion, EMT

  9. Hypo- and achlorhydria are associated with false-positive secretin stimulation testing for Zollinger-Ellison syndrome

    Science.gov (United States)

    Shah, Pari; Singh, Maneesh H.; Yang, Yu-Xiao; Metz, David C.

    2013-01-01

    Objectives Secretin stimulation testing (SST) is used to evaluate patients with hypergastrinemia in the diagnosis of Zollinger-Ellison syndrome (ZES). Case series have documented false-positive SST in patients with achlorhydria. This study reviews our experience with SST in hypo- and achlorhydric patients. Methods We examined 27 patients with hypo- or achlorhydria based on a predefined basal acid output (BAO) measurement of hypochlorhydria (BAO=0.5mEq/hr). These false-positive test results were confirmed by structural and functional imaging studies. Conclusions We have identified a 14.8% false-positive rate in SST in patients with hypo- or achlorhydria. Growing literature has identified severe consequences associated with discontinuing anti-secretory treatment for testing; therefore, SST will require interpretation in the setting of gastric acid suppression and needs to be interpreted in this context. PMID:23851430

  10. Correlation between secretin-enhanced MRCP findings and histopathologic severity of chronic pancreatitis in a cat model.

    Science.gov (United States)

    Zhang, Ting-Ting; Wang, Li; Wang, Deng-bin; Huang, Zhi-Jun; Li, Yu-hua; Lu, Jian-Ping

    2013-01-01

    To evaluate the usefulness of secretin-enhanced magnetic resonance cholangiopancreatography (S-MRCP) in chronic pancreatitis (CP), we compared the severity of disease determined histopathologically with that indicated by S-MRCP imaging parameters in an induced CP cat model. An experimental group of randomly chosen cats (n = 24) underwent ligation of the pancreatic duct to induce CP, and cats in a similarly chosen control group (n = 8) were sham-operated. MRCP was performed prior to secretin stimulation, and 5 and 15 min afterward, noting in particular the pancreatic duct caliber change (PDC) and the increasing degree of fluid volume (IDFV). Histopathological changes were observed in pancreatic samples processed for hematoxylin-eosin and Sirius red staining, and CP was classified as normal, minimal, moderate, or advanced. Correlations were investigated between these groups and the PDC at 5 min and the IDFV at 15 min. Between cats with minimal CP and the controls, the differences in mean IDFV and PDC were not significant although diseased cats showed a downward trend in both parameters. However, compared with the control group both the mean IDFV and PDC were significantly lower in cats with moderate (IDFV, P = 0.001; PDC, P = 0.013) or advanced (IDFV, P = 0.013; PDC, P = 0.001) CP. The S-MRCP parameters IDFV and PDC correlated with the histopathological severity of induced CP. S-MRCP could be used to evaluate the severity of CP, although it is somewhat insensitive for depicting very early disease. Copyright © 2013 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  11. Expression of Grb2, MMP-3, and MMP-9 in cholangiocarcinoma and its significance

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    ZHAO Tingkuan

    2015-07-01

    Full Text Available Objective To investigate the expression of growth factor receptor-bound protein-2 (Grb2, matrix metalloproteinase-3 (MMP-3, and MMP-9 in cholangiocarcinoma and its significance. Methods The expression of Grb2, MMP-3, and MMP-9 in cholangiocarcinoma tissues of 47 cases and normal tissues was measured using immunohistochemistry, and the correlations of Grb2 expression with clinical pathology and MMP-3 and MMP-9 expression were analyzed. Comparison of continuous data was made using t test, and the correlation of Grb2 expression with MMP-3 and MMP-9 expression was analyzed using the multivariate linear regression model. Results The expression of Grb2 in cholangiocarcinoma tissues was significantly higher than that in normal bile duct tissues (t=5.935, P<0.001; the expression of Grb2 in cholangiocarcinoma tissues and normal bile duct tissues showed no significant correlation with age, sex, and differentiation level; the expression of Grb2 in cholangiocarcinoma tissues with lymph node or distant metastasis was significantly higher than that in cholangiocarcinoma tissues without metastasis (t=3.882, P=0.003. The expression of Grb2 was positively correlated with the expression of MMP-3 and MMP-9 (r2=0.3667, P=0.018; r2=0.5133, P=0.007. Conclusion The expression of Grb2 in cholangiocarcinoma tissues is higher than that in normal bile duct tissues, and it is closely related to the invasion and metastasis of carcinoma. Further study shows that the expression of Grb2 is positively correlated with the expression of MMP-3 and MMP-9.

  12. Untangling the Complexity of Liver Fluke Infection and Cholangiocarcinoma in NE Thailand Through Transdisciplinary Learning.

    Science.gov (United States)

    Ziegler, A D; Echaubard, P; Lee, Y T; Chuah, C J; Wilcox, B A; Grundy-Warr, C; Sithithaworn, P; Petney, T N; Laithevewat, L; Ong, X; Andrews, R H; Ismail, T; Sripa, B; Khuntikeo, N; Poonpon, K; Tungtang, P; Tuamsuk, K

    2016-06-01

    This study demonstrates how a transdisciplinary learning approach provided new insights for explaining persistent Opisthorchis viverrini infection in northern Thailand, as well as elucidating problems of focusing solely on the parasite as a means of addressing high prevalence of cholangiocarcinoma. Researchers from diverse backgrounds collaborated to design an investigative homestay program for 72 Singaporean and Thai university students in five northeast Thai villages. The students explored how liver fluke infection and potential cholangiocarcinoma development are influenced by local landscape dynamics, aquatic ecology, livelihoods, food culture and health education. Qualitative fieldwork was guided daily by the researchers in a collaborative, co-learning process that led to viewing this health issue as a complex system, influenced by interlinked multidimensional factors. Our transdisciplinary experience has led us to believe that an incomplete understanding of these linkages may reduce the efficacy of interventions. Further, viewing liver fluke infection and cholangiocarcinoma as the same issue is inadvisable. Although O. viverrini infection is an established risk factor for the development of cholangiocarcinoma, multiple factors are known to influence the likelihood of acquiring either. Understanding the importance of the current livelihood transition, landscape modification and the resulting mismatch between local cultures and new socio-ecological settings on cholangiocarcinoma initiation and liver fluke transmission is of critical importance as it may help readjust our view of the respective role of O. viverrini and other socioeconomic risk factors in cholangiocarcinoma etiology and refine intervention strategies. As demonstrated in this study, transdisciplinary approaches have the potential to yield more nuanced perspectives to complex diseases than research that focuses on specific aspects of their epidemiology. They may therefore be valuable when designing

  13. Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans.

    Science.gov (United States)

    Li, Lei; Che, Li; Tharp, Kevin M; Park, Hyo-Min; Pilo, Maria G; Cao, Dan; Cigliano, Antonio; Latte, Gavinella; Xu, Zhong; Ribback, Silvia; Dombrowski, Frank; Evert, Matthias; Gores, Gregory J; Stahl, Andreas; Calvisi, Diego F; Chen, Xin

    2016-06-01

    Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. These malignancies have limited treatment options, resulting in poor patient outcomes. Metabolism reprogramming, including increased de novo lipogenesis, is one of the hallmarks of cancer. Fatty acid synthase (FASN) catalyzes the de novo synthesis of long-chain fatty acids from acetyl-coenzyme A and malonyl-coenzyme A. Increased FASN expression has been reported in multiple tumor types, and inhibition of FASN expression has been shown to have tumor-suppressing activity. Intriguingly, we found that while FASN is up-regulated in human HCC samples, its expression is frequently low in human ICC specimens. Similar results were observed in mouse ICC models induced by different oncogenes. Ablating FASN in the mouse liver did not affect activated AKT and Notch (AKT/Notch intracellular domain 1) induced ICC formation in vivo. Furthermore, while both HCC and ICC lesions develop in mice following hydrodynamic injection of AKT and neuroblastoma Ras viral oncogene homolog oncogenes (AKT/Ras), deletion of FASN in AKT/Ras mice triggered the development almost exclusively of ICCs. In the absence of FASN, ICC cells might receive lipids for membrane synthesis through exogenous fatty acid uptake. In accordance with the latter hypothesis, ICC cells displayed high expression of fatty acid uptake-related proteins and robust long-chain fatty acid uptake. Our data demonstrate that FASN dependence is not a universal feature of liver tumors: while HCC development is highly dependent of FASN and its mediated lipogenesis, ICC tumorigenesis can be insensitive to FASN deprivation; our study supports novel therapeutic approaches to treat this pernicious tumor type with the inhibition of exogenous fatty acid uptake. (Hepatology 2016;63:1900-1913). © 2016 by the American Association for the Study of Liver Diseases.

  14. Amino acid sequence homology between protein products of oncogenes and hormones (v-myc--gastrin and oxytocin; v-sis--secretin).

    Science.gov (United States)

    Korec, E; Hlozánek, I; Korcová, H; Simůnek, J

    1985-01-01

    Computer comparisons of amino acid sequences from 8 retroviral oncogenes and 26 protein hormones were done with respect to structure similarity and so-called uninterrupted structure similarity. Sequence homology was found between v-myc, the transforming protein of MC29 virus, and human gastrin and oxytocin on the one hand, and between v-sis, the transforming protein of simian sarcoma virus, and secretin on the other.

  15. Automatic gallbladder segmentation using combined 2D and 3D shape features to perform volumetric analysis in native and secretin-enhanced MRCP sequences.

    Science.gov (United States)

    Gloger, Oliver; Bülow, Robin; Tönnies, Klaus; Völzke, Henry

    2017-11-24

    We aimed to develop the first fully automated 3D gallbladder segmentation approach to perform volumetric analysis in volume data of magnetic resonance (MR) cholangiopancreatography (MRCP) sequences. Volumetric gallbladder analysis is performed for non-contrast-enhanced and secretin-enhanced MRCP sequences. Native and secretin-enhanced MRCP volume data were produced with a 1.5-T MR system. Images of coronal maximum intensity projections (MIP) are used to automatically compute 2D characteristic shape features of the gallbladder in the MIP images. A gallbladder shape space is generated to derive 3D gallbladder shape features, which are then combined with 2D gallbladder shape features in a support vector machine approach to detect gallbladder regions in MRCP volume data. A region-based level set approach is used for fine segmentation. Volumetric analysis is performed for both sequences to calculate gallbladder volume differences between both sequences. The approach presented achieves segmentation results with mean Dice coefficients of 0.917 in non-contrast-enhanced sequences and 0.904 in secretin-enhanced sequences. This is the first approach developed to detect and segment gallbladders in MR-based volume data automatically in both sequences. It can be used to perform gallbladder volume determination in epidemiological studies and to detect abnormal gallbladder volumes or shapes. The positive volume differences between both sequences may indicate the quantity of the pancreatobiliary reflux.

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

    Science.gov (United States)

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

    2015-06-20

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

  17. An inguinal hernia sac tumor of extrahepatic cholangiocarcinoma origin

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    Yamazaki Hidehiro

    2006-03-01

    Full Text Available Abstract Background Metastatic hernia sac tumor from biliary malignancy is extremely rare with only one such case previously reported. We herein report an additional case of extrahepatic cholangiocarcinoma presenting as a hernia sac tumor. Case presentation A 78-year-old man presented with an irreducible right inguinal hernia associated with a firm tumor, 2.0 cm in diameter. A computed tomography scan demonstrated a soft tissue density mass with heterogeneous enhancement within the right inguinal canal. The patient underwent a hernia repair and the hernia sac tumor was resected. Histological examination of the tumor revealed a metastatic adenocarcinoma suggesting the tumor was of pancreato-biliary origin. Further investigation using imaging studies disclosed a primary tumor in the upper bile duct. The patient died of the disease nine months after the resection. Conclusion Hernia sac tumors should be considered when an irreducible, growing mass appears within an inguinal hernia. Computed tomography may be useful for the early detection of hernia sac tumors from undiagnosed intra-abdominal malignancies.

  18. Cholangiocarcinoma and its mimickers in primary sclerosing cholangitis.

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    Lee, Jonghun John; Schindera, Sebastian T; Jang, Hyun-Jung; Fung, Scott; Kim, Tae Kyoung

    2017-12-01

    Cholangiocarcinoma (CCA) is the most common malignancy in primary sclerosing cholangitis (PSC). Approximately half of CCA are diagnosed within two years of initial diagnosis and often have a poor prognosis because of advanced tumor stage at the time of diagnosis. Thus, rigorous initial imaging evaluation for detecting CCA is important. CCA in PSC usually manifests as intrahepatic mass-forming or perihilar periductal-infiltrating type. Imaging diagnosis is often challenging due to pre-existing biliary strictures and heterogeneous liver. Multimodality imaging approach and careful comparison with prior images are often helpful in detecting small CCA. Ultrasound is widely used as an initial test, but has a limited ability to detect small tumors in the heterogeneous liver with PSC. MRI combined with MRCP is excellent to demonstrate focal biliary abnormalities as well as subtle liver masses. Contrast-enhanced ultrasound is useful to demonstrate CCA by demonstrating rapid and marked washout. In addition, there are other disease entities that mimic CCA including hepatocellular carcinoma, confluent hepatic fibrosis, IgG4-related sclerosing cholangitis, inflammatory mass, and focal fat deposition. In this pictorial essay, imaging findings of CCA in PSC is described and discuss the challenges in imaging surveillance for CCA in the patients with PSC. Imaging findings of the mimickers of CCA in PSC and their differentiating features are also discussed.

  19. Expression of thioredoxin during progression of hamster and human cholangiocarcinoma.

    Science.gov (United States)

    Yoon, Byung-Il; Kim, Yeong-Hun; Yi, Jung-Yeon; Kang, Min-Soo; Jang, Ja-June; Joo, Kyoung-Hwan; Kim, Yongbaek; McHugh Law, J; Kim, Dae-Yong

    2010-01-01

    Thioredoxin (Trx) is a multifunctional redox protein that has growth-promoting and anti-apoptotic effects on cells and protects cells from endogenous and exogenous free radicals. Recently, altered expression of Trx has been reported in various cancers. In the present study, we investigated altered expression of Trx at the precancerous and carcinogenic phases during cholangiocarcinogenesis in a hamster cholangiocarcinoma (ChC) model, using semiquantitative immunohistochemical and Western blot analyses. Moreover, to determine if the results correlated well with those in human ChCs, we carried out a comparative immunohistochemical study for Trx in tissue-arrayed human ChCs with different grades of tumor cell differentiation. Trx was found highly expressed in the cytoplasm of dysplastic bile ducts with highly abnormal growth patterns and ChCs irrespective of tumor type or tumor cell differentiation. Overexpression of Trx at the precancerous and carcinogenic phases was further supported by significant elevation of Trx protein in Western blotting. The results from the hamster ChCs were in good agreement with those from human ChCs. Our results strongly suggested that the redox regulatory function of Trx plays an important role in bile duct cell transformation and tumor progression during cholangiocarcinogenesis.

  20. The Inner Membrane Protein PilG Interacts with DNA and the Secretin PilQ in Transformation.

    Science.gov (United States)

    Frye, Stephan A; Lång, Emma; Beyene, Getachew Tesfaye; Balasingham, Seetha V; Homberset, Håvard; Rowe, Alexander D; Ambur, Ole Herman; Tønjum, Tone

    2015-01-01

    Expression of type IV pili (Tfp), filamentous appendages emanating from the bacterial surface, is indispensable for efficient neisserial transformation. Tfp pass through the secretin pore consisting of the membrane protein PilQ. PilG is a polytopic membrane protein, conserved in Gram-positive and Gram-negative bacteria, that is required for the biogenesis of neisserial Tfp. PilG null mutants are devoid of pili and non-competent for transformation. Here, recombinant full-length, truncated and mutated variants of meningococcal PilG were overexpressed, purified and characterized. We report that meningococcal PilG directly binds DNA in vitro, detected by both an electromobility shift analysis and a solid phase overlay assay. PilG DNA binding activity was independent of the presence of the consensus DNA uptake sequence. PilG-mediated DNA binding affinity was mapped to the N-terminus and was inactivated by mutation of residues 43 to 45. Notably, reduced meningococcal transformation of DNA in vivo was observed when PilG residues 43 to 45 were substituted by alanine in situ, defining a biologically significant DNA binding domain. N-terminal PilG also interacted with the N-terminal region of PilQ, which previously was shown to bind DNA. Collectively, these data suggest that PilG and PilQ in concert bind DNA during Tfp-mediated transformation.

  1. AlgK is a TPR-containing Protein and the Periplasmic Component of a Novel Exopolysaccharide Secretin

    Energy Technology Data Exchange (ETDEWEB)

    Keiski, C.; Harwich, M; Jain, S; Neculai, A; Whitney, J; Yip, P; Robinson, H; Riley, L; Burrows, L; et al.

    2010-01-01

    The opportunistic pathogen Pseudomonas aeruginosa causes chronic biofilm infections in cystic fibrosis patients. During colonization of the lung, P. aeruginosa converts to a mucoid phenotype characterized by overproduction of the exopolysaccharide alginate. Here we show that AlgK, a protein essential for production of high molecular weight alginate, is an outer membrane lipoprotein that contributes to the correct localization of the porin AlgE. Our 2.5 {angstrom} structure shows AlgK is composed of 9.5 tetratricopeptide-like repeats, and three putative sites of protein-protein interaction have been identified. Bioinformatics analysis suggests that BcsA, PgaA, and PelB, involved in the production and export of cellulose, poly-{beta}-1,6-N-Acetyl-d-glucosamine, and Pel exopolysaccharide, respectively, share the same topology as AlgK/E. Together, our data suggest that AlgK plays a role in the assembly of the alginate biosynthetic complex and represents the periplasmic component of a new type of outer membrane secretin that differs from canonical bacterial capsular polysaccharide secretion systems.

  2. Targeting of vasoactive intestinal peptide receptor 2, VPAC2, a secretin family G-protein coupled receptor, to primary cilia

    Directory of Open Access Journals (Sweden)

    Livana Soetedjo

    2013-05-01

    Primary cilia protrude from the cell surface of many cell types in the human body and function as cellular antennae via ciliary membrane localized receptors. Neurons and glial cells in the brain possess primary cilia, and the malfunction of primary cilia may contribute to neurological deficits present in many cilia-associated disorders. Several rhodopsin family G-protein coupled receptors (GPCRs are specifically localized to a subset of neuronal primary cilia. However, whether other family GPCRs target to neuronal cilia and whether glial primary cilia harbor any GPCRs are not known. We conducted a screening of GPCRs to determine their ability to target to primary cilia, and identified a secretin family member, Vasoactive Intestinal Receptor 2 (VPAC2, as a novel ciliary GPCR. Here, we show that endogenous VPAC2 targets to primary cilia in various brain regions, including the suprachiasmatic nuclei and the thalamus. Surprisingly, VPAC2 not only localizes to neuronal cilia but also to glial cilia. In addition, we show that VPAC2's C-terminus is both necessary and sufficient for its ciliary targeting and we define a novel ciliary targeting signal: the tetrapeptide RDYR motif in the C-terminus of VPAC2. Furthermore, we demonstrate that VPAC2 ciliary targeting is dependent on Tubby, the BBSome (a complex of Bardet–Biedl syndrome proteins and the BBSome targeting factor, Arl6.

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

    Directory of Open Access Journals (Sweden)

    Cheng CT

    2015-07-01

    Full Text Available Chi-Tung Cheng,1,* Yin-Yi Chu,2,* Chun-Nan Yeh,1 Shih-Chiang Huang,3 Ming Huang Chen,4 Shang-Yu Wang,1 Chun-Yi Tsai,1 Kun-Chun Chiang,5 Yen-Yang Chen,6,7 Ming-Chun Ma,6,7 Chien-Ting Liu,6,7 Tsung-Wen Chen,1 Ta-Sen Yeh11Department of Surgery, 2Department of Gastroenterology and Hepatology, 3Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan; 4Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 5Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan; 6Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 7Chang Gung University, Taoyuan, Taiwan*These authors contributed equally to this workBackground 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

  4. Expert consensus on precise diagnosis and treatment of hilar cholangiocarcinoma guided by three-dimensional visualization technology

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    Chinese Society of Digital Medicine

    2017-01-01

    Full Text Available The three-dimensional (3D visualization technology in hilar cholangiocarcinoma could offer decision-making support to preoperative diagnosis, individualized surgical planning and then proffer operative approach. In addition,the 3D printing technology helps to realize the leapfrog development from 3D image to 3D physical models and proffers better guidance of the precise surgery for patients with hilar cholangiocarcinoma. To standardize the application of 3D visualization and 3D printing technology in the precise diagnosis and treatment of hilar cholangiocarcinoma ,Chinese Society of Digital Medicine and Chinese Research Hospital Association of Digital Surgery Committee organized experts in related fields to formulate this consensus.

  5. Prognostic significance of snail expression in hilar cholangiocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kong, Dalu [Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Hexi District, Tianjin (China); Liang, Jun [Department of Oncology, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong Province (China); Li, Rong [Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Hexi District, Tianjin (China); Liu, Shihai [Department of Laboratory Center, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong Province (China); Wang, Jigang [Department of Oncology, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong Province (China); Zhang, Kejun; Chen, Dong [Department of General Surgery, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong Province (China)

    2012-05-11

    Many patients with hilar cholangiocarcinoma (HC) have a poor prognosis. Snail, a transcription factor and E-cadherin repressor, is a novel prognostic factor in many cancers. The aim of this study was to evaluate the relationship between snail and E-cadherin protein expression and the prognostic significance of snail expression in HC. We examined the protein expression of snail and E-cadherin in HC tissues from 47 patients (22 males and 25 females, mean age 61.2 years) using immunohistochemistry and RT-PCR. Proliferation rate was also evaluated in the same cases by the MIB1 index. High, low and negative snail protein expression was recorded in 18 (38%), 17 (36%), and 12 (26%) cases, respectively, and 40.4% (19/47) cases showed reduced E-cadherin protein expression in HC samples. No significant correlation was found between snail and E-cadherin protein expression levels (P = 0.056). No significant correlation was found between snail protein expression levels and gender, age, tumor grade, vascular or perineural invasion, nodal metastasis and invasion, or proliferative index. Cancer samples with positive snail protein expression were associated with poor survival compared with the negative expresser groups. Kaplan-Meier curves comparing different snail protein expression levels to survival showed highly significant separation (P < 0.0001, log-rank test). With multivariate analysis, only snail protein expression among all parameters was found to influence survival (P = 0.0003). We suggest that snail expression levels can predict poor survival regardless of pathological features and tumor proliferation. Immunohistochemical detection of snail protein expression levels in routine sections may provide the first biological prognostic marker.

  6. Low dose mTHPC photodynamic therapy for cholangiocarcinoma

    Science.gov (United States)

    Stepp, Herbert; Kniebühler, Gesa; Pongratz, Thomas; Betz, Christian S.; Göke, Burkhard; Sroka, Ronald; Schirra, Jörg

    2013-06-01

    Objective: Demonstration of whether a low dose of mTHPC (temoporfin , Foscan) is sufficient to induce an efficient clinical response in palliative PDT of non-resectable cholangiocarcinoma (CC), while showing a low side effect profile as compared to the standard Photofrin PDT. Materials and Methods: 13 patients (14 treatment sessions) with non-resectable CC were treated with stenting and PDT (3 mg Foscan per treatment, 0.032-0.063 mg/kg body weight, 652 nm, 50 J/cm). Fluorescence measurements were performed with a single bare fiber for 5/13 patients prior to PDT at the tumor site to determine the fluorescence contrast. For another 7/13 patients, long-term fluorescence-kinetics were measured on the oral mucosa to determine the time of maximal relative fluorescence intensity. Results: Foscan fluorescence could clearly be identified spectroscopically as early as 20 hours after administration. It was not significantly different between lesion and normal tissue within the bile duct. Fluorescence kinetics assessed at the oral mucosa were highest at 72-96 hours after administration. The DLI was therefore extended from 20 hours to approx. 70 hours for the last 5 patients treated. The treatment effect was promising with a median survival of 11 months for the higher grade tumors (Bismuth types III and IV). Local side effects occurred in one patient (pancreatitis), systemic side effects were much reduced compared to prior experience with Photofrin. Conclusion: Combined stenting and photodynamic therapy (PDT) performed with a low dose of Foscan results in comparable survival times relative to standard Photofrin PDT, while lowering the risk of side effects significantly.

  7. Pathological classification of intrahepatic cholangiocarcinoma based on a new concept.

    Science.gov (United States)

    Nakanuma, Yasuni; Sato, Yasunori; Harada, Kenichi; Sasaki, Motoko; Xu, Jing; Ikeda, Hiroko

    2010-12-27

    Intrahepatic cholangiocarcinoma (ICC) arises from the lining epithelium and peribiliary glands of the intrahepatic biliary tree and shows variable cholangiocytic differentiation. To date, ICC was largely classified into adenocarcinoma and rare variants. Herein, we propose to subclassify the former, based on recent progress in the study of ICC including the gross classification and hepatic progenitor/stem cells and on the pathological similarities between biliary and pancreatic neoplasms. That is, ICC is classifiable into the conventional (bile duct) type, the bile ductular type, the intraductal neoplasm type and rare variants. The conventional type is further divided into the small duct type (peripheral type) and large bile duct type (perihilar type). The former is a tubular or micropapillary adenocarcinoma while the latter involves the intrahepatic large bile duct. Bile ductular type resembles proliferated bile ductules and shows a replacing growth of the hepatic parenchyma. Hepatic progenitor cell or stem cell phenotypes such as neural cell adhesion molecule expression are frequently expressed in the bile ductular type. Intraductal type includes papillary and tubular neoplasms of the bile duct (IPNBs and ITNBs) and a superficial spreading type. IPNB and ITNB show a spectrum from a preneoplastic borderline lesion to carcinoma and may have pancreatic counterparts. At invasive sites, IPNB is associated with the conventional bile duct ICC and mucinous carcinoma. Biliary mucinous cystic neoplasm with ovarian-like stroma in its wall is different from IPNB, particularly IPNB showing cystic dilatation of the affected ducts. Rare variants of ICC include squamous/adenosquamous cell carcinoma, mucinous/signet ring cell carcinoma, clear cell type, undifferentiated type, neuroendocrine carcinoma and so on. This classification of ICC may open up a new field of research of ICC and contribute to the clinical approach to ICC.

  8. The Results of Postoperative Radiation Therapy for Perihilar Cholangiocarcinoma

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    Lee, Yu Sun; Park, Jae Won; Park, Jin Hong [Asan Medical Center, Seoul (Korea, Republic of)] (and others)

    2009-12-15

    The aim of this study was to evaluate the results of postoperative radiotherapy in a case of perihilar cholagiocarcinoma by analyzing overall survival rate, patterns of failure, prognostic factors for overall survival, and toxicity. Between January 1998 and March 2008, 38 patients with perihilar cholangiocarcinoma underwent a surgical resection and adjuvant radiotherapy. The median patient age was 59 years (range, 28 to 72 years), which included 23 men and 15 women. The extent of surgery was complete resection in 9 patients, microscopically positive margins in 25 patients, and a subtotal resection in 4 patients. The tumor bed and regional lymphatics initially received 45 Gy or 50 Gy, but was subsequently boosted to a total dose of 59.4 Gy or 60 Gy in incompletely resected patients. The median radiotherapy dose was 59.4 Gy. Concurrent chemotherapy was administered in 30 patients. The median follow-up period was 14 months (range, 6 to 45 months). The 3-year overall survival and 3-year progression free survival rates were 30% and 8%, respectively. The median survival time was 28 months. A multivariate analysis showed that differentiation was the only significant factor for overall survival. The 3-year overall survival was 34% in R0 patients and 20% in R1 patients. No statistically significant differences in survival were found between the 2 groups (p=0.3067). The first site of failure was local in 18 patients (47%). No patient experienced grade 3 or higher acute toxicity and duodenal bleeding developed in 2 patients. Our results suggest that adjuvant RT might be a significant factor in patients with a positive margin following a radical resection. However, there was still a high locoregional recurrence rate following surgery and postoperative radiotherapy. Further study is necessary to enhance the effect of the adjuvant radiotherapy.

  9. Validation of the Mayo Clinic Staging System in Determining Prognoses of Patients With Perihilar Cholangiocarcinoma

    NARCIS (Netherlands)

    Coelen, Robert J. S.; Gaspersz, Marcia P.; Labeur, Tim A.; van Vugt, Jeroen L. A.; van Dieren, Susan; Willemssen, François E. J. A.; Nio, Chung Y.; Ijzermans, Jan N. M.; Klümpen, Heinz-Josef; Groot Koerkamp, Bas; van Gulik, Thomas M.

    2017-01-01

    BACKGROUND & AIMS: Most systems for staging perihilar cholangiocarcinoma (PHC) have been developed for the minority of patients with resectable disease. The recently developed Mayo Clinic system for staging PHC requires only clinical and radiologic variables, but has not yet been validated. We

  10. Reversal of Jaundice in Two Patients with Inoperable Cholangiocarcinoma Treated with Cisplatin and Gemcitabine Combination

    Directory of Open Access Journals (Sweden)

    Maarten Criel

    2012-01-01

    Full Text Available Two patients are presented with severe jaundice, due to inoperable cholangiocarcinoma. The chemotherapeutic approach in patients with severe jaundice is discussed. Many schedules of chemotherapy were developed in this tumor type with normal serum bilirubin. We report here the first successful use of cisplatin and gemcitabine combination chemotherapy in these patients. Tolerability was good and liver function tests gradually improved.

  11. Anti-NY-ESO-1 autoantibody may be a tumor marker for intrahepatic cholangiocarcinoma.

    Science.gov (United States)

    Zhang, Zhen; Li, Fan-Fan; Lu, Ming-Dian; Zhang, Shang-Xin; Li, Yong-Xiang

    2017-11-28

    Anti-NY-ESO-1 antibody is observed in a multitude of malignancies. This study was aimed to evaluate the expression of serum anti-NY-ESO-1 antibodies and its prognostic value in intrahepatic cholangiocarcinoma. A total of 103 patients with intrahepatic cholangiocarcinoma were enrolled in the study. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the serum level of anti-NY-ESO-1 antibody. Western blotting was performed to assess the NY-ESO-1 expression in tumor and adjacent tissues. The serum NY-ESO-1 antibody was detected in 18.4% of patients with intrahepatic cholangiocarcinoma, a value that was significantly higher than that in patients with chronic Hepatitis B. Serum NY-ESO-1 antibody was positively correlated with tumor differentiation, lymphatic metastasis, cTNM stage and abdominal pain. Finally, there was a higher cumulative survival rate in patients with serum NY-ESO-1 positivity than in those with serum NY-ESO-1 negativity among the patients with stage III + IV. Our data uncovered that NY-ESO-1 antibody might be a helpful tumor marker and prognostic predictor in intrahepatic cholangiocarcinoma.

  12. Survival after resection of perihilar cholangiocarcinoma-Development and external validation of a prognostic nomogram

    NARCIS (Netherlands)

    B. Groot Koerkamp (Bas); J.K. Wiggers (Jimme K.); M. Gonen (Mithat); A. Doussot (Alexandre); P.J. Allen (Peter); M.G. Besselink (Marc); L.H. Blumgart; O.R. Busch (O.); M.I. D'Angelica (Michael I.); R.P. DeMatteo (Ronald P.); D.J. Gouma (Dirk); T.P. Kingham (T. Peter); T.M. van Gulik (Thomas); W.R. Jarnagin (William R.)

    2015-01-01

    textabstractBackground: The objective of this study was to derive and validate a prognostic nomogram to predict disease-specific survival (DSS) after a curative intent resection of perihilar cholangiocarcinoma (PHC). Patients and methods: A nomogram was developed from 173 patients treated at

  13. Genetic and Epigenetic Abnormalities in Primary Sclerosing Cholangitis-associated Cholangiocarcinoma

    NARCIS (Netherlands)

    Timmer, Margriet R.; Beuers, Ulrich; Fockens, Paul; Ponsioen, Cyriel Y.; Rauws, Erik A.; Wang, Kenneth K.; Krishnadath, Kausilia K.

    2013-01-01

    Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiology, characterized by chronic inflammation of the biliary tree with subsequent fibrosis and cirrhosis of the liver. Patients with PSC are at increased risk for the development of cholangiocarcinoma (CCA), a highly

  14. High mobility group A1 enhances tumorigenicity of human cholangiocarcinoma and confers resistance to therapy

    DEFF Research Database (Denmark)

    Quintavalle, Cristina; Burmeister, Katharina; Piscuoglio, Salvatore

    2017-01-01

    High mobility group A1 (HMGA1) protein has been described to play an important role in numerous types of human carcinoma. By the modulation of several target genes HMGA1 promotes proliferation and epithelial-mesenchymal transition of tumor cells. However, its role in cholangiocarcinoma (CCA) has...

  15. [(18)F]FDG accumulation in an experimental model of multistage progression of cholangiocarcinoma.

    NARCIS (Netherlands)

    Laverman, P.; Blokx, W.A.M.; Morsche, R.H.M. te; Frielink, C.; Boerman, O.C.; Oyen, W.J.G.; Drenth, J.P.H.

    2007-01-01

    Aim: The diagnosis of cholangiocarcinoma (CCA) is difficult, and due to the insidious course of the disease, most cases present at a relatively late stage. Positron emission tomography (PET), using [(18)F]fluoro-2-deoxyglucose ([(18)F]FDG) as a tracer is one the most powerful molecular imaging

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

    Science.gov (United States)

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

  17. Expression and prognostic value of soluble CD97 and its ligand CD55 in intrahepatic cholangiocarcinoma.

    Science.gov (United States)

    Meng, Ze-Wu; Liu, Min-Chao; Hong, Hai-Jie; Du, Qiang; Chen, Yan-Ling

    2017-03-01

    The incidence rate of intrahepatic cholangiocarcinoma is rising, and treatment options are limited. Therefore, new biological markers of intrahepatic cholangiocarcinoma are needed. Immunohistochemistry and enzyme-linked immunosorbent assay were applied to analyze the expressions of CD97, CD55, and soluble CD97 in 71 patients with intrahepatic cholangiocarcinoma and 10 patients with hepatolithiasis. CD97 and CD55 were not expressed in hepatolithiatic tissues, but positive expression was observed in 76.1% (54/71) and 70.4% (50/71) of intrahepatic cholangiocarcinoma patients. The univariate analyses indicated that the positive expressions of CD97 and CD55 were related to short intrahepatic cholangiocarcinoma survival of patients (both p = 0.001). Furthermore, CD97 and CD55 expressions and biliary soluble CD97 levels were significantly associated with histological grade (p = 0.004, 0.002, and 0.012, respectively), lymph node metastases (p = 0.020, 0.038, and 0.001, respectively), and venous invasion (p = 0.003, 0.002, and 0.001, respectively). The multivariate analyses indicated that lymph node metastases (hazard ratio: 2.407, p = 0.003), positive CD55 expression (hazard ratio: 4.096, p = 0.003), and biliary soluble CD97 levels (hazard ratio: 2.434, p = 0.002) were independent risk factors for the intrahepatic cholangiocarcinoma survival. The receiver operating characteristic (ROC) curve analysis indicated that when the cutoff values of biliary soluble CD97 were 1.15 U/mL, the diagnostic value for predicting lymph node metastasis had a sensitivity of 87.5% and a specificity of 51.3%. For intrahepatic cholangiocarcinoma patient death within 60 months at a cutoff value of 0.940 U/mL, the diagnostic value sensitivity was 89.3% and the specificity was 93.3%. Biliary soluble CD97 may be a new biological marker for early diagnosis, prediction of lymph node metastasis and poor prognosis, and discovery of a therapeutic target.

  18. The E-cadherin repressor slug and progression of human extrahepatic hilar cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Wang Xin-sheng

    2010-07-01

    Full Text Available Abstract Objectives This study explored the expression and function of Slug in human extrahepatic hilar cholangiocarcinoma (EHC to identify its role in tumor progression. Methods The expression of Snail and Slug mRNA in 52 human tissue samples of EHC was investigated. The mRNA of Snail and Slug were quantified using reverse transcriptase-PCR, and correlations with E-cadherin expression and clinicopathological factors were investigated. We then investigated transfection of Slug cDNA in endogenous E-cadherin-positive human EHC FRH0201 cells, selectively induced the loss of E-cadherin protein expression, and then small interfering RNA (siRNA for inhibition of Slug expression in endogenous Slug-positive human EHC QBC939 cells, selectively induced the loss of Slug protein expression. A Boyden chamber transwell assay was used for invasion. Results Slug mRNA was overexpressed in 18 cases (34.6% of EHC compared with adjacent noncancerous tissue. E-Cadherin protein expression determined in the same 52 cases by immunohistochemistry was significantly down-regulated in those cases with Slug mRNA overexpression (P = 0.0001. The tumor and nontumor ratio of Slug mRNA was correlated with nodal metastasis(p = 0.0102, distant metastasis (p = 0.0001and Survival time(p = 0.0443. However, Snail mRNA correlated with neither E-cadherin expression nor tumor invasiveness. By inhibiting Slug expression by RNA interference, we found that reduced Slug levels upregulated E-cadherin and decreased invasion in QBC939 cell. When the QBC939 cells was infected with Slug cDNA,, significant E-cadherin was downregulated and increased invasion in QBC939 cell. Conclusions The results suggested that Slug expression plays an important role in both the regulation of E-cadherin expression and in the acquisition of invasive potential in human EHC. Slug is possibly a potential target for an antitumor therapy blocking the functions of invasion and metastasis in human EHCs.

  19. Lower incidence of complications in endoscopic nasobiliary drainage for hilar cholangiocarcinoma.

    Science.gov (United States)

    Kawakubo, Kazumichi; Kawakami, Hiroshi; Kuwatani, Masaki; Haba, Shin; Kudo, Taiki; Taya, Yoko A; Kawahata, Shuhei; Kubota, Yoshimasa; Kubo, Kimitoshi; Eto, Kazunori; Ehira, Nobuyuki; Yamato, Hiroaki; Onodera, Manabu; Sakamoto, Naoya

    2016-05-10

    To identify the most effective endoscopic biliary drainage technique for patients with hilar cholangiocarcinoma. In total, 118 patients with hilar cholangiocarcinoma underwent endoscopic management [endoscopic nasobiliary drainage (ENBD) or endoscopic biliary stenting] as a temporary drainage in our institution between 2009 and 2014. We retrospectively evaluated all complications from initial endoscopic drainage to surgery or palliative treatment. The risk factors for biliary reintervention, post-endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis, and percutaneous transhepatic biliary drainage (PTBD) were also analyzed using patient- and procedure-related characteristics. The risk factors for bilateral drainage were examined in a subgroup analysis of patients who underwent initial unilateral drainage. In total, 137 complications were observed in 92 (78%) patients. Biliary reintervention was required in 83 (70%) patients. ENBD was significantly associated with a low risk of biliary reintervention [odds ratio (OR) = 0.26, 95%CI: 0.08-0.76, P = 0.012]. Post-ERCP pancreatitis was observed in 19 (16%) patients. An absence of endoscopic sphincterotomy was significantly associated with post-ERCP pancreatitis (OR = 3.46, 95%CI: 1.19-10.87, P = 0.023). PTBD was required in 16 (14%) patients, and Bismuth type III or IV cholangiocarcinoma was a significant risk factor (OR = 7.88, 95%CI: 1.33-155.0, P = 0.010). Of 102 patients with initial unilateral drainage, 49 (48%) required bilateral drainage. Endoscopic sphincterotomy (OR = 3.24, 95%CI: 1.27-8.78, P = 0.004) and Bismuth II, III, or IV cholangiocarcinoma (OR = 34.69, 95%CI: 4.88-736.7, P < 0.001) were significant risk factors for bilateral drainage. The endoscopic management of hilar cholangiocarcinoma is challenging. ENBD should be selected as a temporary drainage method because of its low risk of complications.

  20. Serum p53 antibody as a potential tumor marker in extrahepatic cholangiocarcinoma.

    Science.gov (United States)

    Okada, Rei; Shimada, Hideaki; Otsuka, Yuichiro; Tsuchiya, Masaru; Ishii, Jun; Katagiri, Toshio; Maeda, Tetsuya; Kubota, Yoshihisa; Nemoto, Tetsuo; Kaneko, Hironori

    2017-12-01

    Only a few studies have evaluated the clinicopathological significance of the p53 protein expression and s-p53-Abs level in patients with cholangiocarcinoma. We therefore analyzed the clinicopathological and prognostic significance of s-p53-Abs in patients with extrahepatic cholangiocarcinoma. We prospectively evaluated s-p53-Abs levels before and after surgery in 61 patients with extrahepatic cholangiocarcinoma to determine the relationship between clinicopathological factors and the prognostic significance of s-p53-Abs. Among a total of 61 primary extrahepatic cholangiocarcinoma cases, 23% were positive for s-p53-Abs. Combination of s-p53-Abs with the conventional serum markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) significantly increased the rate of positive extrahepatic cholangiocarcinoma cases (57% for CEA and/or CA19-9 vs. 75% for CEA and/or CA19-9 and/or s-p53-Abs, P = 0.035). There were no significant differences in clinicopathological factors between the p53-seropositive and p53-seronegative patients. An immunohistochemical analysis showed the presence of significant associations between the intensity (P = 0.003) and extent (P = 0.001) of p53 immunoreactivity and p53-seropositivitly. Although s-p53-Abs was not a significant prognostic factor for the survival in either univariate or multivariate analyses, p53 immunoreactivity was independently associated with a poor survival. Among patients positive for s-p53-Abs before surgery, the s-p53-Abs levels were reduced after surgery in most. These findings suggested that s-p53-Abs might be associated with p53 immunoreactivity. In addition, s-p53-Abs may be useful for a diagnosis, but was not useful for predicting tumor recurrence or the survival. This study was registered as UMIN000014530.

  1. A massive hepatic tumor demonstrating hepatocellular, cholangiocarcinoma and neuroendocrine lineages: A case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Rachel E. Beard

    2017-01-01

    Conclusion: This is one of the only reports of a hepatic tumor arising from hepatocellular carcinoma, cholangiocarcinoma and neuroendocrine lineages. Increased awareness of this tumor type may optimize improve future management.

  2. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.

    Directory of Open Access Journals (Sweden)

    Chaitanya R Churi

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

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

    Science.gov (United States)

    Buisson, Y

    2017-02-01

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

  4. Hypochlorhydria and achlorhydria are associated with false-positive secretin stimulation testing for Zollinger-Ellison syndrome.

    Science.gov (United States)

    Shah, Pari; Singh, Maneesh H; Yang, Yu-Xiao; Metz, David C

    2013-08-01

    Secretin stimulation testing (SST) is used to evaluate patients with hypergastrinemia in the diagnosis of Zollinger-Ellison syndrome. Case series have documented false-positive SST in patients with achlorhydria. This study reviews our experience with SST in hypochlorhydric and achlorhydric patients. We examined 27 patients with hypochlorhydria or achlorhydria based on a predefined basal acid output (BAO) measurement of less than 5.0 mEq/h who also underwent SST for diagnosis of Zollinger-Ellison syndrome. We report the frequency of false-positive SST results in this setting. Three hundred thirty patients underwent gastric analysis of which 27 had BAO of less than 5.0 mEq/h and SST conducted. The mean (SD) fasting gastrin level was 247 (304) pg/mL, and the mean (SD) BAO measurement was 1.6 (1.8) mEq/h. Twenty patients were off, and 7 were on antisecretory therapy at time of testing. Four patients had false-positive SST results: 3 with gastric atrophy (BAO = 0 mEq/h) and 1 with drug-induced hypochlorhydria (BAO = 0.5 mEq/hr). These false-positive test results were confirmed by structural and functional imaging studies. We have identified a 14.8% false-positive rate in SST in patients with hypochlorhydria or achlorhydria. Growing literature has identified severe consequences associated with discontinuing antisecretory treatment for testing; therefore, SST will require interpretation in the setting of gastric acid suppression and needs to be interpreted in this context.

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

    Science.gov (United States)

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

    2014-07-01

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

  6. 67 laminin receptor promotes the malignant potential of tumour cells up-regulating lysyl oxidase-like 2 expression in cholangiocarcinoma.

    Science.gov (United States)

    Xu, Jing; Li, Dajing; Li, Xiaowu; Liu, Zipei; Li, Tianyu; Jiang, Peng; He, Qiang; Tian, Feng; Gao, Yang; Wang, Dechun; Wang, Shuguang

    2014-08-01

    67 laminin receptor (67LR) plays an important role in the invasion and metastasis of cholangiocarcinoma, but its mechanism remains unclear. We investigated the clinical significance of 67LR and its relation to lysyl oxidase-like 2 (LOXL2) in 67LR-mediated invasion and metastasis in cholangiocarcinoma. The clinical significance of 67LR and LOXL2 expression and the prognosis of patients were investigated in 73 cancerous and 32 paracancerous tissues by immunohistochemistry. The impact of LOXL2 on invasion, metastasis and 67LR expression was evaluated in cholangiocarcinoma cells by shRNA or expressed-plasmid transfection. Expression of 67LR was recognized in 35.62% cholangiocarcinoma tissue, and none in paracancerous tissues. LOXL2 was positively correlated with expression of 67LR. Expression of 67LR or LOXL2 in cholangiocarcinomas was significantly associated with lymph node metastasis, differentiation and poor overall survival. Cox analysis showed that 67LR can act as an independent prognostic biomarker of prognosis in cholangiocarcinoma patients. Expression of LOXL2 decreased by knockdown of 67LR and increased by overexpression of 67LR in cholangiocarcinoma cells. Knockdown of LOXL2 reduced invasion and metastasis in vitro and in vivo. 67LR may regulate the expression of LOXL2 to promote invasion and metastasis in cholangiocarcinoma cells. It could be used as an independent prognostic marker in cholangiocarcinoma patients. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  7. Methyl-CpG binding protein MBD2 is implicated in methylation-mediated suppression of miR-373 in hilar cholangiocarcinoma.

    Science.gov (United States)

    Chen, Yongjun; Gao, Wei; Luo, Jian; Tian, Rui; Sun, Huawen; Zou, Shengquan

    2011-02-01

    Aberrant expression of miRNAs is associated with particular cancers showing tissue- and clinical-feature-specificity patterns. Some miRNA genes harboring or being embedded in CpG islands undergo methylation mediated silencing. MBP, methyl CpG binding protein, suppresses transcription through binding to methylated CpG dinucleotides. Expression of miR-373 has been reported to be suppressed in malignant bile duct cell lines. Bioinformatic prediction reveals that the transcription start site (TSS) of miR-373 is implanted in a 402 bp canonical CpG island containing 26 CpG dinucleotides. In this study, we aim to determine the epigenetic regulation of miR-373 gene in hilar cholangiocarcinoma. Taqman microRNA assay shows that down-regulation of miR-373 is closely associated with poor cell differentiation, advanced clinical stage and shorter overall and disease-free survival in hilar cholangiocarcinomas. Methylation analysis shows that the promoter-associated CpG island is hypermethylated which is consistent with the inhibition of miR-373. Chromatin immunoprecipitation (ChIP) assay indicates that down-regulation of miR-373 results from the selective recruitment of MBD2 to methylated CpG islands. In contrast, MBD2 knock-down by use of a specific siRNA promoted the expression of miR-373. Reactivation of miR-373 by pharmacologic induction of 5-aza-CdR and trichostatin A (TSA) led to decreased enrichment of MBD2 at CpG island regions. Enhanced expression of exogenous MBD2 in stable QBC939 cells which stably express pGL4-m373-prom induces strengthened recruitment of MBD2. Our findings suggest that miR-373 is a methylation-mediated gene and the implication of MBD2 in methylation-mediated suppression of miR-373 plays an important role in tumourigenesis and development in hilar cholangiocarcinoma.

  8. Endopancreatic Bile Duct Cholangiocarcinoma in a Patient with Peutz-Jeghers Syndrome

    Directory of Open Access Journals (Sweden)

    Alexandros K. Charalabopoulos

    2011-01-01

    Full Text Available Peutz-Jeghers syndrome is a rare autosomal dominant inherited disease characterized by a special type of hamartomatous gastrointestinal polyps combined with mucocutaneous melanin pigmentations. Patients with the syndrome have a high risk of developing neoplasia, with colon, small bowel, and stomach being the most common gastrointestinal sites. Herein, we present the occurrence of a rare tumor in patients with Peutz-Jeghers syndrome; a cholangiocarcinoma of the endopancreatic bile duct. A minireview is also presented. It can be concluded that cholangiocarcinoma remains a possible diagnosis in PJS patients, as in others that present with biliary obstruction. PJS patients may be at higher risk than others in view of their propensity for malignancy.

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

    Science.gov (United States)

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

    2017-03-14

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

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

    Directory of Open Access Journals (Sweden)

    Farshad Farshidfar

    2017-03-01

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

  11. Secretin-stimulated MR cholangiopancreatography (MRCP): visualization of the normal pancreatic duct in comparison with ERCP; Sekretinstimulierte Magnetresonanzcholangiopankreatikographie: Darstellung des normalen Pankreasgangs im Vergleich zur ERCP

    Energy Technology Data Exchange (ETDEWEB)

    Heverhagen, J.T.; Battmann, A.; Kirsch, M.; Klose, K.J.; Wagner, H.J. [Klinik fuer Strahlendiagnostik, Medizinisches Zentrum fuer Radiologie, Philipps Univ., Marburg (Germany); Eissele, R. [Klinik fuer Gastroenterologie, Medizinisches Zentrum fuer Innere Medizin, Philipps Univ., Marburg (Germany)

    2002-09-01

    Purpose: To determine whether the application of secretin improves the depiction of the normal pancreatic duct and to document the time course of any possible improved visualisation. Patients and Methods: Twenty-eight patients with a normal pancreatic ductal system, proved by ERCP, were prospectively enrolled in our study. MRCP was carried out in a 1.0 Tesla unit using a thick slab single-shot turbo-echo sequence (TR: {infinity}, TE: 1100 ms, FA: 150 , slab thickness: 65 mm). Following acquisition of a non-enhanced image, 1 clinical unit/kg bodyweight of secretin was injected intravenously. During the subsequent ten minutes the MR measurement was repeated every 30 seconds. The images were independently evaluated by two investigators. Results: The improvement in quality after administration of secretin was statistically significant for both investigators (p < 0.05), but no significant difference was found between both investigators concerning the quality of the images (p = 0.49). Prior to the secretin application, the entire ductal system only be evaluated in ten cases (35.7%) by both investigators, afterwards in 26 cases (92.9%). Improvement was achieved after a mean time of 1.5 minutes and lasted until the ninth minute. Conclusion: Intravenous application of secretin improves image quality of MRCP also in patients with no pancreatic pathology. Improvement begins after 1.5 minutes and lasts for about seven minutes. (orig.) [German] Ziel: Wir wollten pruefen, ob die Visualisierung des gesunden Pankreasgangsystems durch die Applikation von Sekretin verbessert wird und ueber welchen Zeitraum sich eine moegliche Verbesserung dokumentieren laesst. Patienten und Methoden: 28 Patienten mit gesundem Pankreasgangsystem, nachgewiesen durch ERCP, wurden prospektiv in die Studie eingeschlossen. Die MRCP wurde in einem 1,0 Tesla Scanner mit einer single-shot Turbo-Spin-Echo Sequenz (TR: {infinity}, TE: 1100 ms, FA: 150 , Slabdicke: 65 mm) durchgefuehrt. Nach der Akquisition von

  12. Genetic and expression alterations in association with the sarcomatous change of cholangiocarcinoma cells

    OpenAIRE

    Yoo, Hee-Jung; Yun, Bo-Ra; Kwon, Jung-Hee; Ahn, Hyuk-Soo; Seol, Min-A; Lee, Mi-Jin; Yu, Goung-Ran; Yu, Hee-Chul; Hong, BeeHak; Choi, KwanYong; Kim, Dae-Ghon

    2009-01-01

    Cholangiocarcinoma (CC) is an intrahepatic bile duct carcinoma with a high mortality rate and a poor prognosis. Sarcomatous change/epithelial mesenchymal transition (EMT) of CC frequently leads to aggressive intrahepatic spread and metastasis. The aim of this study was to identify the genetic alterations and gene expression pattern that might be associated with the sarcomatous change in CC. Previously, we established 4 human CC cell lines (SCK, JCK1, Cho-CK, and Choi-CK). In the present study...

  13. Enhancement pattern of hilar cholangiocarcinoma: Contrast-enhanced ultrasound versus contrast-enhanced computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Xu Huixiong, E-mail: xuhuixiong@hotmail.co [Department of Medical Ultrasonics, The First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, 58 Zhongshan Road 2, Guangzhou 510080 (China); Chen Lida; Xie Xiaoyan; Xie Xiaohua; Xu Zuofeng; Liu Guangjian; Lin Manxia; Wang Zhu [Department of Medical Ultrasonics, The First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-Sen University, 58 Zhongshan Road 2, Guangzhou 510080 (China); Lu Mingde, E-mail: lumd@21cn.co [Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road 2, Guangzhou 510080 (China)

    2010-08-15

    Objective: To compare the enhancement pattern of hilar cholangiocarcinoma on contrast-enhanced ultrasound (CEUS) with that on contrast-enhanced computed tomography (CECT). Methods: Thirty-two consecutive patients with pathologically proven hilar cholangiocarcinomas were evaluated by both low mechanical index CEUS and CECT. The enhancement feature of the tumor, portal vein infiltration, and lesion conspicuity on them was investigated. Results: In the arterial phase, the numbers of the lesions showing hyperenhancement, isoenhancement, and hypoenhancement, were 14 (43.8%), 14 (43.8%), and 4 (12.6%), on CEUS, and 12 (37.5%), 9 (28.1%), and 11 (34.4%), on CECT (P = 0.162). In portal phase, the numbers of the lesions showing hypoenhancement, isoenhancement, and hyperenhancement were 30 (93.8%), 1 (3.1%), and 1 (3.1%), on CEUS, and 23 (71.9%), 8 (25.0%), and 1 (3.1%), on CECT (P = 0.046). The detection rates for portal vein infiltration were 84.2% (16/19) for baseline ultrasound, 89.5% (17/19) for CEUS, and 78.9% (15/19) for CECT (all P > 0.05 between every two groups). CEUS significantly improved the lesion conspicuity in comparison with CECT. CEUS and CECT made correct diagnoses in 30 (93.8%) and 25 (78.1%) lesions prior to pathological examination (P = 0.125). Conclusion: The enhancement pattern of hilar cholangiocarcinoma on CEUS was similar with that on CECT in arterial phase, whereas in portal phase hilar cholangiocarcinoma shows hypoenhancement more likely on CEUS. CEUS and CECT lead to similar results in evaluating portal vein infiltration and diagnosis of this entity.

  14. The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer

    Directory of Open Access Journals (Sweden)

    Abigail Zabron

    2013-03-01

    Full Text Available Cholangiocarcinoma is a fatal cancer of the biliary epithelium and has an incidence that is increasing worldwide. Survival beyond a year of diagnosis is less than 5%, and therapeutic options are few. Known risk factors include biliary diseases such as primary sclerosing cholangitis and parasitic infestation of the biliary tree, but most cases are not associated with any of these underlying diseases. Numerous in vitro and in vivo models, as well as novel analytical techniques for human samples, are helping to delineate the many pathways implicated in this disease, albeit at a frustratingly slow pace. As yet, however, none of these studies has been translated into improved patient outcome and, overall, the pathophysiology of cholangiocarcinoma is still poorly understood. There remains an urgent need for new approaches and models to improve management of this insidious and devastating disease. In this review, we take a bedside-to-bench approach to discussing cholangiocarcinoma and outline research opportunities for the future in this field.

  15. Cholangiocarcinoma presenting as a solitary epididymal metastasis: a case report and review of the literature

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    Bailey David M

    2007-08-01

    Full Text Available Abstract Background Solid tumor metastasis to the epididymis is a rare occurrence and is mostly discovered incidentally at autopsy or after therapeutic orchidectomy for prostate cancer. Other primary carcinomas that have been demonstrated to metastasize to the paratesticular region include those originating in the stomach, kidney, ileum, and colon. Case presentation A 72-year-old gentleman presented with a firm and tender mass involving the right epididymis. On examination, he was jaundiced. Computed tomography of the abdomen demonstrated an obstructive stricture of the extra-hepatic bile ducts, in keeping with a cholangiocarcinoma, through which a metal stent was endoscopically inserted for symptomatic relief. Subsequent right radical orchidectomy yielded a diffusely infiltrative adenocarcinoma obliterating the epididymis, extending into the rete testis, vas deferens and spermatic cord and showing widespread vascular and perineural invasion. Residual epididymal, rete, and testicular tubules showed no in situ neoplasia. Morphologically and immunohistochemically the features were in keeping with a metastasis from a primary cholangiocarcinoma. Conclusion Only two cases of bile duct carcinoma metastasising to the male genital tract have previously been reported in the literature, the testis being the main site of metastasis in both cases. To our knowledge, this is the first described case of cholangiocarcinoma metastasising primarily to the epididymis, and presenting as a solitary epididymal metastasis in the absence of disseminated disease. It serves to highlight the importance of performing a thorough examination of the male external genitalia both clinically, in the follow up of cancer patients, and at autopsy.

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

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    Takashi Yuri

    2014-05-01

    Full Text Available 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.

  17. Pathological spectrum of bile duct lesions from chronic bile duct injury to invasive cholangiocarcinoma corresponding to bile duct imaging findings of occupational cholangiocarcinoma.

    Science.gov (United States)

    Kinoshita, Masahiko; Kubo, Shoji; Nakanuma, Yasuni; Sato, Yasunori; Takemura, Shigekazu; Tanaka, Shogo; Hamano, Genya; Ito, Tokuji; Terajima, Hiroaki; Yamada, Terumasa; Nakamori, Shoji; Arimoto, Akira; Fujikawa, Masahiro; Sugawara, Yasuhiko; Yamamoto, Takatsugu; Abue, Makoto; Nakagawa, Kei; Unno, Michiaki; Mizuguchi, Toru; Takenaka, Kenji; Shirabe, Ken; Shibata, Toshihiko

    2016-02-01

    We aimed to identify the pathological characteristics of occupational cholangiocarcinoma. We examined the location and distribution of the carcinomas: atypical epithelium including biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB); and chronic bile duct injuries in operative or autopsy liver specimens from 16 patients. We examined the detailed pathological findings and diagnostic imaging of three patients. Immunohistochemical analysis using primary antibodies against γH2AX and S100P was performed. BilIN and chronic bile duct injury were observed in 16 patients, and IPNB or invasive IPNB was observed in 11 patients. BilIN, IPNB, and/or chronic bile duct injury were observed in almost all the large bile ducts. Regional dilatation of the bile ducts without tumor-induced obstruction revealed such pathological changes. Highly positive results for the γH2AX and S100P markers were noted in invasive carcinoma, BilIN, and IPNB, whereas positive results for γH2AX and negative results for S100P were noted in non-neoplastic biliary epithelium. The carcinogenic process of occupational cholangiocarcinoma comprised chronic bile duct injury and DNA damage in almost all the large bile ducts, along with induction of precancerous lesions and development of invasive carcinoma. Such pathological findings reflected radiological changes on diagnostic imaging. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  18. Effect of sorafenib and celecoxib combination therapy on proliferation of the human cholangiocarcinoma cell line SK-ChA-1 in vitro

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    WAN Yunyan

    2013-01-01

    Full Text Available ObjectiveTo investigate the effect of sorafenib and celecoxib combination therapy on proliferation of human cholangiocarcinoma (CC cells, using the cultured SK-ChA-1 cell line. MethodsInhibition of SK-ChA-1 cell proliferation by sorafenib alone and in combination with celecoxib was studied in vitro using the MTT assay. The anti-neoplastic mechanisms of sorafenib alone and in combination with celecoxib were assessed by Western blot detection of changes in the caspase cleavage substrate poly ADP-ribose polymerase (PARP. ResultsSK-ChA-1 cells treated with sorafenib alone showed a dose-dependent growth inhibition and degradation of PARP. Combination treatment with sorafenib and celecoxib synergistically increased the growth inhibition effects and enhanced the degradation of PARP. ConclusionCombination treatment with sorafenib and celecoxib results in a synergistic anti-proliferative effect in the human CC cell line SK-ChA-1; the addition of celecoxib enhances sorafenib-induced apoptosis.

  19. Secretin stimulation test

    Science.gov (United States)

    ... the pancreas to release a fluid that contains digestive enzymes. These enzymes break down food and help the ... these conditions, there may be a lack of digestive enzymes or other chemicals in the fluid that comes ...

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

    Science.gov (United States)

    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.

  1. Topology and Structure/Function Correlation of Ring- and Gate-forming Domains in the Dynamic Secretin Complex of Thermus thermophilus.

    Science.gov (United States)

    Salzer, Ralf; D'Imprima, Edoardo; Gold, Vicki A M; Rose, Ilona; Drechsler, Moritz; Vonck, Janet; Averhoff, Beate

    2016-07-08

    Secretins are versatile outer membrane pores used by many bacteria to secrete proteins, toxins, or filamentous phages; extrude type IV pili (T4P); or take up DNA. Extrusion of T4P and natural transformation of DNA in the thermophilic bacterium Thermus thermophilus requires a unique secretin complex comprising six stacked rings, a membrane-embedded cone structure, and two gates that open and close a central channel. To investigate the role of distinct domains in ring and gate formation, we examined a set of deletion derivatives by cryomicroscopy techniques. Here we report that maintaining the N0 ring in the deletion derivatives led to stable PilQ complexes. Analyses of the variants unraveled that an N-terminal domain comprising a unique βββαβ fold is essential for the formation of gate 2. Furthermore, we identified four βαββα domains essential for the formation of the N2 to N5 rings. Mutant studies revealed that deletion of individual ring domains significantly reduces piliation. The N1, N2, N4, and N5 deletion mutants were significantly impaired in T4P-mediated twitching motility, whereas the motility of the N3 mutant was comparable with that of wild-type cells. This indicates that the deletion of the N3 ring leads to increased pilus dynamics, thereby compensating for the reduced number of pili of the N3 mutant. All mutants exhibit a wild-type natural transformation phenotype, leading to the conclusion that DNA uptake is independent of functional T4P. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Radical operation for hilar cholangiocarcinoma in comparable Eastern and Western centers: Outcome analysis and prognostic factors.

    Science.gov (United States)

    Kimura, Norihisa; Young, Alastair L; Toyoki, Yoshikazu; Wyatt, Judith I; Toogood, Giles J; Hidalgo, Ernest; Prasad, K Rajendra; Kudo, Daisuke; Ishido, Keinosuke; Hakamada, Kenichi; Lodge, J Peter A

    2017-09-01

    Extensive resection for hilar cholangiocarcinoma is the most effective treatment, but high morbidity and poor prognosis remain concerns. Previous data have shown marked differences in outcomes between comparable Eastern and Western centers. We compared the outcomes of the management for hilar cholangiocarcinoma at one Japanese and one British institution with comparable experience. Of 298 consecutive patients with hilar cholangiocarcinoma evaluated at Hirosaki University Hospital, Japan and St. James's University Hospital, Leeds, UK, 183 underwent radical resection. Clinicopathologic variables and postoperative outcomes were compared. Significant differences were not observed between the Hirosaki and Leeds cohorts in overall outcomes despite several differences in the patient characteristics. Although there was a difference in 90-day mortality (2.5% vs 13.6%, respectively), disease-specific 5-year survival rates were 32.8% and 31.9%, respectively (P = .767). Multivariate analysis identified trisectionectomy (odds ratio = 2.32; P = .010), combined pancreatoduodenectomy (odds ratio = 7.88; P = .010), and perioperative blood transfusion (odds ratio = 1.88; P = .045) were associated with postoperative major complications, while preoperative biliary drainage associated with postoperative major complications, while preoperative biliary drainage (risk ratio = 2.21; P = .018), perioperative blood transfusion (risk ratio = 1.58; P = .029), lymph node metastasis (risk ratio = 2.00; P = .002), moderate/poorly differentiated tumor (risk ratio = 1.72; P = .029), microvascular invasion (risk ratio = 1.63; P = .046), and R1 resection (risk ratio = 1.90; P = .005) were risk factors for poor survival. Disease-specific survival and prognostic factors were similar in both centers. Meticulous operative technique to avoid perioperative blood transfusion may improve long-term survival. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. [Application values of computer-assisted preoperative planning of hilar cholangiocarcinoma].

    Science.gov (United States)

    Li, Huixing; Shi, Xianjie; Liang, Yurong; He, Lei; Chen, Mingyi; Wang, Hongguang; Lü, Shaocheng; Wang, Xuedong; Meng, Xiangfei

    2015-02-10

    To explore the application value of computer-assisted preoperative planning of hilar cholangiocarcinoma. Retrospective analyses were conducted for the clinical data of 47 patients with hilar cholangiocarcinoma undergoing radical resection plus hemihepatectomy from January to December 2013. According to whether computer-assisted preoperative planning was used, they were divided two groups of computer-assisted surgical planning (CASP) and without computer-assisted surgical planning (WCASP). Then we analyzed the data including preoperative examinations, preoperative planning, intraoperative findings and postoperative complications. There were 31 cases of hilar vascular invasion by tumor. Among 29 cases of CASP, left hepatic artery originated from left gastric artery (n = 6), right posterior bile duct drained into left hepatic bile duct (n = 1) and right posterior bile duct run into common hepatic bile duct (n = 2). The mean operative duration of CASP was (6.5 ± 1.3) h and the mean volume of intraoperative bleeding (672.0 ± 214.3) ml; while the mean operative duration of WCASP was (7.9 ± 2.9) h and the mean volume of intraoperative bleeding (870.0 ± 330.1) ml. By statistical analysis, the inter-group differences of mean operative duration had statistical difference (P = 0.028) and the inter-group differences of mean volume of intraoperative bleeding had statistical difference (P = 0.016). The ratio of first negative test in group CASP was higher than that of group WCASP and the inter-group differences had statistical significance (P = 0.043). But the inter-group rate of postoperative complications had no significant difference (P = 0.419). The computer-assisted surgical planning system provides accurate information so that an optimal surgical protocol may be designed by surgeons. And it has great application values in preoperative surgical planning for hilar cholangiocarcinoma and enjoys wide prospects in precise liver surgery.

  4. Different carcinogenic process in cholangiocarcinoma cases epidemically developing among workers of a printing company in Japan.

    Science.gov (United States)

    Sato, Yasunori; Kubo, Shoji; Takemura, Shigekazu; Sugawara, Yasuhiko; Tanaka, Shogo; Fujikawa, Masahiro; Arimoto, Akira; Harada, Kenichi; Sasaki, Motoko; Nakanuma, Yasuni

    2014-01-01

    Recently, cholangiocarcinoma has epidemically developed among young adult workers of a printing company in Japan. Exposure to organic solvents including 1,2-dichloropropane and/or dichloromethane is supposed to be associated with the carcinoma development. The metabolism of dichloromethane proceeds through a Theta-class glutathione S-transferase (GST) T1-1-catalyzed pathway, where its reactive intermediates have been implicated in genotoxicity and carcinogenicity. This study examined features of the carcinogenic process of the cholangiocarcinoma developed in the printing company. Surgically resected specimens of the cholangiocarcinoma cases were analyzed, where all cases were associated with precursor lesions such as biliary intraepithelial neoplasia (BilIN) and/or intraductal papillary neoplasm of the bile duct (IPNB). Immunohistochemical analysis confirmed constitutional expression of GST T1-1 in normal hepatobiliary tract. Immunostaining of γ-H2AX, a marker of DNA double strand break, showed that its expression was significantly increased in foci of BilIN, IPNB and invasive carcinoma as well as in non-neoplastic biliary epithelial cells of the printing company cases when compared to that of control groups. In the printing company cases, immunohistochemical expression of p53 was observed in non-neoplastic biliary epithelial cells and BilIN-1. Mutations of KRAS and GNAS were detected in foci of BilIN in one out of 3 cases of the printing company. These results revealed different carcinogenic process of the printing company cases, suggesting that the exposed organic solvents might act as a carcinogen for biliary epithelial cells by causing DNA damage, thereby contributing to the carcinoma development.

  5. Different carcinogenic process in cholangiocarcinoma cases epidemically developing among workers of a printing company in Japan

    Science.gov (United States)

    Sato, Yasunori; Kubo, Shoji; Takemura, Shigekazu; Sugawara, Yasuhiko; Tanaka, Shogo; Fujikawa, Masahiro; Arimoto, Akira; Harada, Kenichi; Sasaki, Motoko; Nakanuma, Yasuni

    2014-01-01

    Recently, cholangiocarcinoma has epidemically developed among young adult workers of a printing company in Japan. Exposure to organic solvents including 1,2-dichloropropane and/or dichloromethane is supposed to be associated with the carcinoma development. The metabolism of dichloromethane proceeds through a Theta-class glutathione S-transferase (GST) T1-1-catalyzed pathway, where its reactive intermediates have been implicated in genotoxicity and carcinogenicity. This study examined features of the carcinogenic process of the cholangiocarcinoma developed in the printing company. Surgically resected specimens of the cholangiocarcinoma cases were analyzed, where all cases were associated with precursor lesions such as biliary intraepithelial neoplasia (BilIN) and/or intraductal papillary neoplasm of the bile duct (IPNB). Immunohistochemical analysis confirmed constitutional expression of GST T1-1 in normal hepatobiliary tract. Immunostaining of γ-H2AX, a marker of DNA double strand break, showed that its expression was significantly increased in foci of BilIN, IPNB and invasive carcinoma as well as in non-neoplastic biliary epithelial cells of the printing company cases when compared to that of control groups. In the printing company cases, immunohistochemical expression of p53 was observed in non-neoplastic biliary epithelial cells and BilIN-1. Mutations of KRAS and GNAS were detected in foci of BilIN in one out of 3 cases of the printing company. These results revealed different carcinogenic process of the printing company cases, suggesting that the exposed organic solvents might act as a carcinogen for biliary epithelial cells by causing DNA damage, thereby contributing to the carcinoma development. PMID:25197345

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

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    Alice Fraveto

    Full Text Available 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

  7. Combined hepatocellular-cholangiocarcinoma in a Yellow-headed Amazon (Amazona oratrix).

    Science.gov (United States)

    Tennakoon, Anusha Hemamali; Izawa, Takeshi; Fujita, Daisuke; Denda, Yuki; Seto, Eiko; Sasai, Hiroshi; Kuwamura, Mitsuru; Yamate, Jyoji

    2013-11-01

    A 9-year-old male Yellow-headed Amazon (Amazona oratrix) with a history of anorexia and vomiting died of a liver tumor. The tumor consisted of neoplastic cells with hepatocellular and cholangiocellular differentiations and their intermingled areas. Neoplastic hepatocytes showed islands or trabecular growth with vacuolated eosinophilic cytoplasm. Cells showing biliary differentiation formed ducts or tubules lined by cytokeratin AE1/AE3-positive epithelia, accompanied by desmoplasia consisting of myofibroblasts reacting to α-smooth muscle actin and desmin. The tumor was diagnosed as a combined hepatocellular-cholangiocarcinoma, which is very rare in the avian.

  8. Percutaneous Irreversible Electroporation of Unresectable Hilar Cholangiocarcinoma (Klatskin Tumor): A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Melenhorst, Marleen C. A. M., E-mail: m.melenhorst@vumc.nl; Scheffer, Hester J., E-mail: hj.scheffer@vumc.nl; Vroomen, Laurien G. P. H., E-mail: la.vroomen@vumc.nl [VU University Medical Center, Department of Radiology and Nuclear Medicine (Netherlands); Kazemier, Geert, E-mail: g.kazemier@vumc.nl; Tol, M. Petrousjka van den, E-mail: mp.vandentol@vumc.nl [VU University Medical Center, Department of Surgery (Netherlands); Meijerink, Martijn R., E-mail: mr.meijerink@vumc.nl [VU University Medical Center, Department of Radiology and Nuclear Medicine (Netherlands)

    2016-01-15

    Irreversible electroporation (IRE) is a novel image-guided ablation technique that is rapidly gaining popularity in the treatment of malignant tumors located near large vessels or bile ducts. The presence of metal objects in the ablation zone, such as Wallstents, is generally considered a contraindication for IRE, because tissue heating due to power conduction may lead to thermal complications. This report describes a 66-year-old female with a Bismuth–Corlette stage IV unresectable cholangiocarcinoma with a metallic Wallstent in the common bile duct, who was safely treated with percutaneous IRE with no signs for relapse 1 year after the procedure.

  9. [Primary cholangiocarcinoma in a case of Caroli's disease: case report and literature review].

    Science.gov (United States)

    Kasper, H-U; Stippel, D L; Töx, U; Drebber, U; Dienes, H P

    2006-07-01

    Caroli's disease is a liver disease with segmental cystic dilatation of the intrahepatic bile ducts. It belongs to the group of congenital ductal plate malformations. With an incidence of only 0.05% of all liver cases in the Liver Registry of the University of Cologne, it is a very rare disorder. Caroli's disease is usually combined with cholangitis and bile duct stones. Control of these infections and maintenance of biliary drainage are the main therapeutic aims. The development of intra epithelial neoplasia and invasive carcinoma are rare complications. We report a case of Caroli's disease with the development of cholangiocarcinoma and review the literature.

  10. The multidisciplinary team meeting in the UK from the patients’ perspective: comments and observations from cholangiocarcinoma patients and their families

    Directory of Open Access Journals (Sweden)

    Morement H

    2017-09-01

    Full Text Available Helen Morement,1 Rachel Harrison,2 Simon D Taylor-Robinson3 1AMMF – The Cholangiocarcinoma Charity, Enterprise House, Stansted, Essex, 2Department of South East Asia, School of Oriental and African Studies, London, 3Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, London, UK Background: The multidisciplinary team (MDT meeting has become the hallmark for cancer care in the UK. While standardizing care through adherence to guidelines, the MDT process can make the decision-making process somewhat remote from the patient perspective. The Cholangiocarcinoma Charity (AMMF is the UK’s only cholangiocarcinoma charity and is at the forefront of patient empowerment for those with this condition and for their families. It provides much needed support not only via personal contact but also through its website and on the social media platforms, Facebook and Twitter. Methods: AMMF conducted a survey of patient attitudes to and experience of the MDT process through a simple questionnaire posted on Facebook in 2014. We report the results of the responses received, which we believe are worthy of further thought. Findings: In the main, while treatment decisions are not queried, there is distress at the lack of involvement, the lack of representation, the lack of communication and at not knowing who to approach for answers to questions. Conclusion: This snapshot, although small, provides some insight to clinicians not to forget the constituency they serve, as communication is all important. Keywords: cholangiocarcinoma, multidisciplinary team meeting, management, patient perspectives

  11. Ablation with irreversible electroporation in patients with advanced perihilar cholangiocarcinoma (ALPACA): a multicentre phase I/II feasibility study protocol

    NARCIS (Netherlands)

    Coelen, Robert J. S.; Vogel, Jantien A.; Vroomen, Laurien G. P. H.; Roos, Eva; Busch, Olivier R. C.; van Delden, Otto M.; van Delft, Foke; Heger, Michal; van Hooft, Jeanin E.; Kazemier, Geert; Klümpen, Heinz-Josef; van Lienden, Krijn P.; Rauws, Erik A. J.; Scheffer, Hester J.; Verheul, Henk M.; de Vries, Jan; Wilmink, Johanna W.; Zonderhuis, Barbara M.; Besselink, Marc G.; van Gulik, Thomas M.; Meijerink, Martijn R.

    2017-01-01

    Introduction The majority of patients with perihilar cholangiocarcinoma (PHC) has locally advanced disease or distant lymph node metastases on presentation or exploratory laparotomy, which makes them not eligible for resection. As the prognosis of patients with locally advanced PHC or lymph node

  12. Decrease of deleted in malignant brain tumour-1 (DMBT-1) expression is a crucial late event in intrahepatic cholangiocarcinoma

    DEFF Research Database (Denmark)

    Sasaki, M; Huang, S-F; Chen, M-F

    2003-01-01

    AIMS: To investigate the participation of DMBT-1, a candidate tumour suppressor gene, in the development of intrahepatic cholangiocarcinoma via intraductal papillary neoplasm of the liver (IPN-L) arising in hepatolithiasis. DMBT-1 plays a role in mucosal immune defence. METHODS AND RESULTS: The e...

  13. Spontaneous biloma due to an intrahepatic cholangiocarcinoma: An extremely rare case report with long term survival and literature review

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    Georgios K. Georgiou

    2017-02-01

    Intraperitoneal rupture of bile ducts and subsequent spontaneous biloma formation, due to an intrahepatic cholangiocarcinoma which completely obstructed the left main hepatic duct, is a unique situation and this is the first time to be reported. Prompt surgical management can lead to successful treatment of this rare and difficult entity.

  14. Expression of novel tumor markers of pancreatic adenocarcinomas in intrahepatic cholangiocarcinomas

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    Zong M

    2013-01-01

    Full Text Available Meijuan Zong,1 Lei Jia,1 Liang Li21Zibo Vocational Institute, 2Department of General Surgery, Zibo Central Hospital, Zibo, ChinaAbstract: Intrahepatic cholangiocarcinomas (IHCCs are morphologically and biologically similar to pancreatic ductal adenocarcinomas (PDACs, so newly identified PDAC-associated genes or proteins could provide clues for screening novel biomarkers for IHCC. In this study, the expression of three novel PDAC tumor markers (T-box transcription factor-4 [TBX4], heat shock protein-60 [HSP60], and Parkinson protein-7 [DJ-1] identified in previous proteomic studies in IHCC tumors were immunohistochemically detected. The current study confirmed that three novel pancreatic cancer biomarkers TBX4, HSP60, and DJ-1 were also overexpressed in IHCC tumors, but with a relatively lower expression level than PDAC. No significant association was found between tumor marker expression and the clinicopathological characteristics of IHCC patients except that TBX4 expression correlated with tumor grades. Moreover, DJ-1 was demonstrated to be an independent prognostic factor for these patients. The current findings suggest that DJ-1 might play an important role in the malignant progression of IHCC, and its exact mechanism during IHCC progression deserves further investigation.Keywords: intrahepatic cholangiocarcinomas, biomarker, TBX4, HSP60, DJ-1

  15. Prognostic impact of the site of portal vein invasion in patients with surgically resected perihilar cholangiocarcinoma.

    Science.gov (United States)

    Nakanishi, Yoshitsugu; Tsuchikawa, Takahiro; Okamura, Keisuke; Nakamura, Toru; Tamoto, Eiji; Murakami, Soichi; Ebihara, Yuma; Kurashima, Yo; Noji, Takehiro; Asano, Toshimichi; Shichinohe, Toshiaki; Hirano, Satoshi

    2016-06-01

    The aim of this study was to determine the impact of the site of portal vein invasion on survival after hepatectomy for perihilar cholangiocarcinoma. This study classified 168 patients undergoing resection for perihilar cholangiocarcinoma histologically as without portal vein resection or tumor invasion to the portal vein (PV0), with tumor invasion to unilateral branches of the portal vein (PVt3), or with tumor invasion to the main portal vein or its bilateral branches, or to unilateral second-order biliary radicals with contralateral portal vein involvement (PVt4). Patients in PVt4 were subclassified into the A-M group (cancer invasion limited to the tunica adventitia or media) or the I group (cancer invasion reaching the tunica intima). Of the patients, 121 were in PV0, 21 were in PVt3, and 26 were in PVt4. There was no difference in survival between the PV0 and PVt3 groups (P = .267). The PVt4 group had a worse prognosis than the PVt3 group (P = .046). In addition, the A-M (n = 19) and I subgroups (n = 7) of PVt4 had worse prognoses than the PV0 or PVt3 groups (P = .005 and portal vein invasion, although patients with tumor invasion to the main or contralateral branches of the portal vein, especially with tunica intima invasion, had extremely poor prognoses. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Isolated Liver Hilar Infiltration by IgG4 Inflammation Mimicking Cholangiocarcinoma

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    Laurent Bochatay

    2016-10-01

    Full Text Available IgG4-related disease represents a heterogeneous group of disease characterized by infiltration of various tissues by IgG4 plasmocytes. In case of liver infiltration, this condition classically mimics primary sclerosing cholangitis or multifocal cholangiocarcinoma due to inflammation that preferentially affects the intra- and extrahepatic bile duct. Diagnostic criteria have recently been reviewed in order to better define the disease and help physicians make the diagnosis. Herein, we present the case of a patient who died after liver surgery for suspected cholangiocarcinoma that finally turned out to be IgG4-associated liver disease, a condition being out of current consensual criteria. The patient presented with progressive cholestasis identified by MR cholangiography as an isolated hilar mass responsible for dilatation of the left and right intrahepatic bile duct suspicious for a Klatskin tumor. The IgG4 blood level was normal as was biliary cytology. The patient underwent right portal embolization followed by right extended hepatectomy. Pathologic examination found no tumor but intense fibrosclerotic infiltration with a marked inflammatory infiltrate characterized by IgG4-positive plasmocytes. Despite immunosuppressive treatment, cholestasis was never controlled and successive biopsies of the remaining liver showed progressive cholestasis, liver infiltrate and no bile duct regeneration. The patient finally presented an upper gastrointestinal hemorrhage leading to death 4 months after hepatectomy and appropriate immunosuppressive therapy.

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

    Science.gov (United States)

    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

  18. Combination of Praziquantel and Aspirin Minimizes Liver Pathology of Hamster Opisthorchis viverrini Infection Associated Cholangiocarcinoma.

    Science.gov (United States)

    Sudsarn, Pakkayanee; Boonmars, Thidarut; Ruangjirachuporn, Wipaporn; Namwat, Nisana; Loilome, Watcharin; Sriraj, Pranee; Aukkanimart, Ratchadawan; Nadchanan, Wonkchalee; Jiraporn, Songsri

    2016-01-01

    Opisthorchiasis is one of the major risk factors for cholangiocarcinoma (CCA) in northeastern Thailand. An effective drug for killing this parasite is praziquantel. Recently, several reports have shown that with frequent use, praziquantel may itself be a CCA risk and can cause liver cell damage from an immunopathological response after parasite death. Aspirin has many properties including anti-inflammation and anti-cancer. Therefore, we use of aspirin (As) and praziquantel (Pz) to improve hepatobiliary system function in hamsters infected with Opisthorchis viverrini (OV) and or administered N-nitrosodimethylamine (ND). Livers of OVNDAsPz, appeared healthy macroscopically, suggesting slow progression of cholangiocarcinoma evident by extent of fibrosis and bile duct cell proliferation was less than OVND although aggregations of inflammatory cells remained. Proliferating cell nuclear antigen (PCNA), cytokeratin 19 (CK19), and cancer antigen (CA19-9) staining were strongly positive in OVND, but were only slight in OVNDAs. Moreover, OVNDAsPz, appeared a few inflammatory infiltrations, bile duct proliferation, fibrosis and CCA area than the OVNDAs group. Thirty seven point five percent of hamster in this group could not develop CCA. These findings suggest that using aspirin combination with praziquantel treatment can improve the hepatobiliary system after O. viverrini infection and reduce the risk of CCA.

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

    Directory of Open Access Journals (Sweden)

    Yasuni Nakanuma

    2014-01-01

    Full Text Available 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.

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

    Directory of Open Access Journals (Sweden)

    Ting-Ting Liu

    Full Text Available 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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2017-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Jean Amede Roch

    2008-10-01

    Full Text Available

    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.

  4. Intrahepatic Cholangiocarcinoma Presenting as the Budd-Chiari Syndrome: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Joanna K Law

    2005-01-01

    Full Text Available Intrahepatic cholangiocarcinoma, an increasingly recognized primary tumour of the liver, is associated with a very poor prognosis. A patient with this tumour who presented with Budd-Chiari syndrome (the first to the authors' knowledge in Western literature and only the third patient overall secondary to extensive thrombosis in his inferior vena cava extending from the right atrium down to his iliac vessels is described. Neither curative nor palliative intervention was deemed to be an option in this patient, who deteriorated rapidly while on anti-coagulants. Postmortem examination confirmed the radiological findings, and histological analysis revealed characteristic appearances of this tumour within the biliary tree and invasion into the inferior vena cava. Furthermore, biliary dysplasia, which can be a precursor to this cancer, was also noted within some of the bile ducts.

  5. Biliary-Pleural Fistula following Portal Vein Embolization for Perihilar Cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Mujtaba Mohammed

    2017-05-01

    Full Text Available Biliary-pleural fistula (BPF, an abnormal communication between the biliary tract and pleural space, is a rare but potentially life-threatening complication following percutaneous biliary intervention. We report a case of BPF following portal vein embolization (PVE in a 79-year-old woman with obstructive jaundice secondary to perihilar cholangiocarcinoma. The patient successfully underwent right-sided PVE; however, the patient developed a symptomatic right-sided bilious pleural effusion the following day. Despite aggressive drainage of the pleural effusion with a large-bore chest tube and maximal medical management, the patient died from respiratory failure and pneumonia. Although rare, knowledge of this complication is important when performing PVE in patients with biliary obstruction because it can be life-threatening. Early recognition and management of this complication are crucial to avoid a poor outcome.

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

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    Yeh CN

    2014-12-01

    Full Text Available Chun-Nan Yeh,1 Feng-Jen Hsieh,1 Kun-Chun Chiang,1 Jen-Shi Chen,2 Ta-Sen Yeh,1 Yi-Yin Jan,1 Miin-Fu Chen1 1Department of General Surgery, 2Department of Medical Oncology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan 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

  7. Infection with Helicobacter bilis but not Helicobacter hepaticus was Associated with Extrahepatic Cholangiocarcinoma.

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    Segura-López, Fany K; Avilés-Jiménez, Francisco; Güitrón-Cantú, Alfredo; Valdéz-Salazar, Hilda A; León-Carballo, Samuel; Guerrero-Pérez, Leoncio; Fox, James G; Torres, Javier

    2015-06-01

    The biliary tract cancer or cholangiocarcinoma (CCA) represents the sixth leading cause of gastrointestinal tumors in the Western world, and mortality varies across the world, with regions such as Chile, Thailand, Japan, and northeastern India presenting the highest rates. CCA may develop in the bile duct, gallbladder, or ampulla of Vater; and risk factors include obesity, parity, genetic background, geographical and environmental factors. Inflammation induced by bacterial infections might play a role in the pathogenesis of CCA. In this work, we investigated whether there is an association between extrahepatic cholangiocarcinoma (ECCA) and infection with S. typhi, H. hepaticus, or H. bilis in a Mexican population. A total of 194 patients were included and divided into 91 patients with benign biliary pathology (controls) and 103 with ECCA (cases). Tumor samples were taken during endoscopic retrograde cholangiopancreatography by biliary brushing, followed by DNA extraction and PCR testing for infections. We found that 44/103 cases were positive for H. bilis, compared with 19/91 controls (p = 0.002; OR 2.83, 95% CI 1.49-5.32), and when analyzed by sub-site, H. bilis infection was significantly more associated with cancer in the common bile duct (p = 0.0005; OR 3.56, 95% CI 1.77-7.17). In contrast, H. hepaticus infection was not different between cases (17/103) and controls (13/91) (p = 0.82; OR 1.19, 95% CI 0.54-2.60). None of the samples were positive for S. typhi infection. In conclusion, infection with H. bilis but neither H. Hepaticus nor S. typhi was significantly associated with ECCA, particularly with tumors located in the common bile duct. © 2015 John Wiley & Sons Ltd.

  8. Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

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    Frampton, Gabriel; Coufal, Monique [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Li, Huang [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Ramirez, Jonathan [Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States); DeMorrow, Sharon, E-mail: demorrow@medicine.tamhsc.edu [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States)

    2010-05-15

    The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the {gamma}-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-{gamma}-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the {gamma}-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

  9. MR imaging and MR cholangiopancreatography of cholangiocarcinoma developing in printing company workers.

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    Koyama, Koichi; Kubo, Shoji; Ueki, Ai; Shimono, Taro; Takemura, Shigekazu; Tanaka, Shogo; Kinoshita, Masahiko; Hamano, Genya; Miki, Yukio

    2017-05-01

    To retrospectively investigate magnetic resonance (MR) imaging findings of occupational cholangiocarcinoma (oCC) occurring among workers in printing companies in Japan, compared to those of non-occupational cholangiocarcinoma (nCC), primary sclerosing cholangitis (PSC), and age-matched normal controls (NORs). Participants comprised 27 consecutive patients (oCC, n = 5; nCC, n = 8; PSC, n = 6; NOR, n = 8) who underwent MR imaging between May 2009 and October 2012. MR imaging was evaluated with respect to tumor characteristics, abnormal MR cholangiographic findings (PSC-like findings), bile duct stricture, and signal changes of the hepatic parenchyma. Tumors were detected in all nCCs and four oCCs. Tumors displayed a mass-forming type in all nCCs and two oCCs, and an intraductal growth type in two oCCs. Abnormal cholangiographic findings were detected in all oCCs and PSCs, but not in any nCCs or NORs. All oCCs and seven nCCs showed biliary strictures longer than 1 cm; five PSCs showed biliary strictures shorter than 1 cm. Both intra- and extrahepatic biliary strictures were detected in three PSCs and two oCCs. Peripheral hepatic hyperintensity on T2-weighted imaging was detected in two nCCs, two PSCs, and two oCCs. These results indicated that MR imaging of oCC showed findings of both PSC and nCC.

  10. A combination of liver fluke infection and traditional northeastern Thai foods associated with cholangiocarcinoma development.

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    Sriraj, Pranee; Boonmars, Thidarut; Aukkanimart, Ratchadawan; Songsri, Jiraporn; Sripan, Panupan; Ratanasuwan, Panaratana; Boonjaraspinyo, Sirintip; Wongchalee, Nadchanan; Laummaunwai, Porntip

    2016-10-01

    Opisthorchis viverrini infection is one of the risk factors for cholangiocarcinoma (CCA) in northeast Thailand, a region with one of the highest reported incidence rates of CCA. The traditional practice of eating raw fish, repeated exposure to liver flukes, and consumption of nitrosamine-contaminated food are major risk factors for CCA. So far, there have been no reports about which northeastern traditional dishes may be involved in CCA development. The present study, thus, investigated the effects of traditional foods. It focused specifically on the consumption of fermented foods in combination with O. viverrini infection in hamsters. Syrian hamsters were divided into six groups: (i) normal hamsters, (ii) O. viverrini infection only and (iii)-(vi) O. viverrini infection plus fermented foods (pla som-fish fermented for 1 day), som wua-fermented beef, som phag-fermented vegetables, and pla ra-fish fermented for 6 months. Syrian hamster livers were used for analysis of histopathological changes through hematoxylin and eosin; Sirius Red; and immunohistostaining for cytokeratin-19, proliferating cell nuclear antigen, and CA19-9. Hamster sera were used for liver and kidney function tests. Results of all O. viverrini-infected groups and fermented food groups showed that histopathological changes consisted primarily of aggregations of inflammatory cells surrounding the hepatic bile duct, especially at the hilar region. However, there was a difference in virulence. Interestingly, aggregations of inflammatory cells, new bile duct formation, and fibrosis were observed in subcapsular hepatic tissue, which correlated to positive immunohistochemical staining and increased liver function test. The present study suggests that fermented food consumption can exacerbate cholangitis and cholangiofibrosis, which are risk factors for cholangiocarcinoma-associated opisthorchiasis.

  11. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.

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    Mitesh J Borad

    2014-02-01

    Full Text Available 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.

  12. Combined hepatocellular-cholangiocarcinoma in a patient with Abernethy malformation and tetralogy of Fallot: A case report.

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    Happaerts, Sofie; Foucault, Amélie; Billiard, Jean Sébastien; Nguyen, Bich; Vandenbroucke-Menu, Franck

    2016-11-01

    Abernethy malformation is a rare congenital anomaly of the portal vein where the portal blood bypasses the liver. We report the first case of a patient with Abernethy malformation and tetralogy of Fallot associated with nodular regenerative hyperplasia and focal nodular hyperplasia (FNH), which finally evolved to a giant hepatocellular-cholangiocarcinoma (HCC-CC) of the liver, successfully resected. (Hepatology 2016;64:1800-1802). © 2016 by the American Association for the Study of Liver Diseases.

  13. Skeletal muscle anabolism is a side effect of therapy with the MEK inhibitor: selumetinib in patients with cholangiocarcinoma.

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    Prado, C M M; Bekaii-Saab, T; Doyle, L A; Shrestha, S; Ghosh, S; Baracos, V E; Sawyer, M B

    2012-05-08

    Cancer cachexia is characterised by skeletal muscle wasting; however, potential for muscle anabolism in patients with advanced cancer is unproven. Quantitative analysis of computed tomography images for loss/gain of muscle in cholangiocarcinoma patients receiving selumetinib (AZD6244; ARRY-142886) in a Phase II study, compared with a separate standard therapy group. Selumetinib is an inhibitor of mitogen-activated protein/extracellular signal-regulated kinase and of interleukin-6 secretion, a putative mediator of muscle wasting. Overall, 84.2% of patients gained muscle after initiating selumetinib; mean overall gain of total lumbar muscle cross-sectional area was 13.6 cm(2)/100 days (∼2.3 kg on a whole-body basis). Cholangiocarcinoma patients who began standard treatment were markedly catabolic, with overall muscle loss of -7.3 cm(2)/100 days (∼1.2 kg) and by contrast only 16.7% of these patients gained muscle. Our findings suggest that selumetinib promotes muscle gain in patients with cholangiocarcinoma. Specific mechanisms and relevance for cachexia therapy remain to be investigated.

  14. Metformin potentiates the effect of arsenic trioxide suppressing intrahepatic cholangiocarcinoma: roles of p38 MAPK, ERK3, and mTORC1.

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    Ling, Sunbin; Xie, Haiyang; Yang, Fan; Shan, Qiaonan; Dai, Haojiang; Zhuo, Jianyong; Wei, Xuyong; Song, Penghong; Zhou, Lin; Xu, Xiao; Zheng, Shusen

    2017-02-28

    Arsenic trioxide (ATO) is commonly used in the treatment of acute promyelocytic leukemia (APL), but does not benefit patients with solid tumors. When combined with other agents or radiation, ATO showed treatment benefits with manageable toxicity. Previously, we reported that metformin amplified the inhibitory effect of ATO on intrahepatic cholangiocarcinoma (ICC) cells more significantly than other agents. Here, we investigated the chemotherapeutic sensitization effect of metformin in ATO-based treatment in ICC in vitro and in vivo and explored the underlying mechanisms. ICC cell lines (CCLP-1, RBE, and HCCC-9810) were treated with metformin and/or ATO; the anti-proliferation effect was evaluated by cell viability, cell apoptosis, cell cycle, and intracellular-reactive oxygen species (ROS) assays. The in vivo efficacy was determined in nude mice with CCLP-1 xenografts. The active status of AMPK/p38 MAPK and mTORC1 pathways was detected by western blot. In addition, an antibody array was used screening more than 200 molecules clustered in 12 cancer-related pathways in CCLP-1 cells treated with metformin and/or ATO. Methods of genetic modulation and pharmacology were further used to demonstrate the relationship of the molecule. Seventy-three tumor samples from ICC patients were used to detect the expression of ERK3 by immunohistochemistry. The correlation between ERK3 and the clinical information of ICC patients were further analyzed. Metformin and ATO synergistically inhibited proliferation of ICC cells by promoting cell apoptosis, inducing G0/G1 cell cycle arrest, and increasing intracellular ROS. Combined treatment with metformin and ATO efficiently reduced ICC growth in an ICC xenograft model. Mechanistically, the antibody array revealed that ERK3 exhibited the highest variation in CCLP-1 cells after treatment with metformin and ATO. Results of western blot confirm that metformin and ATO cooperated to inhibit mTORC1, activate AMP-activated protein kinase (AMPK

  15. Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis.

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    Jendrek, Sebastian Torben; Gotthardt, Daniel; Nitzsche, Thomas; Widmann, Laila; Korf, Tobias; Michaels, Maike Anna; Weiss, Karl-Heinz; Liaskou, Evaggelia; Vesterhus, Mette; Karlsen, Tom Hemming; Mindorf, Swantje; Schemmer, Peter; Bär, Florian; Teegen, Bianca; Schröder, Torsten; Ehlers, Marc; Hammers, Christoph Matthias; Komorowski, Lars; Lehnert, Hendrik; Fellermann, Klaus; Derer, Stefanie; Hov, Johannes Roksund; Sina, Christian

    2017-01-01

    Pancreatic autoantibodies (PABs), comprising antibodies against glycoprotein 2 (anti-GP2), are typically associated with complicated phenotypes in Crohn's disease, but have also been observed with variable frequencies in patients with UC. In a previous study, we observed a high frequency of primary sclerosing cholangitis (PSC) in patients with anti-GP2-positive UC. We therefore aimed to characterise the role of anti-GP2 in PSC. In an evaluation phase, sera from 138 well-characterised Norwegian patients with PSC were compared with healthy controls (n=52), and patients with UC without PSC (n=62) for the presence of PABs by indirect immunofluorescence. Further, 180 German patients with PSC served as a validation cohort together with 56 cases of cholangiocarcinoma without PSC, 20 of secondary sclerosing cholangitis (SSC) and 18 of autoimmune hepatitis. Anti-GP2 IgA specifically occurred at considerable rates in large bile duct diseases (cholangiocarcinoma=36%, PSC and SSC about 50%). In PSC, anti-GP2 IgA consistently identified patients with poor survival during follow-up (Norwegian/German cohort: p Log Rank=0.016/0.018). Anti-GP2 IgA was associated with the development of cholangiocarcinoma in both PSC cohorts, yielding an overall OR of cholangiocarcinoma in patients with anti-GP2 IgA-positive PSC of 5.0 (p=0.001). Importantly, this association remained independent of disease duration, bilirubin level and age. Anti-GP2 IgA can be hypothesised as a novel marker in large bile duct diseases. In particular, in PSC, anti-GP2 IgA identified a subgroup of patients with severe phenotype and poor survival due to cholangiocarcinoma. Anti-GP2 IgA may therefore be a clinically valuable tool for risk stratification in PSC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  16. Development of a Health Education Modification Program Regarding Liver Flukes and Cholangiocarcinoma in High Risk Areas of Nakhon Ratchasima Province Using Self-Efficacy and Motivation Theory.

    Science.gov (United States)

    Kaewpitoon, Soraya J; Rujirakul, Ratana; Wakkuwattapong, Parichart; Benjaoran, Fuangfa; Norkaew, Jun; Kujapun, Jirawoot; Ponphimai, Sukanya; Chavenkun, Wasugree; Kompor, Porntip; Padchasuwan, Natnapa; Kaewpitoon, Natthawut

    2016-01-01

    A quasi-experimental study was conducted to develop a health education modification program based on self-efficacy and motivation regarding liver flukes and cholangiocarcinoma development in Keang Sanam Nang district, Nakhon Ratchasima province, Thailand. A total of 36 individuals were invited to participate in the program and were screened for population at risk of liver fluke infection and cholangiocarcinoma using SUT-OV-001 and SUT-CCA-001. Development of health education modification program regarding liver fluke and cholangiocarcinoma prevention included 3 steps: (1) preparation, (2) health education program, and (3) follow-up and evaluation. The study was implemented for 10 weeks. Pre-and-post-test knowledge was measured with questionnaires, Kuder-Richardson-20: KR-20 = 0.718,and Cronbach's Alpha Coefficient = 0.724 and 0.716 for perception and outcome expectation questionnaires. Paired and independent t-tests were applied for data analysis. The majority of the participants were female (55.6%), aged between ≤50 and 60 years old (36.1%), married (86.1%), education level of primary school (63.9%), agricultural occupation (80.6%), and income education program, the experimental group had a mean score of knowledge, perception, and outcome expectation regarding liver fluke and cholangiocarcinoma prevention significantly higher than before participation and in the control group. In conclusion, this successful health education modification program for liver fluke and cholangiocarcinoma, therefore may useful for further work behavior modification in other epidemic areas.

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

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    Yang GW

    2015-05-01

    Full Text Available Guo-Wei Yang,* Qing Zhao,* Sheng Qian, Liang Zhu, Xu-Dong Qu, Wei Zhang, Zhi-Ping Yan, Jie-Min Cheng, Qing-Xin Liu, Rong Liu, Jian-Hua Wang Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work 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

  18. Factors Associated with Diffusely Increased Splenic F-18 FDG Uptake in Patients with Cholangiocarcinoma

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    Kim, Keunyoung; Kim, Seongjang; Kim, Injoo; Kim, Dong Uk; Kim, Heeyoung; Kim, Sojung; Ahn, Sang Hyun [Pusan National Univ. Hospital, Busan (Korea, Republic of)

    2014-06-15

    Although diffuse splenic {sup 18}F-fluorodeoxyglucose (F-18 FDG) uptake exceeding hepatic activity, is considered abnormal, its clinical significance is rarely discussed in the literature. The aim of this study was to determine the contributing factors causing diffusely increased splenic FDG uptake in patients with cholangiocarcinoma. From January 2010 to March 2013, 140 patients (84 men, 56 women) were enrolled in this study. All patients had been diagnosed with cholangiocarcinoma and underwent F-18 FDG positron emission tomography/computed tomography (PET/CT) for the pretreatment staging work up. Clinical records were reviewed retrospectively. Various hematological parameters, C-reactive protein (CRP) level, CEA, CA19-9, pancreatic enzymes and liver function tests were conducted within 2 days after the F-18 FDG PET/CT study. Diffuse splenic uptake was observed in 23 patients (16.4%). Of those, 19 patients (82.6%) underwent endoscopic retrograde cholangiopancreastography (ERCP) 7 days before F-18 FDG PET/CT. The CRP level (p <0.001) and white blood cell count (p =0.023) were significantly higher in the group of patients with diffuse splenic FDG uptake. The hemoglobin (p <0.001) and the hematocrit (p <0.001) were significantly lower in patients with diffuse splenic FDG uptake. Pancreatic enzymes, liver function test results, and tumor markers were not significantly different between the patients who did or did not have diffusely increased splenic FDG uptake. The significant factors for diffuse splenic F-18 FDG uptake exceeding hepatic F-18 FDG uptake on multivariate analysis included: performing ERCP before F-18 FDG PET-CT (odds ratio [OR], 77.510; 95% CI, 7.624-132.105), and the presence of leukocytosis (OR, 12.436; 95% CI, 2.438-63.445) or anemia (OR, 1.211; 95% CI, 1.051-1.871). In conclusion, our study demonstrated that concurrent inflammation could be associated with diffusely increased splenic FDG uptake. We suggest that performing ERCP before F-18 FDG PET

  19. Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models

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    Plengsuriyakarn Tullayakorn

    2012-03-01

    Full Text Available Abstract Background Chemotherapy of cholangiocarcinoma (CCA, a devastating cancer with increasing worldwide incidence and mortality rates, is largely ineffective. The discovery and development of effective chemotherapeutics is urgently needed. Methods/Design The study aimed at evaluating anticancer activities, toxicity, and pharmacological activities of the curcumin compound (CUR, the crude ethanolic extracts of rhizomes of Zingiber officinale Roscoe (Ginger: ZO and Atractylodes lancea thung. DC (Khod-Kha-Mao: AL, fruits of Piper chaba Hunt. (De-Plee: PC, and Pra-Sa-Prao-Yhai formulation (a mixture of parts of 18 Thai medicinal plants: PPF were investigated in animal models. Anti-cholangiocarcinoma (anti-CCA was assessed using CCA-xenograft nude mouse model. The antihypertensive, analgesic, anti-inflammatory, antipyretic, and anti-ulcer activities and effects on motor coordination were investigated using Rota-rod test, CODA tail-cuff system, writhing and hot plate tests, carrageenan-induced paw edema test, brewer's yeast test, and alcohol-induced gastric ulcer test, respectively. Acute and subacute toxicity tests were performed according to the OECD guideline for testing of chemicals with modification. Results Promising anticancer activity against CCA in nude mouse xenograft model was shown for the ethanolic extract of AL at all oral dose levels (1000, 3000, and 5000 mg/kg body weight as well as the extracts of ZO, PPF, and CUR compound at the highest dose level (5000, 4000, and 5000 mg/kg body weight, respectively. PC produced no significant anti-CCA activity. Results from acute and subacute toxicity tests both in mice and rats indicate safety profiles of all the test materials in a broad range of dose levels. No significant toxicity except stomach irritation and general CNS depressant signs were observed. Investigation of pharmacological activities of the test materials revealed promising anti-inflammatory (ZO, PPF, and AL, analgesic (CUR and

  20. Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis.

    Science.gov (United States)

    Han, Yuyan; Onori, Paolo; Meng, Fanyin; DeMorrow, Sharon; Venter, Julie; Francis, Heather; Franchitto, Antonio; Ray, Debolina; Kennedy, Lindsey; Greene, John; Renzi, Anastasia; Mancinelli, Romina; Gaudio, Eugenio; Glaser, Shannon; Alpini, Gianfranco

    2014-11-01

    Biliary hyperplasia and liver fibrosis are common features in cholestatic liver disease. Melatonin is synthesized by the pineal gland as well as the liver. Melatonin inhibits biliary hyperplasia of bile duct-ligated (BDL) rats. Since melatonin synthesis (by the enzyme serotonin N-acetyltransferase, AANAT) from the pineal gland increases after dark exposure, we hypothesized that biliary hyperplasia and liver fibrosis are diminished by continuous darkness via increased melatonin synthesis from the pineal gland. Normal or BDL rats (immediately after surgery) were housed with light-dark cycles or complete dark for 1 wk before evaluation of 1) the expression of AANAT in the pineal gland and melatonin levels in pineal gland tissue supernatants and serum; 2) biliary proliferation and intrahepatic bile duct mass, liver histology, and serum chemistry; 3) secretin-stimulated ductal secretion (functional index of biliary growth); 4) collagen deposition, liver fibrosis markers in liver sections, total liver, and cholangiocytes; and 5) expression of clock genes in cholangiocytes. In BDL rats exposed to dark there was 1) enhanced AANAT expression/melatonin secretion in pineal gland and melatonin serum levels; 2) improved liver morphology, serum chemistry and decreased biliary proliferation and secretin-stimulated choleresis; and 4) decreased fibrosis and expression of fibrosis markers in liver sections, total liver and cholangiocytes and reduced biliary expression of the clock genes PER1, BMAL1, CLOCK, and Cry1. Thus prolonged dark exposure may be a beneficial noninvasive therapeutic approach for the management of biliary disorders.

  1. Quantification of pancreatic exocrine function with secretin-enhanced magnetic resonance cholangiopancreatography: normal values and short-term effects of pancreatic duct drainage procedures in chronic pancreatitis. Initial results

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    Bali, M.A.; Sztantics, A.; Metens, T.; Matos, C. [Universite Libre de Bruxelles, Department of Radiology, Hopital Erasme, Brussels (Belgium); Arvanitakis, M.; Delhaye, M.; Deviere, J. [Universite Libre de Bruxelles, Department of Gastroenterology, Hopital Erasme, Brussels (Belgium)

    2005-10-01

    The aim of this study was to quantify pancreatic exocrine function in normal subjects and in patients with chronic pancreatitis (CP) before and after pancreatic duct drainage procedures (PDDP) with dynamic secretin-enhanced magnetic resonance (MR) cholangiopancreatography (S-MRCP). Pancreatic exocrine secretions [quantified by pancreatic flow output (PFO) and total excreted volume (TEV)] were quantified twice in ten healthy volunteers and before and after treatment in 20 CP patients (18 classified as severe, one as moderate, and one as mild according to the Cambridge classification). PFO and TEV were derived from a linear regression between MR-calculated volumes and time. In all subjects, pancreatic exocrine fluid volume initially increased linearly with time during secretin stimulation. In controls, the mean PFO and TEV were 6.8 ml/min and 97 ml; intra-individual deviations were 0.8 ml/min and 16 ml. In 10/20 patients with impaired exocrine secretions before treatment, a significant increase of PFO and TEV was observed after treatment (P<0.05); 3/20 patients presented post-procedural acute pancreatitis and a reduced PFO. The S-MRCP quantification method used in the present study is reproducible and provides normal values for PFO and TEV in the range of those obtained from previous published intubation studies. The initial results in CP patients have demonstrated non-invasively a significant short-term improvement of PFO and TEV after PDDP. (orig.)

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

    Science.gov (United States)

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

    2016-04-01

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

  3. A case of autoimmune cholangitis misdiagnosed for cholangiocarcinoma: How to avoid unnecessary surgical intervention?

    Directory of Open Access Journals (Sweden)

    Ignjatović Igor I.

    2015-01-01

    Full Text Available Introduction. Autoimmune cholangitis or immunoglobulin G4-associated cholangitis (IAC has been recently regarded as a new clinical and histopathological entity and is a part of a complex autoimmune disorder - IgG4-related systemic disease (ISD. ISD is an autoimmune disease with multi-organic involvement, characterized with IgG4-positive plasmocytic infiltration of various tissues and organs with a consequent sclerosis, which responds well to steroid therapy. Most commonly affected organs are the pancreas (autoimmune pancreatitis, [AIP] and the common bile duct (IAC. IAC and cholangiocarcinoma (CCA share many clinical, laboratory and imaging findings. Case Outline. We present a case of a 60-year-old male with a biliary stricture of a common bile duct, which was clinically considered as a bile duct carcinoma and treated surgically. Definite histopathological findings and immunohistochemistry revealed profound chronic inflammation, showing lymphoplasmacytic IgG-positive infiltration of a resected part of a common bile duct, highly suggestive for the diagnosis of IAC. In addition, postoperative IgG4 serum levels were also increased. Conclusion. It is of primary clinical importance to make a difference between IAC and CCA, in order to avoid unnecessary surgical intervention. Therefore, IAC should be considered in differential diagnosis in similar cases.

  4. A Case of Autoimmune Cholangitis Misdiagnosed for Cholangiocarcinoma: How to Avoid Unnecessary Surgical Intervention?

    Science.gov (United States)

    Ignjatović, Igor I; Matić, Slavko V; Dugalić, Vladimir D; Knežević, Djordje M; Micev, Marjan T; Marko D Bogdanović; Knežević, Srbislav M

    2015-01-01

    Autoimmune cholangitis or immunoglobulin G4-associated cholangitis (IAC) has been recently regarded as a new clinical and histopathological entity and is a part of a complex autoimmune disorder--IgG4-related systemic disease (ISD). ISD is an autoimmune disease with multi-organic involvement, characterized with IgG4-positive plasmocytic infiltration of various tissues and organs with a consequent sclerosis, which responds well to steroid therapy. Most commonly affected organs are the pancreas (autoimmune pancreatitis, [AIP]) and the common bile duct (IAC). IAC and cholangiocarcinoma (CCA) share many clinical, laboratory and imaging findings. We present a case of a 60-year-old male with a biliary stricture of a common bile duct, which was clinically considered as a bile duct carcinoma and treated surgically. Definite histopathological findings and immunohistochemistry revealed profound chronic inflammation, showing lymphoplasmacytic IgG-positive infiltration of a resected part of a common bile duct, highly suggestive for the diagnosis of IAC. In addition, postoperative IgG4 serum levels were also increased. It is of primary clinical importance to make a difference between IAC and CCA, in order to avoid unnecessary surgical intervention. Therefore, IAC should be considered in differential diagnosis in similar cases.

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

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    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 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 6(th) and 7(th) 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. The new staging system based on clinicopathologic features may provide relatively higher accuracy in prognostic prediction for ICC patients after tumor resection.

  6. [Investigation of hepatitis B virus integration sites in hilar cholangiocarcinoma tissues].

    Science.gov (United States)

    Qu, Zhen-liang; Cui, Nai-qiang; Xi, Zhao-hua; Du, Zhi

    2011-08-01

    To study the phenomena of hepatitis B virus (HBV) integration into the tissues of hilar cholangiocarcinoma (HCCA) and to identify the integration sites in the host genome. Ten fresh HCCA samples were collected from the tissues by surgical ablation, 1 normal hilar bile duct sample selected as control. Cellular DNA were extracted by Wizard SV Genomic DNA Purification System. PCR-derived assay (HBV-Alu-PCR) was employed to amplify the viral-host junctions which contain the HBV sequence and the adjacent cellular flanking sequences. The PCR products were purified and subjected to sequencing by ABI-3730XL Auto DNA Analyzer. The sequence analysis of viral-host junctions was performed by DNASIS MAX 3.0 bioinformatics software. The insertion sites between viral and cellular sequences were identified through homology comparison using NCBI BLAST and MapViewer search. In 10 HCCA samples, 5 were demonstrated to have HBV integration fragments with total 6 inserted sites identified. Sequence analysis from viral-host junction showed that HBV X gene inserted into host genome at random distribution with truncated fragments. HBV integration recurrently targeted the unknown region in upstream of CXXC finger protein-1 (CpG-binding protein) gene (4 cases). p53 tumor suppressor gene was also found at the integration site. There is high integration rate of HBV DNA into cellular genome of HCCA. HBV integration is found frequently into or close to cancer-related genes. The findings demonstrate that HBV infection might have association with the pathogenesis of HCCA.

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

    Science.gov (United States)

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

    2014-11-01

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

  8. C-11 Choline and FDG PET/CT Imaging of Primary Cholangiocarcinoma – a Comparative Analysis

    Directory of Open Access Journals (Sweden)

    Chanisa Chotipanich

    2015-01-01

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

  9. Intrahepatic mass-forming cholangiocarcinoma: prognostic value of preoperative gadoxetic acid-enhanced MRI

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    Koh, Jieun; Chung, Yong Eun; Kim, Myeong-Jin; Choi, Jin-Young [Yonsei University, College of Medicine, Department of Radiology, Research Institute of Radiological Science, Seoul (Korea, Republic of); Nahm, Ji Hae; Park, Young Nyun [Yonsei University, College of Medicine, Department of Pathology, Seoul (Korea, Republic of); Kim, Ha Yan [Yonsei University, College of Medicine, Biostatistics Collaboration Unit, Severance Hospital, Seoul (Korea, Republic of); Kim, Kyung-Sik [Yonsei University, College of Medicine, Department of General Surgery, Seoul (Korea, Republic of)

    2016-02-15

    To assess whether gadoxetic acid-enhanced MRI could be used as a prognostic factor for intrahepatic mass-forming cholangiocarcinomas (IMCCs). Forty-one patients with pathologically proven IMCCs who underwent preoperative gadoxetic acid-enhanced MRI were included. The signal intensity of the IMCCs on hepatobiliary phase (HBP) MRI was qualitatively analyzed by two radiologists, and categorized into intermediate or hypointense groups. Analysis of clinicopathological prognostic factors and correlations of imaging and histology were also performed. Survival time and time to recurrence (TTR) were analyzed. Of the 41 IMCCs, 23 were in the intermediate group and 18 were in the hypointense group on HBP MRI. IMCCs in the intermediate group were associated with shorter survival time (P = 0.048) and TTR (P = 0.002) than the IMCCs of the hypointense group. Only the intermediate group on HBP MRI had a significantly shorter TTR on multivariate analysis (P = 0.012). The IMCCs of the intermediate group showed a tendency for more abundant tumour fibrous stroma than those of the hypointense group (P = 0.027). The enhancement of IMCCs on HBP gadoxetic acid-enhanced MRI appears to correlate with tumour aggressiveness and outcomes due to the tumour fibrous stromal component. Thus, HBP images could be a useful prognostic factor for IMCCs after surgery. (orig.)

  10. Oriental cholangiohepatitis masquerading as cholangiocarcinoma: A rare presentation that surgeons need to know.

    Science.gov (United States)

    Singla, Smit; Warner, Anne H; Jain, Ashokkumar; Thomas, Rebecca M; Karachristos, Andreas

    2012-01-01

    The detection of an abnormal hepatic mass with ductal dilatation is highly concerning for malignancy. However, if such patients happen to be immigrants from endemic parts of Asia or South America, further investigations are necessary to rule out oriental cholangiohepatitis, a rare recurrent disease of the hepatobiliary system that can masquerade as cholangiocarcinoma. We report a case of a patient of South Asian origin who presented to us with acute cholangitis and moderately dilated left hepatic ducts. The findings were highly suspicious for advanced hepatic malignancy; however the laboratory and pathological investigations remained normal. We suspected an unlikely etiology and proceeded with conservative hepatic resection. The histology revealed cholangiohepatitis without any evidence of malignancy. Cholangiohepatitis is a complex hepatobiliary disease that commonly manifests as recurrent cholangitis or overt biliary sepsis and can rarely present as an abnormal hepatic mass. It results from the development of intrahepatic or extrahepatic strictures that causes stone formation and biliary dilation in the absence of gallbladder disease. Although it is endemic in many parts of the world, it is rare in the western world, and therefore it can present as a significant diagnostic enigma. Cholangiohepatitis is a rare clinical entity that requires a multi-disciplinary team approach. Surgery plays a dominant role in the management of such patients and therefore surgeons need to be aware of this disease. Copyright © 2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

  11. Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine?

    Science.gov (United States)

    Kumar, Mia; Zhao, Xuelian; Wang, Xin Wei

    2011-01-24

    Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine.

  12. Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine?

    Directory of Open Access Journals (Sweden)

    Kumar Mia

    2011-01-01

    Full Text Available Abstract Hepatocellular carcinoma (HCC and intrahepatic cholangiocarcinoma (ICC are the two major forms of primary liver cancers (PLC, accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine.

  13. Hepatitis viruses infection and risk of intrahepatic cholangiocarcinoma: evidence from a meta-analysis

    Directory of Open Access Journals (Sweden)

    Zhou Yanming

    2012-07-01

    Full Text Available Abstract Background Studies investigating the association between Hepatitis B virus (HBV and hepatitis C virus (HCV infections and intrahepatic cholangiocarcinoma (ICC have reported inconsistent findings. We conducted a meta-analysis of epidemiological studies to explore this relationship. Methods A comprehensive search was conducted to identify the eligible studies of hepatitis infections and ICC risk up to September 2011. Summary odds ratios (OR with their 95% confidence intervals (95% CI were calculated with random-effects models using Review Manager version 5.0. Results Thirteen case–control studies and 3 cohort studies were included in the final analysis. The combined risk estimate of all studies showed statistically significant increased risk of ICC incidence with HBV and HCV infection (OR = 3.17, 95% CI, 1.88-5.34, and OR = 3.42, 95% CI, 1.96-5.99, respectively. For case–control studies alone, the combined OR of infection with HBV and HCV were 2.86 (95% CI, 1.60-5.11 and 3.63 (95% CI, 1.86-7.05, respectively, and for cohort studies alone, the OR of HBV and HCV infection were 5.39 (95% CI, 2.34-12.44 and 2.60 (95% CI, 1.36-4.97, respectively. Conclusions This study suggests that both HBV and HCV infection are associated with an increased risk of ICC.

  14. Radiological diagnosis and intervention of cholangiocarcinomas (CC); Radiologische Diagnostik und Intervention von Cholangiokarzinomen (CC)

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    Vogl, T.J.; Zangos, S.; Eichler, K.; Gruber-Rouh, T.; Hammerstingl, R.M.; Weisser, P. [Frankfurt Univ. (Germany). Inst. fuer Diagnostische und Interventionelle Radiologie; Trojan, J. [Frankfurt Univ. (Germany). Medizinische Klinik I: Gastroenterologie, Endokrinologie, Pneumologie/Allergologie

    2012-10-15

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

  15. Histopathological evidence of neoplastic progression of von Meyenburg complex to intrahepatic cholangiocarcinoma.

    Science.gov (United States)

    Bhalla, Amarpreet; Mann, Steven A; Chen, Shaoxiong; Cummings, Oscar W; Lin, Jingmei

    2017-09-01

    Von Meyenburg complex (VMC) is generally thought to be benign, although its preneoplastic potential for intrahepatic cholangiocarcinoma (iCC) has been a subject of contention. We retrospectively reviewed 86 hepatectomy specimens with a diagnosis of iCC. Morphologically, an association between iCC and VMC was appreciated in 35% of cases that illustrated a gradual neoplastic progression from benign VMC to dysplasia and then to iCC. Among them, 24 cases had VMC lined by epithelial cells with low-grade biliary dysplasia and 13 with high-grade biliary dysplasia. VMC-associated iCCs were smaller in size and well to moderately differentiated, with features of anastomosing glandular architecture, ductal carcinoma in situ-like growth pattern, peritumoral lymphocytic infiltrate, central fibrous scar, and complete pushing border. They often presented as T1 tumors. In contrast, non-VMC-associated iCCs were moderately to poorly differentiated with solid, cribriform or papillary growth patterns. They likely exhibited necrosis, perineural invasion, positive surgical margin, lymphovascular invasion, and high T stage. Additionally, Ki67 and p53 immunostains support the continuing neoplastic evolution from benign VMC to dysplasia and then to iCC. VMC could become neoplastic, serving as an in situ carcinoma lesion to transform to iCC. The underlying molecular alteration and clinical implication of this neoplastic transformation deserves further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Cellular and stromal characteristics in the scirrhous hepatocellular carcinoma: comparison with hepatocellular carcinomas and intrahepatic cholangiocarcinomas.

    Science.gov (United States)

    Okamura, Nobuyoshi; Yoshida, Muneki; Shibuya, Akitaka; Sugiura, Hitoshi; Okayasu, Isao; Ohbu, Makoto

    2005-11-01

    Scirrhous hepatocellular carcinoma (SHCC) is a rare variation of HCC, for which characteristics of tumor cells and the fibrotic stroma have not been clarified in detail. The present study was therefore carried out to elucidate cytological features of tumor and stromal cells and components of the stromal extracellular matrix in 15 SHCC patients undergoing hepatectomy without preoperative transarterial embolization. Diagnosis was on the basis of a scirrhous histological pattern exceeding 50% of the tumor area. Expression of cytoplasmic and extracellular matrix proteins was compared among SHCC, HCC and intrahepatic cholangiocarcinoma (ICC) cases with immunohistochemical staining. The lesions could be histologically divided into radiating and sinusoidal types. Common stromal components of SHCC and ICC were collagen types I and III. There was no expression of laminin-5 in the stroma of SHCC, but it was present in almost all ICC cases. Tenascin-C expression was significantly lower in the SHCC cases and its distribution differed between SHCC and ICC. Matrix metalloproteinase-7 (MMP-7) expression was significantly higher in SHCC compared with HCC. Almost all stromal cells were alpha-smooth muscle actin-positive both in SHCC and ICC, whereas glial fibrillary acid protein (GFAP)-positive stromal cells were significantly more increased in ICC than in SHCC. SHCC clearly differed from HCC with respect to collagen types I, III and MMP-7 expression, and from ICC with regard to stromal components including laminin-5, tenascin-C and GFAP(+) stromal cells.

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

    Science.gov (United States)

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

    2015-01-01

    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. 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. 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. 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.

  18. Adjuvant Gemcitabine-Oxaliplatin (GEMOX) after Curative Surgery in High-risk Patients with Cholangiocarcinoma

    Science.gov (United States)

    Paule, Bernard; Andreani, Paola; Bralet, Marie-Pierre; Guettier, Catherine; Adam, René; Castaing, Denis; Azoulay, Daniel

    2009-01-01

    Background: There is no standard adjuvant chemotherapy to prevent recurrent cholangiocarcinoma (CCA), a rare cancer with poor prognosis. We assessed the efficacy and safety of GEMOX on intrahepatic and hilar CCA with high-risk factors after curative surgery. Patients and Methods: Twenty two patients (mean age: 57 years old) with CCA received 6 cycles of GEMOX: gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2, q3w after a curative surgery. Results: All patients completed 6 cycles of GEMOX. EGFR membranous expression was present in 20 CCA. The 5-year survival rate was 56% (CI 95%: 25.7–85.4); 2-year disease free survival rate was 28% (CI 95%: 3.4–52.6). Median time to progression was 15 months. The rate of recurrence after surgery and chemotherapy was 63% (14/22). Two patients died of disease progression. Twelve patients received cetuximab/GEMOX at the time of relapse. Six died after 12 months (9–48 months), three are still alive suggesting a clinical applicability of EGFR inhibitors in CCA. Conclusion: Adjuvant chemotherapy with GEMOX alone seems ineffective in intrahepatic and hilar CCA with a high risk of relapse. Additional studies including targeted therapies to circumvent such poor chemosensitivity are needed.

  19. A comparison of trends in mortality from primary liver cancer and intrahepatic cholangiocarcinoma in Europe.

    Science.gov (United States)

    Bertuccio, P; Bosetti, C; Levi, F; Decarli, A; Negri, E; La Vecchia, C

    2013-06-01

    To update and compare mortality from primary liver cancer (PLC) and intrahepatic cholangiocarcinoma (ICC) in Europe in 1990-2010. We used data from the World Health Organization (WHO) to compute age-standardized (world population) mortality rates, and used joinpoint analysis to identify substantial changes. Between 2002 and 2007, PLC rates in the European Union (EU) declined from 3.9 to 3.6/100,000 men. Around 2007, the highest male rates were in France (6.2/100,000), Spain (4.9), and Italy (4.0), while the lowest ones were in Sweden (1.1), the Netherlands (1.2), and the UK (1.8). In women, mortality was lower (0.8/100,000 in 2007 in the EU), and showed more favourable trends, with a decline of over 2% per year over the last two decades as compared with 0.4% in men, in the EU. In contrast, the EU mortality from ICC increased by around 9% in both sexes from 1990 to 2008, reaching rates of 1.1/100,000 men and 0.75/100,000 women. The highest rates were in UK, Germany, and France (1.2-1.5/100,000 men, 0.8-1.1/100,000 women). PLC mortality has become more uniform across Europe over recent years, with an overall decline; in contrast, ICC mortality has substantially increased in most Europe.

  20. Prognostic significance of contrast-enhanced CT attenuation value in extrahepatic cholangiocarcinoma

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    Asayama, Yoshiki [Kyushu University, Department of Advanced Imaging and Interventional Radiology, Graduate School of Medical Sciences, Fukuoka (Japan); Nishie, Akihiro; Ishigami, Kousei; Ushijima, Yasuhiro; Takayama, Yukihisa; Okamoto, Daisuke; Fujita, Nobuhiro; Honda, Hiroshi [Kyushu University, Departments of Clinical Radiology, Fukuoka (Japan); Ohtsuka, Takao [Kyushu University, Departments of Surgery and Oncology, Fukuoka (Japan); Yoshizumi, Tomoharu [Kyushu University, Departments of Surgery and Sciences, Fukuoka (Japan); Aishima, Shinichi [Saga University, Pathology and Microbiology, Faculty of Medicine, Saga (Japan); Kyushu University, Departments of Anatomic Pathology, Graduate School of Medical Sciences, Fukuoka (Japan); Oda, Yoshinao [Kyushu University, Departments of Anatomic Pathology, Graduate School of Medical Sciences, Fukuoka (Japan)

    2017-06-15

    To determine whether washout characteristics of dynamic contrast-enhanced computed tomography (CT) could predict survival in patients with extrahepatic cholangiocarcinoma (EHC). This study collected 46 resected cases. All cases were examined by dynamic contrast study on multidetector-row CT. Region-of-interest measurements were obtained at the non-enhanced, portal venous phase and delayed phase in the tumour and were used to calculate the washout ratio as follows: [(attenuation value at portal venous phase CT - attenuation value at delayed enhanced CT)/(attenuation value at portal venous phase CT - attenuation value at unenhanced CT)] x 100. On the basis of the median washout ratio, we classified the cases into two groups, a high-washout group and low-washout group. Associations between overall survival and various factors including washout rates were analysed. The median washout ratio was 29.4 %. Univariate analysis revealed that a lower washout ratio, venous invasion, lymphatic permeation and lymph node metastasis were associated with shorter survival. Multivariate analysis identified the lower washout ratio as an independent prognostic factor (hazard ratio, 3.768; p value, 0.027). The washout ratio obtained from the contrast-enhanced CT may be a useful imaging biomarker for the prediction of survival of patients with EHC. (orig.)

  1. Comparative secretome analysis of cholangiocarcinoma cell line in three-dimensional culture.

    Science.gov (United States)

    Tit-Oon, Phanthakarn; Chokchaichamnankit, Daranee; Khongmanee, Amnart; Sawangareetrakul, Phannee; Svasti, Jisnuson; Srisomsap, Chantragan

    2014-11-01

    Cholangiocarcinoma (CCA) is a lethal malignancy which occurs with relatively high incidence in Thailand. This cancer is often difficult to diagnose and associated with high mortality. The secretome, containing the secreted proteins from cells, are potentially useful as biomarkers of cancers. Since three-dimensional (3D) cell culture may mimic growth characteristics and microenvironment of solid tumors in vivo better than monolayer culture, we have developed culture of CCA in natural collagen-based scaffold, to enable analysis of the secretome by 2DE. Our results indicated that CCA growth in 3D environment alters cell shape significantly and enhances extracellular matrix deposition. Interestingly, more secreted proteins were detected from 3D culture compared to monolayer culture. Secretome analysis using 2DE coupled with LC-MS/MS demonstrated 10 secreted proteins uniquely found in 3D culture. Moreover, 25 proteins were enriched in 3D culture compared to monolayer culture, including 14-3-3 σ, triosephosphate isomerase, phosphoglycerate mutase 1, α-enolase, and L-plastin. Immunoblotting was used to confirm the presence of L-plastin in conditioned media of CCA and of hepatocellular carcinoma (HCC) cell lines. The results revealed that L-plastin, an actin bundling protein, was uniquely expressed only in the CCA cell line and could be a promising biomarker for differential diagnosis of CCA compared to HCC.

  2. Identification of transcription factors (TFs) and targets involved in the cholangiocarcinoma (CCA) by integrated analysis.

    Science.gov (United States)

    Yang, L; Feng, S; Yang, Y

    2016-12-01

    The present study was designed to investigate the upstream transcription factors (TFs) and the signature genes in cholangiocarcinoma (CCA), providing better clues on the regulatory mechanisms and therapeutic applications. Gene expression data sets of CCA were searched in the Gene Expression Omnibus database for integrated analysis. Functional annotation of differently expressed genes (DEGs) was then conducted and the TFs were identified. Moreover, a global transcriptional regulatory network of TFs-targets was constructed. Integrated analysis of five eligible Gene Expression Omnibus data sets led to a set of 993 DEGs and 48 TFs in CCA. The constructed TFs-targets regulatory network consisted of 697 TF-target interactions between 41 TFs and 436 DEGs. The top 10 TFs covering the most downstream DEGs were NFATC2, SOX10, ARID3A, ZNF263, NR4A2, GATA3, EGR1, PLAG1, STAT3 and FOSL1, which may have important roles in the tumorigenesis of CCA. Supporting the fact that defects of cell-cycle surveillance mechanism were closely related to various cancers, we found that cell cycle was the most significantly enriched pathway. KCNN2 and ADCY6 were involved in the bile secretion. Thus, their aberrant expression may be closely related to the pathogenesis of CCA. Particularly, we found that upregulation of EZH2 in CCA is a powerful potential marker for CCA.

  3. Genetic Abnormalities in Biliary Brush Samples for Distinguishing Cholangiocarcinoma from Benign Strictures in Primary Sclerosing Cholangitis

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    Margriet R. Timmer

    2016-01-01

    Full Text Available Background. Primary sclerosing cholangitis (PSC is a chronic inflammatory liver disease and is strongly associated with cholangiocarcinoma (CCA. The lack of efficient diagnostic methods for CCA is a major problem. Testing for genetic abnormalities may increase the diagnostic value of cytology. Methods. We assessed genetic abnormalities for CDKN2A, TP53, ERBB2, 20q, MYC, and chromosomes 7 and 17 and measures of genetic clonal diversity in brush samples from 29 PSC patients with benign biliary strictures and 12 patients with sporadic CCA or PSC-associated CCA. Diagnostic performance of cytology alone and in combination with genetic markers was evaluated by sensitivity, specificity, and area under the curve analysis. Results. The presence of MYC gain and CDKN2A loss as well as a higher clonal diversity was significantly associated with malignancy. MYC gain increased the sensitivity of cytology from 50% to 83%. However, the specificity decreased from 97% to 76%. The diagnostic accuracy of the best performing measures of clonal diversity was similar to the combination of cytology and MYC. Adding CDKN2A loss to the panel had no additional benefit. Conclusion. Evaluation of MYC abnormalities and measures of clonal diversity in brush cytology specimens may be of clinical value in distinguishing CCA from benign biliary strictures in PSC.

  4. Perioperative blood transfusion as a poor prognostic factor after aggressive surgical resection for hilar cholangiocarcinoma.

    Science.gov (United States)

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

    2015-05-01

    Blood transfusion is linked to a negative outcome for malignant tumors. The aim of this study was to evaluate aggressive surgical resection for hilar cholangiocarcinoma (HCCA) and assess the impact of perioperative blood transfusion on long-term survival. Sixty-six consecutive major hepatectomies with en bloc resection of the caudate lobe and extrahepatic bile duct for HCCA were performed using macroscopically curative resection at our institute from 2002 to 2012. Clinicopathologic factors for recurrence and survival were retrospectively assessed. Overall survival rates at 1, 3, and 5 years were 86.7, 47.3, and 35.7 %, respectively. In univariate analysis, perioperative blood transfusion and a histological positive margin were two of several variables found to be significant prognostic factors for recurrence or survival (Pblood transfusion was independently associated with recurrence (hazard ratio (HR)=2.839 (95 % confidence interval (CI), 1.370-5.884), P=0.005), while perioperative blood transfusion (HR=3.383 (95 % CI, 1.499-7.637), P=0.003) and R1 resection (HR=3.125 (95 % CI, 1.025-9.530), P=0.045) were independent risk factors for poor survival. Perioperative blood transfusion is a strong predictor of poor survival after radical hepatectomy for HCCA. We suggest that circumvention of perioperative blood transfusion can play an important role in long-term survival for patients with HCCA.

  5. Three-dimensional imaging identified the accessory bile duct in a patient with cholangiocarcinoma.

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    Miyamoto, Ryoichi; Oshiro, Yukio; Hashimoto, Shinji; Kohno, Keisuke; Fukunaga, Kiyoshi; Oda, Tatsuya; Ohkohchi, Nobuhiro

    2014-08-28

    The development of diagnostic imaging technology, such as multidetector computed tomography (MDCT) and magnetic resonance cholangiopancreatography (MRCP), has made it possible to obtain detailed images of the bile duct. Recent reports have indicated that a 3-dimensional (3D) reconstructed imaging system would be useful for understanding the liver anatomy before surgery. We have investigated a novel method that fuses MDCT and MRCP images. This novel system easily made it possible to detect the anatomical relationship between the vessels and bile duct in the portal hepatis. In this report, we describe a very rare case of extrahepatic cholangiocarcinoma associated with an accessory bile duct from the caudate lobe connecting with the intrapancreatic bile duct. We were unable to preoperatively detect this accessory bile duct using MDCT and MRCP. However, prior to the second operation, we were able to clearly visualise the injured accessory bile duct using our novel 3D imaging modality. In this report, we suggest that this imaging technique can be considered a novel and useful modality for understanding the anatomy of the portal hepatis, including the hilar bile duct.

  6. Clinical analysis of biliary stent placement combined with gamma-knife for the treatment of complex hilar cholangiocarcinoma

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    Zhi-qiang FENG

    2011-05-01

    Full Text Available Objective To evaluate the therapeutic effect of biliary stent placement combined with gamma-knife for the treatment of complex hilar cholangiocarcinoma.Methods Five patients with type IV hilar cholangiocarcinoma,according to Bismuth classification,combined with stenosis of distant common bile duct were treated with biliary stent placement and gamma-knife.The left intrahepatic bile duct was catheterized under the guidance of ultrasound,followed by catheterization of right intrahepatic bile duct aided by percutaneous transhepatic cholangiography for drainage(PTCD.Three biliary stents were inserted to relieve obstruction.Patients then underwent gamma-knife treatment after subsidence of jaundice,and bilirubin,followed by determination of transaminase and observation of the condition of the tumor.Results Total bilrubin,direct bilrubin and alanine transaminase of patients were 289.38±101.43μmol/L,180.42±72.50μmol/L and 148.80±82.65 U/L respectively before PTCD,and 94.2±20.43μmol/L,62.37±30.41μmol/L and 109.27±45.52 U/L,respectively,7 days after PTCD,and they declined to 27.20±14.60μmol/L,20.58±9.33μmol/L and 59.80±35.18 U/L,respectively,one month after PTCD.Five patients survived for 10,13,14,17 and 24 months,respectively.The median survival time was 15 months.Conclusion The combination of insertion of metallic stents and gamma-knife therapy is a safe and effective treatment for complex hilar cholangiocarcinoma,and this therapeutic strategy may improve survival rate and control the rate of grouth of carcinoma.

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

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    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 incorporat...

  8. Post-operative morbidity results in decreased long-term survival after resection for hilar cholangiocarcinoma

    Science.gov (United States)

    Chauhan, Aakash; House, Michael G; Pitt, Henry A; Nakeeb, Attila; Howard, Thomas J; Zyromski, Nicholas J; Schmidt, C Max; Ball, Chad G; Lillemoe, Keith D

    2011-01-01

    Background The purpose of the present study was to demonstrate that post-operative morbidity (PM) associated with resections of hilar cholangiocarcinoma (HCCA) is associated with short- and long-term patient survival. Methods Between 1998 and 2008, 51 patients with a median age of 64 years underwent resection for HCCA at a single institution. Associations between survival and clinicopathologic factors, including peri- and post-operative variables, were studied using univariate and multivariate models. Results Seventy-six per cent of patients underwent major hepatectomy with resection of the extrahepatic bile ducts. The 30- and 90-day operative mortality was 10% and 12%. The overall incidence of PM was 69%, with 68% of all PM as major (Clavien grades III–V). No difference in operative blood loss or peri-operative transfusion rates was observed for patients with major vs. minor or no PM. Patients with major PM received adjuvant chemotherapy less frequently than patients with minor or no complications 29% vs. 52%, P= 0.15. The 1-, 3- and 5-year overall (OS) and disease-specific survival (DSS) rates for all patients were 65%, 36%, 29% and 77%, 46%, 35%, respectively. Using univariate and multivariate analysis, margin status (27% R1), nodal metastasis (35% N1) and major PM were associated with OS and DSS, P operations for HCCA can produce substantial post-operative morbidity. In addition to causing early mortality, major post-operative complications are associated with decreased long-term cancer-specific survival after resection of HCCA. PMID:21241432

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

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    Borghetti Angelo F

    2006-10-01

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

  10. Intrahepatic mass-forming cholangiocarcinoma: enhancement patterns on gadoxetic acid-enhanced MR images.

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    Kang, Yusuhn; Lee, Jeong Min; Kim, Seung Ho; Han, Joon Koo; Choi, Byung Ihn

    2012-09-01

    To evaluate the enhancement patterns of intrahepatic mass-forming cholangiocarcinomas (IMCCs) with emphasis on the hepatobiliary phase (HBP) of gadoxetic acid-enhanced magnetic resonance (MR) imaging. This retrospective study was institutional review board approved, and the requirement for informed consent was waived. Fifty patients (41 men, nine women; mean age, 62.3 years; range, 44-76 years) with IMCC underwent unenhanced and gadoxetic acid-enhanced T1- and T2-weighted MR imaging including dynamic phase and hepatobiliary phase imaging between May 2008 and December 2010. Signal intensity and enhancement patterns of lesions were compared with those of the liver parenchyma in each phase. Conspicuity and margin sharpness of lesions on dynamic phase and HBP images were rated on a 4- or 5-point scale and compared by using the Wilcoxon signed-rank test. Percentage of relative enhancement was compared among pathologic subgroups by using the unpaired Student t test. On dynamic phase images, 29 of 48 (60%) lesions showed a thin peripheral rim with centripetal or gradual progression. On HBP images, 48 of 50 (96%) IMCCs were hypointense, and two of 50 (4%) were hyperintense. Subjective ratings of conspicuity and margin sharpness were significantly higher on HBP (median scores, 5 and 4, respectively) (P images (P enhancement on HBP images was significantly higher in moderately differentiated (66.4% ± 42.1) than in poorly differentiated (36.84% ± 21.5) tumors (P = .039) and in patients without (59.7% ± 28.8) than in those with (24.9% ± 14.7) (P = .036) lymph node metastasis. The most prevalent enhancement pattern on gadoxetic acid-enhanced MR images of IMCCs was a thin peripheral rim with internal heterogeneous enhancement during the dynamic phase. HBP images showed increased lesion conspicuity and better delineation of daughter nodules and intrahepatic metastasis, which may aid in the diagnosis of IMCC. © RSNA, 2012

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

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    Rafi, Shoaib; Piduru, Sarat M. [Emory University School of Medicine, Division of Interventional Radiology and Image Guided Medicine, Department of Radiology (United States); El-Rayes, Bassel; Kauh, John S. [Emory University School of Medicine, Department of Hematology and Medical Oncology (United States); Kooby, David A.; Sarmiento, Juan M. [Emory University School of Medicine, Department of Surgical Oncology in Surgery (United States); Kim, Hyun S., E-mail: kevin.kim@emory.edu [Emory University School of Medicine, Division of Interventional Radiology and Image Guided Medicine, Department of Radiology (United States)

    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.

  12. Serum microRNAs as novel biomarkers for primary sclerosing cholangitis and cholangiocarcinoma.

    Science.gov (United States)

    Bernuzzi, F; Marabita, F; Lleo, A; Carbone, M; Mirolo, M; Marzioni, M; Alpini, G; Alvaro, D; Boberg, K M; Locati, M; Torzilli, G; Rimassa, L; Piscaglia, F; He, X-S; Bowlus, C L; Yang, G-X; Gershwin, M E; Invernizzi, P

    2016-07-01

    The diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC. The levels of 667 miRNAs were evaluated in 90 human serum samples (30 PSC, 30 CC and 30 control subjects) to identify disease-associated candidate miRNAs (discovery phase). The deregulated miRNAs were validated in an independent cohort of 140 samples [40 PSC, 40 CC, 20 primary biliary cirrhosis (PBC) and 40 controls]. Receiver operating characteristic (ROC) curves were established and only miRNAs with an area under the curve (AUC) > 0·70 were considered useful as biomarkers. In the discovery phase we identified the following: 21 miRNAs expressed differentially in PSC, 33 in CC and 26 in both in comparison to control subjects as well as 24 miRNAs expressed differentially between PSC and CC. After the validation phase, miR-200c was found to be expressed differentially in PSC versus controls, whereas miR-483-5p and miR-194 showed deregulated expression in CC compared with controls. We also demonstrate a difference in the expression of miR-222 and miR-483-5p in CC versus PSC. Combination of these specific miRNAs further improved the specificity and accuracy of diagnosis. This study provides a basis for the use of miRNAs as biomarkers for the diagnosis of PSC and CC. © 2016 British Society for Immunology.

  13. Angiopoietin-2 and biliary diseases: elevated serum, but not bile levels are associated with cholangiocarcinoma.

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    Torsten Voigtländer

    Full Text Available BACKGROUND: The diagnosis of cholangiocarcinoma (CC is challenging especially in patients with primary sclerosing cholangitis (PSC and often delayed due to the lack of reliable markers. Angiopoietin-2 (Angpt-2 has been employed as a biomarker of angiogenesis and might be involved in tumor neoangiogenesis. AIM: To evaluate the diagnostic potential of Angpt-2 as a biomarker to detect patients with CC. METHODS: Bile and serum Angpt-2 levels were measured in patients with CC (n=45, PSC (n=74, CC complicating PSC (CC/PSC (n=11 and patients with bile duct stones (n=37 in a cross sectional study. Diagnostic accuracy of Angpt-2 was compared to carbohydrate antigen 19-9 (CA19-9. Fluorescent immunohistochemistry from human CC liver tissue samples was performed to localize the origin of Angpt-2. RESULTS: Serum Angpt-2 concentration was significantly elevated in patients with CC compared to control patients (p<0.05. Diagnostic accuracy of Angpt-2 as determined by receiver operating characteristic (ROC analysis resulted in a higher area under the curve (AUC value compared to CA19-9 (AUC: 0.85 versus 0.77; 95% confidence interval (CI: 0.74-0.93 versus 0.65-0.87, respectively. Angpt-2 was also detectable in bile, but was not associated with the presence of CC. Immunohistochemistry revealed a strong induction of Angpt-2 expression in the tumor vasculature. CONCLUSIONS: Circulating Angpt-2 in serum might be a promising protein candidate locally derived from the tumor vasculature in patients with CC. Measurement of Angpt-2 in serum may be useful for diagnosis and further clinical management of patients with CC.

  14. Predicting IDH mutation status of intrahepatic cholangiocarcinomas based on contrast-enhanced CT features.

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    Zhu, Yong; Chen, Jun; Kong, Weiwei; Mao, Liang; Kong, Wentao; Zhou, Qun; Zhou, Zhengyang; Zhu, Bin; Wang, Zhongqiu; He, Jian; Qiu, Yudong

    2018-01-01

    To explore the difference in contrast-enhanced computed tomography (CT) features of intrahepatic cholangiocarcinomas (ICCs) with different isocitrate dehydrogenase (IDH) mutation status. Clinicopathological and contrast-enhanced CT features of 78 patients with 78 ICCs were retrospectively analysed and compared based on IDH mutation status. There were 11 ICCs with IDH mutation (11/78, 14.1%) and 67 ICCs without IDH mutation (67/78, 85.9%). IDH-mutated ICCs showed intratumoral artery more often than IDH-wild ICCs (p = 0.023). Most ICCs with IDH mutation showed rim and internal enhancement (10/11, 90.9%), while ICCs without IDH mutation often appeared diffuse (26/67, 38.8%) or with no enhancement (4/67, 6.0%) in the arterial phase (p = 0.009). IDH-mutated ICCs showed significantly higher CT values, enhancement degrees and enhancement ratios in arterial and portal venous phases than IDH-wild ICCs (all p IDH mutation, with an area under the curve of 0.798 (p = 0.002). ICCs with and without IDH mutation differed significantly in arterial enhancement mode, and the tumour enhancement degree on multiphase contrast-enhanced CT was helpful in predicting IDH mutation status. • IDH mutation occurred frequently in ICCs. • ICCs with and without IDH mutation differed significantly in arterial enhancement mode. • ICCs with IDH mutation enhanced more than those without IDH mutation. • Enhancement ratio and tumour CT value can predict IDH mutation status.

  15. Safety and feasibility of endoscopic biliary radiofrequency ablation treatment of extrahepatic cholangiocarcinoma.

    Science.gov (United States)

    Laquière, A; Boustière, C; Leblanc, S; Penaranda, G; Désilets, E; Prat, F

    2016-03-01

    Biliary bipolar radiofrequency ablation (RFA) is a new treatment for extrahepatic cholangiocarcinoma (CCA) currently under evaluation. The purpose of this study was to evaluate the safety, particularly biliary fistula occurrence, and the feasibility of biliary RFA in a homogeneous group of patients treated using the same RFA protocol. Twelve patients with inoperable or unresectable CCA were included in a bicentric case series study. After removal of biliary plastic stents, a radiofrequency treatment with a new bipolar probe (Habib™ EndoHBP) was applied. The energy was delivered by a RFA generator (VIO 200 D), supplying electrical energy at 350 kHz and 10 W for 90 s. At the end of the procedure, one or more biliary stents were left in place. Adverse events were assessed per-procedure and during follow-up visits. CCA was confirmed in all patients by histology (66%), locoregional evolution or metastatic evolution. The types of CCA were Bismuth I stage (N = 4), Bismuth II stage (N = 3), Bismuth III stage (N = 2) and Bismuth IV stage (N = 3). No serious adverse events occurred within 30 days following endoscopic treatment: One patient had a sepsis due to bacterial translocation on day 1 and another had an acute cholangitis on day 12 due to early stent migration. No immediate or delayed biliary fistula was reported. The ergonomics of the probe made treatment easy in 100 % of cases. Mean survival was 12.3 months. Endoscopic radiofrequency treatment of inoperable CCA appears without major risks and is feasible. No major adverse events or biliary fistula were identified.

  16. Survival after resection of perihilar cholangiocarcinoma-development and external validation of a prognostic nomogram.

    Science.gov (United States)

    Groot Koerkamp, B; Wiggers, J K; Gonen, M; Doussot, A; Allen, P J; Besselink, M G H; Blumgart, L H; Busch, O R C; D'Angelica, M I; DeMatteo, R P; Gouma, D J; Kingham, T P; van Gulik, T M; Jarnagin, W R

    2015-09-01

    The objective of this study was to derive and validate a prognostic nomogram to predict disease-specific survival (DSS) after a curative intent resection of perihilar cholangiocarcinoma (PHC). A nomogram was developed from 173 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA. The nomogram was externally validated in 133 patients treated at the Academic Medical Center (AMC), Amsterdam, The Netherlands. Prognostic accuracy was assessed with concordance estimates and calibration, and compared with the American Joint Committee on Cancer (AJCC) staging system. The nomogram will be available as web-based calculator at mskcc.org/nomograms. For all 306 patients, the median overall survival (OS) was 40 months and the median DSS 41 months. Median follow-up for patients alive at last follow-up was 48 months. Lymph node involvement, resection margin status, and tumor differentiation were independent prognostic factors in the derivation cohort (MSKCC). A nomogram with these prognostic factors had a concordance index of 0.73 compared with 0.66 for the AJCC staging system. In the validation cohort (AMC), the concordance index was 0.72, compared with 0.60 for the AJCC staging system. Calibration was good in the derivation cohort; in the validation cohort patients had a better median DSS than predicted by the model. The proposed nomogram to predict DSS after curative intent resection of PHC had a better prognostic accuracy than the AJCC staging system. Calibration was suboptimal because DSS differed between the two institutions. The nomogram can inform patients and physicians, guide shared decision making for adjuvant therapy, and stratify patients in future randomized, controlled trials. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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

    Science.gov (United States)

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

    2008-02-01

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

  18. Contrast enhanced CT-scan to diagnose intrahepatic cholangiocarcinoma in patients with cirrhosis.

    Science.gov (United States)

    Iavarone, Massimo; Piscaglia, Fabio; Vavassori, Sara; Galassi, Marzia; Sangiovanni, Angelo; Venerandi, Laura; Forzenigo, Laura Virginia; Golfieri, Rita; Bolondi, Luigi; Colombo, Massimo

    2013-06-01

    Contrast enhanced computed tomography (CT-scan) is a standard of care for the radiological diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. This technique, however, is not validated to exclude intrahepatic cholangiocarcinoma (ICC) which may develop in patients with cirrhosis, as well. To assess the features of contrast CT-scan in the diagnosis of ICC, we reviewed all CT-scan films obtained in cirrhotic patients with a histologically documented ICC, taking in consideration the pattern and dynamics of the arterial, portal venous and delayed phases of contrast uptake. Thirty-two patients had 40 nodules of ICC (22 male; median age 62years; 13 hepatitis C) that were identified either during surveillance with abdominal ultrasound (21 patients, 66%) or incidentally (11 patients, 34%). ICC was either multifocal or ≥ 30 mm in 11 of the former and 10 of the latter group (52% vs. 91%, pCT-scan, while the remaining 38 showed a heterogeneous contrast enhancement pattern, being the arterial peripheral-rim enhancement present in 19 (50%) cases and a progressive homogeneous contrast uptake in 16 (42%) cases during the three vascular phases, with no relation to tumor size. Importantly, all nodules lacked the radiological hallmark of HCC, the only ICC nodule showing a homogeneous wash-in during the arterial phase followed by a wash-out in the delayed venous phase, however showing a homogeneous wash-in during the portal phase too. ICC in cirrhotic patients displays distinct vascular patterns at CT-scan that allow for differentiation from HCC. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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.

  20. Differential expression of anterior gradient protein 3 in intrahepatic cholangiocarcinoma and hepatocellular carcinoma.

    Science.gov (United States)

    Brychtova, Veronika; Zampachova, Vita; Hrstka, Roman; Fabian, Pavel; Novak, Jiri; Hermanova, Marketa; Vojtesek, Borivoj

    2014-06-01

    Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer next to hepatocellular carcinoma (HCC). Despite the significant difference of the therapeutic strategy for both diseases, their histological appearance may be very similar. Thus the correct diagnosis is crucial for treatment choice but is often difficult to achieve. The aim of our study was to evaluate anterior gradient 3 (AGR3) as a new diagnostic marker helping to distinguish between ICC and HCC. AGR3 is a putative transmembrane protein implicated in breast, prostate and ovary tumorigenesis and belongs to the family of protein disulfide isomerases. Since there is little information on how AGR3 is expressed in normal and diseased tissues and what its exact function is, we analyzed its expression pattern in normal liver and tumor tissue of ICC and HCC. The immunohistochemical analysis in normal tissue revealed specific AGR3 expression in intrahepatic bile duct cholangiocytes which was not present in liver hepatocytes. Consequently we analyzed AGR3 expression in 74 representative samples of puncture biopsies, tissue excisions and resection specimens from which 48 samples were diagnosed as HCC and 26 as ICC. Our results showed AGR3 expression negative and weakly positive respectively in hepatocellular carcinomas compared to stronger AGR3 positivity in cholangiocellular carcinomas. AGR3 expression statistically significantly correlated to acid mucopolysaccharide expression and negatively correlated to glypican-3 expression. We conclude that according to receiver operating characteristics (ROC) analysis AGR3 expression is relatively specific for ICC and is potentially linked to mucosecretion, which may indicate potential implication in treatment resistance. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Claudins-4 and -7 might be valuable markers to distinguish hepatocellular carcinoma from cholangiocarcinoma.

    Science.gov (United States)

    Ono, Yusuke; Hiratsuka, Yutaro; Murata, Masaki; Takasawa, Akira; Fukuda, Rieko; Nojima, Masanori; Tanaka, Satoshi; Osanai, Makoto; Hirata, Koichi; Sawada, Norimasa

    2016-10-01

    The claudin family members are the functional components of tight junctions. Expression and localization of claudins vary among organs and tumor types. In this study, we examined expression and localization of tight junction proteins (TJP) in human liver tumors, to estimate their usefulness as differential diagnostic markers. The materials used for immunohistochemical analysis were 47 liver tumor specimens including 29 cases of hepatocellular carcinoma (HCC), 15 cases of cholangiocarcinoma (CC), 3 cases of combined HCC and CC (CHC), and 3 cases of cholangiolocellular carcinoma (CoCC). Samples were examined using semiquantitative and statistical analysis of immunoreactivity. In HCC, claudin-1, occludin, tricellulin, and JAM-A were expressed on the cell membrane as well as in hepatocytes. In CC, claudins-1, -4, and -7, tricellulin, and JAM-A were expressed on the cell membrane and occludin was predominantly expressed in the apicalmost areas of the cell membrane. Significant differences in the immunohistochemical scores of claudin-4 and claudin-7 were observed when comparing HCC and CC. CHC was positive for all of the TJPs examined in this study. The expression pattern of CoCC was found to be similar to that of CC. There were differences in the distribution of intensity scores of claudins-4 and -7 and occludin between CoCC and HCC. In addition, CHC was positive for Glypican-3 and CK-19. CoCC was positive for only CK-19. The results suggest that claudins-4 and -7 might be valuable markers for distinguishing HCC and CC and that CoCC might arise from hepatic ductal cells.

  2. Occult hepatitis B virus infection in Chinese cryptogenic intrahepatic cholangiocarcinoma patient population.

    Science.gov (United States)

    Li, YuQiong; Wang, Hui; Li, DaPeng; Hu, JingYi; Wang, Hao; Zhou, DongXun; Li, QiaoMei; Jiang, XiaoLan; Zhou, HuaBang; Hu, HePing

    2014-01-01

    There is no information available about occult hepatitis B virus (HBV) infection (OBI) in individuals with intrahepatic cholangiocarcinoma (ICC). To investigate the correlation between OBI and ICC. A retrospective case-control study was conducted. The cases were 183 cryptogenic ICC patients (group I), and the controls were 549 healthy individuals (group II). The cases and controls were matched for age, sex, and inhabitancy. Adjusted odds ratios and 95% confidence intervals were calculated. Intrahepatic total HBV DNA in 63 paraffin-embedded samples was collected from patients in group I (n=44), HBV-associated ICC patients (n=3), and hepatic cavernous hemangioma patients with seronegative HBsAg (hepatitis B S antigen) (group III; n=16). We determined the levels of serum and intrahepatic HBV DNA and compared the level of intrahepatic HBV DNA in 44 cryptogenic patients from group I with the level in the patients from group III. Compared with group II, group I had a lower prevalence of anti-HBs (antibody against HBsAg) and a higher prevalence of anti-HBe (antibody against hepatitis B e antigen) and anti-HBc (antibody against hepatitis B c antigen). Multivariate analysis confirmed that anti-HBe and anti-HBc positivity were associated with ICC. The odds ratios and 95% confidence intervals for anti-HBe and anti-HBc were 2.482 and 1.482-4.158, 4.556 and 2.938-7.066, respectively. Compared with group III, cryptogenic ICC cases showed more frequent detection of intrahepatic total HBV DNA (63.64% vs. 18.75%, P=0.002). OBI may represent an important risk factor for ICC. HBsAg seroclearance does not signify eradication of HBV and may not entirely prevent the development of ICC.

  3. Gene copy number variation and protein overexpression of EGFR and HER2 in distal extrahepatic cholangiocarcinoma.

    Science.gov (United States)

    Jung, Min Jung; Woo, Chang Gok; Lee, Saetbyeol; Chin, Susie; Kim, Hee Kyung; Kwak, Jeong Ja; Koh, Eun Suk; Lee, Bora; Jang, Kee-Taek; Moon, Ahrim

    2017-10-01

    EGFR and HER2 are among the most promising therapeutic targets in solid cancers. The expression status of EGFR and HER2 are associated with the prognosis, and with a number of clinicopathological factors, in many cancers. However, few studies have examined this association in distal extrahepatic cholangiocarcinoma (EHCC). Therefore, we investigated EGFR and HER2 protein expression and gene copy number variation (CNV) in distal EHCC. We also studied the association of these factors with clinicopathological parameters and prognosis. Immunostaining, using antibodies against EGFR and HER2, was performed on 84 cases of distal EHCC. All positive (3+) and equivocal (2+) EGFR and HER2 expression cases, together with randomly selected negative (1+ and 0) cases, were evaluated for EGFR and HER2 CNV. Among distal EHCC samples, 6.0% (n=5) were positive (3+) for EGFR expression and 6.0% (n=5) were equivocal (2+). HER2 expression was positively identified in 2.4% of samples (n=2), and was equivocal in 1.2% of samples (n=1). All cases of positive EGFR expression showed amplification (n=1) or high polysomy (n=4) involving the EGFR gene; three cases (60%) of equivocal EGFR expression showed high polysomy of the EGFR gene. All cases of positive or equivocal HER2 expression (n=3, 3.6%) showed amplification of the HER2 gene. In univariate analysis, EGFR expression and CNV were associated with shorter cancer-specific overall survival (p=0.003 and p=0.018, respectively). Multivariate analysis also showed that EGFR CNV was a significant prognostic factor in distal EHCC (p=0.015). Although further study is warranted, our findings suggest that EGFR expression and CNV are factors associated with poor prognosis, and that anticancer therapeutics against EGFR and HER2 receptors may be promising therapeutic options for patients with distal EHCC. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

  4. Yttrium-90 radioembolization for intrahepatic cholangiocarcinoma: safety, response, and survival analysis.

    Science.gov (United States)

    Mouli, Samdeep; Memon, Khairuddin; Baker, Talia; Benson, Al B; Mulcahy, Mary F; Gupta, Ramona; Ryu, Robert K; Salem, Riad; Lewandowski, Robert J

    2013-08-01

    To present data on safety, antitumoral response, and survival following yttrium-90 ((90)Y) radioembolization for patients with unresectable intrahepatic cholangiocarcinoma (ICC). The present study expands on the cohort of 24 patients with ICC described in a pilot study, and includes 46 patients treated with (90)Y radioembolization at a single institution during an 8-year period. Via retrospective review of a prospectively collected database, patients were stratified by performance status, tumor distribution (solitary or multifocal), tumor morphology (infiltrative or peripheral), and presence/absence of portal vein thrombosis. Primary endpoints included biochemical and clinical toxicities, and secondary endpoints included imaging response (World Health Organization [WHO] and European Association for the Study of Liver Disease [EASL] criteria) and survival. Uni-/multivariate analyses were performed. Ninety-two treatments were performed, with a mean of two per patient. Fatigue and transient abdominal pain occurred in 25 patients (54%) and 13 patients (28%), respectively. Treatment-related gastroduodenal ulcer developed in one patient (2%). WHO imaging findings included partial response (n = 11; 25%), stable disease (n = 33; 73%), and progressive disease (n = 1; 2%). EASL imaging findings included partial/complete response (n = 33; 73%) and stable disease (n = 12; 27%). Survival varied based on presence of multifocal (5.7 mo vs 14.6 mo), infiltrative (6.1 mo vs 15.6 mo), and bilobar disease (10.9 mo vs 11.7 mo). Disease was converted to resectable status in five patients, who successfully underwent curative (ie, R0) resection. Radioembolization with (90)Y is safe and demonstrates antitumoral response and survival benefit in select patients with ICC. Results are most pronounced in patients with solitary tumors, for whom conversion to curative resection is possible. Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.

  5. ENBD is Associated with Decreased Tumor Dissemination Compared to PTBD in Perihilar Cholangiocarcinoma.

    Science.gov (United States)

    Higuchi, Ryota; Yazawa, Takehisa; Uemura, Shuichiro; Izumo, Wataru; Chaudhary, Rohan Jagat; Furukawa, Toru; Yamamoto, Masakazu

    2017-09-01

    Little is known regarding the risk of tumor dissemination when percutaneous biliary drainage is used before surgical resection of perihilar cholangiocarcinoma (PHC). We aimed to compare the incidence of tumor dissemination after preoperative endoscopic nasobiliary drainage (ENBD) with that after percutaneous transhepatic biliary drainage (PTBD) for PHC. Data from 208 consecutive patients who underwent PHC resection between 2000 and 2013 were retrospectively analyzed. The influence of drainage type on incidence of tumor dissemination was examined. Seventy-six patients underwent ENBD (37%), 87 underwent PTBD (42%), and 45 underwent surgery without preoperative biliary drainage (WD, 22%). The respective 2- and 5-year estimated cumulative incidences of tumor dissemination in the ENBD group (11.8/14.6%) were lower than in the PTBD group (28.8/35.9%, p = 0.003) and equivalent to that in the WD group (11.2/15.9%, p = NS). PTBD (hazard ratio [HR] vs. ENBD, 2.80) was an independent risk factor for postoperative tumor dissemination in the multivariate analysis. The 2- and 5-year disease-specific survival rates were higher in the ENBD group (67.6/47.3%) than in the PTBD group (56.6/27.8%, p = 0.032) and equivalent to that in the WD group (64.9/53.8%, p = NS). However, drainage type was not an independent risk factor in multivariate analysis of disease-specific survival. For patients with PHC, the associated risk of postoperative tumor dissemination in the ENBD group was lower than in the PTBD group and equivalent to that in the WD group. Thus, ENBD is the ideal procedure for preoperative biliary drainage.

  6. Health-Related Quality of Life and Survival of Cholangiocarcinoma Patients in Northeastern Region of Thailand.

    Directory of Open Access Journals (Sweden)

    Somkiattiyos Woradet

    Full Text Available In northeast Thailand, cholangiocarcinoma (CCA is a major cause of mortality. Patients with CCA have a poor prognosis and short-term survival. The purpose of this study was to investigate the association between health-related quality of life (HRQOL and survival time, and to explore whether change in HRQOL score is related to survival among CCA patients. The study was performed between February 2011 and January 2012, and included 171 patients with newly diagnosed CCA from 5 tertiary hospitals in four provinces of northeast Thailand. The HRQOL was measured at baseline, 1 month, and 2 months after diagnosis by the FACT-Hep questionnaire (Thai version 4. The outcome was survival time from diagnosis. Cox's proportional hazard model was used to evaluate the association between HRQOL and survival time. A higher overall score on HRQOL was associated with a significantly better survival (HR per 5 units increase in HRQOL was 0.92, 95% CI: 0.88-0.96. Two of the separate domains contributing to the overall HRQOL-functional well-being and hepatobiliary cancer subscale-were found to have independent effects on survival, even after adjustment for potential confounding variables, and the other domains of HRQOL. CCA patient whose HRQOL scores had improved (≥9 units at the 1st month of follow up had a reduced probability of dying from the disease (HR: 0.56, 0.32-0.95 after adjustment for the same confounding factors. A positive association between HRQOL at diagnosis and survival time was found. An improvement in HRQOL score in the first months after diagnosis further increases survival.

  7. Endoscopic stenting for hilar cholangiocarcinoma: efficacy of unilateral and bilateral placement of plastic and metal stents in a retrospective review of 480 patients

    Directory of Open Access Journals (Sweden)

    Liberato Manuel José

    2012-08-01

    Full Text Available Abstract Background Endoscopic biliary drainage of hilar cholangiocarcinoma is controversial with respect to the optimal types of stents and the extent of drainage. This study evaluated endoscopic palliation in patients with hilar cholangiocarcinoma using self-expandable metallic stents (SEMS and plastic stents (PS.We also compared unilateral and bilateral stent placement according to the Bismuth classification. Methods Data on 480 patients receiving endoscopic biliary drainage for hilar cholangiocarcinoma between September 1995 and December 2010 were retrospectively reviewed to evaluate the following outcome parameters: technical success (TS, functional success (FS, early and late complications, stent patency and survival. Patients were followed from stent insertion until death or stent occlusion. Patients were divided into 3 groups according to the Bismuth classification (Group 1, type I; Group 2, type II; Group 3, type > III. Results The initial stent insertion was successful in 450 (93.8% patients. TS was achieved in 204 (88.3% patients treated with PS and in 246 (98.8% patients palliated with SEMS (p P P  Conclusions SEMS insertion for the palliation of hilar cholangiocarcinoma offers higher technical and clinical success rates in the ITT analysis as well as lower complication rates and a superior cumulative stent patency when compared with PS placement in all Bismuth classifications. The cumulative patency of bilateral SEMS or PS stents was significantly higher than that of unilateral SEMS or PS stents, with lower occlusion rates in Bismuth II patients.

  8. A Phase I-II dose escalation study of fixed-dose rate gemcitabine, oxaliplatin and capecitabine every two weeks in advanced cholangiocarcinomas

    DEFF Research Database (Denmark)

    Lassen, Ulrik V; Jensen, Lars Henrik; Sorensen, Morten

    2011-01-01

    Abstract Introduction. Gemcitabine based regimens have been widely used in patients with advanced cholangiocarcinoma (CC), but no standard therapy exists. In this study we aimed to find the maximally tolerated dose (MTD) of a two-week schedule of fixed dose rate (FDR) gemcitabine (G), oxaliplatin...

  9. A Phase I-II dose escalation study of fixed-dose rate gemcitabine, oxaliplatin and capecitabine every two weeks in advanced cholangiocarcinomas

    DEFF Research Database (Denmark)

    Lassen, Ulrik; Jensen, Lars Henrik; Sorensen, Morten

    2011-01-01

    Gemcitabine based regimens have been widely used in patients with advanced cholangiocarcinoma (CC), but no standard therapy exists. In this study we aimed to find the maximally tolerated dose (MTD) of a two-week schedule of fixed dose rate (FDR) gemcitabine (G), oxaliplatin (O) and capecitabine (C...

  10. miR-25 targets TNF-related apoptosis inducing ligand (TRAIL) death receptor-4 and promotes apoptosis resistance in cholangiocarcinoma.

    Science.gov (United States)

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

    2012-02-01

    It has been established that microRNA expression and function contribute to phenotypic features of malignant cells, including resistance to apoptosis. Although targets and functional roles for a number of microRNAs have been described in cholangiocarcinoma, many additional microRNAs dysregulated in this tumor have not been assigned functional roles. In this study, we identify elevated miR-25 expression in malignant cholangiocarcinoma cell lines as well as patient samples. In cultured cells, treatment with the Smoothened inhibitor, cyclopamine, reduced miR-25 expression, suggesting Hedgehog signaling stimulates miR-25 production. Functionally, miR-25 was shown to protect cells against TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Correspondingly, antagonism of miR-25 in culture sensitized cells to apoptotic death. Computational analysis identified the TRAIL Death Receptor-4 (DR4) as a potential novel miR-25 target, and this prediction was confirmed by immunoblot, cell staining, and reporter assays. These data implicate elevated miR-25 levels in the control of tumor cell apoptosis in cholangiocarcinoma. The identification of the novel miR-25 target DR4 provides a mechanism by which miR-25 contributes to evasion of TRAIL-induced cholangiocarcinoma apoptosis. Copyright © 2011 American Association for the Study of Liver Diseases.

  11. Immunosuppressive prednisolone enhances early cholangiocarcinoma in Syrian hamsters with liver fluke infection and administration of N-nitrosodimethylamine.

    Science.gov (United States)

    Juasook, Amornrat; Boonmars, Thidarut; Wu, Zhiliang; Loilome, Watcharin; Veteewuthacharn, Kulathida; Namwat, Nissana; Sudsarn, Pakkayanee; Wonkchalee, Orasa; Sriraj, Pranee; Aukkanimart, Ratchadawan

    2013-01-01

    Chronic infection with Opisthorchis viverrini for many years has been associated with the development of hepatobiliary diseases including cholangiocarcinoma. It is well known that inflammation is a key component of the tumor microenvironment, and that chronic inflammation plays an important role in tumorigenesis. Therefore, in this study cholangiocarcinogenesis was induced in Syrian hamsters in order to observe the cancer-related inflammation. The Syrian hamsters were divided into 5 groups: uninfected controls; normal Syrian hamsters infected with O. viverrini (OV); immunosuppressed Syrian hamsters infected with O. viverrini (OVis); normal Syrian hamsters infected with O. viverrini and administered N-nitrosodimethylamine (CCA); and immunosuppressed Syrian hamsters infected with O. viverrini and administered N-nitrosodimethylamine (CCAis). Syrian hamster livers were later observed for gross pathology and histopathological changes; COX2 was analyzed by immunohistochemical staining. We found a decreased number of inflammatory cells surrounding the hepatic bile duct in the OVis group, but not in the OV and CCAis groups. However, in the CCAis group (with suppressed immunity) early appearance and greater severity of cholangiocarcinoma were observed; gross pathological examination revealed many cancer nodularities on the liver surface, and histopathological studies showed the presence of cancer cells, findings which correlated with the predominant expression of COX2. The present study suggests that host immune responses are intended to ameliorate pathology, and they are also crucially associated with pathogenesis in O. viverrini infection; the unbalancing of host immunity may enhance cancer-related inflammation.

  12. The multidisciplinary team meeting in the UK from the patients' perspective: comments and observations from cholangiocarcinoma patients and their families.

    Science.gov (United States)

    Morement, Helen; Harrison, Rachel; Taylor-Robinson, Simon D

    2017-01-01

    The multidisciplinary team (MDT) meeting has become the hallmark for cancer care in the UK. While standardizing care through adherence to guidelines, the MDT process can make the decision-making process somewhat remote from the patient perspective. The Cholangiocarcinoma Charity (AMMF) is the UK's only cholangiocarcinoma charity and is at the forefront of patient empowerment for those with this condition and for their families. It provides much needed support not only via personal contact but also through its website and on the social media platforms, Facebook and Twitter. AMMF conducted a survey of patient attitudes to and experience of the MDT process through a simple questionnaire posted on Facebook in 2014. We report the results of the responses received, which we believe are worthy of further thought. In the main, while treatment decisions are not queried, there is distress at the lack of involvement, the lack of representation, the lack of communication and at not knowing who to approach for answers to questions. This snapshot, although small, provides some insight to clinicians not to forget the constituency they serve, as communication is all important.

  13. Immunohistochemical Examination of a Resected Advanced Hilar Cholangiocarcinoma Arising in a 29-Year-Old Male without Primary Sclerosing Cholangitis

    Directory of Open Access Journals (Sweden)

    Taketoshi Suehiro

    2010-05-01

    Full Text Available A 29-year-old man with advanced hilar cholangiocarcinoma was successfully treated with an extended right lobectomy. The carbohydrate antigen 19-9 (CA19-9 level was elevated to 939 IU/l, and the pathological findings revealed moderately differentiated tubular adenocarcinoma which involved almost the entire thickness of the hepatic duct and the adjacent liver tissue (T3 and which was associated with lymph node metastasis (N1. It was a stage IIB (T3N1M0 tubular adenocarcinoma according to UICC pathological staging. Immunohistochemical examination revealed that Ki-67, cyclin D1, and MMP-7 were positive, and 14-3-3σ and p27 were negative. The pathological and immunohistochemical findings indicated high malignant potential indicating poor prognosis. We administrated the postoperative adjunct gemcitabine combined with S-1 chemotherapy. The patient is alive without recurrence and doing well two years after surgery. We also review other reports of cholangiocarcinoma patients aged less than 30 years.

  14. Cell-SELEX based selection and optimization of DNA aptamers for specific recognition of human cholangiocarcinoma QBC-939 cells.

    Science.gov (United States)

    Wan, Jun; Ye, Ling; Yang, Xiaohai; Guo, Qiuping; Wang, Kemin; Huang, Zhixiang; Tan, Yuyu; Yuan, Baoyin; Xie, Qin

    2015-09-07

    Cholangiocarcinoma (CCA) is a very aggressive biliary tract malignancy with no efficient early diagnosis and therapeutics available, so there is a call for effective molecular probes. Herein, we performed cell-based systematic evolution of ligands by exponential enrichment (cell-SELEX) to obtain aptamers for the specific recognition of human cholangiocarcinoma QBC-939 cells. By coordinating sequence homology analysis and secondary structure analysis, we successfully obtained two aptamers with dissociation constants (Kd) in the low nanomolar range. A 23 nt truncated sequence was identified after further analysis on the secondary structure. More importantly, because hepatocellular carcinoma SMMC-7721 cells were employed as the control in the counter selection, the obtained aptamers demonstrated excellent specificity to the target cells, and no binding to several other hepatocellular carcinoma cell lines was observed. Moreover, the aptamers were initially found to recognize membrane proteins, giving them great potential in the field of biomarker discovery. These newly generated aptamers may play a key role in the early diagnosis and clinical treatment of CCA.

  15. Association between Diabetes Mellitus and Fatty Liver Based on Ultrasonography Screening in the World's Highest Cholangiocarcinoma Incidence Region, Northeast Thailand.

    Science.gov (United States)

    Thinkhamrop, Kavin; Khuntikeo, Narong; Phonjitt, Pichai; Chamadol, Nittaya; Thinkhamrop, Bandit; Moore, Malcolm Anthony; Promthet, Supannee

    2015-01-01

    Fatty liver disease (FLD) can be a precondition for other liver pathology including cholangiocarcinoma (CCA). Diabetes mellitus (DM) has been suggested in some studies to be a risk factor for FLD as well as cancers, including cholangiocellular carcinoma; however, there are currently very few studies on FLD in DM subjects, although the rate of FLD continues to increase annually. To determine the association between DM and FLD ultrasonographic data were analyzed from the Cholangiocarcinoma Screening and Care Program (CASCAP), in northeast Thailand. DM was reported by the subjects based on the CASCAP health questionnaire. Factors that were associated with FLD were determined by prevalence, odds ratio (ORs) and its 95% confidence intervals (CIs) using multiple logistic regression. There were 45,263 subjects with a mean age of 53.46 (±9.25) years. FLD was found in 36.3% of DM subjects but only in 20.7% of non-DM subjects. The association between DM and FLD was adjusted for all other factors including gender, age, education level, relatives diagnosed with CCA, smoking, alcohol consumption, and hepatitis B and C. The risk of DM in subjects having FLD was highly significant compared with the non-DM subjects (OR 2.13; 95%CI: 1.92 to 2.35; p-value < 0.001). Thus DM is significantly associated with FLD which in turn may facilitate the development of several diseases including CCA. DM should be taken into consideration in future ultrasonic investigations of FLD and CCA.

  16. High dose chemoradiation for unresectable hilar cholangiocarcinomas using intensity modulated external beam radiotherapy: a single tertiary care centre experience

    Science.gov (United States)

    Mehta, Shaesta; Kalyani, Nikhil; Chaudhari, Suresh; Dharia, Tejas; Shetty, Nitin; Chopra, Supriya; Goel, Mahesh; Kulkarni, Suyash; Shrivastava, Shyam Kishore

    2017-01-01

    Background We present results of patients diagnosed with unresectable hilar cholangiocarcinomas treated with high dose radiotherapy and concurrent chemotherapy. Methods From Aug 2005 to Dec 2012, 68 consecutive patients were treated. Fifty patients (group 1) presenting to us with obstructive jaundice were planned for endobiliary brachytherapy (EBBT 14 Gy) followed external beam radiotherapy (EBRT 45 Gy). Twenty-two patients (group 2) who had previously undergone biliary drainage underwent EBRT (57 Gy). All patients received injection Gemcitabine 300 mg/m2/weekly along with EBRT. Results Twenty-nine patients in group 1 and 22 patients in group 2 completed the treatment. Twenty-six (55%) patients achieved complete radiological response, 16 (64%) belonging to group 1 and 8 (44%) of group 2 (P=0.05). The median overall survival (MOS) was 17.5 and 16 months for group 1 and 2 respectively (P=0.07). The 1- and 2-year survival was 63%, and 18% for group I and 61% and 22% for group II respectively. The MOS was 5 months and 1 year survival was 14% for patients receiving EBBT only. MOS was significantly better after complete response (P=0.001). Conclusions Intensity modulated radiotherapy (IMRT) modulated high dose radiotherapy used either alone or with brachytherapy demonstrates potential to prolonged overall survival in unresectable hilar cholangiocarcinomas. PMID:28280622

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

    Energy Technology Data Exchange (ETDEWEB)

    Schernthaner, Ruediger Egbert [The Johns Hopkins Hospital, Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology (United States); Lin, MingDe [Philips Research North America, Ultrasound and Interventions (United States); Duran, Rafael; Chapiro, Julius; Wang, Zhijun; Geschwind, Jean-François, E-mail: jfg@jhmi.edu [The Johns Hopkins Hospital, Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology (United States)

    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.

  18. Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts.

    Science.gov (United States)

    Nakanuma, Yasuni; Sasaki, Motoko; Sato, Yasunori; Ren, Xiangshan; Ikeda, Hiroko; Harada, Kenichi

    2009-10-31

    Flat-type "biliary intraepithelial neoplasia (BilIN)" and papillary-type "intraductal papillary neoplasm of the bile duct (IPN-B)" are proposed as precursors of invasive, perihilar intrahepatic cholangiocarcinoma (ICC). Three carcinogenetic pathways are proposed: BilIN progressing to tubular adenocarcinoma, and IPN-B progressing to tubular adenocarcinoma or to colloid carcinoma. Carcinogenesis via BilIN was characterized by mucin core protein 2-/cytokeratin 20-(MUC2-/CK20-) with MUC1 expression, while carcinogenesis via IPN-B leading to tubular adenocarcinoma was associated with MUC1 expression or that to colloid carcinoma with MUC1-negativity. In both the BilIN and IPNB series, the expression of p21, p53, and cyclin D1 was upregulated with histological progression. Interestingly, p53 expression was upregulated at the invasive stage of BilIN, but was low in noninvasive BilIN, while p53 expression was upregulated in IPN-B1 and reached a plateau in IPN-B2 and invasive ICC. Expression of p16(INK4a), which was frequent in BilIN1, was decreased in BilIN-2/3 and invasive carcinoma. EZH2 expression showed a stepwise increase from BilIN to invasive carcinoma. Membranous expression of β-catenin and E-cadherin was more markedly decreased in ICC with BilIN than in ICC with IPNB. Interestingly, disruption of the membranous distribution of β-catenin and E-cadherin seems to result in the invasion and metastasis of carcinoma cells of BilIN and IPN-B expressing MMP-7 and MT1-MMP. Increased expression of cyclin D1 and c-myc was more frequent in the IPNB lineage than BilIN lineage, possibly related to the Wnt signaling pathway associated with the nuclear accumulation of β-catenin. In conclusion, BilIN and IPN-B progress to invasive ICC through characteristic multistep processes.

  19. Trends in liver cancer incidence between 1985 and 2009, Khon Kaen, Thailand: cholangiocarcinoma.

    Science.gov (United States)

    Kamsa-ard, Supot; Wiangnon, Surapon; Suwanrungruang, Krittika; Promthet, Supannee; Khuntikeo, Narong; Kamsa-ard, Siriporn; Mahaweerawat, Suwannee

    2011-01-01

    The Khon Kaen Cancer Registry (KKCR), having both hospital and population-based registration, was established in 1984 at the Faculty of Medicine, Khon Kaen University. Liver cancer is the most frequent malignancy among Thais from northeastern Thailand, but there has hitherto been no assessment of trends over time. To perform a statistical assessment of the incidence trends between 1985 and 2009 of liver cancer, specifically focusing on cholangiocarcinoma (CHCA). Cases of CHCA, registered between 1985 and 2009, were retrieved from the KKCR and all those with a specific ICD-O-3rd diagnosis with a coding of C22.1, C24.0, C24.8 and C24.9 were selected. Incidence trends were calculated using the generalized linear model method (GLM), which generates incidence rate based logarithms. Jointpoint analysis was used to identify the best fitting model. Of the 18,589 cases of liver cancer 42% (7,859) were hepatocellular carcinoma and 58% (10,731) were CHCA. Among persons with CHCA, males were affected two times more frequently than females. Three-quarters of the cases were between 55 and 69 years of age. Morphology verified through a cytological or histological examination of tissue from the primary site (%MV) was only 10.8 % (1,141). The respective overall Age Standardized Rate (ASR) for CHCA from 1985 to 2009 was 16.8 to 62.0 per 100,000 among males and 4.8 to 25.6 per 100,000 among females. The respective, overall, ASR of CHCA among males vs. females was 44.3 per 100,000 (95% CI: 38.9 to 49.7) vs. 17.6 (95% CI: 14.5 to 20.7). Among males vs. females, the respective incidence from 1990 to 2009 has been significantly decreasing by -0.7% per year (Annual Percent Change, APC: -0.7%, 95%CI: -2.1% to +0.8%) vs. -0.4% per year (APC: -0.4%, 95% CI: -2.1% to +1.4%). The rate increase in the first 5 to 6 years may be due to improved completeness of the registry, since in the subsequent 10 to 12 years there is a rather stable rate. It may be, however, that the recent decline in

  20. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study.

    Science.gov (United States)

    Ibrahim, Saad M; Mulcahy, Mary F; Lewandowski, Robert J; Sato, Kent T; Ryu, Robert K; Masterson, Elizabeth J; Newman, Steven B; Benson, Al; Omary, Reed A; Salem, Riad

    2008-10-15

    The objective of this report was to present data from an open-label cohort study in which patients with intrahepatic cholangiocarcinoma (ICC) underwent radioembolization with yttrium-90 ((90)Y) microspheres. Twenty-four patients with histologically proven ICC were treated. The planned target dose was 120 Gray. Patients were stratified according to Eastern Cooperation Oncology Group (ECOG) performance status, tumor morphology (infiltrative vs peripheral), tumor distribution (solitary vs multifocal), and the presence or absence of portal vein thrombosis (PVT). Before and after the procedure, the following variables were assessed: 1) biochemical and clinical toxicity, 2) imaging (computed tomography/magnetic resonance imaging) response according to World Health Organization and European Association for the Study of Liver Disease (EASL) criteria, and 3) median survival after the first treatment using Kaplan-Meier methodology. In total, 48 (90)Y treatments were administered to hepatic segments or lobes. Fatigue and transient abdominal pain were reported in 18 patients (75%) and 10 patients (42%), respectively. One patient (4%) developed grade 3 bilirubin toxicity. One patient (4%) developed a treatment-related gastroduodenal ulcer. On imaging follow-up of 22 patients, tumors demonstrated a partial response in 6 patients (27%), stable disease in 15 patients (68%), and progressive disease in 1 patient (5%). By using EASL guidelines, 17 patients (77%) showed >50% tumor necrosis on imaging follow-up. Two patients (9%) demonstrated 100% tumor necrosis. The median overall survival for the entire cohort (n = 24) was 14.9 months. The median survival for patients with an ECOG performance status of 0, 1, and 2 was 31.8 months, 6.1 months, and 1 month, respectively (P < .0001); the median survival for patients without and with PVT was 31.8 months and 5.7 months, respectively (P = .0003); and the median survival for patients with peripheral versus periductal-infiltrative tumors was

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

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    Woo, Hyunsik [SMG-SNU Boramae Medical Center, Department of Radiology, Seoul (Korea, Republic of); Han, Joon Koo; Kim, Jung Hoon [Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Hong, Sung-Tae [Seoul National University, Department of Parasitology, College of Medicine, Seoul (Korea, Republic of); Uddin, M.H. [Seoul National University, Adult Stem Cell Research Center, Laboratory of Stem Cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine, Seoul (Korea, Republic of); Jang, Ja-June [Seoul National University, Department of Pathology, College of Medicine, Seoul (Korea, Republic of)

    2017-04-15

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

  2. miR-29b, miR-205 and miR-221 enhance chemosensitivity to gemcitabine in HuH28 human cholangiocarcinoma cells.

    Directory of Open Access Journals (Sweden)

    Kinya Okamoto

    Full Text Available BACKGROUND AND AIMS: Cholangiocarcinoma (CCA is highly resistant to chemotherapy, including gemcitabine (Gem treatment. MicroRNAs (miRNAs are endogenous, non-coding, short RNAs that can regulate multiple genes expression. Some miRNAs play important roles in the chemosensitivity of tumors. Here, we examined the relationship between miRNA expression and the sensitivity of CCA cells to Gem. METHODS: Microarray analysis was used to determine the miRNA expression profiles of two CCA cell lines, HuH28 and HuCCT1. To determine the effect of candidate miRNAs on Gem sensitivity, expression of each candidate miRNA was modified via either transfection of a miRNA mimic or transfection of an anti-oligonucleotide. Ontology-based programs were used to identify potential target genes of candidate miRNAs that were confirmed to affect the Gem sensitivity of CCA cells. RESULTS: HuCCT1 cells were more sensitive to Gem than were HuH28 cells, and 18 miRNAs were differentially expressed whose ratios over ± 2log2 between HuH28 and HuCCT1. Among these 18 miRNAs, ectopic overexpression of each of three downregulated miRNAs in HuH28 (miR-29b, miR-205, miR-221 restored Gem sensitivity to HuH28. Suppression of one upregulated miRNA in HuH28, miR-125a-5p, inhibited HuH28 cell proliferation independently to Gem treatment. Selective siRNA-mediated downregulation of either of two software-predicted targets, PIK3R1 (target of miR-29b and miR-221 or MMP-2 (target of miR-29b, also conferred Gem sensitivity to HuH28. CONCLUSIONS: miRNA expression profiling was used to identify key miRNAs that regulate Gem sensitivity in CCA cells, and software that predicts miRNA targets was used to identify promising target genes for anti-tumor therapies.

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

    Science.gov (United States)

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

    2017-09-08

    Several studies have examined controlling nutritional status (CONUT), which is one of the useful biomarkers for predicting patients' prognosis following cancer treatment. The aim of this study was to evaluate the value of CONUT as a postoperative prognostic marker in patients with intrahepatic cholangiocarcinoma (ICC) following curative hepatectomy. We retrospectively analyzed 71 patients who underwent curative hepatectomy for ICC between May 2002 and November 2016. Patients were divided into two groups according to their preoperative CONUT score (i.e., CONUT ≧ 2 or CONUT current study, a high CONUT score was not associated with postoperative complications (Clavien-Dindo classification ≧ III or more). CONUT may be useful for the preoperative assessment of prognosis in patients with ICC who have undergone curative hepatectomy.

  4. [A case of cholangiolocellular carcinoma combined with intrahepatic cholangiocarcinoma diagnosed after 4 years follow-up for hepatic hemangioma].

    Science.gov (United States)

    Koga, Yurie; Nagahama, Hiroyasu; Tateyama, Masakuni; Fukubayashi, Koutarou; Kamiya, Yasuyuki; Tanaka, Motohiko; Tashima, Rumiko; Beppu, Toru; Baba, Hideo; Iyama, Kenichi; Sasaki, Yutaka

    2012-02-01

    We report a rare case which had been followed up for hepatic hemangioma and in whom was surgical resection revealed with cholangiolocellular carcinoma (CoCC) combined with intrahepatic cholangiocarcinoma (ICC). A 69-year-old man who was an HBV carrier had been regularly followed up with hepatic hemangioma from November, 2005. Because the arterial phase of dynamic CT scan exhibited an enhanced lesion in the dorsal portion of the hemangioma on November, 2009, the patient was admitted for intensive examination of the liver tumor. After surgical resection of the tumor, histological examination revealed small irregular tubules in the outer part and scattered small duct structures in the inner part of the tumor. In addition, immunohistochemical analysis demonstrated that cytokeratin (CK) 7, CK19 and epithelial membrane antigen (EMA) were all positive in the outer part, and EMA was only negative in the inner part of the tumor. From these findings, this case was diagnosed as CoCC combined with ICC.

  5. Banking on the future: biobanking for "omics" approaches to biomarker discovery for Opisthorchis-induced cholangiocarcinoma in Thailand.

    Science.gov (United States)

    Mulvenna, Jason; Yonglitthipagon, Ponlapat; Sripa, Banchob; Brindley, Paul J; Loukas, Alex; Bethony, Jeffrey M

    2012-03-01

    Cholangiocarcinoma (CCA)--bile duct cancer--is associated with late presentation, poses challenges for diagnosis, and has high mortality. These features t highlight the desperate need for biomarkers than can be measured early and in accessible body fluids such as plasma of people at risk for developing this lethal cancer. In this manuscript, we address previous limitations in the discovery stage of biomarker(s) for CCA and indicate how new generation of "omics" technologies could be used for biomarker discovery in Thailand. A key factor in the success of this biomarker program for CCA is the combination of cutting edge technology with strategic sample acquisition by a biorepositories. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  6. Utilization of Google Earth for Distribution Mapping of Cholangiocarcinoma: a Case Study in Satuek District, Buriram, Thailand.

    Science.gov (United States)

    Rattanasing, Wannaporn; Kaewpitoon, Soraya J; Loyd, Ryan A; Rujirakul, Ratana; Yodkaw, Eakachai; Kaewpitoon, Natthawut

    2015-01-01

    Cholangiocarcinoma (CCA) is a serious public health problem in the Northeast of Thailand. CCA is considered to be an incurable and rapidly lethal disease. Knowledge of the distribution of CCA patients is necessary for management strategies. This study aimed to utilize the Geographic Information System and Google EarthTM for distribution mapping of cholangiocarcinoma in Satuek District, Buriram, Thailand, during a 5-year period (2008-2012). In this retrospective study data were collected and reviewed from the OPD cards, definitive cases of CCA were patients who were treated in Satuek hospital and were diagnosed with CCA or ICD-10 code C22.1. CCA cases were used to analyze and calculate with ArcGIS 9.2, all of data were imported into Google Earth using the online web page www.earthpoint.us. Data were displayed at village points. A total of 53 cases were diagnosed and identified as CCA. The incidence was 53.57 per 100,000 population (65.5 for males and 30.8 for females) and the majority of CCA cases were in stages IV and IIA. The average age was 67 years old. The highest attack rate was observed in Thung Wang sub-district (161.4 per 100,000 population). The map display at village points for CCA patients based on Google Earth gave a clear visual deistribution. CCA is still a major problem in Satuek district, Buriram province of Thailand. The Google Earth production process is very simple and easy to learn. It is suitable for the use in further development of CCA management strategies.

  7. Epithelial cell adhesion molecule-positive human hepatic neoplastic cells: development of combined hepatocellular-cholangiocarcinoma in mice.

    Science.gov (United States)

    Ogasawara, Sachiko; Akiba, Jun; Nakayama, Masamichi; Nakashima, Osamu; Torimura, Takuji; Yano, Hirohisa

    2015-02-01

    Human combined hepatocellular-cholangiocarcinoma (CHC) expresses several hepatic stem/progenitor cell (HSPC) markers, suggesting this neoplasm originates from HSPCs. We examined the significance of HSPC marker in CHC using a human CHC cell line. We used a human CHC cell line (KMCH-1) previously established in our laboratory. The original tumor was classified as CHC, showing areas of typical hepatocellular carcinoma (HCC) and cholangiocarcinoma (ChC). We examined the expression of HSPC markers and hepatocyte markers in KMCH-1 by flow cytometry (FCM) and quantitative real-time polymerase chain reaction. EpCAM(+) and EpCAM(-) KMCH-1 cells were isolated. Subsequently, their morphological features, HSPC marker expression, and biological characteristics were examined in vitro and in vivo. FCM showed expression of EpCAM, K7, K19, and ABCG2 in KMCH-1, with various degrees. EpCAM(+) cells expressed K19 mRNA, but did not express α-fetoprotein (AFP). In contrast, EpCAM(-) cells expressed AFP mRNA, but did not express K19. EpCAM(+) cells produced both EpCAM(+) and EpCAM(-) cells, but EpCAM(-) cells produced only EpCAM(-) cells in vitro. EpCAM(+) cells showed higher tumorigenicity and formed larger tumors than EpCAM(-) cells. Inoculation of EpCAM(+) and EpCAM(-) cells produced both ChC and HCC-like component and HCC-like component only, respectively. It is speculated that some CHCs may originate from EpCAM(+) neoplastic cells, and that these cells may affect malignant behavior and progression in such CHCs. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  8. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: A population-based study in SEER-Medicare.

    Directory of Open Access Journals (Sweden)

    Jessica L Petrick

    Full Text Available Intrahepatic (ICC and extrahepatic (ECC cholangiocarcinomas are rare tumors that arise from the epithelial cells of the bile ducts, and the etiology of both cancer types is poorly understood. Thus, we utilized the Surveillance, Epidemiology, and End Results (SEER-Medicare resource to examine risk factors and novel preexisting medical conditions that may be associated with these cancer types.Between 2000 and 2011, 2,092 ICC and 2,981 ECC cases and 323,615 controls were identified using the SEER-Medicare database. Logistic regression was used to calculate adjusted odds ratios (OR and 95% confidence intervals (CI.Non-alcoholic fatty liver disease was associated with approximately 3-fold increased risks of ICC (OR = 3.52, 95% CI: 2.87-4.32 and ECC (OR = 2.93, 95% CI: 2.42-3.55. Other metabolic conditions, including obesity and type 2 diabetes, were also associated with increased risks of both cancer types. Smoking was associated with a 46% and 77% increased ICC and ECC risk, respectively. Several autoimmune/inflammatory conditions, including type 1 diabetes and gout, were associated with increased risks of ICC/ECC. As anticipated, viral hepatitis, alcohol-related disorders, and bile duct conditions were associated with both cancer types. However, thyrotoxicosis and hemochromatosis were associated with an increased risk of ICC but not ECC, but did not remain significantly associated after Bonferroni correction.In this study, risk factors for ICC and ECC were similar, with the exceptions of thyrotoxicosis and hemochromatosis. Notably, metabolic conditions were associated with both cancer types. As metabolic conditions are increasing in prevalence, these could be increasingly important risk factors for both types of cholangiocarcinoma.

  9. Percutaneous biliary drainage is oncologically inferior to endoscopic drainage: a propensity score matching analysis in resectable distal cholangiocarcinoma.

    Science.gov (United States)

    Komaya, Kenichi; Ebata, Tomoki; Fukami, Yasuyuki; Sakamoto, Eiji; Miyake, Hideo; Takara, Daisuke; Wakai, Kenji; Nagino, Masato

    2016-06-01

    The aim of this study was to evaluate whether percutaneous transhepatic biliary drainage (PTBD) increases the incidence of seeding metastasis and shortens postoperative survival compared with endoscopic biliary drainage (EBD). A total of 376 patients with distal cholangiocarcinoma who underwent pancreatoduodenectomy following either PTBD (n = 189) or EBD (n = 187) at 30 hospitals between 2001 and 2010 were retrospectively reviewed. Seeding metastasis was defined as peritoneal/pleural dissemination and PTBD sinus tract recurrence. Univariate and multivariate analyses followed by propensity score matching analysis were performed to adjust the data for the baseline characteristics between the two groups. The overall survival of the PTBD group was significantly shorter than that of the EBD group (34.2 % vs 48.8 % at 5 years; P = 0.003); multivariate analysis showed that the type of biliary drainage was an independent predictor of survival (P = 0.036) and seeding metastasis (P = 0.001). After two new cohorts with 82 patients each has been generated after 1:1 propensity score matching, the overall survival rate in the PTBD group was significantly less than that in the EBD group (34.7 % vs 52.5 % at 5 years, P = 0.017). The estimated recurrence rate of seeding metastasis was significantly higher in the PTBD group than in the EBD group (30.7 % vs 10.7 % at 5 years, P = 0.006), whereas the recurrence rates at other sites were similar between the two groups (P = 0.579). Compared with EBD, PTBD increases the incidence of seeding metastasis after resection for distal cholangiocarcinoma and shortens postoperative survival.

  10. BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma.

    Science.gov (United States)

    Parasramka, Mansi; Yan, Irene K; Wang, Xue; Nguyen, Phuong; Matsuda, Akiko; Maji, Sayantan; Foye, Catherine; Asmann, Yan; Patel, Tushar

    2017-01-25

    Genetic alterations in chromatin modulators such as BRCA-1 associated protein-1 (BAP1) are the most frequent genetic alteration in intrahepatic cholangiocarcinomas (CCA). We evaluated the contribution of BAP1 expression on tumor cell behavior and therapeutic sensitivity to identify rationale therapeutic strategies. The impact of BAP1 expression on sensitivity to therapeutic agents was evaluated in CCA cells with a 7-fold difference in BAP1 expression (KMBC-low, HuCCT1-high) and genetically engineered haplo-insufficient BAP1 knockout cells. We also identified long non-coding RNA genes associated with loss of BAP1 and their role in therapeutic sensitivity. Sensitivity to gemcitabine was greater in low BAP1 expressing or BAP1 knockout cells compared with the high BAP1 expressing cells or control haplo-insufficient cells respectively. Similar results were observed with TSA, olaparib, b-AP15 but not with GSK126. A differential synergistic effect was observed in combinations of gemcitabine with olaparib or GSK126 in KMBC cells and TSA or bAP15 in HuCCT1 cells, indicating BAP1 dependent target-specific synergism and sensitivity to gemcitabine. A BAP1 dependent alteration in expression of lncRNA NEAT-1 was identified by RT-PCR based lncRNA expression profiling, and an inverse relationship between this lncRNA and BAP1 was observed in analysis of the Tumor Cancer Genome Atlas cholangiocarcinoma dataset. Exogenous modulation of NEAT-1 and/or BAP1 expression altered tumor cell phenotype and modulated sensitivity to gemcitabine. NEAT-1 is a downstream effector of gemcitabine sensitivity in CCA. The expression of BAP1 is a determinant of sensitivity to therapeutic drugs that can be exploited to enhance responses through combination strategies.

  11. Improved oncologic outcome with chemoradiotherapy followed by surgery in unresectable intrahepatic cholangiocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Yeona; Kim, Tae Hyung; Seong, Jinsil [Yonsei University College of Medicine, Department of Radiation Oncology, Yonsei Cancer Center, Seoul (Korea, Republic of)

    2017-08-15

    To investigate the ability of chemoradiotherapy (CRT) to down-stage unresectable intrahepatic cholangiocarcinoma (IHCC) to resectable lesions, as well as the factors associated with achieving such down-staging. The study cohort comprised 120 patients diagnosed with stage I-IVA IHCC between 2001 and 2012. Of these patients, 56 underwent surgery and 64 received CRT as their initial treatment. The rate of curative resections for patients who received CRT was assessed, and the locoregional failure-free survival (LRFFS) and overall survival (OS) rates of these patients were compared to those of patients who underwent CRT alone. Median follow-up was 36 months. A partial response after CRT was observed in 25% of patients, whereas a biologic response (a >70% decrease of CA19-9) was observed in 35%. Eight patients (12.5%) received curative resection after CRT and showed significantly improved LRFFS and OS compared to those treated with CRT alone (3-year LRFFS: 50 vs. 15.7%, respectively, p = 0.03; 3-year OS: 50 vs. 11.2%, respectively, p = 0.012); these rates were comparable to those of patients who received initial surgery. Factors associated with curative surgery after CRT were gemcitabine administration, higher radiotherapy dose (biological effective dose ≥55 Gy with α/β = 10), and a >70% reduction of CA19-9. Upfront CRT could produce favorable outcomes by converting unresectable lesions to resectable tumors in selected patients. Higher radiotherapy doses and gemcitabine-based chemotherapy yielded a significant reduction of CA19-9 after CRT; patients with these characteristics had a greater chance of curative resection and improved OS. (orig.) [German] Untersuchung der Faehigkeit der Radiochemotherapie (CRT), unauffaellige intrahepatische Cholangiokarzinome (IHCC) auf resezierbare Laesionen herunterzustufen sowie der Faktoren, die mit dem Erreichen einer solchen Herabstufung verbunden sind. Die Studienkohorte umfasste 120 Patienten mit einem zwischen 2001 und 2012

  12. The role of F-18 FDG PET/CT in intrahepatic cholangiocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Yeong Joo; Yoo, Le Ryung; Boo, Sun Ha; Kim, Hyoung Woo; Park, Hye Lim; O, Joo Hyun [Dept. of Radiology, Seoul St. Mary' s Hospital, College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of)

    2017-03-15

    The aim of this study was to evaluate the diagnostic and prognostic role of metabolic parameters of FDG PET/CT in patients with intrahepatic cholangiocarcinoma (ICC). From December 2008 to December 2013, 76 FDG PET/CT scans performed for initial staging of ICC in a single institution (57 male and 19 female; mean age 68 ± 9 years) were retrospectively reviewed. Patients with history of other known malignancy were excluded. Detection rates of regional lymph node and distant metastasis by FDG PET/CT were analyzed in comparison with conventional imaging modalities such as CT or MRI. Metabolic parameters including maximum, peak and mean standardized uptake values (SUV{sub max}, SUV{sub peak}, SUV{sub mean}), metabolic tumor volume (MTV), total lesion glycolysis (TLG), glucose corrected SUV (SUV{sub gluc}), and glucose corrected TLG (TLG{sub gluc}) were measured for the primary tumor. Cut-off values for the metabolic parameters were calculated by ROC curve analysis, and used to dichotomize the patient groups. The overall survival time (OS) was calculated and compared using the Cox proportional hazard regression analysis. The median duration of follow-up period was 5.4 months (interquartile range: 1.45∼15.45). FDG PET/CT showed higher sensitivity than conventional imaging modalities in detection of regional node involvement (74.5 % vs. 61.8 %, p = 0.013). In six patients, distant metastasis was identified only by FDG PET/CT. The mean SUV{sub max}, SUV{sub peak}, SUV{sub mean}, MTV, and TLG for the primary tumor were 8.2 ± 3.1, 6.8 ± 2.5, 4.0 ± 0.8, 192.7 ± 360.5 cm{sup 3}, and 823.7 ± 1615.4, respectively. Patients with higher (≥7.3, HR: 4.280, p = 0.001), higher SUV{sub peak} (≥6.5, HR: 2.333, p = 0.020), higher SUV{sub mean} (≥3.9, HR: 2.799, p = 0.004), higher SUV{sub gluc} (≥8.1, HR: 2.648, p = 0.012), and higher TLG{sub gluc} (≥431.6, HR: 2.186, p = 0.030) showed significantly shorter survival time. By

  13. Liver parenchyma transection-first approach in hemihepatectomy with en bloc caudate lobectomy for hilar cholangiocarcinoma: A safe technique to secure favorable surgical outcomes.

    Science.gov (United States)

    Kawabata, Yasunari; Hayashi, Hikota; Yano, Seiji; Tajima, Yoshitsugu

    2017-06-01

    Although hemihepatectomy with total caudate lobectomy (hemiHx-tc) is essential for the surgical treatment of hilar cholangiocarcinoma, the advantage of an anterior approach for hemiHx-tc has not been fully discussed technically; the significance of an anterior approach without liver mobilization for preventing infectious complications also remains unknown. The liver parenchyma transection-first approach (Hp-first) technique is an early transection of the hepatic parenchyma without mobilization of the liver that utilizes a modified liver-hanging maneuver to avoid damaging the future remnant liver. Between May 2010 and August 2016, a total of 40 consecutive patients underwent surgery for hilar cholangiocarcinoma. Of these, 19 patients underwent a conventional hemihepatectomy with total caudate lobectomy (cHx), while 21 patients received a Hp-first. The patients in the Hp-first group had significantly less intraoperative blood loss (P < 0.001) and blood transfusion (P < 0.001), a lower incidence of postoperative hyperbilirubinemia (p = 0.023), a lower incidence of liver failure (p = 0.038), a lower hospital death rate (p = 0.042), and a better 2-year disease-free survival rate (p = 0.010) than those in the cHx group. The liver parenchyma transection-first approach is the preferred technique for hemiHx-tc in hilar cholangiocarcinoma because it resulted in improved surgical outcomes as compared with the conventional approach. © 2017 Wiley Periodicals, Inc.

  14. Differentiation of infiltrative cholangiocarcinoma from benign common bile duct stricture using three-dimensional dynamic contrast-enhanced MRI with MRCP.

    Science.gov (United States)

    Yu, X-R; Huang, W-Y; Zhang, B-Y; Li, H-Q; Geng, D-Y

    2014-06-01

    To retrospectively evaluate the criteria for discriminating infiltrative cholangiocarcinoma from benign common bile duct (CBD) stricture using three-dimensional dynamic contrast-enhanced (3D-DCE) magnetic resonance imaging (MRI) combined with magnetic resonance cholangiopancreatography (MRCP) imaging and to determine the predictors for cholangiocarcinoma versus benign CBD stricture. 3D-DCE MRI and MRCP images in 28 patients with infiltrative cholangiocarcinoma and 23 patients with benign causes of CBD stricture were reviewed retrospectively. The final diagnosis was based on surgical or biopsy records. Two radiologists analysed the MRI images for asymmetry, including the wall thickness, length, and enhancement pattern of the narrowed CBD segment, and upstream CBD dilatation. MRI findings that could be used as predictors were identified by univariate analysis and multivariable stepwise logistic regression analysis. Malignant strictures were significantly thicker (4.4 ± 1.2 mm) and longer (16.7 ± 7.7 mm) than the benign strictures (p < 0.05), and upstream CBD dilatation was larger in the infiltrative cholangiocarcinoma cases (20.7 ± 5.7 mm) than in the benign cases (16.5 ± 5.2 mm; p = 0.018). During both the portal venous and equilibrium phases, hyperenhancement was more frequently observed in malignant cases than in benign cases (p < 0.001). The results of the multivariable stepwise logistic regression analysis showed that both hyperenhancement of the involved CBD during the equilibrium phase and the ductal thickness were significant predictors for malignant strictures. When two diagnostic predictive values were used in combination, almost all patients with malignant strictures (n = 26, 92.9%) and benign strictures (n = 21, 91.3%) were correctly identified; the overall accuracy was 92.2% with correct classifications in 47 of the 51 patients. Infiltrative cholangiocarcinoma and benign CBD strictures could be effectively differentiated using DCE-MRI and MRCP based

  15. ETL, a novel seven-transmembrane receptor that is developmentally regulated in the heart. ETL is a member of the secretin family and belongs to the epidermal growth factor-seven-transmembrane subfamily.

    Science.gov (United States)

    Nechiporuk, T; Urness, L D; Keating, M T

    2001-02-09

    Using differential display of rat fetal and postnatal cardiomyocytes, we have identified a novel seven-transmembrane receptor, ETL. The cDNA-predicted amino acid sequence of ETL indicated that it encodes a 738-aa protein composed of a large extracellular domain with epidermal growth factor (EGF)-like repeats, a seven-transmembrane domain, and a short cytoplasmic tail. ETL belongs to the secretin family of G-protein-coupled peptide hormone receptors and the EGF-TM7 subfamily of receptors. The latter are characterized by a variable number of extracellular EGF and cell surface domains and conserved seven transmembrane-spanning regions. ETL mRNA expression is up-regulated in the adult rat and human heart. In situ hybridization analyses revealed expression in rat cardiomyocytes and abundant expression in vascular and bronchiolar smooth muscle cells. In COS-7 cells transfected with Myc-tagged rat ETL, rat ETL exists as a stable dimer and undergoes endoproteolytic cleavage of the extracellular domain. The proteolytic activity can be abolished by a specific mutation, T455A, in this domain. In transfected mammalian cells, ETL is associated with cell membranes and is also observed in cytoplasmic vesicles. ETL is the first seven-transmembrane receptor containing EGF-like repeats that is developmentally regulated in the heart.

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

    Science.gov (United States)

    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; Zhu, Andrew X

    2015-09-01

    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. 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. 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. 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. 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 unresectable or metastatic disease, and the current study is the first to

  17. Influence of exogenous overexpression of KAI1 on the expression of laminin receptor in human cholangiocarcinoma cell line

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    Xiao-ming DENG

    2011-02-01

    Full Text Available Objective To investigate the effects of exogenous overexpression of KAI1 on laminin receptor(LNR in human cholangiocarcinoma QBC939 cell line.Methods Human cholangiocarcinoma QBC939 cells were cultured in vitro and divided into two groups:control group(transfecting empty vector,pIRES2-EGFP and experimental group(transfecting recombinant eukaryotic vector,pIRES2-EGFP-KAI1.The pIRES2-EGFP and pIRES2-EGFP-KAI1 were transfected into QBC939 cells line with Lipofectamine 2000.After being screened with G418,the mRNA was then extracted and detected by reverse transcription-polymerase chain reaction(RT-PCR analysis using KAI1 and LNR-specific primers,and an aliquot of protein from each sample was subjected to Western blotting analysis using KAI1 and LNR antibodies.The protein expressions of KAI1 and LNR in two groups were also measured by immunocytochemistry.Results The mRNA and protein levels of KAI1 were significantly higher in experimental group(0.49±0.07 and 1.06±0.05 than in control group(0.22±0.02 and 0.59±0.02,P < 0.01.On the contrary,The mRNA and protein levels of LNR were significantly lower in experimental group(0.38±0.04 and 0.29±0.03 than in control group(0.73±0.05 and 0.68±0.02,P < 0.05.As Compared with the control group,the staining in cytoplasm of KAI1 was intensified and LNR diminished after pIRES2-EGFP-KAI1 plasmid was transfected.Conclusion Exogenous overexpression of KAI1 may down-regulate the LNR mRNA and protein expression in QBC939 cells in vitro.

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

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    Zhang C

    2016-10-01

    Full Text Available Chenyue Zhang,1,2 Haiyong Wang,1,3 Zhouyu Ning,1,2 Litao Xu,1,2 Liping Zhuang,1,2 Peng Wang,1,2 Zhiqiang Meng1,2 1Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 3Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, People’s Republic of China Objective: The significance of the prognostic nutritional index (PNI has been widely reported and confirmed in many types of cancers. However, few studies are available indicating its prognostic power in patients with intrahepatic cholangiocarcinoma (ICC. Thus, we investigated its relationship with overall survival (OS to evaluate its role in predicting survival in patients with ICC. Patients and methods: Between October 2011 and October 2015, 173 consecutive patients with pathologically confirmed locally advanced or metastatic ICC were enrolled. First, the correlations between PNI and clinical factors were analyzed among these patients. Next, univariate and multivariate analyses were conducted to evaluate the association between PNI and OS among these patients with ICC. In addition, the relationships between PNI and three typical systemic inflammatory response (SIR markers – the neutrophil/lymphocyte ratio (NLR, the platelet/lymphocyte ratio (PLR, and the lymphocyte/monocyte ratio (LMR – were also assessed. Results: A lower PNI was linked with a shorter OS in patients with ICC, as reflected obviously in the Kaplan–Meier analyses. The patients with ICC were divided into the locally advanced group and the metastatic group. Further analyses revealed that PNI is not associated with OS in the locally advanced group. However, in the subgroup of patients with metastatic ICC, a lower PNI significantly correlated with a worsened OS. The OS for patients with a low PNI is 5 months, whereas the OS is 10.17 months for patients with a high PNI. Multivariate analyses revealed

  19. SOX17 Regulates Cholangiocyte Differentiation and Acts as a Tumor Suppressor in Cholangiocarcinoma

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    Merino-Azpitarte, M; Lozano, E; Perugorria, M J

    2017-01-01

    the expression of biliary markers and primary cilium length. In human CCA, SOX17 promoter was found hypermethylated and its expression inversely correlates with the methylation grade. In NHC, Wnt3a decreased SOX17 expression in a DNMT-dependent manner, whereas in CCA, DNMT1 inhibition or silencing upregulated...

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

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    Andrej Wagner

    2015-11-01

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

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

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    Le-Hang Guo

    2015-01-01

    Full Text Available 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.

  2. Spread of hilar cholangiocarcinomas via peribiliary gland network: a hither-to-unrecognized route of periductal infiltration

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    Sato, Hirohide; Nakanuma, Yasuni; Kozaka, Kazuto; Sato, Yasunori; Ikeda, Hiroko

    2013-01-01

    Cholangiocarcinomas (CCs) show intraluminal spread to bile ducts and periductal infiltration associated with vascular, lymphatic and perineural invasion in addition to direct penetration. Recently, the peribiliary gland networks located around the hilar and extrahepatic bile ducts have been reportedly to be involved in a variety of biliary diseases. However, the pathological features and roles of these networks in the carcinogenesis and progression of CCs remain to be explored. Recently, we experienced two cases of hilar CC showing a nodular sclerosing growth grossly and histologically well-differentiated adenocarcinomas, with an extensive involvement of the peribiliary gland networks. In situ like spread of carcinoma cells in the bile duct lumen was focal in one case and not identifiable in the other. In contrast, other 4 cases of ordinary hilar CC which were also well-differentiated adenocarcinomas, showed variable intraductal luminal spread and also extensive periductal infiltration irrespective of the peribiliary gland network. In conclusion, the present study showed a unique form of periductal spread of CCs with preferential and extensive involvement of the peribiliary gland networks. PMID:23330019

  3. Fruit and Vegetables Consumption: A Pointer for Cholangiocarcinoma Prevention in Northeast Thailand, the Highest Incidence Area in the World.

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    Songserm, Nopparat; Woradet, Somkiattiyos; Charoenbut, Pattaraporn

    2016-01-01

    Cholangiocarcinoma (CCA) caused by opisthorchiasis is a specific public health problem in the Greater Mekong subregional countries. The Northeast Thailand is considered a world's prime area of CCA. Many epidemiological studies found the association between fruit and vegetables consumption and CCA, but their results were inconclusive. Therefore, this meta-analysis aimed to investigate the relationship between fruit and vegetables consumption and CCA prevention in the Northeast Thailand. The authors conducted a comprehensive search of scholarships on MEDLINE, EMBASE, and SCOPUS published during 1990 and 2015. Selected studies about fruit and vegetables consumption and CCA were analyzed. The fixed-effect model was used to estimate pool odds ratios for the consumption vs. nonconsumption. Based on a meta-analysis, consumption of mixed fruit [odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.65-0.96], mixed vegetables (OR = 0.61; 95% CI: 0.50-0.75), and combined fruit and vegetables (OR = 0.68; 95% CI: 0.57-0.80) was associated with the reduction of CCA risk statistically. These findings support that fruit and vegetables consumption is associated with CCA risk reduction. If implemented in a larger geographical area, the study will shed light on possibilities to future reduction of CCA. Educators can replicate the study to solve CCA or other types of cancer and discover the best practice.

  4. Humoral Hypercalcemia of Malignancy with a Parathyroid Hormone-Related Peptide-Secreting Intrahepatic Cholangiocarcinoma Accompanied by a Gastric Cancer

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    Katsushi Takeda

    2017-01-01

    Full Text Available Humoral hypercalcemia of malignancy (HHM is caused by the oversecretion of parathyroid hormone-related peptide (PTHrP from malignant tumors. Although any tumor may cause HHM, that induced by intrahepatic cholangiocarcinoma (ICC or gastric cancer (GC is rare. We report here a 74-year-old male who displayed HHM with both ICC and GC and showed an elevated serum PTHrP level. Treatment of the hypercalcemia with saline, furosemide, elcatonin, and zoledronic acid corrected his serum calcium level and improved symptoms. Because treatment of ICC should precede that of GC, we chose chemotherapy with cisplatin (CDDP and gemcitabine (GEM. Chemotherapy reduced the size of the ICC and decreased the serum PTHrP level. One year after diagnosis, the patient was alive in the face of a poor prognosis for an ICC that produced PTHrP. Immunohistochemical staining for PTHrP was positive for the ICC and negative for the GC, leading us to believe that the cause of the HHM was a PTHrP-secreting ICC. In conclusion, immunohistochemical staining for PTHrP may be useful in discovering the cause of HHM in the case of two cancers accompanied by an elevated serum PHTrP level. Chemotherapy with CDDP and GEM may be the most appropriate treatment for a PTHrP-secreting ICC.

  5. Cholangiocarcinomas: New Insights from the Discovery of Stem Cell Niches in Peribiliary Glands of the Biliary Tree

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    Vincenzo Cardinale

    2014-01-01

    Full Text Available Peribiliary glands (PBGs are located in the large intrahepatic and extrahepatic bile ducts. Although they were described many years ago, their functions have been elucidated only in the last couple of years when our group demonstrated that PBGs are niches of multipotent stem/progenitor cells of endodermal origin. These cells express genes of multipotency and can be rapidly differentiated in vitro into hepatocytes, cholangiocytes, and endocrine pancreatic cells. PBGs share common features, in terms of stem/progenitor cell niches, with pancreatic duct glands and colon crypts, glandular structures representing in the adult life the endodermal remnants of fetal life. PBG stem/progenitor cells participate in the renewal of surface biliary epithelium and are active players in chronic pathologies of the biliary tree as well as in cholangiocarcinomas (CCA. Specifically, a large amount of recent evidence indicates that the pure mucin-CCA originates from PBGs; this could explain the similarities with pancreatic ductal adenocarcinoma and colorectal cancer, which also originate from transformed gland cells. In this paper, we summarized our recent findings concerning structure and functions of PBGs with the implications for liver pathophysiology and, specifically, for cancers of the biliary tree.

  6. Inducible liver-specific overexpression of gankyrin in zebrafish results in spontaneous intrahepatic cholangiocarcinoma and hepatocellular carcinoma formation.

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    Huang, Shin-Jie; Cheng, Chih-Lun; Chen, Jim-Ray; Gong, Hong-Yi; Liu, Wangta; Wu, Jen-Leih

    2017-08-26

    Liver cancer is the second leading cause of death worldwide. As such, establishing animal models of the disease is important for both basic and translational studies that move toward developing new therapies. Gankyrin is a critical oncoprotein in the genetic control of liver pathology. In order to evaluate the oncogenic role of gankyrin without cancer cell inoculation and drug treatment, we overexpressed gankyrin under the control of the fabp10a promoter. A Tet-Off system was used to drive expression in hepatocytes. At seven to twelve months of age, gankyrin transgenic fish spontaneously incurred persistent hepatocyte damage, steatosis, cholestasis, cholangitis, fibrosis and hepatic tumors. The tumors were both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). ICC is the second most frequent primary liver cancer in human patients and the first to develop in this tumor model. We further investigated the role of complement C3, a central molecule of the complement system, and found the expression levels of both in mRNA and protein are decreased during tumorigenesis. Together, these findings suggest that gankyrin can promote malignant transformation of liver cells in the context of persistent liver injury. This transformation may be related to compensatory proliferation and the inflammatory microenvironment. The observed decrease in complement C3 may allow transforming cells to escape coordinated induction of the immune response. Herein, we demonstrate an excellent zebrafish model for liver cancers that will be useful for studying the molecular mechanisms of tumorgenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Risk stratification and prognostic nomogram for post-recurrence overall survival in patients with recurrent extrahepatic cholangiocarcinoma.

    Science.gov (United States)

    Kim, Byoung Hyuck; Kim, Kyubo; Chie, Eui Kyu; Kwon, Jeanny; Jang, Jin-Young; Kim, Sun Whe; Oh, Do-Youn; Bang, Yung-Jue

    2017-05-01

    This study aimed to investigate post-recurrence overall survival (PROS) in patients with recurrent extrahepatic cholangiocarcinoma (EHC) and to indicate which groups of patients need active salvage treatments. We retrospectively reviewed the records of 251 consecutive patients who underwent curative surgery followed by adjuvant chemoradiotherapy for EHC. Among these, 144 patients experienced a recurrence and were included for further analysis. The median PROS was 7 months (range, 1-130). In multivariate analysis, poorly differentiated histology, short disease-free survival, poor performance status, and elevated CA 19-9 were identified as significant prognosticators for poor PROS. Based on this, we stratified study patients into three categories by the number of risk factors: group 1 (0 or 1 factors), group 2 (2 factors) and group 3 (3-4 factors). Median PROS for groups 1, 2, and 3 were 13, 7, and 5 months, respectively (p < 0.001). Group 1 patients showed a significant benefit from salvage treatment, but groups 2 and 3 did not demonstrate clear benefit. In addition, we developed a nomogram to specifically identify individual patient's prognosis. Our simple risk stratification as well as proposed nomogram can classify patients into subgroups with different prognosis and will help facilitate personalized strategies after recurrence. Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

  8. Mass-forming intrahepatic cholangiocarcinoma: Enhancement patterns in the arterial phase of dynamic hepatic CT - Correlation with clinicopathological findings

    Energy Technology Data Exchange (ETDEWEB)

    Fujita, Nobuhiro; Asayama, Yoshiki; Nishie, Akihiro; Ishigami, Kousei; Ushijima, Yasuhiro; Okamoto, Daisuke; Moirta, Koichiro; Honda, Hiroshi [Kyushu University, Department of Clinical Radiology, Graduate School of Medical Sciences, Higashi-ku, Fukuoka (Japan); Takayama, Yukihisa [Kyushu University, Department of Radiology Informatics and Network, Graduate School of Medical Sciences, Higashi-ku, Fukuoka (Japan); Shirabe, Ken [Kyushu University, Department of Surgery and Science, Graduate School of Medical Sciences, Higashi-ku, Fukuoka (Japan); Aishima, Shinichi [Saga University Hospital, Department of Pathology and Microbiology, Faculty of Medicine, Saga City, Saga (Japan); Wang, Huanlin; Oda, Yoshinao [Kyushu University, Department of Anatomic Pathology, Graduate School of Medical Sciences, Higashi-ku, Fukuoka (Japan)

    2017-02-15

    To evaluate the relationship between the enhancement pattern of intrahepatic cholangiocarcinomas (ICCs) in the hepatic arterial phase (HAP) of dynamic hepatic CT and the clinicopathological findings with special reference to the perihilar type and the peripheral type. Forty-seven patients with pathologically proven ICCs were enrolled. Based on the enhancement pattern in the HAP, the lesions were classified into three groups: a hypovascular group (n=13), rim-enhancement group (n=18), and hypervascular group (n=16). The clinicopathological findings were compared among the three groups. Perihilar-type ICCs were significantly more frequently observed in the hypovascular group than in the rim-enhancement and hypervascular groups (p=0.006 and p <0.001, respectively). Lymphatic invasion, perineural invasion, and biliary invasion were significantly more frequent in the hypovascular group than the rim- enhancement group (p=0.001, p=0.025 and p=0.029, respectively) or hypervascular group (p <0.001, p <0.001 and p=0.025, respectively). Patients with hypovascular lesions showed significantly poorer disease-free survival than patients with rim-enhancing or hypervascular lesions (p=0.001 and p=0.001, respectively). Hypovascularity was an independent preoperative prognostic factor for disease-free survival (p<0.001). Hypovascular ICCs in the HAP tend to be of perihilar type and to have more malignant potential than other ICCs. (orig.)

  9. Ultrasonography as a tool for monitoring the development and progression of cholangiocarcinoma in Opisthorchis viverrini/ dimethylnitrosamine-induced hamsters.

    Science.gov (United States)

    Plengsuriyakarn, Tullayakorn; Eursitthichai, Veerachai; Labbunruang, Nipawan; Na-Bangchang, Kesara; Tesana, Smarn; Aumarm, Waraporn; Pongpradit, Ananya; Viyanant, Vithoon

    2012-01-01

    Cholangiocarcinoma (CCA) is the most common cancer in northeastern Thailand. At present, effective diagnosis of CCA either in humans or animals is not available. Monitoring the development and progression of CCA in animal models is essential for research and development of new promising chemotherapeutics. Ultrasonography has been widely used for screening of bile duct obstruction in CCA patients. In this study, we preliminarily investigated the applicability of ultrasonography to monitor the development and progression of CCA in Syrian golden hamsters (n=8) induced by Opisthorchis viverrini (OV)/dimethylnitrosamine (DMN) administration. Ultrasonography and histopathological examination of hamsters was performed at week 0, 20, 24 and 28 of OV infection or at the start of water/Tween-80 administration to controls. The ultrasonographic images of liver parenchyma and gallbladders of OV/DMN-induced CCA hamsters showed sediments in gallbladder, thickening of gallbladder wall, and hypoechogenicity of liver parenchyma cells. The ultrasonographic images of liver tissues were found to correlate well with histopathological examination. Although ultrasonography does not directly detect the occurrence of CCA, it reflects the thickening of bile ducts and abnormality of liver tissues. It may be applied as a reliable tool for monitoring the development and progression of CCA in animal models in research and development of new promising chemotherapeutics for CCA.

  10. Differentiation of intrahepatic mass-forming cholangiocarcinoma from hepatocellular carcinoma on gadoxetic acid-enhanced liver MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Rihyeon; Shin, Cheong-Il; Yoon, Jeong Hee; Joo, Ijin; Kim, Seong Ho; Hwang, Inpyeong [Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Lee, Jeong Min; Han, Joon Koo [Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Seoul National University Hospital, Institute of Radiation Medicine, Seoul (Korea, Republic of); Lee, Eun Sun; Choi, Byung Ihn [Chung-Ang University Hospital, Department of Radiology, Seoul (Korea, Republic of)

    2016-06-15

    To determine the different imaging features of intrahepatic mass-forming cholangiocarcinoma (IMCC) from hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced magnetic resonance imaging (MRI). This retrospective study was institutional review board approved and the requirement for informed consent was waived. Patients who underwent gadoxetic acid-enhanced MRI with histologically confirmed IMCCs (n = 46) or HCCs (n = 58) were included. Imaging features of IMCCs and HCCs on gadoxetic acid-enhanced MRI including T2- and T1-weighted, diffusion weighted images, dynamic study and hepatobiliary phase (HBP) images were analyzed. Univariate and multivariate logistic regression analyses were performed to identify relevant differentiating features between IMCCs and HCCs. Multivariate analysis revealed heterogeneous T2 signal intensity and a hypointense rim on the HBP as suggestive findings of IMCCs and the wash-in and ''portal wash-out'' enhancement pattern as well as focal T1 high signal intensity foci as indicative of HCCs (all, p < 0.05). When we combined any three of the above four imaging features, we were able to diagnose IMCCs with 94 % (43/46) sensitivity and 86 % (50/58) specificity. Combined interpretation of enhancement characteristics including HBP images, morphologic features, and strict application of the ''portal wash-out'' pattern helped more accurate discrimination of IMCCs from HCCs. (orig.)

  11. Tumour cell–derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth

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    Hiroaki Haga

    2015-01-01

    Full Text Available The contributions of mesenchymal stem cells (MSCs to tumour growth and stroma formation are poorly understood. Tumour cells can transfer genetic information and modulate cell signalling in other cells through the release of extracellular vesicles (EVs. We examined the contribution of EV-mediated inter-cellular signalling between bone marrow MSCs and tumour cells in human cholangiocarcinoma, highly desmoplastic cancers that are characterized by tumour cells closely intertwined within a dense fibrous stroma. Exposure of MSCs to tumour cell–derived EVs enhanced MSC migratory capability and expression of alpha-smooth muscle actin mRNA, in addition to mRNA expression and release of CXCL-1, CCL2 and IL-6. Conditioned media from MSCs exposed to tumour cell–derived EVs increased STAT-3 phosphorylation and proliferation in tumour cells. These effects were completely blocked by anti-IL-6R antibody. In conclusion, tumour cell–derived EVs can contribute to the generation of tumour stroma through fibroblastic differentiation of MSCs, and can also selectively modulate the cellular release of soluble factors such as IL-6 by MSCs that can, in turn, alter tumour cell proliferation. Thus, malignant cells can “educate” MSCs to induce local microenvironmental changes that enhance tumour cell growth.

  12. TGF-β signaling is an effective target to impair survival and induce apoptosis of human cholangiocarcinoma cells: A study on human primary cell cultures.

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    Anna Maria Lustri

    Full Text Available Cholangiocarcinoma (CCA and its subtypes (mucin- and mixed-CCA arise from the neoplastic transformation of cholangiocytes, the epithelial cells lining the biliary tree. CCA has a high mortality rate owing to its aggressiveness, late diagnosis and high resistance to radiotherapy and chemotherapeutics. We have demonstrated that CCA is enriched for cancer stem cells which express epithelial to mesenchymal transition (EMT traits, with these features being associated with aggressiveness and drug resistance. TGF-β signaling is upregulated in CCA and involved in EMT. We have recently established primary cell cultures from human mucin- and mixed-intrahepatic CCA. In human CCA primary cultures with different levels of EMT trait expression, we evaluated the anticancer effects of: (i CX-4945, a casein kinase-2 (CK2 inhibitor that blocks TGF-β1-induced EMT; and (ii LY2157299, a TGF-β receptor I kinase inhibitor. We tested primary cell lines expressing EMT trait markers (vimentin, N-cadherin and nuclear catenin but negative for epithelial markers, and cell lines expressing epithelial markers (CK19-positive in association with EMT traits. Cell viability was evaluated by MTS assays, apoptosis by Annexin V FITC and cell migration by wound-healing assay.at a dose of 10 μM, CX4945 significantly decreased cell viability of primary human cell cultures from both mucin and mixed CCA, whereas in CK19-positive cell cultures, the effect of CX4945 on cell viability required higher concentrations (>30μM. At the same concentrations, CX4945 also induced apoptosis (3- fold increase vs controls which correlated with the expression level of CK2 in the different CCA cell lines (mucin- and mixed-CCA. Indeed, no apoptotic effects were observed in CK19-positive cells expressing lower CK2 levels. The effects of CX4945 on viability and apoptosis were associated with an increased number of γ-H2ax (biomarker for DNA double-strand breaks foci, suggesting the active role of CK2 as

  13. Robotic surgery twice performed in the treatment of hilar cholangiocarcinoma with deep jaundice: delayed right hemihepatectomy following the right-hepatic vascular control.

    Science.gov (United States)

    Zhu, Zhenyu; Liu, Quanda; Chen, Junzhou; Duan, Weihong; Dong, Maosheng; Mu, Peiyuan; Cheng, Di; Che, Honglei; Zhang, Tao; Xu, Xiaoya; Zhou, Ningxin

    2014-10-01

    To explore and find a new method to treat hilar cholangiocarcinoma with deep jaundice assisted by Da Vinci robot. A hilar cholangiocarcinoma patient of type Bismuch-Corlette IIIa was found with deep jaundice (total bilirubin: 635 µmol/L). On the first admission, we performed Da Vinci robotic surgery including drainage of left hepatic duct, dissection of right hepatic vessels (right portal vein and right hepatic artery), and placement of right-hepatic vascular control device. Three weeks later on the second admission when the jaundice disappeared we occluded right-hepatic vascular discontinuously for 6 days and then sustained later. On the third admission after 3 weeks of right-hepatic vascular control, the right hemihepatectomy was performed by Da Vinci robot for the second time. The future liver remnant after the right-hepatic vascular control increased from 35% to 47%. The volume of left lobe increased by 368 mL. When the total bilirubin and liver function were all normal, right hemihepatectomy was performed by Da Vinci robot 10 weeks after the first operation. The removal of atrophic right hepatic lobe with tumor in bile duct was found with no pathologic cancer remaining in the margin. The patient was followed up at our outpatient clinic every 3 months and no tumor recurrence occurs by now (1 y). Under the Da Vinci robotic surgical system, a programmed treatment can be achieved: first, the hepatic vessels were controlled gradually together with biliary drainage, which results in liver's partial atrophy and compensatory hypertrophy in the other part. Then a radical hepatectomy could be achieved. Such programmed hepatectomy provides a new treatment for patients of hilar cholangiocarcinoma with deep jaundice who have the possibility of radical heptolobectomy.

  14. Management of empyema of gallbladder with percutaneous cholecysto-duodenal stenting in a case of hilar cholangiocarcinoma treated with common bile duct metallic stenting

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    Sheo Kumar

    2011-01-01

    Full Text Available Empyema of the gallbladder develops when the gallbladder neck is obstructed in the presence of infection, preventing pus from draining via the cystic duct. Treatment options include cholecystectomy or, in patients with comorbidities, drainage via percutaneous cholecystostomy, later followed by cholecystectomy. Here, we describe a 59-year-old man who presented with complaints of recurrent hiccups and was found to have cholangiocarcinoma causing obstruction to cystic duct drainage. The patient was managed successfully by percutaneous transhepatic cholecysto-duodenal self-expandable covered metal stent.

  15. Distribution of the Population at Risk of Cholangiocarcinoma in Bua Yai District, Nakhon Ratchasima of Thailand Using Google Map.

    Science.gov (United States)

    Kaewpitoon, Soraya J; Rujirakul, Ratana; Sangkudloa, Amnat; Kaewthani, Sarochinee; Khemplila, Kritsakorn; Cherdjirapong, Karuna; Kujapun, Jirawoot; Norkaew, Jun; Chavengkun, Wasugree; Ponphimai, Sukanya; Polsripradist, Poowadol; Padchasuwan, Natnapa; Joosiri, Apinya; Wakkhuwattapong, Parichart; Loyd, Ryan A; Matrakool, Likit; Tongtawee, Taweesak; Panpimanmas, Sukij; Kaewpitoon, Natthawut

    2016-01-01

    Cholangiocarcinoma (CCA), a major problem of health in Thailand, particularly in Northeastern and Northern regions, is generally incurable and rapidly lethal because of presentation in stage 3 or 4. Early diagnosis of stage 1 and 2 could allow better survival. Therefore, this study aimed to provide a distribution map of populations at risk for CCA in BuaYai district of Nakhon Ratchasima province, Northeast Thailand. A cross-sectional survey was carried out in 10 sub-districts and 122 villages, during June and November 2015. The populations at risk for CCA were screened using the Korat CCA verbal screening test (KCVST) and then risk areas were displayed by using Google map (GM). A total of 11,435 individuals from a 26,198 population completed the KCVST. The majority had a low score of risk for CCA (1-4 points; 93.3%). High scores with 6, 7 and 8 points accounted for 1.20%, 0.13% and 0.02%. The population at risk was found frequently in sub-district municipalities, followed by sub-district administrative organization and town municipalities, (F=396.220, P-value=0.000). Distribution mapping comprised 11 layers: 1, district; 2, local administrative organization; 3, hospital; 4, KCVST opisthorchiasis; 5, KCVST praziquantel used; 6, KCVST cholelithiasis; 7, KCVST raw fish consumption; 8, KCVST alcohol consumption; 9, KCVST pesticide used; 10, KCVST relative family with CCA; and 11, KCVST naive northeastern people. Geovisual display is now available online. This study indicated that the population at high risk of CCA in Bua Yai district is low, therefore setting a zero model project is possible. Key success factors for disease prevention and control need further study. GM production is suitable for further CCA surveillance and monitoring of the population with a high risk score in this area.

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

    Science.gov (United States)

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

    2015-09-01

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

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

    Science.gov (United States)

    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; Wang, Wei-Hu

    2015-04-01

    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. 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). 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. 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.

  18. An S100P-positive biliary epithelial field is a preinvasive intraepithelial neoplasm in nodular-sclerosing cholangiocarcinoma.

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    Nakanuma, Yasuni; Uchida, Tsuneyuki; Sato, Yasunori; Uesaka, Katsuhiko

    2017-02-01

    Nodular-sclerosing cholangiocarcinoma (NS-CCA) is a common CCA of the intrahepatic large, perihilar, and distal bile ducts. Intraepithelial biliary neoplasms, such as the mucosal extension of carcinoma and preinvasive neoplastic lesions (ie, biliary intraepithelial neoplasia) reportedly occur in the bile ducts around CCA. In the present study, we collectively refer to these intraepithelial lesions as "intraepithelial neoplasms of the bile duct (IENBs)". We examined the IENBs in 57 surgically resected cases of NS-CCA. S100P immunostaining was used to help detect IENBs. The IENBs formed field(s) of continuous neoplastic biliary epithelial cells and showed a flat, micropapillary, or papillotubular configuration. IENBs could be classified into 3 categories based on their atypia: group A (neoplastic but not enough for malignancy), B (neoplastic and sufficiently well differentiated for high-grade dysplasia), and C (overtly malignant and variably differentiated). IENB was found in 31 of 57 cases, with group C the most common (26 cases) followed by group B (22 cases) and group A (16 cases). The expression of cancer-related molecules and MIB-1 index of groups A and B differed from those of invasive CCA, whereas these features of group C were relatively similar to those of invasive CCA. In conclusion, IENB was not infrequently found in NS-CCA and could be classified into 3 grades. Preinvasive lesions (biliary intraepithelial neoplasias) are likely to be found in groups A and B, whereas cancerization would be included in group C. The classification of IENB may be useful for future studies of the preinvasive intraepithelial neoplastic lesions of NS-CCAs. Copyright © 2016. Published by Elsevier Inc.

  19. Addition of Molecular Adsorbent Recirculating System (MARS® Albumin Dialysis for the Preoperative Management of Jaundiced Patients with Hilar Cholangiocarcinoma

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    Jean-Marc Regimbeau

    2013-09-01

    Full Text Available The preoperative management of hilar cholangiocarcinoma (HC with jaundice focuses on decreasing the total serum bilirubin level (SBL by performing preoperative biliary drainage (PBD. However, it takes about 6-8 weeks for the SBL to fall at a sufficient extent. The objective of this preliminary study was to evaluate the impact of Molecular Adsorbent Recirculating System (MARS® dialysis (in association with PBD on SBL decrease. From January 2010 to January 2011, we prospectively selected all jaundiced patients admitted to our university hospital for resectable HC and requiring PBD prior to major hepatectomy. The PBD was followed by 3 sessions of MARS dialysis over a period of 72 h. A total of 10 patients with HC were screened and two of them were included (Bismuth-Corlette stage IIIa, gender ratio 1, median age 68 years. The initial SBL in the two patients was 328 and 242 μmol/l, respectively. After three MARS dialysis sessions, the SBL had fallen by 30 and 52%, respectively. After the end of each session, there was a SBL rebound of about 10 μmol/l. The MARS decreased the serum creatinine level, the platelet count and the prothrombin index, but did not modify the serum albumin level. Pruritus disappeared after one and two sessions, respectively. MARS-related morbidity included hypotension (n = 1, tachycardia (n = 1, thrombocytopenia (n = 2 and anaemia (n = 1. When combined with PBD, MARS dialysis appears to accelerate the decrease in SBL and thus may enable earlier surgery. This hypothesis must be validated in a larger study.

  20. MicroRNAs in Serum and Bile of Patients with Primary Sclerosing Cholangitis and/or Cholangiocarcinoma.

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    Torsten Voigtländer

    Full Text Available Patients with primary sclerosing cholangitis (PSC are at high risk for the development of cholangiocarcinoma (CC. Analysis of micro ribonucleic acid (MiRNA patterns is an evolving research field in biliary pathophysiology with potential value in diagnosis and therapy. Our aim was to evaluate miRNA patterns in serum and bile of patients with PSC and/or CC.Serum and bile from consecutive patients with PSC (n = 40 (serum, n = 52 (bile, CC (n = 31 (serum, n = 19 (bile and patients with CC complicating PSC (PSC/CC (n = 12 (bile were analyzed in a cross-sectional study between 2009 and 2012. As additional control serum samples from healthy individuals were analyzed (n = 12. The miRNA levels in serum and bile were determined with global miRNA profiling and subsequent miRNA-specific polymerase chain reaction-mediated validation.Serum analysis revealed significant differences for miR-1281 (p = 0.001, miR-126 (p = 0.001, miR-26a (p = 0.001, miR-30b (p = 0.001 and miR-122 (p = 0.034 between patients with PSC and patients with CC. All validated miRNAs were significantly lower in healthy individuals. MiR-412 (p = 0.001, miR-640 (p = 0.001, miR-1537 (p = 0.003 and miR-3189 (p = 0.001 were significantly different between patients with PSC and PSC/CC in bile.Patients with PSC and/or CC have distinct miRNA profiles in serum and bile. Furthermore, miRNA concentrations are different in bile of patients with CC on top of PSC indicating the potential diagnostic value of these miRNAs.

  1. MicroRNAs in Serum and Bile of Patients with Primary Sclerosing Cholangitis and/or Cholangiocarcinoma

    Science.gov (United States)

    Voigtländer, Torsten; Gupta, Shashi K.; Thum, Sabrina; Fendrich, Jasmin; Manns, Michael P.; Lankisch, Tim O.; Thum, Thomas

    2015-01-01

    Background and Aim Patients with primary sclerosing cholangitis (PSC) are at high risk for the development of cholangiocarcinoma (CC). Analysis of micro ribonucleic acid (MiRNA) patterns is an evolving research field in biliary pathophysiology with potential value in diagnosis and therapy. Our aim was to evaluate miRNA patterns in serum and bile of patients with PSC and/or CC. Methods Serum and bile from consecutive patients with PSC (n = 40 (serum), n = 52 (bile)), CC (n = 31 (serum), n = 19 (bile)) and patients with CC complicating PSC (PSC/CC) (n = 12 (bile)) were analyzed in a cross-sectional study between 2009 and 2012. As additional control serum samples from healthy individuals were analyzed (n = 12). The miRNA levels in serum and bile were determined with global miRNA profiling and subsequent miRNA-specific polymerase chain reaction-mediated validation. Results Serum analysis revealed significant differences for miR-1281 (p = 0.001), miR-126 (p = 0.001), miR-26a (p = 0.001), miR-30b (p = 0.001) and miR-122 (p = 0.034) between patients with PSC and patients with CC. All validated miRNAs were significantly lower in healthy individuals. MiR-412 (p = 0.001), miR-640 (p = 0.001), miR-1537 (p = 0.003) and miR-3189 (p = 0.001) were significantly different between patients with PSC and PSC/CC in bile. Conclusions Patients with PSC and/or CC have distinct miRNA profiles in serum and bile. Furthermore, miRNA concentrations are different in bile of patients with CC on top of PSC indicating the potential diagnostic value of these miRNAs. PMID:26431155

  2. Impact of Salinomycin on human cholangiocarcinoma: induction of apoptosis and impairment of tumor cell proliferation in vitro

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    Lieke Thorsten

    2012-10-01

    Full Text Available Abstract Background Cholangiocarcinoma (CC is a primary liver cancer with increasing incidence worldwide. Despite all efforts made in past years, prognosis remains to be poor. At least in part, this might be explained by a pronounced resistance of CC cells to undergo apoptosis. Thus, new therapeutic strategies are imperatively required. In this study we investigated the effect of Salinomycin, a polyether ionophore antibiotic, on CC cells as an appropriate agent to treat CC. Salinomycin was quite recently identified to induce apoptosis in cancer stem cells and to overcome apoptosis-resistance in several leukemia-cells and other cancer cell lines of different origin. Methods To delineate the effects of Salinomycin on CC, we established an in vitro cell culture model using three different human CC cell lines. After treatment apoptosis as well as migration and proliferation behavior was assessed and additional cell cycle analyses were performed by flowcytometry. Results By demonstrating Annexin V and TUNEL positivity of human CC cells, we provide evidence that Salinomycin reveals the capacity to break apoptosis-resistance in CC cells. Furthermore, we are able to demonstrate that the non-apoptotic cell fraction is characterized by sustainable impaired migration and proliferation. Cell cycle analyses revealed G2-phase accumulation of human CC cells after treatment with Salinomycin. Even though apoptosis is induced in two of three cell lines of CC cells, one cell line remained unaffected in regard of apoptosis but revealed as the other CC cells decreased proliferation and migration. Conclusion In this study, we are able to demonstrate that Salinomycin is an effective agent against previously resistant CC cells and might be a potential candidate for the treatment of CC in the future.

  3. Application of Joint Detection of AFP, CA19-9, CA125 and CEA in Identification and Diagnosis of Cholangiocarcinoma.

    Science.gov (United States)

    Li, Yong; Li, Da-Jiang; Chen, Jian; Liu, Wei; Li, Jian-Wei; Jiang, Peng; Zhao, Xin; Guo, Fei; Li, Xiao-Wu; Wang, Shu-Guang

    2015-01-01

    To explore the application of joint detection of serum AFP, CA19-9, CA125 and CEA in identification and diagnosis of cholangiocarcinoma (CC). The levels of serum AFP, CA19-9, CA125 and CEA of both 30 patients with CC and 30 patients with hepatocellular carcinoma (HCC) were assessed. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic effects of single and joint detection of those 4 kinds of tumor markers for CC. The levels of serum CA19-9, CA125 and CEA in CC patients were higher than that in HCC patients,whereas that of serum AFP was significantly lower s. The area under ROC curve of single detection of serum AFP, CA19-9, CA125 and CEA were 0.05, 0.86, 0.84 and 0.83, with the optimal cutoff values of 15.4 ng/ml, 125.1 U/ml, 95.7 U/ml and 25.9 ng/ml, correspondingly, and the percentage correct single diagnosis was AFP, CA19-9, CA125 and CEA was the highest, with an area under the ROC curve of 0.94 (95%CI 0.88~0.99). Single detection of serum CA19-9, CA125 and EA is not meaningful. The sensitivity, specificity, the rate of correct diagnosis and the area under ROC curve of joint detection of AFP, CA19-9, CA125 and CEA are highest, indicating that the joint detection of these 4 tumor markers is of great importance in the diagnosis of CC.

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

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    Jiang Wei

    2010-09-01

    Full Text Available Abstract 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.

  5. Low Skeletal Muscle Density Is Associated with Early Death in Patients with Perihilar Cholangiocarcinoma Regardless of Subsequent Treatment.

    Science.gov (United States)

    van Vugt, Jeroen L A; Gaspersz, Marcia P; Vugts, Jaynee; Buettner, Stefan; Levolger, Stef; de Bruin, Ron W F; Polak, Wojciech G; de Jonge, Jeroen; Willemssen, François E J A; Groot Koerkamp, Bas; IJzermans, Jan N M

    2018-02-16

    Low skeletal muscle mass is associated with increased postoperative morbidity and worse survival following resection for perihilar cholangiocarcinoma (PHC). We investigated the predictive value of skeletal muscle mass and density for overall survival (OS) of all patients with suspected PHC, regardless of treatment. Baseline characteristics and parameters regarding disease and treatment were collected from all patients with PHC from 2002 to 2014. Skeletal muscle mass and density were measured at the level of the third lumbar vertebra on CT. The association between skeletal muscle mass and density with OS was investigated using the Kaplan-Meier method and Cox survival. Median OS in 233 included patients did not differ between those with and without low skeletal muscle mass (p = 0.203), whereas a significantly different median OS (months) was observed between patients with low (HR 7.0, 95% CI 4.7-9.3) and high (HR 12.1, 95% CI 8.1-16.1) skeletal muscle density (p = 0.004). Low skeletal muscle density was independently associated with decreased OS (HR 1.78, 95% CI 1.03-3.07, p = 0.040) within the first 6 months but not after 6 months (HR 0.68, 95% CI 0.44-1.07, p = 0.093), after adjusting for age, tumour size and suspected peritoneal or other distant metastases on imaging. A time-dependent effect of skeletal muscle density on OS was found in patients with PHC, regardless of subsequent treatment. Low skeletal muscle density may identify patients at risk for early death. © 2018 The Author(s) Published by S. Karger AG, Basel.

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

    Science.gov (United States)

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

    2017-07-01

    Selective internal radiation therapy (SIRT) is emerging as a potential therapy for unresectable intra-hepatic cholangiocarcinoma (iCCA) able to prolong life-expectancy. Aim of this study was to collect available literature meta-analyse data and results and investigate sources of heterogeneity through a meta-regression approach before suggesting SIRT as a valuable option. A systematic review of studies published until 1 September 2016 in PubMed and Scopus databases was performed. Patient survival was the primary outcome measure. Meta-analysis was performed using a random-effects model. Meta-regression was applied to investigate relationships existing between clinical and tumour features and the primary outcome. Nine observational studies were included in the analysis involving 224 patients. The 1-, 2- and 3-year pooled survival estimates were 55.7%, 33.1% and 20.2%. Clinical and tumour characteristics showed medium-to-considerable heterogeneity (I2 >50%). Meta-regression analysis showed that determinants of best survivals were the presence of mass-forming iCCA type (median survival=19.9 months vs 8.1 months for the infiltrative type; P=.002) that also accounted for most of the heterogeneity between included studies (residual I2 =0); SIRT as first-line therapy (median survival=24 months vs 11.5 months for non-naïve patients; P=.048) and the adoption of concomitant chemotherapy (median survival 19.5 months vs 5.5 months in patients not receiving chemotherapy; P=.042). There is considerable heterogeneity between studies highlighting that indications for SIRT are extremely varied. To ameliorate SIRT results naïve patients with mass-forming iCCA should be selected as the best candidates with the possibility of adding concomitant standard chemotherapy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Plasma autoantibodies against heat shock protein 70, enolase 1 and ribonuclease/angiogenin inhibitor 1 as potential biomarkers for cholangiocarcinoma.

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    Rucksak Rucksaken

    Full Text Available The diagnosis of cholangiocarcinoma (CCA is often challenging, leading to poor prognosis. CCA arises via chronic inflammation which may be associated with autoantibodies production. This study aims to identify IgG antibodies directed at self-proteins and tumor-associated antigens. Proteins derived from immortalized cholangiocyte cell line (MMNK1 and CCA cell lines (M055, M214 and M139 were separated using 2-dimensional electrophoresis and incubated with pooled plasma of patients with CCA and non-neoplastic controls by immunoblotting. Twenty five immunoreactive spots against all cell lines-derived proteins were observed on stained gels and studied by LC-MS/MS. Among these, heat shock protein 70 (HSP70, enolase 1 (ENO1 and ribonuclease/angiogenin inhibitor 1 (RNH1 obtained the highest matching scores and were thus selected for further validation. Western blot revealed immunoreactivity against HSP70 and RNH1 in the majority of CCA cases and weakly in healthy individuals. Further, ELISA showed that plasma HSP70 autoantibody level in CCA was significantly capable to discriminate CCA from healthy individuals with an area under the receiver operating characteristic curve of 0.9158 (cut-off 0.2630, 93.55% sensitivity and 73.91% specificity. Plasma levels of IgG autoantibodies against HSP70 were correlated with progression from healthy individuals to cholangitis to CCA (r = 0.679, P<0.001. In addition, circulating ENO1 and RNH1 autoantibodies levels were also significantly higher in cholangitis and CCA compared to healthy controls (P<0.05. Moreover, the combinations of HSP70, ENO1 or RNH1 autoantibodies positivity rates improved specificity to over 78%. In conclusion, plasma IgG autoantibodies against HSP70, ENO1 and RNH1 may represent new diagnostic markers for CCA.

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

    Science.gov (United States)

    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=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

  9. Gemcitabine in combination with EGF-Receptor antibody (Cetuximab as a treatment of cholangiocarcinoma: a case report

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    Schadmand-Fischer Simin

    2006-07-01

    Full Text Available Abstract Background Extensive disease of cholangiocarcinoma (CC determines the overall outcome and limits curative resection. Despite chemotherapy, which has been introduced to improve the outcome of biliary tract malignancies, the benefit in survival is still marginal. Case presentation We report a 69-year-old patient with non-resectable CC showing hepatic metastasis and peritoneal carcinomatosis. Diagnosis was based on computed tomography, mini-laparoscopy and bioptic specimens. Histology revealed an adenocarcinoma of the biliary tract with expression of epithelial growth factor receptor. After informed consent the patient received experimental gemcitabine (1000 mg/m2 every other week and cetuximab (250 mg/m2 weekly for palliative chemotherapy. During the reported follow up (since time of first presentation 20 cycles of chemotherapy were administered. Relevant chemotherapy-related toxicity was limited on gemcitabine-associated side effects. Predominantly, haematological toxicity (CTC, grade 3 and neutropenic fever (CTC, grade 3 promoted by catheter-related sepsis were observed. Cetuximab caused only mild skin toxicity (CTC, grade 1. Chemotherapy led to a partial response (> 30% reduction, according to RECIST of the target lesions and disappearance of the peritoneal carcinomatosis as shown by computed tomography. Partial response occurred after 17 weeks of treatment and remained stable during the entire course of chemotherapy for 9.7 months. In parallel, Ca 19-9 serum levels, which were elevated 5-fold at time of diagnosis, returned to normal after 16 weeks of treatment. The performance status stabilized and intravenous alimentation could be discontinued. Conclusion Our experience from one patient with CC suggests, that a combination of cytotoxic chemotherapy together with cetuximab may show promising efficacy in respect to survival and quality of life. Therefore cetuximab, as a component of palliative chemotherapy in biliary tract cancer

  10. Mass-forming intrahepatic cholangiocarcinoma with portal vein tumor thrombus and bile duct tumor thrombus: A case report.

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    Iwaki, Kentaro; Kaido, Toshimi; Yamamoto, Gen; Kamo, Naoko; Yagi, Shintaro; Taura, Kojiro; Uemoto, Shinji

    2017-01-01

    We report the first case of mass-forming intrahepatic cholangiocarcinoma (ICC) with portal vein tumor thrombus (PVTT) and bile duct tumor thrombus (BDTT), where the extrahepatic bile duct was preserved with thrombectomy. A 70-year-old male. Magnetic resonance imaging (MRI) showed the tumor extending from the hepatic hilum to the left hepatic duct with complete obstruction of the left hepatic duct and a defect at the left portal vein. We planned to perform extended left lobectomy, lymph node dissection, extra hepatic bile duct resection and reconstruction based on the diagnosis of mass-forming ICC with left portal vein and left hepatic duct infiltration (cT3N0M0 Stage III). Intraoperative cholangiography revealed a crab claw-like filling defect at the left hepatic duct, which suggested tumor thrombus. Accordingly, we performed thrombectomy. The margin of the left hepatic duct was tumor negative, so we performed extended left lobectomy, lymph node dissection and thrombectomy. Pathologically, the tumor was diagnosed as ICC (pT4N0M0 Stage IVA, vp3, b3). Tumors in the left hepatic duct and left portal vein proved to be tumor thrombus. The postoperative course was uneventful. He is doing well without recurrence. Thrombectomy is performed for hepatocellular carcinoma (HCC) with tumor thrombus. Furthermore, extrahepatic bile duct resection and reconstruction are recommended for ICC. In this case, intraoperative cholangiography was effective for precisely diagnosing. Thrombectomy could reduce surgical stress and prevent complications. Thrombectomy can be a valid option for ICC with tumor thrombus, as well as for HCC. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial

    NARCIS (Netherlands)

    Stein, Alexander; Arnold, Dirk; Bridgewater, John; Goldstein, David; Jensen, Lars Henrik; Klümpen, Heinz-Josef; Lohse, Ansgar W.; Nashan, Björn; Primrose, John; Schrum, Silke; Shannon, Jenny; Vettorazzi, Eik; Wege, Henning

    2015-01-01

    Despite complete resection, disease-free survival (DFS) of patients with cholangiocarcinoma (CCA) is less than 65 % after one year and not more than 35 % after three years. For muscle invasive gallbladder carcinoma (GBCA), prognosis is even worse, with an overall survival (OS) of only 30 % after

  12. [Synchronous Triple Malignant Tumors (Hilar Cholangiocarcinoma, Ascending Colon Cancer, Liposarcoma) Resected in a Two-Stage Procedure--A Case Report].

    Science.gov (United States)

    Yasuta, Sho; Yamauchi, Junichiro; Satoh, Ataru; Ikeda, Tomoya; Fujita, Shota; Matsuda, Yasufumi; Kobayashi, Shin; Ajiki, Takashi; Tsuchihara, Katsuo; Kondo, Noriko; Ishiyama, Shuichi

    2015-11-01

    A 70-year-old man with a history of myocardial infarction (MI) and taking 2 antiplatelet drugs was diagnosed with anemia his 6-month post-MI checkup. A lower gastrointestinal endoscopy detected ascending colon cancer, and contrast-enhanced a computed tomography scan revealed hilar cholangiocarcinoma as well as lesions suspicious for gastrointestinal stromal tumors of the small intestine. The patient was given a preoperative diagnosis of synchronous triple malignant tumors. The decision to perform a two-stage procedure was made for the following reasons: the impossibility of discontinuing antiplatelet drugs 6 months after drug-eluting stent placement, continuous bleeding due to colon cancer and the possibility of suffering severe stress from surgery while at high risk for diseases such as hepatic failure. In the initial procedure, a right hemicolectomy and surgical resection of the mesenteric tumor (later diagnosed as a liposarcoma) were performed after portal vein embolization. Confirmation of an enlarged residual liver was confirmed 2 months after the initial procedure. The patient underwent right hepatectomy and resection of the extrahepatic bile duct and the biliary tract was surgically reconstructed. Safe resection of tumors was successfully performed by choosing a two-stage procedure for triple malignancy, including hilar cholangiocarcinoma, ascending colon cancer, and liposarcoma, in a single patient.

  13. Augmented reality navigation in open surgery for hilar cholangiocarcinoma resection with hemihepatectomy using video-based in situ three-dimensional anatomical modeling

    Science.gov (United States)

    Tang, Rui; Ma, Longfei; Xiang, Canhong; Wang, Xuedong; Li, Ang; Liao, Hongen; Dong, Jiahong

    2017-01-01

    Abstract Rationale: Patients who undergo hilar cholangiocarcinoma (HCAC) resection with concomitant hepatectomy have a high risk of postoperative morbidity and mortality due to surgical trauma to the hepatic and biliary vasculature. Patient concerns: A 58-year-old Chinese man with yellowing skin and sclera, abdominal distension, pruritus, and anorexia for approximately 3 weeks. Diagnoses: Magnetic resonance cholangiopancreatography and enhanced computed tomography (CT) scanning revealed a mass over the biliary tree at the porta hepatis, which diagnosed to be s a hilar cholangiocarcinoma. Intervention: Three-dimensional (3D) images of the patient's hepatic and biliary structures were reconstructed preoperatively from CT data, and the 3D images were used for preoperative planning and augmented reality (AR)-assisted intraoperative navigation during open HCAC resection with hemihepatectomy. A 3D-printed model of the patient's biliary structures was also used intraoperatively as a visual reference. Outcomes: No serious postoperative complications occurred, and the patient was tumor-free at the 9-month follow-up examination based on CT results. Lessons: AR-assisted preoperative planning and intraoperative navigation might be beneficial in other patients with HCAC patients to reduce postoperative complications and ensure disease-free survival. In our postoperative analysis, we also found that, when the3D images were superimposed 3D-printed model using a see-through integral video graphy display device, our senses of depth perception and motion parallax were improved, compared with that which we had experienced intraoperatively using the videobased AR display system. PMID:28906410

  14. Cholangiocarcinoma associated with limbic encephalitis and early cerebral abnormalities detected by 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography-positron emission tomography: a case report.

    Science.gov (United States)

    Schmidt, Sergio L; Schmidt, Juliana J; Tolentino, Julio C; Ferreira, Carlos G; de Almeida, Sergio A; Alvarenga, Regina P; Simoes, Eunice N; Schmidt, Guilherme J; Canedo, Nathalie H S; Chimelli, Leila

    2016-07-20

    Limbic encephalitis was originally described as a rare clinical neuropathological entity involving seizures and neuropsychological disturbances. In this report, we describe cerebral patterns visualized by positron emission tomography in a patient with limbic encephalitis and cholangiocarcinoma. To our knowledge, there is no other description in the literature of cerebral positron emission tomography findings in the setting of limbic encephalitis and subsequent diagnosis of cholangiocarcinoma. We describe a case of a 77-year-old Caucasian man who exhibited persistent cognitive changes 2 years before his death. A cerebral scan obtained at that time by 2-deoxy-2-[fluorine-18]fluoro- D -glucose integrated with computed tomography-positron emission tomography showed low radiotracer uptake in the frontal and temporal lobes. Cerebrospinal fluid analysis indicated the presence of voltage-gated potassium channel antibodies. Three months before the patient's death, a lymph node biopsy indicated a cholangiocarcinoma, and a new cerebral scan obtained by 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography-positron emission tomography showed an increment in the severity of metabolic deficit in the frontal and parietal lobes, as well as hypometabolism involving the temporal lobes. Two months before the patient's death, cerebral metastases were detected on a contrast-enhanced computed tomographic scan. Postmortem examination revealed a cholangiocarcinoma with multiple metastases including the lungs and lymph nodes. The patient's brain weighed 1300 g, and mild cortical atrophy, ex vacuo dilation of the ventricles, and mild focal thickening of the cerebellar leptomeninges, which were infiltrated by neoplastic epithelial cells, were observed. These findings support the need for continued vigilance in malignancy surveillance in patients with limbic encephalitis and early cerebral positron emission tomographic scan abnormalities. The difficulty in early

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

    Directory of Open Access Journals (Sweden)

    Zhu JY

    2014-02-01

    Full Text Available Jianyong Zhu,1,* XiaoDong Guo,2,* Baoan Qiu,1 Zhiyan Li,2 Nianxin Xia,1 Yingxiang Yang,1 Peng Liu1 1Department of Hepatobiliary Surgery, Navy General Hospital, PLA, Beijing, People's Republic of China; 2302 Hospital of PLA, Beijing, People's Republic of China *These authors contributed equally to this work 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

  16. Development and characterization of a hydrogen peroxide-resistant cholangiocyte cell line: A novel model of oxidative stress-related cholangiocarcinoma genesis

    Energy Technology Data Exchange (ETDEWEB)

    Thanan, Raynoo [Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 (Thailand); Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 (Thailand); Techasen, Anchalee [Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 (Thailand); Faculty of Associated Medical Science, Khon Kaen University, Khon Kaen 40002 (Thailand); Hou, Bo [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507 (Japan); Jamnongkan, Wassana; Armartmuntree, Napat [Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 (Thailand); Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 (Thailand); Yongvanit, Puangrat, E-mail: puangrat@kku.ac.th [Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 (Thailand); Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 (Thailand); Murata, Mariko, E-mail: mmurata@doc.medic.mie-u.ac.jp [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507 (Japan)

    2015-08-14

    Oxidative stress is a cause of inflammation–related diseases, including cancers. Cholangiocarcinoma is a liver cancer with bile duct epithelial cell phenotypes. Our previous studies in animal and human models indicated that oxidative stress is a major cause of cholangiocarcinoma development. Hydrogen peroxide (H{sub 2}O{sub 2}) can generate hydroxyl radicals, which damage lipids, proteins, and nucleic acids, leading to cell death. However, some cells can survive by adapting to oxidative stress conditions, and selective clonal expansion of these resistant cells would be involved in oxidative stress-related carcinogenesis. The present study aimed to establish H{sub 2}O{sub 2}-resistant cell line from an immortal cholangiocyte cell line (MMNK1) by chronic treatment with low-concentration H{sub 2}O{sub 2} (25 μM). After 72 days of induction, H{sub 2}O{sub 2}-resistant cell lines (ox-MMNK1-L) were obtained. The ox-MMNK1-L cell line showed H{sub 2}O{sub 2}-resistant properties, increasing the expression of the anti-oxidant genes catalase (CAT), superoxide dismutase-1 (SOD1), superoxide dismutase-2 (SOD2), and superoxide dismutase-3 (SOD3) and the enzyme activities of CAT and intracellular SODs. Furthermore, the resistant cells showed increased expression levels of an epigenetics-related gene, DNA methyltransferase-1 (DNMT1), when compared to the parental cells. Interestingly, the ox-MMNK1-L cell line had a significantly higher cell proliferation rate than the MMNK1 normal cell line. Moreover, ox-MMNK1-L cells showed pseudopodia formation and the loss of cell-to-cell adhesion (multi-layers) under additional oxidative stress (100 μM H{sub 2}O{sub 2}). These findings suggest that H{sub 2}O{sub 2}-resistant cells can be used as a model of oxidative stress-related cholangiocarcinoma genesis through molecular changes such as alteration of gene expression and epigenetic changes. - Highlights: • An H{sub 2}O{sub 2}-resistant ox-MMNK1-L cells was established from

  17. Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis.

    Science.gov (United States)

    Al Mamari, Said; Djordjevic, Jelena; Halliday, John S; Chapman, Roger W

    2013-02-01

    Normalization of serum alkaline phosphatase (SAP) was recently shown to correlate with better prognosis in Primary Sclerosing Cholangitis (PSC). We aimed at evaluating the impact of SAP improvement to below 1.5 the upper limit of normal (ULN) on the prognosis of this cholestatic liver disease. Oxford PSC database was screened for cases diagnosed between 1980 and 2004. Cases which met the inclusion criteria were retrospectively examined for clinical parameters, laboratory values, and clinical end points (liver decompensation, liver transplantation, and liver-related deaths including cholangiocarcinoma). Cases were followed-up to 31/12/2010. 139 patients were included, (87 males). Improvement of SAP to below 1.5 ULN was achieved by 55 (40%) patients in a median time of 2 years, compared to 84 (60%) who did not. 3/55 (6%) patients with SAP improvement reached an end point compared to 32/84 (38%) patients with no SAP improvement (p Liver. All rights reserved.

  18. Intrahepatic cholangiocarcinoma with intrahepatic biliary lithiasis arising 47 years after the excision of a congenital biliary dilatation: report of a case.

    Science.gov (United States)

    Yamashita, Suguru; Arita, Junichi; Sasaki, Takashi; Kaneko, Junichi; Aoki, Taku; Beck, Yoshihumi; Sugawara, Yasuhiko; Hasegawa, Kiyoshi; Kokudo, Norihiro

    2012-04-01

    We report a case of intrahepatic cholangiocarcinoma with biliary lithiasis arising 47 years after surgery for a congenital biliary dilatation (CBD). A 62-year-old woman was admitted for the investigation of a liver tumor. She had undergone a choledochoduodenostomy at the age of 15 years for CBD and resection of an extrahepatic bile duct with choledochojejunostomy because of cholangitis at the age of 55 years. An enhanced computed tomography (CT) revealed a liver tumor 50 mm in diameter in the S6 region with surrounding lymph node swelling and intrahepatic metastatic lesions in the S8 region. A drip infusion cholangiographic CT showed biliary lithiases in the left liver. An extended right hepatectomy and lymph node dissection was considered but was abandoned because of suspicions of liver functional insufficiency as a result of biliary lithiasis. She underwent biliary lithotomy through a percutaneous transhepatic cholangioscopy and subsequent systemic chemotherapy.

  19. Corrosion inhibition..

    African Journals Online (AJOL)

    ABSTRACT. The corrosion inhibition of carbon steel in 3% de-aerated NaCl acidic solution with amine—fatty acid corrosion inhibitor, KI384, .... reduction reaction causing no decrease in the limiting current density of that process. On the .... value when compared to the base solution. This provides a support to the physical ...

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

    Science.gov (United States)

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

    2017-03-01

    To evaluate the value of resin-based yttrium-90 ( 90 Y) radioembolization for unresectable and failed first-line chemotherapy (cisplatin plus gemcitabine) intrahepatic cholangiocarcinoma (ICC). From February 2006 to September 2015, a retrospective study was conducted of all patients who underwent resin-based 90 Y therapy for unresectable and failed first-line chemotherapy ICC. Tumor response was assessed using modified RECIST criteria; side effects were assessed using Common Terminology Criteria for Adverse Events version 4.03; survivals were calculated from the date of diagnosis of ICC, beginning of first-line chemotherapy and first 90 Y procedure, respectively; effects of factors on survival were analyzed by Cox regression model. Twenty-four patients (eight male and 16 female) were included in this study. Mean 5.6 ± 1.6 cycles of first-line chemotherapy were performed prior to 90 Y treatment. The mean delivered activity of 90 Y was 1.6 ± 0.4 GBq with a total of 27 treatments. Disease control rate was 81.8% at 3 months after 90 Y therapy, with partial response (n = 8, 36.4%), stable disease (n = 10, 45.5%) and progressive disease (n = 6, 18.2%). CA199 changes pre- and 1 month post-treatment were complete (n = 2), partial (n = 2), none (n = 5) and progression (n = 2), respectively. Side effects included fatigue (n = 21, 87.5%), anorexia (n = 19, 79.2%), nausea (n = 15, 62.5%), abdominal pain (n = 10, 58.3%), vomiting (n = 4, 16.7%) and fever (n = 3, 12.5%). Radiation-induced gastrointestinal ulcer was identified in one patient. The mean follow-up was 11.3 ± 6.6 months, and the median survivals from the time of diagnosis of ICC, beginning of first-line chemotherapy and first 90 Y procedure were 24.0, 16.0 and 9.0 months, respectively, and the 6-, 12-, 18-, 24- and 30-month survival after 90 Y therapy were 69.9, 32.6, 27.2, 20.4 and 20.4%, respectively. ECOG performance status (P = 0.002) and lymph node metastases (P = 0

  1. Neoadjuvant therapy protocol and liver transplantation in combination with pancreatoduodenectomy for the treatment of hilar cholangiocarcinoma occurring in a case of primary sclerosing cholangitis: case report with a more than 8-year disease-free survival.

    Science.gov (United States)

    Gringeri, E; Bassi, D; D'Amico, F E; Boetto, R; Polacco, M; Lodo, E; D'Amico, F; Vitale, A; Boccagni, P; Zanus, G; Cillo, U

    2011-05-01

    Cholangiocarcinoma has historically represented a major contraindication to liver transplantation at many centers because of its high recurrence rate and low disease-free survival rate, even after radical surgery. Novel neoadjuvant therapy protocols combined with demolitive surgery and liver transplantation seem to achieve successful results in terms of overall and disease-free survivals. Surgery frequently seems to be unsatisfactory only for patients also suffering from chronic cirrhosis or end-stage liver disease. We have reported a case of hilar cholangiocarcinoma occurring in a case of primary sclerosing cholangitis treated with neoadjuvant radiochemotherapy and endoscopic brachytherapy, followed by liver transplantation combined with pancreatoduodenectomy, who has survived free of disease for >8 years. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. Interest of the PET/T.D.M. with 18 F.D.G. in the cholangio-carcinoma; Interet de la TEP/TDM au 18F-FDG dans le cholangiocarcinome

    Energy Technology Data Exchange (ETDEWEB)

    Morvan, J.; El Esper, I.; Moullart, V.; Saidi, L.; Meyer, M.E. [Service de medecine nucleaire, CHU Amiens Sud, (France); Demuynck, F.; Yzet, T. [service de radiologie digestive, CHU Amiens Nord, (France); Fuks, D.; Regimbeau, J.M. [service de chirurgie viscerale, CHU Amiens Nord, (France); Chatelain, D. [service d' anatomopathologie, CHU Amiens Nord, (France)

    2009-05-15

    The specificity of the PET/T.D.M. for the evaluation of the ganglion attack is superior to the scanner one. The PET/T.D.M. is more noticeable than the scanner in the detection of metastases. It appears as complementary to other modalities of imaging in the staging of cholangio-carcinoma and seems indicated among patients judged operable by conventional imaging. (N.C.)

  3. Clonorchis sinensis excretory-secretory products regulate migration and invasion in cholangiocarcinoma cells via extracellular signal-regulated kinase 1/2/nuclear factor-κB-dependent matrix metalloproteinase-9 expression.

    Science.gov (United States)

    Pak, Jhang Ho; Shin, Jimin; Song, In-Sung; Shim, Sungbo; Jang, Sung-Wuk

    2017-01-01

    Matrix metalloproteinase-9 plays an important role in the invasion and metastasis of various types of cancer cells. We have previously reported that excretory-secretory products from Clonorchis sinensis increases matrix metalloproteinase-9 expression. However, the regulatory mechanisms through which matrix metalloproteinase-9 expression affects cholangiocarcinoma development remain unclear. In the current study, we examined the potential role of excretory-secretory products in regulating the migration and invasion of various cholangiocarcinoma cell lines. We demonstrated that excretory-secretory products significantly induced matrix metalloproteinase-9 expression and activity in a concentration-dependent manner. Reporter gene and chromatin immunoprecipitation assays showed that excretory-secretory products induced matrix metalloproteinase-9 expression by enhancing the activity of nuclear factor-kappa B. Moreover, excretory-secretory products induced the degradation and phosphorylation of IκBα and stimulated nuclear factor-kappa B p65 nuclear translocation, which was regulated by extracellular signal-regulated kinase 1/2. Taken together, our findings indicated that the excretory-secretory product-dependent enhancement of matrix metalloproteinase-9 activity and subsequent induction of IκBα and nuclear factor-kappa B activities may contribute to the progression of cholangiocarcinoma. Copyright © 2016 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.

  4. [Intrahepatic cholangiocarcinoma: case report].

    Science.gov (United States)

    Cione, G P; Arciero, G; De Angelis, C P; Marano, A; Farella, N; Cerrone, C; Cerbone, D; Parmeggiani, D; Cimmino, G; Perrotta, M; Giglio, D

    2005-01-01

    The primitive tumors of the liver are relatively rare in the Western countries (around the 0.7% of all the neoplasms) while they present more elevated incidence in Africa and in the South Asian East. While the hepatocellular carcinoma rises up in the 50-70% of the cases in livers cirrosis, this correlation is not valid for the form of carcinoma to departure from the learned intra and extra biliar. The etiology of the intrahepatic colangiocarcinoma (CC) stays unknown. They have stayed observe, on the other hand, of the conditions sometimes correlated to the development of the CC (Carolí morbs, ulcerative colitis, asbestosis). The CC usually rises up from the epithelial cells of surface that delimit the biliary ducts, although different studies suggest that these tumors can also originate from the learned smaller biliary ducts, from the hepatic cysts of the policistic illness and from the complexes of von Meyenburg. The low incidence of the CC, the clinical atypical debut, the not facility of a precise diagnosis have aroused our interest so that the present job wants to be a modest scientific contribution to this type of pathology.

  5. The correlation between poor prognosis and increased yes-associated protein 1 expression in keratin 19 expressing hepatocellular carcinomas and cholangiocarcinomas.

    Science.gov (United States)

    Lee, KyuHo; Lee, Kyoung-Bun; Jung, Hae Yoen; Yi, Nam-Joon; Lee, Kwang-Woong; Suh, Kyung-Suk; Jang, Ja-June

    2017-06-23

    The Hippo pathway plays a vital role in liver regeneration and development by determining cellular lineage and regulating cell proliferation and apoptosis. In this study, we aimed to assess the role of the Hippo pathway in hepatic carcinogenesis and morphogenesis by examining Yes-associated protein 1 (YAP1) expression in the spectrum of hepatic carcinomas based on cellular lineage. We examined 913 primary hepatic carcinomas, including hepatocellular carcinomas (HCCs), combined hepatocellular and cholangiocarcinomas (cHC-CCAs), intrahepatic cholangiocarcinomas (IHCCAs) and perihilar extrahepatic bile duct carcinomas (EHBCAs). Our study group was categorized into 8 disease groups, based on histological diagnosis and cytokeratin 19 (CK19) expression, and immunohistochemistry was used to detect and compare YAP1 expression levels between the groups. The eight disease groups we identified were: 1) CK19(-) HCC, 2) CK19(-) scirrhous HCC, 3) CK19(+) HCC, 4) stem cell feature of cHC-CCA, 5) classical cHC-CCA, 6) cholangiolocellular IHCCA, 7) non-cholangiolocellular IHCCA, and 8) EHBCA. Positive rates of YAP1 were the highest in the EHBCA group (21%). CK19(+) HCC and non-cholangiolocellular IHCCA groups also showed high expression levels (10% -11%), while the CK19 (-) HCC, CK19 (-) scirrhous HCC, cHC-CCA, and cholangiolocellular IHCCA groups showed low expression levels, ranging between 0% and 5%. Survival analysis, restricted to pT1 stage HCCs and IHCCAs, showed poor overall survival for YAP1(+) IHCCA patients (39 ± 17 vs. 109 ± 10 months, mean ± SD, log rank p-value 0.005). For HCCs, a trend of poor progression-free survival for YAP1(+) HCCs was observed (39 ± 18 vs. 81 ± 5 months, mean ± SD, log rank p-value 0.205) CONCLUSIONS: YAP1 activation was more commonly found in CCAs than in pure HCCs. However, a differing pattern of YAP1 expression between cHC-CCAs and CK19(+) HCCs and the poor prognosis of YAP1 positive hepatic carcinomas suggests that YAP1

  6. Capsule, septum, and T2 hyperintense foci for differentiation between large hepatocellular carcinoma (≥5 cm) and intrahepatic cholangiocarcinoma on gadoxetic acid MRI

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Jiyoung; Hong, Seong Sook; Kim, Hyun-joo [Soonchunhyang University College of Medicine, Department of Radiology, Seoul Hospital, Seoul (Korea, Republic of); Kim, Young Kon; Min, Ji Hye; Jeong, Woo Kyung [Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Seoul (Korea, Republic of); Choi, Seo-Youn [Soonchunhyang University College of Medicine, Department of Radiology, Bucheon Hospital, Bucheon (Korea, Republic of); Ahn, Soohyun; Ahn, Hyeon Seon [Research Institute for Future Medicine, Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Seoul (Korea, Republic of)

    2017-11-15

    To determine the added value of capsule, septum, and T2 hyperintense foci for differentiating large hepatocellular carcinoma (HCC; ≥ 5 cm) from intrahepatic cholangiocarcinoma (ICC) using gadoxetic acid MRI. The study included 116 patients (94 men, 22 women; mean age, 56.8 years) with surgically confirmed HCCs (n = 87, 5.0-18.0 cm) or ICCs (n = 29, 5.0-14.0 cm) who underwent gadoxetic acid MRI. Three observers independently reviewed MRIs in two sessions, examining enhancement patterns only and then adding capsule, septum, and T2 hyperintense foci. Reviewers used a five-point scale to score accuracy, sensitivity, and specificity. A significant increase was observed in accuracy when ancillary features (96.1-98.3%) were added compared to enhancement pattern only (83.6-88.4%; p ≤ 0.02). Sensitivity was significantly increased with combined reading (97.1-98.3%) compared to enhancement features only (81.6-88.5%; p ≤ 0.006) for two observers, with no difference in specificity (84.5-89.7% vs. 86.2-98.3%; p > 0.05). We found substantial to excellent interobserver agreement for ancillary features (0.598-0.976). Adding capsule, septum, and T2 hyperintense foci to enhancement patterns for gadoxetic acid MRI increased diagnostic performance for characterizing large HCC by differentiating it from ICC. (orig.)

  7. Clinicopathological characterization of so-called “cholangiocarcinoma with intraductal papillary growth” with respect to “intraductal papillary neoplasm of bile duct (IPNB)”

    Science.gov (United States)

    Nakanuma, Yasuni; Sato, Yasunori; Ojima, Hidenori; Kanai, Yae; Aishima, Shinichi; Yamamoto, Masakazu; Ariizumi, Shun-ichi; Furukawa, Toru; Hayashi, Hiroki; Unno, Michiaki; Ohta, Tetsuo

    2014-01-01

    Cholangiocarcinoma (CC) of the biliary tract occasionally presents a predominant intraductal papillary growth in the bile ducts, called as biliary tract carcinoma (BTC) of papillary growth (PG) and intrahepatic CC (ICC) of intraductal growth (IG) type. Recently, intraductal papillary neoplasm of bile duct (IPNB) has been proposed as a pre-invasive biliary neoplasm. This study was performed to characterize pathologically BTC of PG type and ICC of IG type with respect to IPNB. It was found that 126 of such 154 CCs (81.8%) fulfilled the criteria of IPNB, while the remaining 28 cases showed different histologies, such as tubular adenocarcinoma and carcinosarcoma. These IPNBs occurred in old aged patients with a male predominance, and the left lobe was rather frequently affected in the liver. A majority of these cases were high grade IPNB (43 cases) and invasive IPNB (77 cases), while low grade IPNB was rare (6 cases). Pancreatobiliary type was predominant (48 cases) followed by gastric (30 cases), intestinal (29 cases) and oncocytic (19 cases) types. Mucus hypersecretion was found in 45 cases, and this was frequent in IPNB at the intrahepatic large bile duct and hilar bile ducts but rare at the extrahepatic bile ducts. Interestingly, 36 cases of high grade and invasive IPNBs contained foci of moderately differentiated adenocacinoma within the intraductal papillary tumor. In conclusion, a majority of ICC of IG type and BTC of PG type could be regarded as a IPNB lineage, and clinically detectable IPNBs were already a malignant papillary lesion. PMID:25031730

  8. Diagnostic performance of CT and MRI in distinguishing intraductal papillary neoplasm of the bile duct from cholangiocarcinoma with intraductal papillary growth

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yubao; Zhong, Xiaomei; Yan, Lifen; Zheng, Junhui; Liu, Zaiyi; Liang, Changhong [Guangdong Academy of Medical Sciences, Department of Radiology, Guangdong General Hospital, Guangzhou (China)

    2015-07-15

    We aimed to evaluate the diagnostic performance of CT and MRI for distinguishing intraductal papillary neoplasm of the bile duct (IPNB) from cholangiocarcinoma (CC) with intraductal papillary growth (IPG). Forty-two patients with either IPNB or CC with IPG proven by histopathology were independently reviewed in retrospect. Strict criteria for diagnosis of IPNB included presence of the designated imaging features as follows: local dilatation of the bile duct, nodule within the dilated bile duct, growing along the interior wall of bile duct. Any lesion that was not consistent with the criteria was classified as CC with IPG. Sensitivity, specificity, positive and negative predictive values for characterization of IPNB were calculated, and k test was used to assess the level of agreement. Two imaging reviewers correctly identified 21 of 26 (80.8 %) and 22 of 26 (84.6 %) IPNB cases, respectively. Alternatively, they correctly identified 14 of 16 (87.5 %) and 15 of 16 (93.8 %) CC with IPG, respectively. Agreement between the two reviewers was perfect (k = 0.81) for the diagnosis of IPNB and differentiation from CC with IPG. By using our designated diagnostic criteria of CT and MRI, IPNB can be accurately identified and possible to be distinguished from CC with IPG. (orig.)

  9. Colangiocarcinoma associado a Retocolite Ulcerativa: relato de caso e revisão de literatura Cholangiocarcinoma and Ulcerative Colitis: case report and literature review

    Directory of Open Access Journals (Sweden)

    Juvenal da Rocha Torres Neto

    2010-03-01

    Full Text Available A Retocolite Ulcerativa (RCU é uma doença inflamatória intestinal crônica, que acomete a camada mucosa do intestino grosso, e que pode estar associada a manifestações extra-intestinais, como a colangite esclerosante que pode malignizar para colangiocarcinoma. Relatamos um caso de paciente do gênero masculino, 21 anos, procedente de Poço Redondo-SE, natural de Cubatão-SP, admitido no Hospital Universitário da Universidade Federal de Sergipe em 23 de maio de 2008, com RCU associada à colangite esclerosante e colangiocarcinoma.The Ulcerative Colitis (UC is a cronic inflamatory bowel disease, that affects the mucosa of the large bowel and which can be associated with extra-intestinal manifestations, such as slcerosing cholangitis, an illness that could become a cholangicarcinoma. We reported a case of a male patient, 21-year-aged, from Poço Redondo-SE, who was born in Cubatão-SP and admitted in the Hospital Universitário of the Universidade Federal de Sergipe, on may 23 at the year 2008 with UC associated with sclerosing cholangitis and cholangiocarcinoma.

  10. The impact of perioperative CA19-9 change on the survival and recurrence patterns after adjuvant chemoradiotherapy in resectable extrahepatic cholangiocarcinoma.

    Science.gov (United States)

    Kim, Byoung Hyuck; Kim, Eunji; Kim, Kyubo; Jang, Jin-Young; Kim, Sun Whe; Oh, Do-Youn; Chie, Eui Kyu

    2017-09-20

    Perioperative CA19-9 value in pancreato-biliary cancers has been recognized as a prognostic factor. Herein, we investigated survival differences and recurrence patterns after adjuvant chemoradiotherapy by perioperative CA19-9 change in surgically resected extrahepatic cholangiocarcinoma. Patients were divided into those with preoperative normal CA19-9 (Group 1, n = 52), those with high preoperative and normalized postoperative CA19-9 (Group 2, n = 80), and those with both high pre- and postoperative CA19-9 (Group 3, n = 21). Depending on the group defined above, the 5-year overall survival (OS) (59.6%, 38.7%, and 9.5%, P < 0.001) and disease-free survival (55.8%, 31.2%, and 9.5%, P < 0.001) between the three groups differed. On multivariable analysis in patients other than group 1, poor prognosticators for OS were high postoperative CA19-9 (HR 2.26, P = 0.008) and N1 disease (HR 2.33, P = 0.001). Group 3, compared with group 2, showed higher distant metastasis rate, shorter disease-free interval, and higher CA19-9 at the time of recurrence. Survival and recurrence patterns after adjuvant chemoradiotherapy are significantly affected by perioperative CA19-9 change. This may have important implications in patient selection for adjuvant chemoradiotherapy and clinical trial design. © 2017 Wiley Periodicals, Inc.

  11. Impact of Preoperative Three-Dimensional Computed Tomography Cholangiography on Postoperative Resection Margin Status in Patients Operated due to Hilar Cholangiocarcinoma

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    A. Andert

    2017-01-01

    Full Text Available Introduction. The purpose of this study was to analyse the value of 3-dimensional computed tomography cholangiography (3D-ERC compared to conventional retrograde cholangiography in the preoperative diagnosis of hilar cholangiocarcinoma (HC with special regard to the resection margin status (R0/R1. Patients and Methods. All hepatic resections performed between January 2011 and November 2013 in patients with HC at the Department of General, Visceral and Transplant Surgery of the RWTH Aachen University Hospital were analysed. All patients underwent an ERC and contrast-enhanced multiphase CT scan or a 3D-ERC. Results. The patient collective was divided into two groups (group ERC: n=17 and group 3D-ERC: n=16. There were no statistically significant differences between the two groups with regard to patient characteristics or intraoperative data. Curative liver resection with R0 status was reached in 88% of patients in group ERC and 87% of patients in group 3D-ERC (p=1.00. We could not observe any differences with regard to postoperative complications, hospital stay, and mortality rate between both groups. Conclusion. Based on our findings, preoperative imaging with 3D-ERC has no benefit for operative planning and R0 resection status. It cannot replace the exploration by an experienced surgeon in a centre for hepatobiliary surgery.

  12. Evaluation of the 8th edition American Joint Commission on Cancer (AJCC) staging system for patients with intrahepatic cholangiocarcinoma: A surveillance, epidemiology, and end results (SEER) analysis.

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    Kim, Yuhree; Moris, Dimitrios P; Zhang, Xu-Feng; Bagante, Fabio; Spolverato, Gaya; Schmidt, Carl; Dilhoff, Mary; Pawlik, Timothy M

    2017-06-12

    The objective of this study was to assess the prognostic performance of American Joint Committee on Cancer (AJCC) 8th edition in patients with intrahepatic cholangiocarcinoma (ICC) using a cancer registry. The Surveillance, Epidemiology, and End Results (SEER) cancer registry was queried to identify 1008 patients who underwent surgical resection of ICC during 1998-2013. Kaplan-Meier method and Cox proportional hazards regression models were used to analyze long-term survival. The relative discriminative abilities were assessed using the Harrell's concordance index. Median patient age was 62 years and 47.6% of the patients were male. Most tumors were T1 or T2 (n = 413, 41.0% and n = 329, 32.6%, respectively) and 22.1% of patients had lymph node (LN) metastasis. Median tumor size was 5.5 cm. With a median follow-up of 18 months, median survival was 27 months and 5-year OS was 30.6%. The OS c-index for the AJCC 8th staging system was 0.669, which was comparable with the c-index for the 7th edition AJCC staging system (c-index: 0.667); the AJCC 8th-edition did provide more discrete stratification of patients. The new AJCC 8th-edition staging system for ICC was largely comparable to the 7th-edition version and did not provide a marked improvement in overall prognostic discrimination. © 2017 Wiley Periodicals, Inc.

  13. Analysis of U2 small nuclear RNA fragments in the bile differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders.

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    Baraniskin, Alexander; Nöpel-Dünnebacke, Stefanie; Schumacher, Brigitte; Gerges, Christian; Bracht, Thilo; Sitek, Barbara; Meyer, Helmut E; Gerken, Guido; Dechene, Alexander; Schlaak, Jörg F; Schroers, Roland; Pox, Christian; Schmiegel, Wolff; Hahn, Stephan A

    2014-07-01

    Up to now the diagnosis of early stage cholangiocarcinoma (CC) has remained difficult, with low sensitivities reported for current diagnostic methods. Based on recent promising findings about circulating U2 small nuclear RNA fragments (RNU2-1f) as novel blood-based biomarkers for pancreatic and colorectal adenocarcinoma, we studied the utility of RNU2-1f as a diagnostic marker of CC in bile fluid. Bile fluid was collected from patients with CC (n = 12), controls (patients with choledocholithiasis) (n = 11) and with primary sclerosing cholangitis (PSC; n = 11). RNU2-1f levels were measured by real-time polymerase chain reaction normalized to cel-54. Measurement of RNU2-1f levels in bile fluids enabled the differentiation of patients with CC from controls in all cases. Furthermore, RNU2-1f levels in bile fluids of patients with CC were significantly higher than in patients with PSC, resulting in a receiver-operating characteristic curve area of 0.856, with sensitivity of 67 % and specificity of 91 %. Our data suggest that the measurement of RNU2-1 fragments detected in the bile fluid can be used as a diagnostic marker for CC and should be included in future prospective diagnostic studies for this disease entity.

  14. A long-term survivor of hilar cholangiocarcinoma with resection of recurrent peritoneal dissemination after R0 surgery: a case report.

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    Miyata, Tatsunori; Okabe, Hirohisa; Chikamoto, Akira; Yamao, Takanobu; Umezaki, Naoki; Tsukamoto, Masayo; Kitano, Yuki; Arima, Kota; Nakagawa, Shigeki; Imai, Katsunori; Hashimoto, Daisuke; Yamashita, Yo-Ichi; Baba, Hideo

    2017-10-16

    Although hilar cholangiocarcinoma (HCCA) has a very poor prognosis, there are cases in which long-term survival is rarely obtained by multidisciplinary treatment. A 61-year-old man diagnosed with HCCA was referred to our hospital. We performed an extended left hemi-hepatectomy and caudate lobectomy with extrahepatic bile duct resection. The tumor stage was T2aN0M0, stage II, based on the TNM classification, seventh edition. R0 resection was successfully performed. Adjuvant chemotherapy was not administered. After 38 months, computed tomography revealed peritoneal dissemination. The patient received chemotherapy with tegafur-gimeracil-oteracil-potassium (S-1) and gemcitabine. The peritoneal dissemination was successfully controlled for more than 50 months. During the treatment, levels of CEA and CA19-9 kept rising slowly, which was followed by bowel obstruction due to peritoneal dissemination of HCCA. The patient underwent resection of transverse colon with tumor nodules, and the tumor was pathologically diagnosed as metastasis of HCCA. Tumor markers decreased to normal levels, and the patient has been free from tumor relapse for 6 months. We here report a rare case of HCCA patient with recurrent peritoneal dissemination 3 years after R0 surgery which was sensitive to chemotherapy. The patient successfully received resection of peritoneal dissemination 50 months after the induction of chemotherapy and survived for 10 years.

  15. Surveillance of Populations at Risk of Cholangiocarcinoma Development in Rural Communities of Thailand Using the Korat-CCA Verbal Screening Test.

    Science.gov (United States)

    Kaewpitoon, Soraya J; Rujirakul, Ratana; Loyd, Ryan A; Panpimanmas, Sukij; Matrakool, Likit; Tongtawee, Taweesak; Kompor, Porntip; Norkaew, Jun; Chavengkun, Wasugree; Wakkhuwattapong, Parichart; Kujapun, Jirawoot; Ponphimai, Sukanya; Phatisena, Tanida; Eaksunti, Thawatchai; Polsripradist, Poowadol; Joosiri, Apinya; Sukkasam, Inchat; Padchasuwan, Natnapa; Kaewpitoon, Natthawut

    2016-01-01

    Cholangiocarcinoma (CCA) is a serious problem in Thailand, particularly in the northeastern region. Active surveillance in rural communities with an appropriat low-cost screening tool is required to facilitate early detection. Therefore, this study aimed to investigate the population at risk of CCA in Bua Yai district, Nakhon Ratchasima province, Northeastern Thailand using the Korat-CCA verbal screening test (KCVST) during June to October 2015. Reliability of KCVST demonstrated a Cronbach alpha coefficient=0.75 Stepwise-multiple regression showed that alcohol consumption was important for CCA screened, followed by agriculture and pesticide use, under-cooked cyprinoid fish consumption, praziquantel use, naïve northeastern people, opisthorchiasis, family relatives with CCA, and cholangitis or cholecystitis or gallstones, respectively. Population at risk for CCA was classified to low risk (63.4%), moderate risk (33.7%), and high risk (1.32%) for CCA. When CCA was screened using ultrasonography, 4 of 32 high risk participants had an abnormal biliary tract with dilated bile ducts. This study indicates that KCVST is a potential useful too which decrease the cost of large scale CCA screening.

  16. Percutaneous Intraductal Radiofrequency Ablation for Extrahepatic Distal Cholangiocarcinoma: A Method for Prolonging Stent Patency and Achieving Better Functional Status and Quality of Life

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    Wu, Tian-tian, E-mail: matthewwu1979@hotmail.com; Li, Wei-min, E-mail: weimin-li-surgery@126.com [The 309th Hospital of PLA, Hepatobiliary Surgery Department (China); Li, Hu-cheng, E-mail: hucheng-li-surgery@126.com [The 307th Hospital of PLA, General Surgery Department (China); Ao, Guo-kun, E-mail: guokun-ao-radiology@126.com [The 309th Hospital of PLA, Radiology Department (China); Zheng, Fang, E-mail: fang-zheng-surgery@126.com [The 309th Hospital of PLA, Hepatobiliary Surgery Department (China); Lin, Hu, E-mail: hu-lin-radiology@126.com [The 309th Hospital of PLA, Radiology Department (China)

    2017-02-15

    PurposeThe clinical efficacy of intraductal radiofrequency ablation (RFA) with Habib™ EndoHPB catheter, a newly developed intervention for malignant extrahepatic biliary obstruction, remains uncertain. The aim of this study was to investigate the clinical efficacy of intraductal RFA.MethodsData from 71 patients with extrahepatic distal cholangiocarcinoma were retrospectively analyzed. The study patients were divided into RFA and control groups. The RFA group had undergone percutaneous transhepatic intraductal RFA with a Habib™ EndoHPB catheter, followed by placement of covered or uncovered biliary self-expandable metallic stents (SEMs) whereas the control group had undergone percutaneous transhepatic covered or uncovered SEMs placement. Procedure-related complications, stent patency, patient survival, and postoperative serum bilirubin concentrations were compared between the two groups. The Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire was administered to evaluate functional status, improvement in clinical manifestations, and quality of life.ResultsThe RFA group had a longer median stent patency than the control group (p = 0.001 for uncovered SEMs placement). Higher functional well-being, hepatobiliary-specific cancer subscale, Trial Outcome Index, and total FACT-Hep scores were observed during post-procedure follow-up in the RFA group. However, median survival did not differ significantly between the two groups (p > 0.05).ConclusionsProlongation of stent patency and better functional status and quality of life, which are all important clinical endpoints, were observed in patients treated with intraductal RFA. Prospective randomized controlled clinical trials are necessary to further investigate the clinical efficacy and long-term benefits of intraductal RFA.

  17. Imaging features of hepatocellular carcinoma compared to intrahepatic cholangiocarcinoma and combined tumor on MRI using liver imaging and data system (LI-RADS) version 2014.

    Science.gov (United States)

    Horvat, Natally; Nikolovski, Ines; Long, Niamh; Gerst, Scott; Zheng, Jian; Pak, Linda Ma; Simpson, Amber; Zheng, Junting; Capanu, Marinela; Jarnagin, William R; Mannelli, Lorenzo; Do, Richard Kinh Gian

    2018-01-01

    To evaluate the prevalence of major and ancillary imaging features from liver imaging reporting and data systems (LI-RADS) version 2014 and their interreader agreement when comparing hepatocellular carcinoma (HCC) to intrahepatic cholangiocarcinoma (ICC) and combined tumor (cHCC-CC). The Institutional Review Board approved this HIPAA-compliant retrospective study and waived the requirement for patients' informed consent. Patients with resected HCC (n = 51), ICC (n = 40), and cHCC-CC (n = 11) and available pre-operative contrast-enhanced MRI were included from 2000 to 2015. Imaging features and final LI-RADS category were evaluated by four radiologists. Imaging features were compared by Fisher's exact test and interreader agreements were assessed by κ statistics. None of the features were unique to either HCC or non-HCC. Imaging features that were significantly more common among HCC compared to ICC and cHCC-CC included washout (76%-78% vs. 10%-35%, p Features that were more common among ICC and cHCC-CC included peripheral arterial phase hyperenhancement (40%-64% vs. 10%-14%, p features (κ = 0.41-0.55). Moderate agreement was also achieved in the assignment of LR-M (κ = 0.53), with an overall sensitivity and specificity for non-HCC malignancy of 86.3% and 78.4%, respectively. HCC and non-HCC show significant differences in the prevalence of imaging features defined by LI-RADS, and are identified by radiologists with moderate interreader agreement. Using LI-RADS, radiologists also achieved moderate interreader agreement in the assignment of the LR-M category.

  18. Addition of Molecular Adsorbent Recirculating System (MARS(®)) Albumin Dialysis for the Preoperative Management of Jaundiced Patients with Hilar Cholangiocarcinoma.

    Science.gov (United States)

    Regimbeau, Jean-Marc; Fuks, David; Chapuis-Roux, Emilie; Yzet, Thierry; Cosse, Cyril; Bartoli, Eric; N'guyen-Khac, Eric; Robert, Brice; Lobjoie, Eric

    2013-01-01

    The preoperative management of hilar cholangiocarcinoma (HC) with jaundice focuses on decreasing the total serum bilirubin level (SBL) by performing preoperative biliary drainage (PBD). However, it takes about 6-8 weeks for the SBL to fall at a sufficient extent. The objective of this preliminary study was to evaluate the impact of Molecular Adsorbent Recirculating System (MARS(®)) dialysis (in association with PBD) on SBL decrease. From January 2010 to January 2011, we prospectively selected all jaundiced patients admitted to our university hospital for resectable HC and requiring PBD prior to major hepatectomy. The PBD was followed by 3 sessions of MARS dialysis over a period of 72 h. A total of 10 patients with HC were screened and two of them were included (Bismuth-Corlette stage IIIa, gender ratio 1, median age 68 years). The initial SBL in the two patients was 328 and 242 μmol/l, respectively. After three MARS dialysis sessions, the SBL had fallen by 30 and 52%, respectively. After the end of each session, there was a SBL rebound of about 10 μmol/l. The MARS decreased the serum creatinine level, the platelet count and the prothrombin index, but did not modify the serum albumin level. Pruritus disappeared after one and two sessions, respectively. MARS-related morbidity included hypotension (n = 1), tachycardia (n = 1), thrombocytopenia (n = 2) and anaemia (n = 1). When combined with PBD, MARS dialysis appears to accelerate the decrease in SBL and thus may enable earlier surgery. This hypothesis must be validated in a larger study.

  19. Long-Term Outcome of Distal Cholangiocarcinoma after Pancreaticoduodenectomy Followed by Adjuvant Chemoradiotherapy: A 15-Year Experience in a Single Institution.

    Science.gov (United States)

    Kim, Byoung Hyuck; Kim, Kyubo; Chie, Eui Kyu; Kwon, Jeanny; Jang, Jin-Young; Kim, Sun Whe; Oh, Do-Youn; Bang, Yung-Jue

    2017-04-01

    This study was conducted to evaluate the long-term outcome in patients undergoing pancreaticoduodenectomy (PD) followed by adjuvant chemoradiotherapy for distal cholangiocarcinoma (DCC) in a high-volume center and to identify the prognostic impact of clinicopathologic factors. A total of 132 consecutive patients who met the inclusion criteria were retrieved from the institutional database from January 1995 to September 2009. All patients received adjuvant treatments at a median of 45 days after the surgery. Median follow-up duration was 57 months (range, 6 to 225 months) for all patients and 105 months for survivors (range, 13 to 225 months). The 5-year locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates were 70.7%, 55.7%, 49.4%, and 48.1%, respectively. Univariate analysis revealed poorly differentiated (P/D) tumors and lymph node (LN) metastasis were significantly associated with DMFS and OS. Additionally, preoperative carbohydrate antigen 19-9 level was significantly correlated with DFS, LRRFS, and DMFS. Upon multivariate analysis for OS, P/D tumors (p=0.015) and LN metastasis (p=0.003) were significant prognosticators that predicted inferior OS. Grade 3 or higher late gastrointestinal toxicity occurred in only one patient (0.8%). Adjuvant chemoradiotherapy after PD for DCC is an effective and tolerable strategy without significant side effects. During long-term follow-up, we found that prognosis of DCC was mainly influenced by histologic differentiation and LN metastasis. For patients with these risk factors, further research should focus on improving adjuvant strategies as well as other treatment approaches.

  20. Expression levels and significance of nuclear factor-κB and epidermal growth factor receptor in hepatolithiasis associated with intrahepatic cholangiocarcinoma.

    Science.gov (United States)

    Zhou, Quanbo; Gong, Yuanfeng; Huang, Feng; Lin, Qing; Zeng, Bing; Li, Zhihua; Chen, Rufu

    2013-01-01

    An increasing incidence of cholangiocarcinoma (CCA) and CCA mortality rates has been observed around the world. Patients with intrahepatic biliary stones have a 10% risk of developing CCA, and up to 70% of patients with histologically confirmed CCA have hepatolithiasis. Few previous studies have addressed the associations between the expression of nuclear factor (NF)-κB and epidermal growth factor receptor (EGFR) and clinicopathological prognosis in patients with hepatolithiasis-associated intrahepatic CCA. This study was designed to investigate the clinicopathological and prognostic significance of NF-κB and EGFR expression in hepatolithiasis-associated intrahepatic CCA and hepatolithiasis. A total of 90 liver specimens were immunohistochemically stained for NF-κB and EGFR expression, and the characteristics of 90 individual patients were retrospectively reviewed. Differences in the positive rates of NF-κB and EGFR expression between the hepatolithiasis-associated intrahepatic CCA group, intrahepatic lithiasis group, and control group were found to be statistically significant. EGFR expression was closely associated with the degree of differentiation and depth of invasion (p < 0.05). The 1-, 3-, and 5-year overall survival rates were respectively 42.8, 21.0, and 10.3% in intrahepatic CCA groups. The survival rate of the EGFR-negative group was higher than in the EGFR-positive group (p < 0.01). Lymph node metastasis (HR 1.24, 95% CI 1.02-1.51) and EGFR positivity (HR 1.74, 95% CI 1.30-2.23) were associated with decreases in the survival rate. The expression of NF-κB may be an early step in intrahepatic cholangiocarcinogenesis. Overexpression of EGFR is associated with the degree of malignancy and with poor prognosis. NF-κB and EGFR may cooperate during intrahepatic cholangiocarcinogenesis and progression. Lymph node metastasis and EGFR positivity were associated with decreases in the survival rate. Copyright © 2013 S. Karger AG, Basel.

  1. GIS Database and Google Map of the Population at Risk of Cholangiocarcinoma in Mueang Yang District, Nakhon Ratchasima Province of Thailand.

    Science.gov (United States)

    Kaewpitoon, Soraya J; Rujirakul, Ratana; Joosiri, Apinya; Jantakate, Sirinun; Sangkudloa, Amnat; Kaewthani, Sarochinee; Chimplee, Kanokporn; Khemplila, Kritsakorn; Kaewpitoon, Natthawut

    2016-01-01

    Cholangiocarcinoma (CCA) is a serious problem in Thailand, particularly in the northeastern and northern regions. Database of population at risk are need required for monitoring, surveillance, home health care, and home visit. Therefore, this study aimed to develop a geographic information system (GIS) database and Google map of the population at risk of CCA in Mueang Yang district, Nakhon Ratchasima province, northeastern Thailand during June to October 2015. Populations at risk were screened using the Korat CCA verbal screening test (KCVST). Software included Microsoft Excel, ArcGIS, and Google Maps. The secondary data included the point of villages, sub-district boundaries, district boundaries, point of hospital in Mueang Yang district, used for created the spatial databese. The populations at risk for CCA and opisthorchiasis were used to create an arttribute database. Data were tranfered to WGS84 UTM ZONE 48. After the conversion, all of the data were imported into Google Earth using online web pages www.earthpoint.us. Some 222 from a 4,800 population at risk for CCA constituted a high risk group. Geo-visual display available at following www.google.com/maps/d/u/0/ edit?mid=zPxtcHv_iDLo.kvPpxl5mAs90 and hl=th. Geo-visual display 5 layers including: layer 1, village location and number of the population at risk for CCA; layer 2, sub-district health promotion hospital in Mueang Yang district and number of opisthorchiasis; layer 3, sub-district district and the number of population at risk for CCA; layer 4, district hospital and the number of population at risk for CCA and number of opisthorchiasis; and layer 5, district and the number of population at risk for CCA and number of opisthorchiasis. This GIS database and Google map production process is suitable for further monitoring, surveillance, and home health care for CCA sufferers.

  2. Silencing of miR-370 in human cholangiocarcinoma by allelic loss and interleukin-6 induced maternal to paternal epigenotype switch.

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    Fangmei An

    Full Text Available Cholangiocarcinoma (CCA is a highly lethal malignant tumor arising from the biliary tract epithelium. Interleukin-6 (IL-6 is a major mediator of inflammation and contributor to carcinogenesis within the biliary tree. Previous studies suggested that enforced IL-6 contributes to cholangiocarcinogenesis through hypermethylation of several genes implicated in CCA. However, the precise mechanisms of IL-6 effects in CCA remain unclear. We now demonstrate that microRNA (miR-370 is underexpressed in a large cohort of human CCA vs. normal liver tissues. In addition, we show that IL-6 induces a time-dependent silencing of miR-370. In addition, demethylation of CCA cells results in upregulation of miR-370. Furthermore, we demonstrate that miR-370 is imprinted, and that the Intergenic Differentially Methylated Region (IG-DMR responsible for imprinting regulation of this genomic locus is hypermethylated in response to IL-6 treatment. In addition, the IG-DMR is hypermethylated in human CCA specimens compared to normal matched controls, in the same location as the IL-6 induced hypermethylation. Finally, miR-370 was found to regulate WNT10B in luciferase as well as western blotting experiments. Our data indicate that the paternal allele of miR-370 is normally silenced through genomic imprinting and that the overexpression of IL-6 in CCA effectively suppresses the expression of miR-370 from the maternal allele, lending support to the theory that miR-370 silencing in human CCA follows a classic two-hit mechanism.

  3. PTFE Graft as a "Bridge" to Communicating Veins Maturation in the Treatment of an Intrahepatic Cholangiocarcinoma Involving the 3 Hepatic Veins. The Minor-but-Complex Liver Resection.

    Science.gov (United States)

    Urbani, Lucio; Balestri, Riccardo; Sidoti, Francesco; Bernardini, Juri Riccardo; Arces, Francesco; Licitra, Gabriella; Leoni, Chiara; Forfori, Francesco; Colombatto, Piero; Boraschi, Piero; Castagna, Maura; Buccianti, Piero

    2016-12-01

    Parenchyma-sparing liver surgery allows resecting hepatic veins (HV) at the hepatocaval confluence with minor (<3 adjacent segments) liver resections. PTFE graft can be used as a bridge to communicating-veins maturation to ensure the correct outflow of the spared liver. We present a video of an intrahepatic cholangiocarcinoma (IC) involving the three HV at the hepatocaval confluence treated with this approach. In a 50-year old obese (BMI 44.8) male a 6-cm IC involving the hepatocaval confluence was identified during the follow-up for a kidney malignancy. At the preoperative CT scan the left HV was not detectable, the middle HV was incorporated within the tumor, and right HV had a 3-cm contact with the tumor. No communicating veins were evident at preoperative imaging. After a J-shape thoracophrenolaparotomy, the resection of segments II-III-IVa was partially extended to segment VIII-VII and I. The right HV was detached from the tumor, and the middle HV was reconstructed with a 7-mm ringed-armed PTFE graft anastomosed to V8. Surgery lasted 20 h and 55 min with an estimated blood loss of 3500 ml, but the postoperative course was uneventful and the patient was discharged on the 14th postoperative day. One month later the CT scan showed a patent PTFE graft with the maturation of communicating-veins. One year later a complete thrombosis of the PTFE graft was observed with normal liver perfusion and function, and the patient was disease-free. PTFE-based parenchyma-sparing liver resection is a new tool to treat tumors located at the hepatocaval confluence exploiting the maturation of intrahepatic communicating-veins between main HV.

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

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

    2015-01-01

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

  5. LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

    Directory of Open Access Journals (Sweden)

    Wen-Tao Wang

    2016-11-01

    Full Text Available Abstract Background Long non-coding RNAs (lncRNAs are known to play important roles in different cell contexts, including cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA, a cholangiocyte malignancy with poor prognosis, associated with chronic inflammation and damage to the biliary epithelium. The aim of the study is to identify if any lncRNA might associate with inflammation or oxidative stress in CCA and regulate the disease progression. Methods In this study, RNA-seqs datasets were used to identify aberrantly expressed lncRNAs. Small interfering RNA and overexpressed plasmids were used to modulate the expression of lncRNAs, and luciferase target assay RNA immunoprecipitation (RIP was performed to explore the mechanism of miRNA-lncRNA sponging. Results We firstly analyzed five available RNA-seqs datasets to investigate aberrantly expressed lncRNAs which might associate with inflammation or oxidative stress. We identified that two lncRNAs, H19 and HULC, were differentially expressed among all the samples under the treatment of hypoxic or inflammatory factors, and they were shown to be stimulated by short-term oxidative stress responses to H2O2 and glucose oxidase in CCA cell lines. Further studies revealed that these two lncRNAs promoted cholangiocyte migration and invasion via the inflammation pathway. H19 and HULC functioned as competing endogenous RNAs (ceRNAs by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4. Conclusions Our study revealed that H19 and HULC, up-regulated by oxidative stress, regulate CCA cell migration and invasion by targeting IL-6 and CXCR4 via ceRNA patterns of sponging let-7a/let-7b and miR-372/miR-373, respectively. The results suggest that these lncRNAs might be the chief culprits of CCA pathogenesis and progression. The study provides new insight into the mechanism linking lncRNA function with CCA and

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

    Directory of Open Access Journals (Sweden)

    Md Hafiz Uddin

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

  7. External Validation of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) Risk Model to Predict Operative Risk in Perihilar Cholangiocarcinoma.

    Science.gov (United States)

    Coelen, Robert J S; Olthof, Pim B; van Dieren, Susan; Besselink, Marc G H; Busch, Olivier R C; van Gulik, Thomas M

    2016-12-01

    Resection of perihilar cholangiocarcinoma (PHC) is high-risk surgery, with reported operative mortality up to 17%. Therefore, preoperative risk assessment is needed to identify high-risk patients and anticipate postoperative adverse outcomes. To provide external validation of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) risk model in a Western PHC cohort. The E-PASS variables were obtained from a database that included 156 consecutive patients who underwent resection for suspected PHC between January 1, 2000, and December 31, 2015, at the Academic Medical Center, Amsterdam, the Netherlands. The accuracy of E-PASS using intraoperative variables and its modified form that can be used before surgery (mE-PASS) in predicting mortality was assessed by area under the curve analysis (discrimination) and by the Hosmer-Lemeshow goodness-of-fit test (calibration). In-hospital mortality, severe morbidity (Clavien-Dindo grade≥III), and a high Comprehensive Complication Index. Among 156 patients included in the study, the median age was 63 years, and 62.8% (n = 98) were male. Of them, 85.3% (n = 133) underwent major liver resection. Severe morbidity occurred in 51.3% (n = 80), and in-hospital mortality was 13.5% (n = 21). Both E-PASS and mE-PASS had adequate discriminative performance, with areas under the curve of 0.78 (95% CI, 0.67-0.88) and 0.79 (95% CI, 0.70-0.89), respectively, while E-PASS showed better calibration (P = .33 vs P = .02, Hosmer-Lemeshow goodness-of-fit test). The ratios of observed to expected mortality were 1.31 for E-PASS and 1.24 for mE-PASS. Both models were able to distinguish groups with low risk, intermediate risk, and high risk, with observed mortality rates of 0.0% to 3.6%, 8.3% to 9.0%, and 25.0% to 28.3%, respectively. Severe morbidity and a high Comprehensive Complication Index were more frequently observed among high-risk patients. Both E-PASS models accurately identify patients at high risk of

  8. Synthesis and characterization of boron fenbufen and its F-18 labeled homolog for boron neutron capture therapy of COX-2 overexpressed cholangiocarcinoma.

    Science.gov (United States)

    Yeh, Chun-Nan; Chang, Chi-Wei; Chung, Yi-Hsiu; Tien, Shi-Wei; Chen, Yong-Ren; Chen, Tsung-Wen; Huang, Ying-Cheng; Wang, Hsin-Ell; Chou, You-Cheng; Chen, Ming-Huang; Chiang, Kun-Chun; Huang, Wen-Sheng; Yu, Chung-Shan

    2017-09-30

    Boron neutron capture therapy (BNCT) is a binary therapy that employs neutron irradiation on the boron agents to release high-energy helium and alpha particles to kill cancer cells. An optimal response to BNCT depends critically on the time point of maximal 10B accumulation and highest tumor to normal ratio (T/N) for performing the neutron irradiation. The aggressive cholangiocarcinoma (CCA) representing a liver cancer that overexpresses COX-2 enzyme is aimed to be targeted by COX-2 selective boron carrier, fenbufen boronopinacol (FBPin). Two main works were performed including: 1) chemical synthesis of FBPin as the boron carrier and 2) radiochemical labeling with F-18 to provide the radiofluoro congener, m-[18F]fluorofenbufen ester boronopinacol (m-[18F]FFBPin), to assess the binding affinity, cellular accumulation level and distribution profile in CCA rats. FBPin was prepared from bromofenbufen via 3 steps with 82% yield. The binding assay employed [18F]FFBPin to compete FBPin for binding to COX-1 (IC50=0.91±0.68μM) and COX-2 (IC50=0.33±0.24μM). [18F]FFBPin-derived 60-min dynamic PET scans predict the 10B-accumulation of 0.8-1.2ppm in liver and 1.2-1.8ppm in tumor and tumor to normal ratio=1.38±0.12. BNCT was performed 40-55min post intravenous administration of FBPin (20-30mg) in the CCA rats. CCA rats treated with BNCT display more tumor reduction than that by NCT with respect of 2-[18F]fluoro-2-deoxy glucose uptake in the tumor region of interest, 20.83±3.00% (n=12) vs. 12.83±3.79% (n=10), P=0.05. The visualizing agent [18F]FFBPin resembles FBPin to generate the time-dependent boron concentration profile. Optimal neutron irradiation period is thus determinable for BNCT. A boron-substituted agent based on COX-2-binding features has been prepared. The moderate COX-2/COX-1 selectivity index of 2.78 allows a fair tumor selectivity index of 1.38 with a mild cardiovascular effect. The therapeutic effect from FBPin with BNCT warrants a proper COX-2 targeting

  9. Corrosion inhibiting organic coatings

    Energy Technology Data Exchange (ETDEWEB)

    Sasson, E.

    1984-10-16

    A corrosion inhibiting coating comprises a mixture of waxes, petroleum jelly, a hardener and a solvent. In particular, a corrosion inhibiting coating comprises candelilla wax, carnauba wax, microcrystalline waxes, white petrolatum, an oleoresin, lanolin and a solvent.

  10. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer.

    Science.gov (United States)

    Saha, Supriya K; Parachoniak, Christine A; Ghanta, Krishna S; Fitamant, Julien; Ross, Kenneth N; Najem, Mortada S; Gurumurthy, Sushma; Akbay, Esra A; Sia, Daniela; Cornella, Helena; Miltiadous, Oriana; Walesky, Chad; Deshpande, Vikram; Zhu, Andrew X; Hezel, Aram F; Yen, Katharine E; Straley, Kimberly S; Travins, Jeremy; Popovici-Muller, Janeta; Gliser, Camelia; Ferrone, Cristina R; Apte, Udayan; Llovet, Josep M; Wong, Kwok-Kin; Ramaswamy, Sridhar; Bardeesy, Nabeel

    2014-09-04

    Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.

  11. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial

    DEFF Research Database (Denmark)

    Stein, A.; Arnold, D.; Bridgewater, J.

    2015-01-01

    Background: Despite complete resection, disease-free survival (DFS) of patients with cholangiocarcinoma (CCA) is less than 65 % after one year and not more than 35 % after three years. For muscle invasive gallbladder carcinoma (GBCA), prognosis is even worse, with an overall survival (OS) of only....... Due to the different prognosis and treatment susceptibility of muscle invasive carcinoma, two separate cohorts (CCA and GBCA) were included to capture the potentially different treatment effects. Randomization is stratified for lymph node status for both cohorts and localization for CCA. The primary...... endpoint is DFS and secondary endpoints include OS, safety and tolerability of chemotherapy, quality of life, and patterns of disease recurrence. For CCA, adjuvant chemotherapy should increase DFS 24 months post-surgery from 40 to 55 % to be considered relevant. With a power of 80 % and a significance...

  12. Chemoradiation in patients with unresectable extrahepatic and hilar cholangiocarcinoma or at high risk for disease recurrence after resection.. Analysis of treatment efficacy and failure in patients receiving postoperative or primary chemoradiation

    Energy Technology Data Exchange (ETDEWEB)

    Habermehl, D.; Lindel, K.; Rieken, S.; Haase, K.; Welzel, T.; Debus, J.; Combs, S.E. [University Hospital of Heidelberg (Germany). Dept. of Radiation Oncology; Goeppert, B.; Schirmacher, P. [Heidelberg Univ. (Germany). Inst. of Pathology; Buechler, M.W. [University Hospital of Heidelberg (Germany). Dept. of Visceral Surgery

    2012-09-15

    Background: The purpose of this work was to determine efficacy, toxicity, and patterns of recurrence after concurrent chemoradiation (CRT) in patients with extrahepatic bile duct cancer (EHBDC) and hilar cholangiocarcinoma (Klatskin tumours) in case of incomplete resection or unresectable disease. Patients and methods: From 2003-2010, 25 patients with nonmetastasized EHBDC and hilar cholangiocarcinoma were treated with radiotherapy and CRT at our institution in an postoperative setting (10 patients, 9 patients with R1 resections) or in case of unresectable disease (15 patients). Median age was 63 years (range 38-80 years) and there were 20 men and 5 women. Median applied dose was 45 Gy in both patient groups. Results: Patients at high risk (9 times R1 resection, 1 pathologically confirmed lymphangiosis) for tumour recurrence after curative surgery had a median time to disease progression of 8.7 months and an estimated mean overall survival of 23.2 months (6 of 10 patients are still under observation). Patients undergoing combined chemoradiation in case of unresectable primary tumours are still having a poor prognosis with a progression-free survival of 7.1 months and a median overall survival of 12.0 months. The main site of progression was systemic (liver, peritoneum) in both patient groups. Conclusion: Chemoradiation with gemcitabine is safe and can be applied safely in either patients with EHBDC or Klatskin tumours at high risk for tumour recurrence after resection and patients with unresectable tumours. Escalation of systemic and local treatment should be investigated in future clinical trials. (orig.)

  13. Effect of Y-box binding protein 1 overexpression on the prognosis of patients with intrahepatic cholangiocarcinoma undergoing postoperative adjuvant chemotherapy

    Directory of Open Access Journals (Sweden)

    LIU Heng

    2017-02-01

    Full Text Available ObjectiveTo investigate the association between Y-box binding protein 1 (YB-1 overexpression and the prognosis of patients with intrahepatic cholangiocarcinoma (ICC undergoing postoperative adjuvant chemotherapy. MethodsThe paraffin-embedded specimens were collected from 58 patients with ICC who underwent surgical treatment and postoperative adjuvant chemotherapy in The First Affiliated Hospital of Anhui Medical University from January 2010 to January 2015. Immunohistochemistry was used to measure the expression of YB-1 in ICC tissue; after ICC cells were transfected with YB-1 plasmid, the thiazolyl blue method was used to observe the change in gemcitabine sensitivity, and qPCR was used to observe the changes in the expression of multidrug resistance genes. The independent samples t-test was used for comparison of continuous data between two groups and a one-way analysis of variance was used for comparison of continuous data between multiple groups; the chi-square test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to calculate survival rates and the log-rank test was used for survival difference analysis. ResultsAmong the 58 patients, 44 (75.9% had high expression of YB-1 in the cytoplasm of ICC cells (cytoplasm YB-1 positive group and 14 (24.1% had no expression of YB-1 in the cytoplasm of ICC cells (cytoplasm YB-1 negative group. Of all patients in the cytoplasm YB-1 positive group, 18 (40.9% also had positive nuclear expression of YB-1 (nuclear YB-1 positive group; the other 40 patients had no nuclear expression of YB-1 (nuclear YB-1 negative group. The nuclear YB-1 negative group had a significantly longer survival time than the nuclear YB-1 positive group (63 months vs 28 months, χ2=17.99, P<0.05. In the control plasmid group, the half-maximal inhibitory concentration (IC50 of gemcitabine in HCCC-9810 cells was 0.054 μmol, and in the pSG5-YB-1 plasma transfection group, IC50 increased to 0

  14. Inhibition of selectin binding

    Energy Technology Data Exchange (ETDEWEB)

    Nagy, Jon O. (Rodeo, CA); Spevak, Wayne R. (Albany, CA); Dasgupta, Falguni (New Delhi, IN); Bertozzi, Carolyn (Albany, CA)

    1999-10-05

    This invention provides a system for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, this system can be used to palliate certain inflammatory and immunological conditions.

  15. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  16. Csseverin inhibits apoptosis through mitochondria-mediated pathways triggered by Ca2 + dyshomeostasis in hepatocarcinoma PLC cells.

    Science.gov (United States)

    Shi, Mengchen; Zhou, Lina; Zhao, Lu; Shang, Mei; He, Tongtong; Tang, Zeli; Sun, Hengchang; Ren, Pengli; Lin, Zhipeng; Chen, Tingjin; Yu, Jinyun; Xu, Jin; Yu, Xinbing; Huang, Yan

    2017-11-01

    Numerous experimental and epidemiological studies have demonstrated a link between Clonorchis sinensis (C. sinensis) infestation and cholangiocarcinoma (CCA) as well as hepatocellular carcinoma (HCC). The underlying molecular mechanism involved in the malignancy of CCA and HCC has not yet been addressed. Csseverin, a component of the excretory/secretory products of C. sinensis (CsESPs), was confirmed to cause obvious apoptotic inhibition in the human HCC cell line PLC. However, the antiapoptotic mechanism is unclear. In the present study, we investigated the cellular features of the antiapoptotic mechanism upon transfection of the Csseverin gene. In the present study, we evaluated the effects of Csseverin gene overexpression on the apoptosis of PLC cells using an Annexin PE/7-AAD assay. Western blotting was applied to quantify the activation of caspase-3 and caspase-9, the mitochondrial translocation of Bax and the release of Cyt c upon Csseverin overexpression in PLC cells. Laser scanning confocal microscopy was used to analyze the changes of intracellular calcium. Fluorescence assay and immunofluorescence assays were performed to observe the changes of the mitochondrial permeability transition pore (MPTP). The overexpression of Csseverin in PLC cells showed apoptosis resistance after the induction of apoptosis. Additionally, the activation of caspase-3 and caspase-9 was specifically weakened in Csseverin overexpression PLC cells. The overexpression of Csseverin reduced the increase in intracellular free Ca2+, thereby inhibiting MPTP opening in PLC cells. Moreover, Bax mitochondrial translocation and the subsequent release of Cyt c were downregulated in apoptotic Csseverin overexpression PLC cells. The present findings suggest that Csseverin, a component of CsESPs, confers protection from human HCC cell apoptosis via the inactivation of membranous Ca2+ channels. Csseverin might be involved in the process of HCC through C. sinensis infestation in affected patients.

  17. Plastics for corrosion inhibition

    CERN Document Server

    Goldade, Victor A; Makarevich, Anna V; Kestelman, Vladimir N

    2005-01-01

    The development of polymer composites containing inhibitors of metal corrosion is an important endeavour in modern materials science and technology. Corrosion inhibitors can be located in a polymer matrix in the solid, liquid or gaseous phase. This book details the thermodynamic principles for selecting these components, their compatibility and their effectiveness. The various mechanisms of metal protection – barrier, inhibiting and electromechanical – are considered, as are the conflicting requirements placed on the structure of the combined material. Two main classes of inhibited materials (structural and films/coatings) are described in detail. Examples are given of structural plastics used in friction units subjected to mechano-chemical wear and of polymer films/coatings for protecting metal objects against corrosion.

  18. Selective inhibition of enzyme synthesis under conditions of respiratory inhibition.

    Science.gov (United States)

    Flavell, R B; Woodward, D O

    1971-09-01

    When Neurospora mycelium is transferred from a medium containing sucrose to one containing acetate as sole source of carbon, a preferential synthesis of many Krebs cycle, glyoxylate cycle, and associated enzymes occurs. Respiration was inhibited during preferential enzyme synthesis in the following ways. (i) The amount of aeration (shaking) was reduced, (ii) cyanide was added to the culture, (iii) the carbon source, acetate, was removed, (iv) a mutant strain was starved of its Krebs cycle intermediates, and (v) respiration was inhibited by mutation. The effect of this respiratory inhibition on the synthesis of a number of enzymes was measured. It was found that the synthesis of nicotinamide adenine dinucleotide (NAD)-linked glutamate dehydrogenase and phosphoenolpyruvate carboxykinase was significantly less inhibited under conditions of respiratory inhibition than was the synthesis of Krebs cycle, glyoxylate cycle, and most other cell proteins synthesized during the adaptation period. This differential inhibition of enzyme synthesis was almost certainly not due to differential repression by regulatory metabolic end product effectors. Inhibition of mitochondrial respiration under these conditions most likely results in a limitation of the energy supply of the cell. Thus, it is suggested that the inhibition of synthesis of most proteins after inhibition of mitochondrial respiration results from a lack of energy in a utilizable form. Possible reasons to account for the relative insensitivity of NAD-linked glutamate dehydrogenase and phosphoenolpyruvate carboxykinase to inhibition under these conditions are discussed.

  19. Pharmacological inhibition of FTO.

    Directory of Open Access Journals (Sweden)

    Fiona McMurray

    Full Text Available In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO's demethylase activity could be therapeutically useful for the treatment of obesity.

  20. Beneficial bacteria inhibit cachexia

    Science.gov (United States)

    Varian, Bernard J.; Goureshetti, Sravya; Poutahidis, Theofilos; Lakritz, Jessica R.; Levkovich, Tatiana; Kwok, Caitlin; Teliousis, Konstantinos; Ibrahim, Yassin M.; Mirabal, Sheyla; Erdman, Susan E.

    2016-01-01

    Muscle wasting, known as cachexia, is a debilitating condition associated with chronic inflammation such as during cancer. Beneficial microbes have been shown to optimize systemic inflammatory tone during good health; however, interactions between microbes and host immunity in the context of cachexia are incompletely understood. Here we use mouse models to test roles for bacteria in muscle wasting syndromes. We find that feeding of a human commensal microbe, Lactobacillus reuteri, to mice is sufficient to lower systemic indices of inflammation and inhibit cachexia. Further, the microbial muscle-building phenomenon extends to normal aging as wild type animals exhibited increased growth hormone levels and up-regulation of transcription factor Forkhead Box N1 [FoxN1] associated with thymus gland retention and longevity. Interestingly, mice with a defective FoxN1 gene (athymic nude) fail to inhibit sarcopenia after L. reuteri therapy, indicating a FoxN1-mediated mechanism. In conclusion, symbiotic bacteria may serve to stimulate FoxN1 and thymic functions that regulate inflammation, offering possible alternatives for cachexia prevention and novel insights into roles for microbiota in mammalian ontogeny and phylogeny. PMID:26933816

  1. Beneficial bacteria inhibit cachexia.

    Science.gov (United States)

    Varian, Bernard J; Goureshetti, Sravya; Poutahidis, Theofilos; Lakritz, Jessica R; Levkovich, Tatiana; Kwok, Caitlin; Teliousis, Konstantinos; Ibrahim, Yassin M; Mirabal, Sheyla; Erdman, Susan E

    2016-03-15

    Muscle wasting, known as cachexia, is a debilitating condition associated with chronic inflammation such as during cancer. Beneficial microbes have been shown to optimize systemic inflammatory tone during good health; however, interactions between microbes and host immunity in the context of cachexia are incompletely understood. Here we use mouse models to test roles for bacteria in muscle wasting syndromes. We find that feeding of a human commensal microbe, Lactobacillus reuteri, to mice is sufficient to lower systemic indices of inflammation and inhibit cachexia. Further, the microbial muscle-building phenomenon extends to normal aging as wild type animals exhibited increased growth hormone levels and up-regulation of transcription factor Forkhead Box N1 [FoxN1] associated with thymus gland retention and longevity. Interestingly, mice with a defective FoxN1 gene (athymic nude) fail to inhibit sarcopenia after L. reuteri therapy, indicating a FoxN1-mediated mechanism. In conclusion, symbiotic bacteria may serve to stimulate FoxN1 and thymic functions that regulate inflammation, offering possible alternatives for cachexia prevention and novel insights into roles for microbiota in mammalian ontogeny and phylogeny.

  2. [Penicillium-inhibiting yeasts].

    Science.gov (United States)

    Benítez Ahrendts, M R; Carrillo, L

    2004-01-01

    The objective of this work was to establish the in vitro and in vivo inhibition of post-harvest pathogenic moulds by yeasts in order to make a biocontrol product. Post-harvest pathogenic moulds Penicillium digitatum, P. italicum, P. ulaiense, Phyllosticta sp., Galactomyces geotrichum and yeasts belonging to genera Brettanomyces, Candida, Cryptococcus, Kloeckera, Pichia, Rhodotorula were isolated from citrus fruits. Some yeasts strains were also isolated from other sources. The yeasts were identified by their macro and micro-morphology and physiological tests. The in vitro and in vivo activities against P. digitatum or P. ulaiense were different. Candida cantarellii and one strain of Pichia subpelliculosa produced a significant reduction of the lesion area caused by the pathogenic moulds P. digitatum and P. ulaiense, and could be used in a biocontrol product formulation.

  3. Propolis inhibits osteoclast maturation.

    Science.gov (United States)

    Pileggi, Roberta; Antony, Kathryn; Johnson, Kristie; Zuo, Jian; Shannon Holliday, L

    2009-12-01

    Propolis, a natural product produced by the honey bee, has been successfully used in medicine as an anti-inflammatory and antimicrobial agent. Traumatic injuries to the teeth, especially avulsion injuries, present a challenging situation for the clinician because of post-treatment complications, such as inflammatory and/or replacement resorption. Agents that reduce osteoclast numbers and activity may be useful in the treatment of traumatic injuries to the teeth. In this study, we evaluated propolis as an anti-resorptive agent. Calcitriol-stimulated mouse marrow cultures, which contain both osteoclasts and osteoblasts, were exposed to the ethanol extracts of propolis or vehicle control and stained for tartrate-resistant acid phosphatase (TRAP)-activity to identify osteoclasts. A significant, dose-dependent reduction in multinuclear TRAP+ cells was demonstrated, although the propolis treatment accommodated cell growth and survival (P Propolis also reduced the formation of actin rings in pure cultures of RAW 264.7 osteoclast-like cells, suggesting that it exerts direct actions on osteoclast maturation. In summary, our data suggest that propolis inhibits late stages of osteoclast maturation including fusion of osteoclasts precursors to form giant cells and formation of actin rings. This supports the hypothesis that it may prove useful as a medicament to reduce resorption associated with traumatic injuries to the teeth.

  4. Can Arousal Modulate Response Inhibition?

    Science.gov (United States)

    Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

    2015-01-01

    The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

  5. [Cabergoline for inhibition of lactation].

    Science.gov (United States)

    Bravo-Topete, Enrique Gómez; Mendoza-Hernández, Freddy; Cejudo-Alvarez, José; Briones-Garduño, Carlos

    2004-01-01

    Despite advances in prevention inhibition of lactation, only administration of estrogens or these combined with androgens show variable effectiveness and are indirectly associated with high percentage for lactation rebound, thrombosis, or pulmonary embolism or both of the later during puerperium; in addition, bromocriptine, also used indirectly for inhibition of lactation, is associated with lactation, rebound in 18-40%. Cabergolin is a new ergoline with efficient and durable prolactin reducer effect with fewer adverse effects. Which will the smallest cabergolin dosage be to inhibit lactation? To demonstrate clinical effectiveness with smallest cabergolina dosage in lactation inhibition. We carried on a the Service Clinical test on patients hospitalization with an indication to inhibit lactation as the Hospital of Gynecology and Obstetrics, Infantil Maternal Institute of the State of Mexico (IMIEM). The study was done 80 patients to who we administered oral 0.5 mg cabergoline to 40 patients and another group of 40 whom we administered 1.0 mg of cabergoline orally at random and blinded by means of out-patient consultation. We studied correlation between dose and inhibition of lactation as well as presence of adverse effects. In the group of patients to whom administered 0.5 mg, we found 65% (n = 26) with lactation inhibition; adverse effects in this group appeared in 32.5% (n = 13) the second group with a dose of 1.0 mg; 95% with adverse effects in 25% P < 0.001. Inhibition of lactation with unique dose of 1.0 has satisfactory clinical effectiveness, this being the smaller dose to inhibit lactation at a suitable percentage.

  6. Memory inhibition across the lifespan

    OpenAIRE

    Teale, Julia C.

    2015-01-01

    Age can affect memory performance. This statement is so often heard that it has become almost a truism. When research surrounding memory inhibition – the ability to ignore irrelevant material to aid in the retrieval of a target memory – is examined specifically, a more mixed picture of findings emerges. Whilst some previous work has found evidence of an age-related deficit, other research has rather found intact memory inhibition in older adults. Less often discussed, too, are the effects of ...

  7. Inhibition of MMPs by alcohols

    Science.gov (United States)

    Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Hoshika, Tomohiro; Uchiyama, Toshikazu; Tjäderhane, Leo; Breschi, Lorenzo; Mazzoni, Annalisa; Thompson, Jeremy M.; McCracken, Courtney E.; Looney, Stephen W.; Tay, Franklin R.; Pashley, David H.

    2011-01-01

    Objectives While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. Methods The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 moles/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC50). Results Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose-dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3-heptanol and 1-octanol gave the strongest inhibition. Significance The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID:21676453

  8. Dihydroxyoctadecamonoenoate esters inhibit the neutrophil ...

    Indian Academy of Sciences (India)

    PRAKASH

    inhibited by methyl 9,10-/12,13-DiHOME. Neutrophil activation is characterized by a wide variety of signal transduction events. Assembly of the multiprotein. NADPH oxidase complex is required for superoxide production and is preceded by the phosphorylation of p47phox and translocation of p47phox to the membrane.

  9. Testing of Biologically Inhibiting Surface

    DEFF Research Database (Denmark)

    Bill Madsen, Thomas; Larsen, Erup

    2003-01-01

    The main purpose of this course is to examine a newly developed biologically inhibiting material with regards to galvanic corrosion and electrochemical properties. More in detail, the concern was how the material would react when exposed to cleaning agents, here under CIP cleaning (Cleaning...

  10. DETECTION OF HAEMAGGLUTINATION—INHIBITION ...

    African Journals Online (AJOL)

    A survey of haemagglutination inhibition lHl) antibodies against influenza A virus was carried out on pigs sera collected at Bodija abattoir, Ibadan between December, 2001 and August 2002. Out of the 107 sera tested, 101. 94.39%) had ill antibodies to influenza A (IhNi) human strain while the remaining 6 (5.61%) were ...

  11. Threat interferes with response inhibition.

    Science.gov (United States)

    Hartikainen, Kaisa M; Siiskonen, Anna R; Ogawa, Keith H

    2012-05-09

    A potential threat, such as a spider, captures attention and engages executive functions to adjust ongoing behavior and avoid danger. We and many others have reported slowed responses to neutral targets in the context of emotional distractors. This behavioral slowing has been explained in the framework of attentional competition for limited resources with emotional stimuli prioritized. Alternatively, slowed performance could reflect the activation of avoidance/freezing-type motor behaviors associated with threat. Although the interaction of attention and emotion has been widely studied, little is known on the interaction between emotion and executive functions. We studied how threat-related stimuli (spiders) interact with executive performance and whether the interaction profile fits with a resource competition model or avoidance/freezing-type motor behaviors. Twenty-one young healthy individuals performed a Go-NoGo visual discrimination reaction time (RT) task engaging several executive functions with threat-related and emotionally neutral distractors. The threat-related distractors had no effect on the RT or the error rate in the Go trials. The NoGo error rate, reflecting failure in response inhibition, increased significantly because of threat-related distractors in contrast to neutral distractors, P less than 0.05. Thus, threat-related distractors temporarily impaired response inhibition. Threat-related distractors associated with increased commission errors and no effect on RT does not suggest engagement of avoidance/freezing-type motor behaviors. The results fit in the framework of the resource competition model. A potential threat calls for evaluation of affective significance as well as inhibition of undue emotional reactivity. We suggest that these functions tax executive resources and may render other executive functions, such as response inhibition, temporarily compromised when the demands for resources exceed availability.

  12. Th2 cytokines inhibit lymphangiogenesis.

    Directory of Open Access Journals (Sweden)

    Ira L Savetsky

    Full Text Available Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2 cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4 and interleukin-13 (IL-13 have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis.

  13. Combined autophagy and proteasome inhibition

    Science.gov (United States)

    Vogl, Dan T; Stadtmauer, Edward A; Tan, Kay-See; Heitjan, Daniel F; Davis, Lisa E; Pontiggia, Laura; Rangwala, Reshma; Piao, Shengfu; Chang, Yunyoung C; Scott, Emma C; Paul, Thomas M; Nichols, Charles W; Porter, David L; Kaplan, Janeen; Mallon, Gayle; Bradner, James E; Amaravadi, Ravi K

    2014-01-01

    The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy. PMID:24991834

  14. RAAS inhibition and cardiorenal syndrome.

    Science.gov (United States)

    Onuigbo, Macaulay Amechi C

    2014-01-01

    The consensus conference on cardio-renal syndromes (2008) defined 'cardio-renal syndromes' as 'disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other' and identified five subtypes of the syndromes. Various pathophysiologic mechanisms underlie cardiorenal syndrome including hemodynamic derangements, reduced cardiac output leading to impaired renal perfusion, reduced stroke volume, raised atrial filling pressures, elevated atrial pressures, sodium and water retention, venous congestion, right ventricular dysfunction and venous hypertension causing increased renal venous pressure, intra-abdominal hypertension, various neurohormonal adaptations including activation of the renin-angiotensin-aldosterone system, adaptive activation of the sympathetic nervous system, cytokine release and oxidative stress. Although there are standardized clinical guidelines for the management of heart failure, and chronic kidney disease, respectively, there are no similar consensus clinical guidelines for the management of the cardiorenal syndromes. RAAS inhibition is advocated in treating systolic heart failure. There is evidence that RAAS inhibition is also useful in cardiorenal syndrome. However, RAAS inhibition, while potentially useful in the management of cardiorenal syndrome, is not the 'magic bullet', is sometimes limited by adverse renal events, is not applicable to all patients, and must be applied by physicians with due diligence and caution. Nevertheless, a more comprehensive multidisciplinary multipronged approach to managing patients with cardiorenal syndrome is even more pragmatic and commonsense given the multiple mechanisms and pathogenetic pathways implicated in the causation and perpetuation of cardiorenal syndrome.

  15. Self-regulation, ego depletion, and inhibition.

    Science.gov (United States)

    Baumeister, Roy F

    2014-12-01

    Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Action inhibition in Tourette syndrome.

    Science.gov (United States)

    Ganos, Christos; Kühn, Simone; Kahl, Ursula; Schunke, Odette; Feldheim, Jan; Gerloff, Christian; Roessner, Veit; Bäumer, Tobias; Thomalla, Götz; Haggard, Patrick; Münchau, Alexander

    2014-10-01

    Tourette syndrome is a neuropsychiatric disorder characterized by tics. Tic generation is often linked to dysfunction of inhibitory brain networks. Some previous behavioral studies found deficiencies in inhibitory motor control in Tourette syndrome, but others suggested normal or even better-than-normal performance. Furthermore, neural correlates of action inhibition in these patients are poorly understood. We performed event-related functional magnetic resonance imaging during a stop-signal reaction-time task in 14 uncomplicated adult Tourette patients and 15 healthy controls. In patients, we correlated activations in stop-signal reaction-time task with their individual motor tic frequency. Task performance was similar in both groups. Activation of dorsal premotor cortex was stronger in the StopSuccess than in the Go condition in healthy controls. This pattern was reversed in Tourette patients. A significant positive correlation was present between motor tic frequency and activations in the supplementary motor area during StopSuccess versus Go in patients. Inhibitory brain networks differ between healthy controls and Tourette patients. In the latter the supplementary motor area is probably a key relay of inhibitory processes mediating both suppression of tics and inhibition of voluntary action. © 2014 International Parkinson and Movement Disorder Society.

  17. Graphene: corrosion-inhibiting coating.

    Science.gov (United States)

    Prasai, Dhiraj; Tuberquia, Juan Carlos; Harl, Robert R; Jennings, G Kane; Rogers, Bridget R; Bolotin, Kirill I

    2012-02-28

    We report the use of atomically thin layers of graphene as a protective coating that inhibits corrosion of underlying metals. Here, we employ electrochemical methods to study the corrosion inhibition of copper and nickel by either growing graphene on these metals, or by mechanically transferring multilayer graphene onto them. Cyclic voltammetry measurements reveal that the graphene coating effectively suppresses metal oxidation and oxygen reduction. Electrochemical impedance spectroscopy measurements suggest that while graphene itself is not damaged, the metal under it is corroded at cracks in the graphene film. Finally, we use Tafel analysis to quantify the corrosion rates of samples with and without graphene coatings. These results indicate that copper films coated with graphene grown via chemical vapor deposition are corroded 7 times slower in an aerated Na(2)SO(4) solution as compared to the corrosion rate of bare copper. Tafel analysis reveals that nickel with a multilayer graphene film grown on it corrodes 20 times slower while nickel surfaces coated with four layers of mechanically transferred graphene corrode 4 times slower than bare nickel. These findings establish graphene as the thinnest known corrosion-protecting coating.

  18. Greener Approach towards Corrosion Inhibition

    Directory of Open Access Journals (Sweden)

    Neha Patni

    2013-01-01

    Full Text Available Corrosion control of metals is technically, economically, environmentally, and aesthetically important. The best option is to use inhibitors for protecting metals and alloys against corrosion. As organic corrosion inhibitors are toxic in nature, so green inhibitors which are biodegradable, without any heavy metals and other toxic compounds, are promoted. Also plant products are inexpensive, renewable, and readily available. Tannins, organic amino acids, alkaloids, and organic dyes of plant origin have good corrosion-inhibiting abilities. Plant extracts contain many organic compounds, having polar atoms such as O, P, S, and N. These are adsorbed on the metal surface by these polar atoms, and protective films are formed, and various adsorption isotherms are obeyed. Various types of green inhibitors and their effect on different metals are mentioned in the paper.

  19. Survival Processing Eliminates Collaborative Inhibition.

    Science.gov (United States)

    Reysen, Matthew B; Bliss, Heather; Baker, Melissa A

    2017-04-11

    The present experiments examined the effect of processing words for their survival value, relevance to moving, and pleasantness on participants' free recall scores in both nominal groups (non-redundant pooled individual scores) and collaborative dyads. Overall, participants recalled more words in the survival processing conditions than in the moving and pleasantness processing conditions. Furthermore, nominal groups in both the pleasantness condition (Experiment 1) and the moving and pleasantness conditions (Experiment 2) recalled more words than collaborative groups, thereby replicating the oft-observed effect of collaborative inhibition. However, processing words for their survival value appeared to eliminate the deleterious effects of collaborative remembering in both Experiments 1 and 2. These results are discussed in the context of the retrieval strategy disruption hypothesis and the effects of both expertise and collaborative skill on group remembering.

  20. Mood stabilizers inhibit cytomegalovirus infection.

    Science.gov (United States)

    Ornaghi, Sara; Davis, John N; Gorres, Kelly L; Miller, George; Paidas, Michael J; van den Pol, Anthony N

    2016-12-01

    Cytomegalovirus (CMV) infection can generate debilitating disease in immunocompromised individuals and neonates. It is also the most common infectious cause of congenital birth defects in infected fetuses. Available anti-CMV drugs are partially effective but are limited by some toxicity, potential viral resistance, and are not recommended for fetal exposure. Valproate, valpromide, and valnoctamide have been used for many years to treat epilepsy and mood disorders. We report for the first time that, in contrast to the virus-enhancing actions of valproate, structurally related valpromide and valnoctamide evoke a substantial and specific inhibition of mouse and human CMV in vitro. In vivo, both drugs safely attenuate mouse CMV, improving survival, body weight, and developmental maturation of infected newborns. The compounds appear to act by a novel mechanism that interferes with CMV attachment to the cell. Our work provides a novel potential direction for CMV therapeutics through repositioning of agents already approved for use in psychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Reduced surround inhibition in musicians.

    Science.gov (United States)

    Shin, Hae-Won; Kang, Suk Y; Hallett, Mark; Sohn, Young H

    2012-06-01

    To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1,000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia.

  2. The pharmacology of visuospatial attention and inhibition

    NARCIS (Netherlands)

    Logemann, H.N.A.

    2013-01-01

    Attention and inhibition are of vital importance in everyday functioning. Problems of attention and inhibition are central to disorders such as Attention Deficit/Hyperactivity Disorder (ADHD). Both bias and disengagement key components of visuospatial attention. Bias refers to neuronal signals that

  3. Optimal Decision Making in Neural Inhibition Models

    Science.gov (United States)

    van Ravenzwaaij, Don; van der Maas, Han L. J.; Wagenmakers, Eric-Jan

    2012-01-01

    In their influential "Psychological Review" article, Bogacz, Brown, Moehlis, Holmes, and Cohen (2006) discussed optimal decision making as accomplished by the drift diffusion model (DDM). The authors showed that neural inhibition models, such as the leaky competing accumulator model (LCA) and the feedforward inhibition model (FFI), can mimic the…

  4. Methanol Extract of Myelophycus caespitosus Inhibits the ...

    African Journals Online (AJOL)

    Methanol Extract of Myelophycus caespitosus Inhibits the Inflammatory Response in Lipopolysaccharidestimulated BV2 Microglial Cells by Downregulating NF-kB via Inhibition of the Akt Signaling Pathway. ... The level of NO production was analyzed using Griess reaction. The release of PGE2 was determined using ...

  5. Factors Impacting the Child with Behavioral Inhibition

    Science.gov (United States)

    Hornbuckle, Suzanne R.

    2010-01-01

    Various factors influence the developmental course of the behaviorally inhibited child. These factors include reciprocating, contextual factors, such as the child's own traits, the environment, the maternal characteristics, and the environment. Behaviorally inhibited children show physiological and behavioral signs of fear and anxiety when…

  6. CORROSION INHIBITION BY CASHEW NUT SHELL LIQUID

    African Journals Online (AJOL)

    MECHANISTIC STUDIES OF CARBON STEEL. CORROSION INHIBITION BY CASHEW NUT SHELL. LIQUID. JYN Philip, J Buchweishaija and LL Mkayula. Department of Chemistry, University of Dar es Salaam,. P. O. Box 35061, Dar es Salaam, Tanzania. ABSTRACT. The inhibition mechanism of the Cashew Nut Shell ...

  7. Adsorptive, Kinetic, Thermodynamic and Inhibitive Properties of ...

    African Journals Online (AJOL)

    The adsorption of Cissus populnea stem extract and its subsequent corrosion inhibition properties on aluminum in 0.5 M HCl solutions have been investigated using weight loss measurements. Inhibition efficiency of the plant extract increased with concentration but decreased with rise in temperature. The adsorption of the ...

  8. Cortisol involvement in mechanisms of behavioral inhibition

    NARCIS (Netherlands)

    Tops, Mattie; Boksem, Maarten A. S.

    We studied whether baseline cortisol is associated with post-error slowing, a measure that depends upon brain areas involved in behavioral inhibition. Moreover, we studied whether this association holds after controlling for positive associations with behavioral inhibition scores and error-related

  9. Inhibition: Mental Control Process or Mental Resource?

    Science.gov (United States)

    Im-Bolter, Nancie; Johnson, Janice; Ling, Daphne; Pascual-Leone, Juan

    2015-01-01

    The current study tested 2 models of inhibition in 45 children with language impairment and 45 children with normally developing language; children were aged 7 to 12 years. Of interest was whether a model of inhibition as a mental-control process (i.e., executive function) or as a mental resource would more accurately reflect the relations among…

  10. A Qualitative Approach to Enzyme Inhibition

    Science.gov (United States)

    Waldrop, Grover L.

    2009-01-01

    Most general biochemistry textbooks present enzyme inhibition by showing how the basic Michaelis-Menten parameters K[subscript m] and V[subscript max] are affected mathematically by a particular type of inhibitor. This approach, while mathematically rigorous, does not lend itself to understanding how inhibition patterns are used to determine the…

  11. Amiodarone Inhibits Apamin-Sensitive Potassium Currents

    Science.gov (United States)

    Turker, Isik; Yu, Chih-Chieh; Chang, Po-Cheng; Chen, Zhenhui; Sohma, Yoshiro; Lin, Shien-Fong; Chen, Peng-Sheng; Ai, Tomohiko

    2013-01-01

    Background Apamin sensitive potassium current (IKAS), carried by the type 2 small conductance Ca2+-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles. Objective To test the hypothesis that amiodarone inhibits IKAS in human embryonic kidney 293 (HEK-293) cells. Methods We used the patch-clamp technique to study IKAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration. Results Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67±0.25 µM with 1 µM intrapipette Ca2+). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6±3.1% of IKAS induced with 1 µM intrapipette Ca2+ (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca2+-dependent: 30 µM amiodarone inhibited 81.5±1.9% of IKAS induced with 1 µM Ca2+ (n = 4), and 16.4±4.9% with 250 nM Ca2+ (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca2+ dependent inhibition of IKAS. Conclusion Both amiodarone and desethylamiodarone inhibit IKAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca2+ concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles. PMID:23922993

  12. Amiodarone inhibits apamin-sensitive potassium currents.

    Directory of Open Access Journals (Sweden)

    Isik Turker

    Full Text Available Apamin sensitive potassium current (I KAS, carried by the type 2 small conductance Ca(2+-activated potassium (SK2 channels, plays an important role in post-shock action potential duration (APD shortening and recurrent spontaneous ventricular fibrillation (VF in failing ventricles.To test the hypothesis that amiodarone inhibits I KAS in human embryonic kidney 293 (HEK-293 cells.We used the patch-clamp technique to study I KAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration.Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67 ± 0.25 µM with 1 µM intrapipette Ca(2+. Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6 ± 3.1% of IKAS induced with 1 µM intrapipette Ca(2+ (n = 3. IKAS inhibition by amiodarone was not voltage-dependent, but was Ca(2+-dependent: 30 µM amiodarone inhibited 81.5±1.9% of I KAS induced with 1 µM Ca(2+ (n = 4, and 16.4±4.9% with 250 nM Ca(2+ (n = 5. Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca(2+ dependent inhibition of I KAS.Both amiodarone and desethylamiodarone inhibit I KAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca(2+ concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles.

  13. BST2/Tetherin Inhibition of Alphavirus Exit

    Directory of Open Access Journals (Sweden)

    Yaw Shin Ooi

    2015-04-01

    Full Text Available Alphaviruses such as chikungunya virus (CHIKV and Semliki Forest virus (SFV are small enveloped RNA viruses that bud from the plasma membrane. Tetherin/BST2 is an interferon-induced host membrane protein that inhibits the release of many enveloped viruses via direct tethering of budded particles to the cell surface. Alphaviruses have highly organized structures and exclude host membrane proteins from the site of budding, suggesting that their release might be insensitive to tetherin inhibition. Here, we demonstrated that exogenously-expressed tetherin efficiently inhibited the release of SFV and CHIKV particles from host cells without affecting virus entry and infection. Alphavirus release was also inhibited by the endogenous levels of tetherin in HeLa cells. While rubella virus (RuV and dengue virus (DENV have structural similarities to alphaviruses, tetherin inhibited the release of RuV but not DENV. We found that two recently identified tetherin isoforms differing in length at the N-terminus exhibited distinct capabilities in restricting alphavirus release. SFV exit was efficiently inhibited by the long isoform but not the short isoform of tetherin, while both isoforms inhibited vesicular stomatitis virus exit. Thus, in spite of the organized structure of the virus particle, tetherin specifically blocks alphavirus release and shows an interesting isoform requirement.

  14. Angiotensin inhibition in heart failure

    Directory of Open Access Journals (Sweden)

    John JV Mcmurray

    2004-03-01

    Full Text Available Survival in patients with heart failure remains very poor, and is worse than that for most common cancers, including bowel cancer in men and breast cancer in women. The renin-angiotensin-aldosterone system (RAAS is not completely blocked by angiotensin-converting enzyme (ACE inhibition. Blockade of the RAAS at the AT1-receptor has the theoretical benefit of more effective blockade of the actions of angiotensin II. ACE inhibitors (ACE-Is prevent the breakdown of bradykinin: this has been blamed for some of the unwanted effects of ACE-Is although bradykinin may have advantageous effects in heart failure. Consequently, ACE-Is and ARBs might be complementary or even additive treatments; recent trials have tested these hypotheses. The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM programme compared the angiotensin receptor blocker (ARB candesartan (target dose 32 mg once daily to placebo in three distinct but complementary populations of patients with symptomatic heart failure. These were: patients with reduced left ventricular ejection fraction (LVEF who were ACE-I-intolerant (CHARM-Alternative; patients with reduced LVEF who were being treated with ACE-Is (CHARM-Added; and patients with preserved left ventricular systolic function (CHARM-Preserved. There were substantial and statistically significant reductions in the primary composite end point (risk of cardiovascular death or hospital admission for heart failure in CHARM-Alternative. This was also the case in CHARM-Added, supporting and extending the findings of Val-HeFT. In CHARM-Preserved, the effect of candesartan on the primary end point did not reach conventional statistical significance though hospital admission for heart failure was reduced significantly with candesartan. In the CHARM-Overall programme there was a statistically borderline reduction in all-cause mortality with a clear reduction in cardiovascular mortality. All-cause mortality was

  15. Angiotensin inhibition in heart failure

    Directory of Open Access Journals (Sweden)

    John JV McMurray

    2004-03-01

    Full Text Available Survival in patients with heart failure remains very poor, and is worse than that for most common cancers, including bowel cancer in men and breast cancer in women. The renin-angiotensin-aldosterone system (RAAS is not completely blocked by angiotensin-converting enzyme (ACE inhibition. Blockade of the RAAS at the AT1-receptor has the theoretical benefit of more effective blockade of the actions of angiotensin II. ACE inhibitors (ACE-Is prevent the breakdown of bradykinin: this has been blamed for some of the unwanted effects of ACE-Is although bradykinin may have advantageous effects in heart failure. Consequently, ACE-Is and ARBs might be complementary or even additive treatments; recent trials have tested these hypotheses.The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM programme compared the angiotensin receptor blocker (ARB candesartan (target dose 32 mg once daily to placebo in three distinct but complementary populations of patients with symptomatic heart failure. These were: patients with reduced left ventricular ejection fraction (LVEF who were ACE-I-intolerant (CHARM-Alternative; patients with reduced LVEF who were being treated with ACE-Is (CHARM-Added; and patients with preserved left ventricular systolic function (CHARM-Preserved.There were substantial and statistically significant reductions in the primary composite end point (risk of cardiovascular death or hospital admission for heart failure in CHARM-Alternative. This was also the case in CHARM-Added, supporting and extending the findings of Val-HeFT. In CHARM-Preserved, the effect of candesartan on the primary end point did not reach conventional statistical significance though hospital admission for heart failure was reduced significantly with candesartan. In the CHARM-Overall programme there was a statistically borderline reduction in all-cause mortality with a clear reduction in cardiovascular mortality. All-cause mortality was

  16. Cellulase Inhibition by High Concentrations of Monosaccharides

    DEFF Research Database (Denmark)

    Hsieh, Chia-Wen; Cannella, David; Jørgensen, Henning

    2014-01-01

    that low free water availability contributes to cellulase inhibition. Of the hydrolytic enzymes involved, those acting on the cellulose substrate, that is, exo- and endoglucanases, were the most inhibited. The β -glucosidases were shown to be less sensitive to high monosaccharide concentrations except......Biological degradation of biomass on an industrial scale culminates in high concentrations of end products. It is known that the accumulation of glucose and cellobiose, end products of hydrolysis, inhibit cellulases and decrease glucose yields. Aside from these end products, however, other...

  17. Studies of Ca2+ ATPase (SERCA) inhibition.

    Science.gov (United States)

    Inesi, Giuseppe; Hua, Suming; Xu, Cheng; Ma, Hailun; Seth, Malini; Prasad, Anand M; Sumbilla, Carlota

    2005-12-01

    The Ca(2+) transport ATPase of intracellular membranes (SERCA) can be inhibited by a series of chemical compounds such as Thapsigargin (TG), 2,5-di(tert-butyl)hydroquinone (DBHQ) and 1,3-dibromo-2,4,6-tris (methyl-isothio-uronium) benzene (Br(2)-TITU). These compounds have specific binding sites in the ATPase protein, and different mechanisms of inhibition. On the other hand, SERCA gene silencing offers a convenient and specific method for suppression of SERCA activity in cells. The physiological and pharmacological implications of SERCA inhibition are discussed.

  18. The IFITMs Inhibit Zika Virus Replication

    Directory of Open Access Journals (Sweden)

    George Savidis

    2016-06-01

    Full Text Available Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses.

  19. Should We Stop Thinking About Inhibition? Searching for Individual and Age Differences in Inhibition Ability.

    Science.gov (United States)

    Rey-Mermet, Alodie; Gade, Miriam; Oberauer, Klaus

    2017-09-28

    Inhibition is often conceptualized as a unitary construct reflecting the ability to ignore and suppress irrelevant information. At the same time, it has been subdivided into inhibition of prepotent responses (i.e., the ability to stop dominant responses) and resistance to distracter interference (i.e., the ability to ignore distracting information). The present study investigated the unity and diversity of inhibition as a psychometric construct, and tested the hypothesis of an inhibition deficit in older age. We measured inhibition in young and old adults with 11 established laboratory tasks: antisaccade, stop-signal, color Stroop, number Stroop, arrow flanker, letter flanker, Simon, global-local, positive and negative compatibility tasks, and n-2 repetition costs in task switching. In both age groups, the inhibition measures from individual tasks had good reliabilities, but correlated only weakly among each other. Structural equation modeling identified a 2-factor model with factors for inhibition of prepotent responses and resistance to distracter interference. Older adults scored worse in the inhibition of prepotent response, but better in the resistance to distracter interference. However, the model had low explanatory power. Together, these findings call into question inhibition as a psychometric construct and the hypothesis of an inhibition deficit in older age. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  20. Nitric oxide synthases: structure, function and inhibition

    National Research Council Canada - National Science Library

    Alderton, W K; Cooper, C E; Knowles, R G

    2001-01-01

    This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family...

  1. Glycerol inhibition of ruminal lipolysis in vitro

    Science.gov (United States)

    Supplemental glycerol inhibits rumen lipolysis, a prerequisite for rumen biohydrogenation, which is responsible for the saturation of dietary fatty acids consumed by ruminant animals. Feeding excess glycerol, however, adversely affects dry matter digestibility. To more clearly define the effect of...

  2. Piperine, a dietary phytochemical, inhibits angiogenesis

    OpenAIRE

    Doucette, Carolyn D.; Hilchie, Ashley L.; Liwski, Robert; Hoskin, David W.

    2012-01-01

    Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G1/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induce...

  3. Aurantiogliocladin inhibits biofilm formation at subtoxic concentrations

    Directory of Open Access Journals (Sweden)

    Kamila Tomoko Yuyama

    2017-01-01

    Full Text Available Infections where pathogens are organized in biofilms are difficult to treat due to increased antibiotic resistances in biofilms. To overcome this limitation new approaches are needed to control biofilms. One way is to screen natural products from organisms living in a wet environment. The rational is that these organisms are preferentially threatened by biofilm formation and may have developed strategies to control pathogens in these biofilms. In a screen of fungal isolates obtained from the Harz mountains in Germany several strains have been found producing compounds for the inhibition of biofilms. One of these strains has been identified as Clonostachys candelabrumproducing aurantiogliocladin. Biological tests showed aurantiogliocladin as a weak antibiotic which was active against Staphylococcus epidermidisbut not S. aureus. Aurantiogliocladin could also inhibit biofilm formation of several of the tested bacterial strains. This inhibition, however, was never complete but biofilm inhibition activity was also found at concentrations below the minimal inhibitory concentrations, e. g. Bacillus cereuswith a MIC of 128 μg mL–1showed at 32 μg mL–1still 37% biofilm inhibition. In agreement with this finding was the observation that aurantiogliocladin was bacteriostatic for the tested bacteria but not bactericidal. Because several closely related toluquinones with different antibiotic activities have been reported from various fungi screening of a chemical library of toluquinones is suggested for the improvement of biofilm inhibition activities.

  4. Inhibition of COX isoforms by nutraceuticals.

    Science.gov (United States)

    Seaver, Ben; Smith, Jerry Robert

    2004-01-01

    Humans have two isoforms of Prostaglandin H Synthase or cyclooxygenase: COX-1 and COX-2. COX-1 is cytoprotective. COX-2 inhibitors reduce inflammation without the risk of ulceration and kidney damage. The ideal nutraceutical would inhibit COX-2 synthesis while preserving COX-1 synthesis. The hypothesis for this research was that COX inhibitors would fall primarily into three categories: COX-2 specific inhibition, non-specific inhibition (COX-1 and COX-2), and minimal inhibition. The human Cayman COX inhibitor screening assay was used to determine the inhibitory concentration 50 (IC50) of COX-1/ COX-2 activity of each nutraceutical. The assay was run, in duplicate, with three concentrations of a suspected inhibitor, a standard curve of eight concentrations, a non-specific binding sample, and a maximum binding sample. The inhibition and concentration of each sample was then put on a multiple regression best-fit line and the IC50 determined. For comparison, ibuprofen, rofecoxib, naproxen, and indomethacin were used. Positive results were seen for ipriflavone, resveratrol, MSV-60, amentoflavone, ruscus extract and notoginseng. Glucosamine, nexrutine, and berberine did not inhibit either isoform.

  5. Inhibition of Heme Peroxidases by Melamine

    Directory of Open Access Journals (Sweden)

    Pattaraporn Vanachayangkul

    2012-01-01

    Full Text Available In 2008 melamine-contaminated infant formula and dairy products in China led to over 50,000 hospitalizations of children due to renal injuries. In North America during 2007 and in Asia during 2004, melamine-contaminated pet food products resulted in numerous pet deaths due to renal failure. Animal studies have confirmed the potent renal toxicity of melamine combined with cyanuric acid. We showed previously that the solubility of melamine cyanurate is low at physiologic pH and ionic strength, provoking us to speculate how toxic levels of these compounds could be transported through the circulation without crystallizing until passing into the renal filtrate. We hypothesized that melamine might be sequestered by heme proteins, which could interfere with heme enzyme activity. Four heme peroxidase enzymes were selected for study: horseradish peroxidase (HRP, lactoperoxidase (LPO, and cyclooxygenase-1 and -2 (COX-1 and -2. Melamine exhibited noncompetitive inhibition of HRP (9.5±0.7mM, and LPO showed a mixed model of inhibition (14.5±4.7mM. The inhibition of HRP and LPO was confirmed using a chemiluminescent peroxidase assay. Melamine also exhibited COX-1 inhibition, but inhibition of COX-2 was not detected. Thus, our results demonstrate that melamine inhibits the activity of three heme peroxidases.

  6. Inhibition of 2-methoxyestradiol glucuronidation by probenecid.

    Science.gov (United States)

    Qian, Yuli; Sherbini, Ahmad; Matin, Bahar; Zhao, Yanli; Castellot, John; Greenblatt, David J

    2015-11-01

    2-Methoxyestradiol (2ME2), a metabolite of estradiol, has antitumour activity in vitro. However, potential clinical applicability has been limited by low oral bioavailability. Probenecid was evaluated in vitro as an inhibitor of 2ME2 glucuronidation for purposes of enhancing 2ME2 oral bioavailability. Human liver microsomes were used to determine kinetic parameters for transformation of 2ME2 to its glucuronide metabolites (M1, M2) and inhibition of the reactions by probenecid. M1 and M2 formation from 2ME2 proceeded with features of substrate inhibition. Probenecid inhibited metabolite formation, with mean inhibition constant (Ki ) values of 0.9 and 2.6 mM, respectively. Inhibition was reversible, with mixed competitive-non-competitive characteristics. The Ki values for probenecid inhibition of 2ME2 glucuronide formation, when compared to maximum probenecid plasma concentrations anticipated clinically, indicate that probenecid co-administration has the potential to augment systemic plasma levels of 2ME2 after oral dosage in humans. © 2015 Royal Pharmaceutical Society.

  7. Piperine, a dietary phytochemical, inhibits angiogenesis

    Science.gov (United States)

    Doucette, Carolyn D.; Hilchie, Ashley L.; Liwski, Robert; Hoskin, David W.

    2012-01-01

    Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G1/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induced angiogenic activity by rat aorta explants and breast cancer cell-induced angiogenesis in chick embryos. Although piperine binds to and activates the cation channel transient receptor potential vanilloid 1 (TRPV1), its effects on endothelial cells did not involve TRPV1 since the antiproliferative effect of piperine was not affected by TRPV1-selective antagonists, nor did HUVECs express detectable TRPV1 mRNA. Importantly, piperine inhibited phosphorylation of Ser 473 and Thr 308 residues of Akt (protein kinase B), which is a key regulator of endothelial cell function and angiogenesis. Consistent with Akt inhibition as the basis of piperine’s action on HUVECs, inhibition of the phosphoinositide-3 kinase/Akt signaling pathway with LY-294002 also inhibited HUVEC proliferation and collagen-induced angiogenesis. Taken together, these data support the further investigation of piperine as an angiogenesis inhibitor for use in cancer treatment. PMID:22902327

  8. Inhibition in the Human Auditory Cortex.

    Directory of Open Access Journals (Sweden)

    Koji Inui

    Full Text Available Despite their indispensable roles in sensory processing, little is known about inhibitory interneurons in humans. Inhibitory postsynaptic potentials cannot be recorded non-invasively, at least in a pure form, in humans. We herein sought to clarify whether prepulse inhibition (PPI in the auditory cortex reflected inhibition via interneurons using magnetoencephalography. An abrupt increase in sound pressure by 10 dB in a continuous sound was used to evoke the test response, and PPI was observed by inserting a weak (5 dB increase for 1 ms prepulse. The time course of the inhibition evaluated by prepulses presented at 10-800 ms before the test stimulus showed at least two temporally distinct inhibitions peaking at approximately 20-60 and 600 ms that presumably reflected IPSPs by fast spiking, parvalbumin-positive cells and somatostatin-positive, Martinotti cells, respectively. In another experiment, we confirmed that the degree of the inhibition depended on the strength of the prepulse, but not on the amplitude of the prepulse-evoked cortical response, indicating that the prepulse-evoked excitatory response and prepulse-evoked inhibition reflected activation in two different pathways. Although many diseases such as schizophrenia may involve deficits in the inhibitory system, we do not have appropriate methods to evaluate them; therefore, the easy and non-invasive method described herein may be clinically useful.

  9. CMP substitutions preferentially inhibit polysialic acid synthesis.

    Science.gov (United States)

    Miyazaki, Tatsuo; Angata, Kiyohiko; Seeberger, Peter H; Hindsgaul, Ole; Fukuda, Minoru

    2008-02-01

    It is widely reported that derivatives of sugar moieties can be used to metabolically label cell surface carbohydrates or inhibit a particular glycosylation. However, few studies address the effect of substitution of the cytidylmonophosphate (CMP) portion on sialyltransferase activities. Here we first synthesized 2'-O-methyl CMP and 5-methyl CMP and then asked if these CMP derivatives are recognized by alpha2,3-sialyltransferases (ST3Gal-III and ST3Gal-IV), alpha2,6-sialyltransferase (ST6Gal-I), and alpha2,8-sialyltransferase (ST8Sia-II, ST8Sia-III, and ST8Sia-IV). We found that ST3Gal-III and ST3Gal-IV but not ST6Gal-I was inhibited by 2'-O-methyl CMP as potently as by CMP, while ST3Gal-III, ST3Gal-IV, and ST6Gal-I were moderately inhibited by 5-methyl CMP. Previously, it was reported that polysialyltransferase ST8Sia-II but not ST8Sia-IV was inhibited by CMP N-butylneuraminic acid. We found that ST8Sia-IV as well as ST8Sia-II and ST8Sia-III are inhibited by 2'-O-methyl CMP as robustly as by CMP and moderately by 5-methyl CMP. Moreover, the addition of CMP, 2'-O-methyl CMP, and 5-methyl CMP to the culture medium resulted in the decrease of polysialic acid expression on the cell surface and NCAM of Chinese hamster ovary cells. These results suggest that 2'-O-methyl CMP and 5-methyl CMP can be used to preferentially inhibit sialyltransferases, in particular, polysialyltransferases in vitro and in vivo. Such inhibition may be useful to determine the function of a carbohydrate synthesized by a specific sialyltransferase such as polysialyltransferase.

  10. Characterization of acetylcholinesterase-inhibition by itopride.

    Science.gov (United States)

    Iwanaga, Y; Kimura, T; Miyashita, N; Morikawa, K; Nagata, O; Itoh, Z; Kondo, Y

    1994-11-01

    Itopride is a gastroprokinetic benzamide derivative. This agent inhibited both electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE). The IC50 of itopride with AChE (2.04 +/- 0.27 microM) was, however, 100-fold less than that with BuChE, whereas in the case of neostigmine with AChE (11.3 +/- 3.4 nM), it was 10-fold less. The recovery of AChE activity inhibited by 10(-7) M neostigmine was partial, but that inhibited by up to 3 x 10(-5) M itopride was complete when the reaction mixture was subjected to ultrafiltration. Double reciprocal plots of the experimental data showed that both Km and Vmax were affected by itopride, suggesting that the inhibition is a "mixed" type, although primarily being an uncompetitive one. The inhibitory effect of itopride on cholinesterase (ChE) activity in guinea pig gastrointestine was much weaker than that on pure AChE. However, in the presence of a low dose of diisopropyl fluorophosphate, just enough to inhibit BuChE but not AChE, the IC50s of itopride against ChE activities were found to be about 0.5 microM. In conclusion, itopride exerts reversible and a "mixed" type of inhibition preferably against AChE. The IC50 of itopride for electric eel and guinea pig gastrointestinal AChE inhibition was 200 times and 50 times as large as that of neostigmine, respectively.

  11. Chunking in task sequences modulates task inhibition.

    Science.gov (United States)

    Koch, Iring; Philipp, Andrea M; Gade, Miriam

    2006-04-01

    In a study of the formation of representations of task sequences and its influence on task inhibition, participants first performed tasks in a predictable sequence (e.g., ABACBC) and then performed the tasks in a random sequence. Half of the participants were explicitly instructed about the predictable sequence, whereas the other participants did not receive these instructions. Task-sequence learning was inferred from shorter reaction times (RTs) in predictable relative to random sequences. Persisting inhibition of competing tasks was indicated by increased RTs in n- 2 task repetitions (e.g., ABA) compared with n- 2 nonrepetitions (e.g., CBA). The results show task-sequence learning for both groups. However, task inhibition was reduced in predictable relative to random sequences among instructed-learning participants who formed an explicit representation of the task sequence, whereas sequence learning and task inhibition were independent in the noninstructed group. We hypothesize that the explicit instructions led to chunking of the task sequence, and that n- 2 repetitions served as chunk points (ABA-CBC), so that within-chunk facilitation modulated the inhibition effect.

  12. Collaborative inhibition in spatial memory retrieval.

    Science.gov (United States)

    Sjolund, Lori A; Erdman, Matthew; Kelly, Jonathan W

    2014-08-01

    Collaborative inhibition refers to the finding that pairs of people working together to retrieve information from memory-a collaborative group-often retrieve fewer unique items than do nominal pairs, who retrieve individually but whose performance is pooled. Two experiments were designed to explore whether collaborative inhibition, which has heretofore been studied using traditional memory stimuli such as word lists, also characterizes spatial memory retrieval. In the present study, participants learned a layout of objects and then reconstructed the layout from memory, either individually or in pairs. The layouts created by collaborative pairs were more accurate than those created by individuals, but less accurate than those of nominal pairs, providing evidence for collaborative inhibition in spatial memory retrieval. Collaborative inhibition occurred when participants were allowed to dictate the order of object placement during reconstruction (Exp. 1), and also when object order was imposed by the experimenter (Exp. 2), which was intended to disrupt the retrieval processes of pairs as well as of individuals. Individual tests of perspective taking indicated that the underlying representations of pair members were no different than those of individuals; in all cases, spatial memories were organized around a reference frame aligned with the studied perspective. These results suggest that inhibition is caused by the product of group recall (i.e., seeing a partner's object placement), not by the process of group recall (i.e., taking turns choosing an object to place). The present study has implications for how group performance on a collaborative spatial memory task may be optimized.

  13. ROCK inhibition activates MCF-7 cells.

    Directory of Open Access Journals (Sweden)

    Seungwon Yang

    Full Text Available Dormant carcinoma cancer cells showing epithelial characteristics can be activated to dissipate into the surrounding tissue or organs through epithelial-mesenchymal transition (EMT. However, the molecular details underlying the activation of dormant cancer cells have been less explored. In this study, we examined the molecular pathway to activate dormant breast cancer cells. Rho-associated kinase (ROCK inhibition disrupted cell junction, promoted cell proliferation and migration / invasion in both two-dimensional and three-dimensional substrates. The disintegration of cell junction upon ROCK inhibition, coupled with the loss of E-cadherin and b-catenin from the cell membrane, was associated with the activation of Rac1 upon ROCK inhibition. Migration / invasion also increased upon ROCK inhibition. However, the activation of MCF-7 cells upon ROCK inhibition was not associated with the up-regulation of typical EMT markers, such as snail and slug. Based on these results, we suggest the potential risk for dormant cancer cells to dissipate through non-typical EMT when ROCK activity is down-regulated.

  14. Inhibition of arylesterase by aliphatic alcohols.

    Science.gov (United States)

    Debord, J; Dantoine, T; Bollinger, J C; Abraham, M H; Verneuil, B; Merle, L

    1998-05-15

    The inhibition of arylesterase (EC 3.1.8.1) by 11 aliphatic alcohols (one to seven carbon atoms) was studied in blood serum from healthy donors. Inhibition curves were described by the Hill equation, with a Hill coefficient (n) close to unity, except for some alcohols, mainly the lowest. The inhibiting activity of the alcohols was highly dependent on their structure, since the C50 values covered about three orders of magnitude. The least active compound was methanol (C50 approximately 1 M) and the most active was heptanol (C50 approximately 7.4 x 10(-4) M). The A and B isozymes (differing by the amino acid at position 191) had similar inhibition parameters with the alcohols tested. Quantitative structure-activity relationships were computed with either the experimental solvation parameters of Abraham [6] or the theoretical parameters of Wilson and Famini [11]. Both methods gave similar results, with a slight advantage to the empirical parameters in terms of simplicity and statistical significance. The two main determinants of inhibition were identified as molecular volume and lack of polarity. The effect of volume was non-linear, tending to a maximum when the length of the alcohol increased. For a given number of carbon atoms, the best inhibitor was the least polar compound. These results point to a binding site consisting mainly of nonpolar aliphatic amino acids, and located in the depth of the protein molecule.

  15. The role of (dis)inhibition in creativity: decreased inhibition improves idea generation.

    Science.gov (United States)

    Radel, Rémi; Davranche, Karen; Fournier, Marion; Dietrich, Arne

    2015-01-01

    There is now a large body of evidence showing that many different conditions related to impaired fronto-executive functioning are associated with the enhancement of some types of creativity. In this paper, we pursue the possibility that the central mechanism associated with this effect might be a reduced capacity to exert inhibition. We tested this hypothesis by exhausting the inhibition efficiency through prolonged and intensive practice of either the Simon or the Eriksen Flanker task. Performance on another inhibition task indicated that only the cognitive resources for inhibition of participants facing high inhibition demands were impaired. Subsequent creativity tests revealed that exposure to high inhibition demands led to enhanced fluency in a divergent thinking task (Alternate Uses Task), but no such changes occurred in a convergent task (Remote Associate Task; studies 1a and 1b). The same manipulation also led to a hyper-priming effect for weakly related primes in a Lexical Decision Task (Study 2). Together, these findings suggest that inhibition selectively affects some types of creative processes and that, when resources for inhibition are lacking, the frequency and the originality of ideas was facilitated. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants.

    Science.gov (United States)

    Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

    2016-01-08

    Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity.

  17. Checkpoint kinase 1 inhibition sensitises transformed cells to dihydroorotate dehydrogenase inhibition

    OpenAIRE

    Arnould, Stéphanie; Rodier, Geneviève; Matar, Gisèle; Vincent, Charles; Pirot, Nelly; Delorme, Yoann; Berthet, Charlène; Buscail, Yoan; Noël, Jean Yohan; Lachambre, Simon; Jarlier, Marta; Bernex, Florence; Delpech, Hélène; Vidalain, Pierre Olivier; Janin, Yves L.

    2017-01-01

    Reduction in nucleotide pools through the inhibition of mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) has been demonstrated to effectively reduce cancer cell proliferation and tumour growth. The current study sought to investigate whether this antiproliferative effect could be enhanced by combining Chk1 kinase inhibition. The pharmacological activity of DHODH inhibitor teriflunomide was more selective towards transformed mouse embryonic fibroblasts than their primary or immortalis...

  18. Anticancer Alkaloid Lamellarins Inhibit Protein Kinases

    Directory of Open Access Journals (Sweden)

    Laurent Meijer

    2008-10-01

    Full Text Available Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, display promising anti-tumor activity. They induce apoptotic cell death through multi-target mechanisms, including inhibition of topoisomerase I, interaction with DNA and direct effects on mitochondria. We here report that lamellarins inhibit several protein kinases relevant to cancer such as cyclin-dependent kinases, dualspecificity tyrosine phosphorylation activated kinase 1A, casein kinase 1, glycogen synthase kinase-3 and PIM-1. A good correlation is observed between the effects of lamellarins on protein kinases and their action on cell death, suggesting that inhibition of specific kinases may contribute to the cytotoxicity of lamellarins. Structure/activity relationship suggests several paths for the optimization of lamellarins as kinase inhibitors.

  19. Mesoporous silica nanoparticles inhibit cellular respiration.

    Science.gov (United States)

    Tao, Zhimin; Morrow, Matthew P; Asefa, Tewodros; Sharma, Krishna K; Duncan, Cole; Anan, Abhishek; Penefsky, Harvey S; Goodisman, Jerry; Souid, Abdul-Kader

    2008-05-01

    We studied the effect of two types of mesoporous silica nanoparticles, MCM-41 and SBA-15, on mitochondrial O 2 consumption (respiration) in HL-60 (myeloid) cells, Jurkat (lymphoid) cells, and isolated mitochondria. SBA-15 inhibited cellular respiration at 25-500 microg/mL; the inhibition was concentration-dependent and time-dependent. The cellular ATP profile paralleled that of respiration. MCM-41 had no noticeable effect on respiration rate. In cells depleted of metabolic fuels, 50 microg/mL SBA-15 delayed the onset of glucose-supported respiration by 12 min and 200 microg/mL SBA-15 by 34 min; MCM-41 also delayed the onset of glucose-supported respiration. Neither SBA-15 nor MCM-41 affected cellular glutathione. Both nanoparticles inhibited respiration of isolated mitochondria and submitochondrial particles.

  20. Silver-Palladium Surfaces Inhibit Biofilm Formation

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Schroll, Casper; Hilbert, Lisbeth Rischel

    2009-01-01

    Undesired biofilm formation is a major concern in many areas. In the present study, we investigated biofilm-inhibiting properties of a silver-palladium surface that kills bacteria by generating microelectric fields and electrochemical redox processes. For evaluation of the biofilm inhibition...... efficacy and study of the biofilm inhibition mechanism, the silver-sensitive Escherichia coli J53 and the silver-resistant E. coli J53[pMG101] strains were used as model organisms, and batch and flow chamber setups were used as model systems. In the case of the silver-sensitive strain, the silver......-palladium surfaces killed the bacteria and prevented biofilm formation under conditions of low or high bacterial load. In the case of the silver-resistant strain, the silver-palladium surfaces killed surface-associated bacteria and prevented biofilm formation under conditions of low bacterial load, whereas under...

  1. The inhibition of monoamine oxidase by esomeprazole.

    Science.gov (United States)

    Petzer, A; Pienaar, A; Petzer, J P

    2013-09-01

    Virtual screening of a library of drugs has suggested that esomeprazole, the S-enantiomer of omeprazole, may possess binding affinities for the active sites of the monoamine oxidase (MAO) A and B enzymes. Based on this finding, the current study examines the MAO inhibitory properties of esomeprazole. Using recombinant human MAO-A and MAO-B, IC50 values for the inhibition of these enzymes by esomeprazole were experimentally determined. To examine the reversibility of MAO inhibition by esomeprazole, the recoveries of the enzymatic activities after dilution of the enzyme-inhibitor complexes were evaluated. In addition, reversibility of inhibition was also examined by measuring the recoveries of enzyme activities after dialysis of enzyme-inhibitor mixtures. Lineweaver-Burk plots were constructed to evaluate the mode of MAO inhibition and to measure Ki values. The results document that esomeprazole inhibits both MAO-A and MAO-B with IC50 values of 23 µM and 48 µM, respectively. The interactions of esomeprazole with MAO-A and MAO-B are reversible and most likely competitive with Ki values for the inhibition of the respective enzymes of 8.99 µM and 31.7 µM. Considering the available pharmacokinetic data and typical therapeutic doses of esomeprazole, these inhibitory potencies are unlikely to be of pharmacological relevance in humans. The MAO inhibitory effects of esomeprazole should however be taken into consideration when using this drug in animal experiments where higher doses are often administered. © Georg Thieme Verlag KG Stuttgart · New York.

  2. Nanostructured Block Copolymer Coatings for Biofouling Inhibition

    Science.gov (United States)

    2015-06-30

    Office of Naval Research 875 North Randolph St. Arlington, VA, 22203-1995 10. SPONSOR/MONITOR’S ACRONYM(S) ONR 11. SPONSOR/MONITOR’S REPORT NUMBER...we hoped. Inhibition, but not highly tunable by change of MW ratio The inhibition of diatoms by the diblocks was not significant (See figure 13). M...OH O a. £ o EC o a. in £ 0 Cu Figure 13 - The initial attachment density of the diatom Navicula on PS-b-PMMA coatings after gentle

  3. Inhibition of spinach bolting by growth regulators

    Directory of Open Access Journals (Sweden)

    Jan Borkowski

    2015-06-01

    Full Text Available Spinach (Spinacia oleracea L. plants must be harvested during a short period of time because they bolt just after producing some edible leaves. Maleic hydrazide (MH and its commercial preparation "Antyrost" were found to inhibit bolting very strongly. The preparation Off-shoot-O showed very weak activity in suppressing bolting but diminished markedly the resistance of spinach plants to fungus diseases. Triiodobenzoic acid stimulated bolting, and the retardant succinic acid-2-2-dimethylhydrazide (SADH did not affect bolting. Application of MH to inhibit spinach bolting cannot be recommended in practice before investigating the residues of this compound in leaves.

  4. Halenaquinone inhibits RANKL-induced osteoclastogenesis.

    Science.gov (United States)

    Tsukamoto, Sachiko; Takeuchi, Tomoharu; Kawabata, Tetsuro; Kato, Hikaru; Yamakuma, Michiko; Matsuo, Kanae; El-Desoky, Ahmed H; Losung, Fitje; Mangindaan, Remy E P; de Voogd, Nicole J; Arata, Yoichiro; Yokosawa, Hideyoshi

    2014-11-15

    Halenaquinone was isolated from the marine sponge Petrosia alfiani as an inhibitor of osteoclastogenic differentiation of murine RAW264 cells. It inhibited the RANKL (receptor activator of nuclear factor-κB ligand)-induced upregulation of TRAP (tartrate-resistant acid phosphatase) activity as well as the formation of multinuclear osteoclasts. In addition, halenaquinone substantially suppressed RANKL-induced IκB degradation and Akt phosphorylation. Thus, these results suggest that halenaquinone inhibits RANKL-induced osteoclastogenesis at least by suppressing the NF-κB and Akt signaling pathways. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

    DEFF Research Database (Denmark)

    Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine Marie Laure

    2011-01-01

    Background: Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine disrupting compounds (EDCs) share a high...... of endocrine disruption. Results: We found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis and it was correlated with a reduced testosterone production. The inhibition of PG synthesis occurs...

  6. Proton pump inhibitors inhibit pancreatic secretion

    DEFF Research Database (Denmark)

    Wang, Jing; Barbuskaite, Dagne; Tozzi, Marco

    2015-01-01

    +/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar...... localizations in duct cell monolayers (Capan-1) and human pancreas, and notably the gastric pumps are localized on the luminal membranes. In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis. Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations...

  7. Peptide inhibition of human cytomegalovirus infection

    Directory of Open Access Journals (Sweden)

    Morris Cindy A

    2011-02-01

    Full Text Available Abstract Background Human cytomegalovirus (HCMV is the most prevalent congenital viral infection in the United States and Europe causing significant morbidity and mortality to both mother and child. HCMV is also an opportunistic pathogen in immunocompromised individuals, including human immunodeficiency virus (HIV- infected patients with AIDS, and solid organ and allogeneic stem cell transplantation recipients. Current treatments for HCMV-associated diseases are insufficient due to the emergence of drug-induced resistance and cytotoxicity, necessitating novel approaches to limit HCMV infection. The aim of this study was to develop therapeutic peptides targeting glycoprotein B (gB, a major glycoprotein of HCMV that is highly conserved across the Herpesviridae family, that specifically inhibit fusion of the viral envelope with the host cell membrane preventing HCMV entry and infection. Results Using the Wimley-White Interfacial Hydrophobicity Scale (WWIHS, several regions within gB were identified that display a high potential to interact with lipid bilayers of cell membranes and hydrophobic surfaces within proteins. The ability of synthetic peptides analogous to WWIHS-positive sequences of HCMV gB to inhibit viral infectivity was evaluated. Human foreskin fibroblasts (HFF were infected with the Towne-GFP strain of HCMV (0.5 MOI, preincubated with peptides at a range of concentrations (78 nm to 100 μM, and GFP-positive cells were visualized 48 hours post-infection by fluorescence microscopy and analyzed quantitatively by flow cytometry. Peptides that inhibited HCMV infection demonstrated different inhibitory concentration curves indicating that each peptide possesses distinct biophysical properties. Peptide 174-200 showed 80% inhibition of viral infection at a concentration of 100 μM, and 51% and 62% inhibition at concentrations of 5 μM and 2.5 μM, respectively. Peptide 233-263 inhibited infection by 97% and 92% at concentrations of 100

  8. Investigation of antihemolytic, xanthine oxidase inhibition ...

    African Journals Online (AJOL)

    Material and methods: To investigate SVEs antihemolytic activity, the 2,2,-azobis (2-amidinopropane) dihydrochloride (AAPH) was used to induce erythrocyte oxidative hemolysis. In XO inhibition test, xanthine was used as substrate and cytochrome c for generating superoxide anions. The antioxidant activity of SVEs was ...

  9. Detection Of Haemagglutination–Inhibition Antibodies Against ...

    African Journals Online (AJOL)

    A survey of haemagglutination inhibition (HI) antibodies against influenza A virus was carried out on pigs sera collected at Bodija abattoir, Ibadan between December, 2001 and August 2002. Out of the 107 sera tested, 101 (94.39%) had HI antibodies to influenza A (H1N1) human strain while the remaining 6 (5.61%) were ...

  10. Nobiletin Inhibits Expression of Inflammatory Mediators and ...

    African Journals Online (AJOL)

    Multi-fold increases in the level of NO were seen. Moreover, increased levels of inflammatory cytokine,. Figure 2: Nobiletin inhibited IL-1β- induced apoptosis of ..... TNF-alpha stimulate. VEGF production by dedifferentiated chondrocytes. Osteoarthritis and. Cartilage 2004; 12: 683-691. 6. Sinkov V, Cymet T. Osteoarthritis: ...

  11. Challenges Inhibiting the Transformation of Subsistence Farming ...

    African Journals Online (AJOL)

    Challenges Inhibiting the Transformation of Subsistence Farming into Thriving Agri-business in Rural Uganda. ... Ghana Journal of Development Studies ... The aim of the study was to find out why there is a difficult transition from subsistence farming to a properly functioning agri-business in rural communities even when ...

  12. Inhibiting Translation One Protein at a Time.

    Science.gov (United States)

    Disney, Matthew D

    2017-06-01

    Historically, translational inhibitors have been confined to anti-bacterials that globally affect translation. Lintner et al. demonstrate that small molecules can specifically inhibit translation of a single disease-associated protein by stalling the ribosome's nascent chain [1], opening up a new therapeutic strategy for 'undruggable' proteins. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Inhibition of lipid peroxidation mediated by indolizines

    NARCIS (Netherlands)

    Nasir, AI; Gundersen, LL; Rise, F; Antonsen, O; Kristensen, T; Langhelle, B; Bast, A; Custers, [No Value; Haenen, GRMM; Wikstrom, H

    1998-01-01

    Esters, ethers, carbonates and carbamates of 1-indolizinols and azaindolizinols exhibit a profound inhibition of lipid peroxidation in vitro. The antioxidants were prepared by cyclization of pyridines and diazines with diphenylcyclopropenone followed by introduction of the O-substituent. (C) 1998

  14. An historic perspective of proteasome inhibition.

    Science.gov (United States)

    Esseltine, Dixie-Lee; Mulligan, George

    2012-07-01

    The ubiquitin-proteasome system (UPS) and associated signaling pathways are regarded today as an exciting area of development for novel therapeutics. However, two decades ago, following the discovery and elucidation of ubiquitin and the 26S proteasome as key mediators of protein turnover, the concept of inhibiting the UPS was not even considered a feasible therapeutic approach due to the assumption that inhibition of this pathway would have widespread deleterious effects. Subsequent clinical developments with the first-in-class proteasome inhibitor bortezomib have radically overturned that view, with the proteasome now recognized as a validated target and proteasome inhibition demonstrated to be a highly successful treatment for a number of hematologic malignancies. Here we provide a historic perspective on the emergence of proteasome inhibition, sharing some of the lessons learned along the way. We describe the development of bortezomib and the elucidation of the effects of its novel mechanism of action, and place the cutting-edge work described elsewhere in this issue in the context of these historic developments. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Probenazole treatment inhibits anthocyanins biosynthesis via ...

    African Journals Online (AJOL)

    It has been found that anthocyanins were accumulated in Arabidopsis under drought or salt stress. In this study, such accumulation was found to be inhibited by external applied probenazole (3-allyloxy-1, 2-benzisothiazole-1,1-dioxide, PBZ), which is the active ingredient in oryzemate used for the protection of rice from ...

  16. Product inhibition of five Hypocrea jecorina cellulases

    DEFF Research Database (Denmark)

    Murphy, Leigh; Westh, Peter; Bohlin, Christina

    2013-01-01

    Product inhibition of cellulolytic enzymes has been deemed a critical factor in the industrial saccharification of cellulosic biomass. Several investigations have addressed this problem using crude enzyme preparations or commercial (mixed) cellulase products, but quantitative information on indiv......Product inhibition of cellulolytic enzymes has been deemed a critical factor in the industrial saccharification of cellulosic biomass. Several investigations have addressed this problem using crude enzyme preparations or commercial (mixed) cellulase products, but quantitative information...... cellulose may be monitored by calorimetry. The key advantage of this approach is that it directly measures the rate of hydrolysis while being essentially blind to the background of added product. We investigated the five major cellulases from Hypocrea jecorina (anamorph: Tricoderma reesei), Cel7A (formerly...... CBH1), Cel6A (CBH2), Cel7B (EG1), Cel5A (EG2) and Cel12A (EG3), for their sensitivity to the products glucose and cellobiose. The strongest inhibition was found for Cel7A, which showed a 50% activity-loss in 19 mM cellobiose (IC50 = 19 mM). The other exoglucanase, Cel6A, was much less inhibited...

  17. Inhibiting Intuitive Thinking in Mathematics Education

    Science.gov (United States)

    Thomas, Michael O. J.

    2015-01-01

    The papers in this issue describe recent collaborative research into the role of inhibition of intuitive thinking in mathematics education. This commentary reflects on this research from a mathematics education perspective and draws attention to some of the challenges that arise in collaboration between research fields with different cultures,…

  18. Targeted inhibition of cancer-inflammation

    NARCIS (Netherlands)

    Gomes Coimbra, M.J.

    2012-01-01

    The new paradigm in cancer treatment that aims to inhibit the smoldering inflammatory response in tumors is explored to develop new anticancer treatments. It appears that targeted drug delivery is essential in this concept as high local levels of anti-inflammatory agents are needed to observe the

  19. Osthole inhibits bone metastasis of breast cancer.

    Science.gov (United States)

    Wu, Chunyu; Sun, Zhenping; Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

    2017-08-29

    Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potential mechanism of this inhibition. In the murine model of breast cancer osseous metastasis, mice that received osthole developed significantly less bone metastases and displayed decreased tumor burden when compared with mice in the control group. Osthole inhibited breast cancer cell growth, migration, and invasion, and induced apoptosis of breast cancer cells. Additionally, it also regulated OPG/RANKL signals in the interactions between bone cells (osteoblasts and osteoclasts) and cancer cells. Besides, it also inhibited TGF-β/Smads signaling in breast cancer metastasis to bone in MDA-231BO cells. The results of this study suggest that osthole has real potential as a therapeutic candidate in the treatment of breast cancer patients with bone metastases.

  20. Linking algal growth inhibition to chemical activity

    DEFF Research Database (Denmark)

    Schmidt, Stine N.; Mayer, Philipp

    2015-01-01

    Recently, high-quality data were published on the algal growth inhibition caused by 50 non-polar narcotic compounds, of which 39 were liquid compounds with defined water solubility. In the present study, the toxicity data for these liquids were applied to challenge the chemical activity range...

  1. Cortisol inhibits apoptosis in carp neutrophilic granulocytes.

    NARCIS (Netherlands)

    Weyts, F.A.A.; Flik, G.; Verburg-van Kemenade, B.M.L.

    1998-01-01

    The direct effect of cortisol treatment on carp neutrophil viability was examined in vitro. Cortisol treatment caused an inhibition of neutrophil apoptosis. The effect was blocked by glucocorticoid receptor blocker RU486, showing that rescue from apoptosis was receptor mediated. Using binding

  2. Temporal Preparation, Response Inhibition and Impulsivity

    Science.gov (United States)

    Correa, Angel; Trivino, Monica; Perez-Duenas, Carolina; Acosta, Alberto; Lupianez, Juan

    2010-01-01

    Temporal preparation and impulsivity involve overlapping neural structures (prefrontal cortex) and cognitive functions (response inhibition and time perception), however, their interrelations had not been investigated. We studied such interrelations by comparing the performance of groups with low vs. high non-clinical trait impulsivity during a…

  3. Hemagglutinin inhibition assay with swine sera

    Science.gov (United States)

    Hemagglutination is based on the ability of certain viruses to agglutinate red blood cells (RBC) of certain animal species by formation of cross-linking lattices between RBC. Antibodies that have the ability to inhibit the hemagglutination property of influenza A viruses are generally thought to pro...

  4. Inhibition of Corneal Neovascularization by Hydrazinocurcumin

    African Journals Online (AJOL)

    This article previously published in Volume 15 Issue 2 of this journal in February 2016 has been retracted in line with the guidelines from the Committee on Publication Ethics (COPE, http://publicationethics.org/resources/guidelines). Retracted: Zhan W, Zhu J, Zhang Y. Inhibition of corneal neovascularization by ...

  5. Retracted: Inhibition of Corneal Neovascularization by ...

    African Journals Online (AJOL)

    This article previously published in Volume 15 Issue 2 of this journal in February 2016 has been retracted in line with the guidelines from the Committee on Publication Ethics (COPE, http://publicationethics.org/resources/guidelines). Retracted: Zhan W, Zhu J, Zhang Y. Inhibition of corneal neovascularization by ...

  6. The Mechanism Underlying Inhibition of Saccadic Return

    Science.gov (United States)

    Ludwig, Casimir J. H.; Farrell, Simon; Ellis, Lucy A.; Gilchrist, Iain D.

    2009-01-01

    Human observers take longer to re-direct gaze to a previously fixated location. Although there has been some exploration of the characteristics of inhibition of saccadic return (ISR), the exact mechanisms by which ISR operates are currently unknown. In the framework of accumulation models of response times, in which evidence is integrated over…

  7. Product inhibition in native-state proteolysis.

    Directory of Open Access Journals (Sweden)

    Joseph R Kasper

    Full Text Available The proteolysis kinetics of intact proteins by nonspecific proteases provides valuable information on transient partial unfolding of proteins under native conditions. Native-state proteolysis is an approach to utilize the proteolysis kinetics to assess the energetics of partial unfolding in a quantitative manner. In native-state proteolysis, folded proteins are incubated with nonspecific proteases, and the rate of proteolysis is determined from the disappearance of the intact protein. We report here that proteolysis of intact proteins by nonspecific proteases, thermolysin and subtilisin deviates from first-order kinetics. First-order kinetics has been assumed for the analysis of native-state proteolysis. By analyzing the kinetics of proteolysis with varying concentrations of substrate proteins and also with cleavage products, we found that the deviation from first-order kinetics results from product inhibition. A kinetic model including competitive product inhibition agrees well with the proteolysis time course and allows us to determine the uninhibited rate constant for proteolysis as well as the apparent inhibition constant. Our finding suggests that the likelihood of product inhibition must be considered for quantitative assessment of proteolysis kinetics.

  8. Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation.

    Science.gov (United States)

    Capozzi, Megan E; Hammer, Sandra S; McCollum, Gary W; Penn, John S

    2016-12-14

    The objective of the present study was to assess the effect of elevating epoxygenated fatty acids on retinal vascular inflammation. To stimulate inflammation we utilized TNFα, a potent pro-inflammatory mediator that is elevated in the serum and vitreous of diabetic patients. In TNFα-stimulated primary human retinal microvascular endothelial cells, total levels of epoxyeicosatrienoic acids (EETs), but not epoxydocosapentaenoic acids (EDPs), were significantly decreased. Exogenous addition of 11,12-EET or 19,20-EDP when combined with 12-(3-adamantane-1-yl-ureido)-dodecanoic acid (AUDA), an inhibitor of epoxide hydrolysis, inhibited VCAM-1 and ICAM-1 expression and protein levels; conversely the diol product of 19,20-EDP hydrolysis, 19,20-DHDP, induced VCAM1 and ICAM1 expression. 11,12-EET and 19,20-EDP also inhibited leukocyte adherence to human retinal microvascular endothelial cell monolayers and leukostasis in an acute mouse model of retinal inflammation. Our results indicate that this inhibition may be mediated through an indirect effect on NFκB activation. This is the first study demonstrating a direct comparison of EET and EDP on vascular inflammatory endpoints, and we have confirmed a comparable efficacy from each isomer, suggesting a similar mechanism of action. Taken together, these data establish that epoxygenated fatty acid elevation will inhibit early pathology related to TNFα-induced inflammation in retinal vascular diseases.

  9. Illustrating Enzyme Inhibition Using Gibbs Energy Profiles

    Science.gov (United States)

    Bearne, Stephen L.

    2012-01-01

    Gibbs energy profiles have great utility as teaching and learning tools because they present students with a visual representation of the energy changes that occur during enzyme catalysis. Unfortunately, most textbooks divorce discussions of traditional kinetic topics, such as enzyme inhibition, from discussions of these same topics in terms of…

  10. Sultam Thiourea Inhibition of West Nile Virus▿

    Science.gov (United States)

    Barklis, Eric; Still, Amelia; Sabri, Mohammad I.; Hirsch, Alec J.; Nikolich-Zugich, Janko; Brien, James; Dhenub, Tenzin Choesang; Scholz, Isabel; Alfadhli, Ayna

    2007-01-01

    We have identified sultam thioureas as novel inhibitors of West Nile virus (WNV) replication. One such compound inhibited WNV, with a 50% effective concentration of 0.7 μM, and reduced reporter expression from cells that harbored a WNV-based replicon. Our results demonstrate that sultam thioureas can block a postentry, preassembly step of WNV replication. PMID:17452483

  11. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A. [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States); Yap, Sook Fan [Faculty of Medicine and Health Sciences, Department of Pre-Clinical Sciences, University of Tunku Abdul Rahman (Malaysia); Ngeow, Yun Fong [Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603 (Malaysia); Chin, Khew-Voon, E-mail: khew-voon.chin@utoledo.edu [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States)

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer Salinomycin inhibits preadipocyte differentiation into adipocytes. Black-Right-Pointing-Pointer Salinomycin inhibits transcriptional regulation of adipogenesis. Black-Right-Pointing-Pointer Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor {gamma}. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  12. Gold Nanoparticles Inhibit Matrix Metalloproteases without Cytotoxicity.

    Science.gov (United States)

    Hashimoto, M; Sasaki, J I; Yamaguchi, S; Kawai, K; Kawakami, H; Iwasaki, Y; Imazato, S

    2015-08-01

    Nanoparticles (NPs) are currently the focus of considerable attention for dental applications; however, their biological effects have not been fully elucidated. The long-term, slow release of matrix metalloproteases (MMPs) digests collagen fibrils within resin-dentin bonds. Therefore, MMP inhibitors can prolong the durability of resin-dentin bonds. However, there have been few reports evaluating the combined effect of MMP inhibition and the cytotoxic effects of NPs for dentin bonding. The aim of this study was to evaluate MMP inhibition and cytotoxic responses to gold (AuNPs) and platinum nanoparticles (PtNPs) stabilized by polyvinylpyrrolidone (PVP) in cultured murine macrophages (RAW264) by using MMP inhibition assays, measuring cell viability and inflammatory responses (quantitative reverse transcription polymerase chain reaction [RT-qPCR]), and conducting a micromorphological analysis by fluorescence and transmission electron microscopy. Cultured RAW264 cells were exposed to metal NPs at various concentrations (1, 10, 100, and 400 µg/mL). AuNPs and PtNPs markedly inhibited MMP-8 and MMP-9 activity. Although PtNPs were cytotoxic at high concentrations (100 and 400 µg/mL), no cytotoxic effects were observed for AuNPs at any concentration. Transmission electron microscopy images showed a significant nonrandom intercellular distribution for AuNPs and PtNPs, which were mostly observed to be localized in lysosomes but not in the nucleus. RT-qPCR analysis demonstrated inflammatory responses were not induced in RAW264 cells by AuNPs or PtNPs. The cytotoxicity of nanoparticles might depend on the core metal composition and arise from a "Trojan horse" effect; thus, MMP inhibition could be attributed to the surface charge of PVP, which forms the outer coating of NPs. The negative charge of the surface coating of PVP binds to Zn(2+) from the active center of MMPs by chelate binding and results in MMP inhibition. In summary, AuNPs are attractive NPs that effectively

  13. Polysulfonate suramin inhibits Zika virus infection.

    Science.gov (United States)

    Tan, Chee Wah; Sam, I-Ching; Chong, Wei Lim; Lee, Vannajan Sanghiran; Chan, Yoke Fun

    2017-07-01

    Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition. Suramin, an FDA-approved anti-parasitic drug, inhibits ZIKV infection with 3-5 log 10  PFU viral reduction with IC 50 value of ∼2.5-5 μg/ml (1.93 μM-3.85 μM). A time-of-drug-addition study revealed that suramin remains potent even when administrated at 1-24 hpi. Suramin inhibits ZIKV infection by preventing viral adsorption, entry and replication. Molecular dynamics simulation revealed stronger interaction of suramin with ZIKV NS3 helicase than with the envelope protein. Suramin warrants further investigation as a potential antiviral candidate for ZIKV infection. Heparan sulfate (HS) is a cellular attachment receptor for multiple flaviviruses. However, no direct ZIKV-heparin interaction was observed in heparin-binding analysis, and downregulate or removal of cellular HS with sodium chlorate or heparinase I/III did not inhibit ZIKV infection. This indicates that cell surface HS is not utilized by ZIKV as an attachment receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Neural synchrony during response production and inhibition.

    Directory of Open Access Journals (Sweden)

    Viktor Müller

    Full Text Available Inhibition of irrelevant information (conflict monitoring and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300-600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations.

  15. Mullerian Inhibiting Substances (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

    National Research Council Canada - National Science Library

    Gupta, Vandana

    2006-01-01

    MIS is a member of the TGF family. The purpose of this study is to test the hypothesis that MIS and IFN-gamma might be more effective in the inhibition of breast cancer cell growth than either agent alone...

  16. Structural requirements of alloxan and ninhydrin for glucokinase inhibition and of glucose for protection against inhibition.

    Science.gov (United States)

    Lenzen, S.; Brand, F. H.; Panten, U.

    1988-01-01

    1. In order to elucidate the mechanism underlying the interactions between glucose and alloxan when competing for the sugar binding site of glucokinase from pancreatic B-cells or liver, the structural requirements of the enzyme for inhibition by alloxan and for protection by glucose were determined. 2. With a half-maximal inhibitory concentration of 5 microM, alloxan was the most potent pyrimidine derivative inhibitor of glucokinase. Uramil was a less potent enzyme inhibitor. A variety of other pyrimidine derivatives and related substances were ineffective. 3. Ninhydrin also inhibited glucokinase with a half-maximal inhibitory concentration of 5 microM. Isatin was a slightly less potent enzyme inhibitor. Several other indoline derivatives were ineffective. 4. Only glucose derivatives with a sufficiently bulky substituent in position C-2, such as the glucokinase substrates glucose and mannose and the inhibitors mannoheptulose, glucosamine, and N-acetylglucosamine, protected glucokinase against inhibition by alloxan by binding to the active site of the enzyme. Glucose epimers which differed in other positions did not protect the enzyme against alloxan inhibition. 5. DTT (dithiothreitol) protected glucokinase against inhibition by alloxan and reversed the inhibition of the enzyme induced by alloxan. Thus the mechanism of glucokinase inhibition by alloxan and other inhibitors, such as uramil and ninhydrin, is an oxidation of functionally essential SH groups of the enzyme, where the most reactive keto group of the inhibitor acts as the hydrogen acceptor. The protective action of glucose and several C-2 epimers demonstrates that these functionally essential SH groups are situated in the sugar binding site of the glucokinase. 6. The present results support our contention, that the pancreatic B-cell glucokinase is the major target mediating the inhibition of insulin secretion by alloxan. PMID:3207996

  17. Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells.

    Science.gov (United States)

    Rangarajan, Parthasarathy; Subramaniam, Dharmalingam; Paul, Santanu; Kwatra, Deep; Palaniyandi, Kanagaraj; Islam, Shamima; Harihar, Sitaram; Ramalingam, Satish; Gutheil, William; Putty, Sandeep; Pradhan, Rohan; Padhye, Subhash; Welch, Danny R; Anant, Shrikant; Dhar, Animesh

    2015-09-29

    Pancreatic cancer is the fourth leading cause of cancer deaths in the US and no significant treatment is currently available. Here, we describe the effect of crocetinic acid, which we purified from commercial saffron compound crocetin using high performance liquid chromatography. Crocetinic acid inhibits proliferation of pancreatic cancer cell lines in a dose- and time-dependent manner. In addition, it induced apoptosis. Moreover, the compound significantly inhibited epidermal growth factor receptor and Akt phosphorylation. Furthermore, crocetinic acid decreased the number and size of the pancospheres in a dose-dependent manner, and suppressed the expression of the marker protein DCLK-1 (Doublecortin Calcium/Calmodulin-Dependent Kinase-1) suggesting that crocetinic acid targets cancer stem cells (CSC). To understand the mechanism of CSC inhibition, the signaling pathways affected by purified crocetinic acid were dissected. Sonic hedgehog (Shh) upon binding to its cognate receptor patched, allows smoothened to accumulate and activate Gli transcription factor. Crocetinic acid inhibited the expression of both Shh and smoothened. Finally, these data were confirmed in vivo where the compound at a dose of 0.5 mg/Kg bw suppressed growth of tumor xenografts. Collectively, these data suggest that purified crocetinic acid inhibits pancreatic CSC, thereby inhibiting pancreatic tumorigenesis.

  18. Measurement and Reliability of Response Inhibition

    Directory of Open Access Journals (Sweden)

    Eliza eCongdon

    2012-02-01

    Full Text Available Response inhibition plays a critical role in adaptive functioning and can be assessed with the Stop-signal task, which requires participants to suppress prepotent motor responses. Evidence suggests that this ability to inhibit a motor response that has already been initiated (reflected as Stop-signal reaction time (SSRT is a quantitative and heritable measure of interindividual variation in brain function. In order to examine the reliability of this measure, we pooled data across three separate studies and examined the influence of multiple SSRT calculation methods and outlier calling on reliability (using Intra-class correlation. Our results suggest that an approach which uses the average of all available sessions, all trials of each session, and excludes outliers based on predetermined lenient criteria yields reliable SSRT estimates, while not excluding too many participants. Our findings support the reliability of SSRT as an index of inhibitory control, and provide support for its continued use as a neurocognitive phenotype.

  19. Direct renin inhibition in chronic kidney disease

    DEFF Research Database (Denmark)

    Persson, Frederik; Rossing, Peter; Parving, Hans-Henrik

    2013-01-01

    that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need...... early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic...... kidney disease by reporting of the studies published so far as well as perspective on the future possibilites....

  20. Transcriptional inhibition by the retinoblastoma protein

    DEFF Research Database (Denmark)

    Fattaey, A; Helin, K; Harlow, E

    1993-01-01

    The retinoblastoma protein, pRB, appears to play a key role in coordinating the regulation of cell cycle position and transcriptional events. pRB undergoes specific cell-cycle-dependent phosphorylation, being underphosphorylated in G1 and heavily phosphorylated in S, G2, and M....... The underphosphorylated form is able to interact with the E2F transcription factor. Recently, we have cloned a cDNA for E2F-1. By using this clone and a series of non-pRB binding mutants, we have been able to show that the binding of pRB to E2F-1 causes inhibition of E2F-mediated transactivation. pRB's inhibition of E2F......-mediated transcription would be lost by mutation in the retinoblastoma gene in human tumours, by pRB's interaction with DNA tumour virus oncoproteins, or by phosphorylation during the cell cycle....