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Sample records for biliary cancer cell

  1. IDH mutations in liver cell plasticity and biliary cancer

    PubMed Central

    Saha, Supriya K; Parachoniak, Christine A; Bardeesy, Nabeel

    2014-01-01

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer associated with the bile ducts within the liver. These tumors are characterized by frequent gain-of-function mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes—that are also common in subsets of neural, haematopoietic and bone tumors, but rare or absent in the other types of gastrointestinal malignancy. Mutant IDH acts through a novel mechanism of oncogenesis, producing high levels of the metabolite 2-hydroxyglutarate, which interferes with the function of α-ketoglutarate-dependent enzymes that regulate diverse cellular processes including histone demethylation and DNA modification. Recently, we used in vitro stem cell systems and genetically engineered mouse models (GEMMs) to demonstrate that mutant IDH promotes ICC formation by blocking hepatocyte differentiation and increasing pools of hepatic progenitors that are susceptible to additional oncogenic hits leading to ICC. We found that silencing of HNF4A—encoding a master transcriptional regulator of hepatocyte identity and quiescence—was critical to mutant IDH-mediated inhibition of liver differentiation. In line with these findings, human ICC with IDH mutations are characterized by a hepatic progenitor cell transcriptional signature suggesting that they are a distinct ICC subtype as compared to IDH wild type tumors. The role of mutant IDH in controlling hepatic differentiation state suggests the potential of newly developed inhibitors of the mutant enzyme as a form of differentiation therapy in a solid tumor. PMID:25485496

  2. Biliary tract cancer.

    PubMed

    Abdalla, E K; Vauthey, J N

    2001-09-01

    Advances in cellular and molecular biology of extrahepatic cholangiocarcinoma and gallbladder adenocarcinoma are providing innovative means for the diagnosis and treatment of biliary tract cancer. Similarly, refinements in noninvasive studies--including helical computed tomography, magnetic resonance cholangiopancreatography, and endoscopic ultrasonography--are enabling more accurate diagnosis, staging, and treatment planning for these tumors. Complete resection remains the only means for cure, and recent reports from major hepatobiliary centers support aggressive wide resection for bile duct and gallbladder cancer. Palliation of malignant strictures has improved with advanced endoscopic techniques, newer polyurethane-covered stents, endoscopic microwave coagulation therapy, and radiofrequency intraluminal endohyperthermia. The preliminary data on such minimally invasive techniques suggest an improvement in quality of life and survival for selected patients. PMID:17031200

  3. PIK3CA mutation detection in metastatic biliary cancer using cell-free DNA.

    PubMed

    Kim, Seung Tae; Lira, Maruja; Deng, Shibing; Lee, Sujin; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Mao, Mao; Heo, Jin Seok; Kwon, Wooil; Jang, Kee-Taek; Lee, Jeeyun; Park, Joon Oh

    2015-11-24

    PIK3CA mutation is considered a good candidate for targeted therapies in cancers, especially biliary tract cancer (BTC). We evaluated the utility of cell free DNA (cfDNA) from serum by using droplet digital PCR (ddPCR) as an alternative source for PIK3CA mutation analysis. To identify matching archival tumour specimens from serum samples of advanced BTC patients, mutation detection using ddPCR with Bio-Rad's PrimePCR mutation and wild type assays were performed for PIK3CA p.E542K, p.E545K, and p.H1047R. Thirty-eight patients with metastatic BTC were enrolled. Only one (BTC 29T) sample (n = 38) was positive for PIK3CA p.E542K and another (BTC 27T) for p.H1047R mutation; none was positive for PIK3CA p.E545K. Matched serum sample (BTC 29P) was positive for PIK3CA p.E542K with 28 mutant copies detected, corresponding to 48 copies/ml of serum and an allelic prevalence of 0.3%. Another matched serum sample (BTC 27P) was positive for PIK3CA p.H1047R with 10 mutant copies detected, i.e. 18 copies/ml and an allelic frequency of 0.2%. High correlation was noted in the PIK3CA mutation status between tumour gDNA and serum cfDNA. Low-level PIK3CA mutations were detectable in the serum indicating the utility of cfDNA as a DNA source to detect cancer-derived mutations in metastatic biliary cancers. PMID:26498688

  4. PIK3CA mutation detection in metastatic biliary cancer using cell-free DNA

    PubMed Central

    Deng, Shibing; Lee, Sujin; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Mao, Mao; Heo, Jin Seok; Kwon, Wooil; Jang, Kee-Taek; Lee, Jeeyun; Park, Joon Oh

    2015-01-01

    PIK3CA mutation is considered a good candidate for targeted therapies in cancers, especially biliary tract cancer (BTC). We evaluated the utility of cell free DNA (cfDNA) from serum by using droplet digital PCR (ddPCR) as an alternative source for PIK3CA mutation analysis. To identify matching archival tumour specimens from serum samples of advanced BTC patients, mutation detection using ddPCR with Bio-Rad's PrimePCR mutation and wild type assays were performed for PIK3CA p.E542K, p.E545K, and p.H1047R. Thirty-eight patients with metastatic BTC were enrolled. Only one (BTC 29T) sample (n = 38) was positive for PIK3CA p.E542K and another (BTC 27T) for p.H1047R mutation; none was positive for PIK3CA p.E545K. Matched serum sample (BTC 29P) was positive for PIK3CA p.E542K with 28 mutant copies detected, corresponding to 48 copies/ml of serum and an allelic prevalence of 0.3%. Another matched serum sample (BTC 27P) was positive for PIK3CA p.H1047R with 10 mutant copies detected, i.e. 18 copies/ml and an allelic frequency of 0.2%. High correlation was noted in the PIK3CA mutation status between tumour gDNA and serum cfDNA. Low-level PIK3CA mutations were detectable in the serum indicating the utility of cfDNA as a DNA source to detect cancer-derived mutations in metastatic biliary cancers. PMID:26498688

  5. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer

    PubMed Central

    Goeppert, B; Frauenschuh, L; Zucknick, M; Stenzinger, A; Andrulis, M; Klauschen, F; Joehrens, K; Warth, A; Renner, M; Mehrabi, A; Hafezi, M; Thelen, A; Schirmacher, P; Weichert, W

    2013-01-01

    Background: Biliary tract cancers (BTC) are relatively rare malignant tumours with poor prognosis. It is known from other solid neoplasms that antitumour inflammatory response has an impact on tumour behaviour and patient outcome. The aim of this study was to provide a comprehensive characterisation of antitumour inflammatory response in human BTC. Methods: Tumour-infiltrating T lymphocytes (CD4+, CD8+, and Foxp3+), natural killer cells (perforin+), B lymphocytes (CD20+), macrophages (CD68+) as well as mast cells (CD117+) were assessed by immunohistochemistry in 375 BTC including extrahepatic (ECC; n=157), intrahepatic (ICC; n=149), and gallbladder (GBAC; n=69) adenocarcinomas. Overall and intraepithelial quantity of tumour-infiltrating immune cells was analysed. Data were correlated with clinicopathological variables and patient survival. Results: The most prevalent inflammatory cell type in BTC was the T lymphocyte. Components of the adaptive immune response decreased, whereas innate immune response components increased significantly in the biliary intraepithelial neoplasia – primary carcinoma – metastasis sequence. BTC patients with intraepithelial tumour-infiltrating CD4+, CD8+, and Foxp3+ T lymphocytes showed a significantly longer overall survival. Number of total intraepithelial tumour-infiltrating Foxp3+ regulatory T lymphocytes (HR: 0.492, P=0.002) and CD4+ T lymphocytes (HR: 0.595, P=0.008) were tumour grade- and UICC-stage-independent prognosticators. The subtype-specific evaluation revealed that the tumour-infiltrating lymphocytic infiltrate is a positive outcome predictor in ECC and GBAC but not in ICC. Conclusion: Our findings characterise the immune response in cholangiocarcinogenesis and identify inflammatory cell types that influence the outcome of BTC patients. Further, we show that BTC subtypes show relevant differences with respect to density, quality of inflammation, and impact on patient survival. PMID:24136146

  6. EC-18, a Synthetic Monoacetyldiacylglyceride, Inhibits Hematogenous Metastasis of KIGB-5 Biliary Cancer Cell in Hamster Model

    PubMed Central

    Kim, Myung-Hwan; Chang, Heung Moon; Kim, Tae Won; Lee, Sung Koo; Park, Jung-Sun; Kim, Young-Hoon; Lee, Tae Yoon; Jang, Se Jin; Suh, Chul-Won; Lee, Tae-Suk; Kim, Sang-Hee B

    2009-01-01

    EC-18 (monoacetyldiacylglyceride) stimulates T cell production of IL-2, IL-4, IL-12, IFN-γ, and GM-CSF in vitro. To study the effects of these cytokines stimulated by EC-18 on cancer cells, we applied hamster biliary cancer model, a difficult cancer to treat. Cancer (KIGB-5) cells were given intravenously to produce hematogenous metastatic lung lesions which were treated with EC-18 at 10, 25, and 50 mg/kg/day respectively. The fourth group was untreated control. At 4th, 8th, and 12th week the lungs were examined. EC-18 treated groups showed only a few microscopic lung lesions and no evidence of metastatic lesion with highest dose whereas widespread gross lung lesions were observed in untreated control. To investigate whether the anti-tumor effect of EC-18 is associated with suppression of tumor cell Toll-like receptor 4 (TLR-4) expression in addition to stimulation of the immune cells, KIGB-5 cells were exposed to LPS with or without EC-18. TLR-4 mRNA and protein expression, measured by reverse transcriptase PCR (RT-PCR), real-time quantitative PCR and western blot analysis, showed suppression of TLR-4 expression in KIGB-5 cells treated with EC-18 compared with control. In conclusion, EC-18 has a significant anti-tumor effect in this experimental model of biliary cancer suggesting potential for clinical application to this difficult cancer. PMID:19543512

  7. MicroRNAs Associated with the Efficacy of Photodynamic Therapy in Biliary Tract Cancer Cell Lines

    PubMed Central

    Wagner, Andrej; Mayr, Christian; Bach, Doris; Illig, Romana; Plaetzer, Kristjan; Berr, Frieder; Pichler, Martin; Neureiter, Daniel; Kiesslich, Tobias

    2014-01-01

    Photodynamic therapy (PDT) is a palliative treatment option for unresectable hilar biliary tract cancer (BTC) showing a considerable benefit for survival and quality of life with few side effects. Currently, factors determining the cellular response of BTC cells towards PDT are unknown. Due to their multifaceted nature, microRNAs (miRs) are a promising analyte to investigate the cellular mechanisms following PDT. For two photosensitizers, Photofrin® and Foscan®, the phototoxicity was investigated in eight BTC cell lines. Each cell line (untreated) was profiled for expression of n = 754 miRs using TaqMan® Array Human MicroRNA Cards. Statistical analysis and bioinformatic tools were used to identify miRs associated with PDT efficiency and their putative targets, respectively. Twenty miRs correlated significantly with either high or low PDT efficiency. PDT was particularly effective in cells with high levels of clustered miRs 25-93*-106b and (in case of miR-106b) a phenotype characterized by high expression of the mesenchymal marker vimentin and high proliferation (cyclinD1 and Ki67 expression). Insensitivity towards PDT was associated with high miR-200 family expression and (for miR-cluster 200a/b-429) expression of differentiation markers Ck19 and Ck8/18. Predicted and validated downstream targets indicate plausible involvement of miRs 20a*, 25, 93*, 130a, 141, 200a, 200c and 203 in response mechanisms to PDT, suggesting that targeting these miRs could improve susceptibility to PDT in insensitive cell lines. Taken together, the miRNome pattern may provide a novel tool for predicting the efficiency of PDT and—following appropriate functional verification—may subsequently allow for optimization of the PDT protocol. PMID:25380521

  8. Influence of Five Potential Anticancer Drugs on Wnt Pathway and Cell Survival in Human Biliary Tract Cancer Cells

    PubMed Central

    WACHTER, Julia; NEUREITER, Daniel; ALINGER, Beate; PICHLER, Martin; FUEREDER, Julia; OBERDANNER, Christian; Di FAZIO, Pietro; OCKER, Matthias; BERR, Frieder; KIESSLICH, Tobias

    2012-01-01

    Background: The role of Wnt signalling in carcinogenesis suggests compounds targeting this pathway as potential anti-cancer drugs. Several studies report activation of Wnt signalling in biliary tract cancer (BTC) thus rendering Wnt inhibitory drugs as potential candidates for targeted therapy of this highly chemoresistant disease. Methods: In this study we analysed five compounds with suggested inhibitory effects on Wnt signalling (DMAT, FH535, myricetin, quercetin, and TBB) for their cytotoxic efficiency, mode of cell death, time- and cell line-dependent characteristics as well as their effects on Wnt pathway activity in nine different BTC cell lines. Results: Exposure of cancer cells to different concentrations of the compounds results in a clear dose-dependent reduction of viability for all drugs in the order FH535 > DMAT > TBB > myricetin > quercetin. The first three substances show high cytotoxicity in all tested cell lines, cause a direct cytotoxic effect by induction of apoptosis and inhibit pathway-specific signal transduction in a Wnt transcription factor reporter activity assay. Selected target genes such as growth-promoting cyclin D1 and the cell cycle progression inhibitor p27 are down- and up-regulated after treatment, respectively. Conclusions: Taken together, these data demonstrate that the small molecular weight inhibitors DMAT, F535 and TBB have a considerable cytotoxic and possibly Wnt-specific effect on BTC cell lines in vitro. Further in vivo investigation of these drugs as well as of new Wnt inhibitors may provide a promising approach for targeted therapy of this difficult-to-treat tumour. PMID:22211101

  9. Phenylethyl isothiocyanate reverses cisplatin resistance in biliary tract cancer cells via glutathionylation-dependent degradation of Mcl-1.

    PubMed

    Li, Qiwei; Zhan, Ming; Chen, Wei; Zhao, Benpeng; Yang, Kai; Yang, Jie; Yi, Jing; Huang, Qihong; Mohan, Man; Hou, Zhaoyuan; Wang, Jian

    2016-03-01

    Biliary tract cancer (BTC) is a highly malignant cancer. BTC exhibits a low response rate to cisplatin (CDDP) treatment, and therefore, an understanding of the mechanism of CDDP resistance is urgently needed. Here, we show that BTC cells develop CDDP resistance due, in part, to upregulation of myeloid cell leukemia 1 (Mcl-1). Phenylethyl isothiocyanate (PEITC), a natural compound found in watercress, could enhance the efficacy of CDDP by degrading Mcl-1. PEITC-CDDP co-treatment also increased the rate of apoptosis of cancer stem-like side population (SP) cells and inhibited xenograft tumor growth without obvious toxic effects. In vitro, PEITC decreased reduced glutathione (GSH), which resulted in decreased GSH/oxidized glutathione (GSSG) ratio and increased glutathionylation of Mcl-1, leading to rapid proteasomal degradation of Mcl-1. Furthermore, we identified Cys16 and Cys286 as Mcl-1 glutathionylation sites, and mutating them resulted in PEITC-mediated degradation resistant Mcl-1 protein. In conclusion, we demonstrate for the first time that CDDP resistance is partially associated with Mcl-1 in BTC cells and we identify a novel mechanism that PEITC can enhance CDDP-induced apoptosis via glutathionylation-dependent degradation of Mcl-1. Hence, our results provide support that dietary intake of watercress may help reverse CDDP resistance in BTC patients. PMID:26848531

  10. Phenylethyl isothiocyanate reverses cisplatin resistance in biliary tract cancer cells via glutathionylation-dependent degradation of Mcl-1

    PubMed Central

    Li, Qiwei; Zhan, Ming; Chen, Wei; Zhao, Benpeng; Yang, Kai; Yang, Jie; Yi, Jing; Huang, Qihong; Mohan, Man; Hou, Zhaoyuan; Wang, Jian

    2016-01-01

    Biliary tract cancer (BTC) is a highly malignant cancer. BTC exhibits a low response rate to cisplatin (CDDP) treatment, and therefore, an understanding of the mechanism of CDDP resistance is urgently needed. Here, we show that BTC cells develop CDDP resistance due, in part, to upregulation of myeloid cell leukemia 1 (Mcl-1). Phenylethyl isothiocyanate (PEITC), a natural compound found in watercress, could enhance the efficacy of CDDP by degrading Mcl-1. PEITC-CDDP co-treatment also increased the rate of apoptosis of cancer stem-like side population (SP) cells and inhibited xenograft tumor growth without obvious toxic effects. In vitro, PEITC decreased reduced glutathione (GSH), which resulted in decreased GSH/oxidized glutathione (GSSG) ratio and increased glutathionylation of Mcl-1, leading to rapid proteasomal degradation of Mcl-1. Furthermore, we identified Cys16 and Cys286 as Mcl-1 glutathionylation sites, and mutating them resulted in PEITC-mediated degradation resistant Mcl-1 protein. In conclusion, we demonstrate for the first time that CDDP resistance is partially associated with Mcl-1 in BTC cells and we identify a novel mechanism that PEITC can enhance CDDP-induced apoptosis via glutathionylation-dependent degradation of Mcl-1. Hence, our results provide support that dietary intake of watercress may help reverse CDDP resistance in BTC patients. PMID:26848531

  11. The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells

    PubMed Central

    Mayr, Christian; Wagner, Andrej; Loeffelberger, Magdalena; Bruckner, Daniela; Jakab, Martin; Berr, Frieder; Di Fazio, Pietro; Ocker, Matthias; Neureiter, Daniel; Pichler, Martin; Kiesslich, Tobias

    2016-01-01

    BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up-regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 μM). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC. PMID:26623561

  12. Veliparib, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Advanced Biliary, Pancreatic, Urothelial, or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-07-01

    Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage III Pancreatic Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Bladder Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Transitional Cell Carcinoma of the Bladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  13. Biliary tract cancer and occupation in Sweden.

    PubMed Central

    Malker, H S; McLaughlin, J K; Malker, B K; Stone, B J; Weiner, J A; Ericsson, J L; Blot, W J

    1986-01-01

    Using the Cancer-Environment Registry, which links the incidence of cancer (1961-79) and the 1960 census data on industry and occupation for all employed individuals in Sweden, the occurrence of biliary tract cancer (ICD 7th rev 155.1-.9) was systematically assessed according to occupational and industrial classifications. Data are presented separately for cancer of the gall bladder (ICD 155.1) and other cancers of the biliary tract (ICD 155.2-.9) including cancers of the extrahepatic bile ducts, ampulla of Vater, and unspecified bile passages. Statistically significant increased risks for cancer of the gall bladder were observed for men employed in petroleum refining, papermills, chemical processing, shoemaking, and repairing, and for both men and women employed in textile work. A significant increase in the incidence of other cancers of the biliary tract (mostly cancers of the bile duct) was found for such asbestos related employment as shipbuilding and in the wholesale construction materials industry and among insulation workers. These findings should be considered only as clues to aetiological factors, although several are consistent with earlier observations from other countries. PMID:3964574

  14. Colon Cancer Metastatic to the Biliary Tree.

    PubMed

    Strauss, Alexandra T; Clayton, Steven B; Markow, Michael; Mamel, Jay

    2016-04-01

    Metastasis of colon adenocarcinoma is commonly found in the lung, liver, or peritoneum. Common bile duct (CBD) tumors related to adenomas from familial adenomatous polyposis metastasizing from outside of the gastrointestinal tract have been reported. We report a case of biliary colic due to metastatic colon adenocarcinoma to the CBD. Obstructive jaundice with signs of acalculous cholecystitis on imaging in a patient with a history of colon cancer should raise suspicion for metastasis to CBD. PMID:27144209

  15. Colon Cancer Metastatic to the Biliary Tree

    PubMed Central

    Clayton, Steven B.; Markow, Michael; Mamel, Jay

    2016-01-01

    Metastasis of colon adenocarcinoma is commonly found in the lung, liver, or peritoneum. Common bile duct (CBD) tumors related to adenomas from familial adenomatous polyposis metastasizing from outside of the gastrointestinal tract have been reported. We report a case of biliary colic due to metastatic colon adenocarcinoma to the CBD. Obstructive jaundice with signs of acalculous cholecystitis on imaging in a patient with a history of colon cancer should raise suspicion for metastasis to CBD. PMID:27144209

  16. Identification of Novel Cellular Targets in Biliary Tract Cancers Using Global Gene Expression Technology

    PubMed Central

    Hansel, Donna E.; Rahman, Ayman; Hidalgo, Manuel; Thuluvath, Paul J.; Lillemoe, Keith D.; Shulick, Richard; Ku, Ja-Lok; Park, Jae-Gahb; Miyazaki, Kohje; Ashfaq, Raheela; Wistuba, Ignacio I.; Varma, Ram; Hawthorne, Lesleyann; Geradts, Joseph; Argani, Pedram; Maitra, Anirban

    2003-01-01

    Biliary tract carcinoma carries a poor prognosis, and difficulties with clinical management in patients with advanced disease are often due to frequent late-stage diagnosis, lack of serum markers, and limited information regarding biliary tumor pathogenesis. RNA-based global analyses of gene expression have led to the identification of a large number of up-regulated genes in several cancer types. We have used the recently developed Affymetrix U133A gene expression microarrays containing nearly 22,000 unique transcripts to obtain global gene expression profiles from normal biliary epithelial scrapings (n = 5), surgically resected biliary carcinomas (n = 11), and biliary cancer cell lines (n = 9). Microarray hybridization data were normalized using dCHIP (http://www.dCHIP.org) to identify differentially up-regulated genes in primary biliary cancers and biliary cancer cell lines and their expression profiles was compared to that of normal epithelial scrapings using the dCHIP software as well as Significance Analysis of Microarrays or SAM (http://www-stat.stanford.edu/∼tibs/SAM/). Comparison of the dCHIP and SAM datasets revealed an overlapping list of 282 genes expressed at greater than threefold levels in the cancers compared to normal epithelium (t-test P <0.1 in dCHIP, and median false discovery rate <10 in SAM). Several pathways integral to tumorigenesis were up-regulated in the biliary cancers, including proliferation and cell cycle antigens (eg, cyclins D2 and E2, cdc2/p34, and geminin), transcription factors (eg, homeobox B7 and islet-1), growth factors and growth factor receptors (eg, hepatocyte growth factor, amphiregulin, and insulin-like growth factor 1 receptor), and enzymes modulating sensitivity to chemotherapeutic agents (eg, cystathionine β synthase, dCMP deaminase, and CTP synthase). In addition, we identified several “pathway” genes that are rapidly emerging as novel therapeutic targets in cancer (eg, cytosolic phospholipase A2, an upstream

  17. Advances in biomarkers of biliary tract cancers.

    PubMed

    Hu, Jun; Yin, Baobing

    2016-07-01

    Tumor biomarkers can be applied for early diagnosis or precise treatment, thereby leading to personalized treatment and better outcomes. Biliary tract cancers (BTCs) are a group of cancers that occurs in different locations and have different clinical or genetic properties. Though the incidence of BTCs is rare, BTCs are among the most lethal cancers in the world and all have very low 5-year survivals. Lack of efficient early diagnostic approaches or adjuvant therapies for BTCs are main reasons. These urge us to broaden the researches into BTC biomarkers. Although few progresses of diagnostic biomarkers for BTCs have been achieved, there are still some advances in prognostic, predictive and therapeutic areas. In this review, we will focus on these achievements. PMID:27261586

  18. Targeted therapy for biliary tract cancers.

    PubMed

    Faris, Jason E; Zhu, Andrew X

    2012-07-01

    Biliary tract cancers (BTCs) are a heterogeneous group of malignancies, with a historically poor prognosis as a whole. Until recently, the development of effective therapeutics was hampered by the relatively low incidence, heterogeneity in patients and tumors, and correspondingly poor clinical trial enrollments. With the publication of the landmark phase III ABC-02 trial demonstrating the superiority of gemcitabine and cisplatin combination chemotherapy, the landscape changed for the development of new agents. Despite this progress, there are currently no approved targeted agents for BTC. This review will focus on recent developments in targeted therapeutics, directed against several key signaling pathways in BTC, including epidermal growth factor receptor, angiogenesis, and the mitogen-activated protein kinase pathway. Data from recent phase I and II trials will be discussed, along with a preview of upcoming trials involving targeted therapies. PMID:22318523

  19. Risk and Surveillance of Cancers in Primary Biliary Tract Disease

    PubMed Central

    Hrad, Valery; Abebe, Yoftahe; Ali, Syed Haris; Velgersdyk, Jared

    2016-01-01

    Primary biliary diseases have been associated in several studies with various malignancies. Understanding the risk and optimizing surveillance strategy of these malignancies in this specific subset of patients are an important facet of clinical care. For instance, primary sclerosing cholangitis is associated with an increased risk for cholangiocarcinoma (which is very challenging to diagnose) and when IBD is present for colorectal cancer. On the other hand, primary biliary cirrhosis patients with cirrhosis or not responding to 12 months of ursodeoxycholic acid therapy are at increased risk of hepatocellular carcinoma. In this review we will discuss in detail the risks and optimal surveillance strategies for patients with primary biliary diseases. PMID:27413366

  20. Primary cancers of extrahepatic biliary passages

    SciTech Connect

    Mittal, B.; Deutsch, M.; Iwatsuki, S.

    1985-04-01

    The records of 22 patients with cancers of extrahepatic biliary passages (EHBP) were analyzed to understand their natural histories and patterns of failure and to evaluate the effectiveness of various treatments. None of the preoperative investigations consistently defined the entire extent of tumor. Percutaneous transhepatic cholangiography (PTHC) was the most helpful (100%) in accurately defining the site of ductal obstruction. Computed tomography was helpful in diagnosing liver metastases in 53% and primary tumor mass in 23% of patients. The most common sites of tumor failure or persistence were: liver (67%), tumor bed (56%), peritoneum (22%), porta hepatis and lymph nodes (17%). The median survival for the entire group was 6.8 months. Surgery plays an important role in managing these tumors and in defining tumor extent for subsequent adjuvant irradiation. Patients receiving radiation doses greater than or equal to 70 TDF had a longer median survival (11 months) than patients receiving less than 70 TDF (4.4 months). All three patients, who were alive and free of disease greater than 1 year, received radiation doses greater than or equal to 70 TDF. From the data, it is difficult to comment on the effectiveness of chemotherapy. The authors have made suggestions regarding radiation volume and doses to various structures. The need for entering these patients into multi-institutional clinical trials is stressed.

  1. Primary cancers of extrahepatic biliary passages.

    PubMed

    Mittal, B; Deutsch, M; Iwatsuki, S

    1985-04-01

    We analyzed the records of 22 patients with cancers of extrahepatic biliary passages (EHBP) to understand their natural histories and patterns of failure and to evaluate the effectiveness of various treatments. None of the preoperative investigations consistently defined the entire extent of tumor. Percutaneous transhepatic cholangiography (PTHC) was the most helpful (100%) in accurately defining the site of ductal obstruction. Computed tomography was helpful in diagnosing liver metastases in 53% and primary tumor mass in 23% of patients. The most common sites of tumor failure or persistence were: liver (67%), tumor bed (56%), peritoneum (22%), porta hepatis and lymph nodes (17%). The median survival for the entire group was 6.8 months. Surgery plays an important role in managing these tumors and in defining tumor extent for subsequent adjuvant irradiation. Patients receiving radiation doses greater than or equal to 70 TDF had a longer median survival (11 months) than patients receiving less than 70 TDF (4.4 months). All three patients, who were alive and free of disease greater than 1 year, received radiation doses greater than or equal to 70 TDF. From our data, it is difficult to comment on the effectiveness of chemotherapy. We have made suggestions regarding radiation volume and doses to various structures. The need for entering these patients into multi-institutional clinical trials is stressed. PMID:3980281

  2. New genomic landscapes and therapeutic targets for biliary tract cancers.

    PubMed

    Simbolo, Michele; Fassan, Matteo; Mafficini, Andrea; Lawlor, Rita T; Ruzzenente, Andrea; Scarpa, Aldo

    2016-01-01

    Biliary tract cancers (BTCs) are a heterogeneous group of neoplasms characterized by a dismal prognosis. At variance with most solid tumors, no effective molecular targeted agent has been currently approved for BTCs treatment and their molecular landscape has only been recently investigated. Comprehensive mutational profiling studies identified IDH1/2 and BAP1 as characteristic of intrahepatic cholangiocarcinomas, while extrahepatic cholangiocarcinomas and gallbladder carcinomas were characterized by frequent KRAS and TP53 alterations. Moreover, targeted next-generation sequencing has uncovered alterations in several key cellular pathways. BTC-specific alterations include disorders of major regulators of cell cycle and chromatin remodeling processes, as well as deregulation of the mTOR-, TGF-beta/Smad- and receptor tyrosine kinases signaling. The next step will be the correlation of these findings with clinical trials to identify predictive biomarkers for the development of personalized therapies. This will permit early access for BTC patients to innovative drugs. PMID:26709801

  3. Role of CD56-expressing immature biliary epithelial cells in biliary atresia

    PubMed Central

    Zhang, Rui-Zhong; Yu, Jia-Kang; Peng, Jiao; Wang, Feng-Hua; Liu, Hai-Ying; Lui, Vincent CH; Nicholls, John M; Tam, Paul KH; Lamb, Jonathan R; Chen, Yan; Xia, Hui-Min

    2016-01-01

    AIM: To analyze the clinical and pathological parameters and expression of the neural cell adhesion molecule (CD56) in patients with biliary atresia (BA). METHODS: Established clinical laboratory markers of hepatic function, including enzyme activity, protein synthesis, and bilirubin metabolism, were evaluated in patients with BA and compared with those in patients with choledochal cysts and neonatal hepatitis. Pathological changes in tissue morphology and fibrosis were examined by histological and tissue collagen staining. Immunohistochemical staining for the biliary epithelial cell markers CD56 and CK19 together with the Notch signaling related molecules Notch1 and Notch2 was performed in the context of alterations in the structure of intrahepatic biliary ducts. RESULTS: Differences in some clinical laboratory parameters among the three diseases examined were observed, but they did not correlate with the pathological classification of fibrosis in BA. Immunohistochemical staining showed the presence of CD56-positive immature bile ducts in most patients (74.5%) with BA but not in patients with choledochal cysts or neonatal hepatitis. The number of CD56-expressing cells correlated with disease severity, with more positive cells present in the later stages of liver damage (81.8% vs 18.2%). Furthermore, bile plugs were mainly found in CD56-positive immature biliary ducts. Notch signaling was a key regulatory pathway in biliary duct formation and played a role in tissue fibrosis. Notch1 was co-expressed in CD56-positive cells, whereas Notch2 was found exclusively in blood vessels in the portal area of patients with BA. CONCLUSION: The maturation of biliary epithelial cells and the expression of Notch may play a role in the pathogenesis of BA. PMID:26937142

  4. Involvement of breast cancer resistance protein (ABCG2) in the biliary excretion mechanism of fluoroquinolones.

    PubMed

    Ando, Tomohiro; Kusuhara, Hiroyuki; Merino, Gracia; Alvarez, Ana I; Schinkel, Alfred H; Sugiyama, Yuichi

    2007-10-01

    Fluoroquinolones are effective antibiotics for the treatment of bile duct infections. It has been shown that the biliary excretion of grepafloxacin is partly accounted for by multidrug resistance-associated protein 2 (MRP2/ABCC2), whereas neither MRP2 nor P-glycoprotein is involved in the biliary excretion of ulifloxacin. In the present study, we examined the involvement of breast cancer resistance protein (BCRP/ABCG2) in the biliary excretion of fluoroquinolones (grepafloxacin, ulifloxacin, ciprofloxacin, and ofloxacin). In Madin-Darby canine kidney II cells expressing human BCRP or mouse Bcrp, the basal-to-apical transport of grepafloxacin and ulifloxacin was greater than that of the mock control, which was inhibited by a BCRP inhibitor, 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143). Plasma and bile concentrations of fluoroquinolones were determined in wild-type and Bcrp(-/-) mice after i.v. bolus injection. The cumulative biliary excretion of fluoroquinolones was significantly reduced in Bcrp(-/-) mice, resulting in a reduction of the biliary excretion clearances to 86, 50, 40, and 16 of the control values, for ciprofloxacin, grepafloxacin, ofloxacin, and ulifloxacin, respectively. Preinfusion of sulfobromophthalein significantly inhibited the biliary excretion of grepafloxacin in Bcrp(-/-) mice. There was no change in the tissue/plasma concentration ratios of fluoroquinolones in the liver or brain, whereas those in the kidney were increased 3.6- and 1.5-fold for ciprofloxacin and grepafloxacin, respectively, in Bcrp(-/-) mice but were unchanged for ofloxacin and ulifloxacin. The present study shows that BCRP mediates the biliary excretion of fluoroquinolones and suggests that it is also involved in the tubular secretion of ciprofloxacin and grepafloxacin. PMID:17639028

  5. CD8 T cells mediate direct biliary ductule damage in NOD autoimmune biliary disease

    PubMed Central

    Yang, Guo-Xiang; Wu, Yuehong; Tsukamoto, Hiroki; Leung, Patrick S.; Lian, Zhe-Xiong; Rainbow, Daniel B.; Hunter, Kara M.; Morris, Gerard A.; Lyons, Paul A.; Peterson, Laurence B.; Wicker, Linda S.; Gershwin, M.E.; Ridgway, William M.

    2016-01-01

    We previously described the NOD.c3c4 mouse, which is protected from type 1 diabetes (T1D) due to protective alleles at multiple insulin-dependent diabetes (Idd) genes, but develops autoimmune biliary disease (ABD) resembling primary biliary cirrhosis (PBC). Here we characterize the NOD.ABD strain, which is genetically-related to the NOD.c3c4 strain but develops both ABD and T1D. Histologically, NOD.ABD biliary disease is indistinguishable from that in NOD.c3c4 mice. The frequency of effector memory (CD44+CD62L-) and central memory (CD44+CD62L+) CD8 T cells is significantly increased in the intrahepatic lymphocyte fraction of NOD.ABD mice, and NOD.ABD CD8 T cells produce more IFN-γ and TNF-α, compared to controls. NOD.ABD splenocytes can transfer ABD and T1D to NOD.c3c4 scid mice, but only T1D to NOD scid mice, suggesting that the genetic origin of the target organ and/or its innate immune cells is critical to disease pathogenesis. The disease transfer model, importantly, shows that biliary duct damage (characteristic of PBC) and inflammation precede biliary epithelial cell proliferation. Unlike T1D where both CD4 and CD8 T cells are required for disease transfer, purified NOD.ABD CD8 T cells can transfer liver inflammation into NOD.c3c4 scid recipients, and disease transfer is ameliorated by co-transferring T regulatory cells. Unlike NOD.c3c4 mice, NOD.ABD mice do not develop antinuclear or anti-Smith autoantibodies; however, NOD.ABD mice do develop the anti-pyruvate dehydrogenase antibodies typical of human PBC. The NOD.ABD strain is a model of immune dysregulation affecting two organ systems, most likely by mechanisms that do not completely coincide. PMID:21169553

  6. Role of Adjuvant Chemoradiotherapy for Resected Extrahepatic Biliary Tract Cancer

    SciTech Connect

    Kim, Tae Hyun; Han, Sung-Sik; Park, Sang-Jae Lee, Woo Jin; Woo, Sang Myung; Moon, Sung Ho; Yoo, Tae; Kim, Sang Soo; Kim, Seong Hoon; Hong, Eun Kyung; Kim, Dae Yong; Park, Joong-Won

    2011-12-01

    Purpose: To evaluate the effect of adjuvant chemoradiotherapy (CRT) on locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) for patients with extrahepatic biliary tract cancer treated with curative resection. Methods and Materials: The study involved 168 patients with extrahepatic biliary tract cancer undergoing curative resection between August 2001 and April 2009. Of the 168 patients, 115 received adjuvant CRT (CRT group) and 53 did not (no-CRT group). Gender, age, tumor size, histologic differentiation, pre- and postoperative carbohydrate antigen 19-9 level, resection margin, vascular invasion, perineural invasion, T stage, N stage, overall stage, and the use of adjuvant CRT were analyzed to identify the prognostic factors associated with LRC, DFS, and OS. Results: For all patients, the 5-year LRC, DFS, and OS rate was 54.8%, 30.6%, and 33.9%, respectively. On univariate analysis, the 5-year LRC, DFS, and OS rates in the CRT group were significantly better than those in the no-CRT group (58.5% vs. 44.4%, p = .007; 32.1% vs. 26.1%, p = .041; 36.5% vs. 28.2%, p = .049, respectively). Multivariate analysis revealed that adjuvant CRT was a significant independent prognostic factor for LRC, DFS, and OS (p < .05). Conclusion: Our results have suggested that adjuvant CRT helps achieve LRC and, consequently, improves DFS and OS in patients with extrahepatic biliary tract cancer.

  7. Genomic Alterations in Biliary Tract Cancer Using Targeted Sequencing1

    PubMed Central

    Yoo, Kwai Han; Kim, Nayoung K.D.; Kwon, Woo Il; Lee, Chung; Kim, Sun Young; Jang, Jiryeon; Ahn, Jungmi; Kang, Mihyun; Jang, Hyojin; Kim, Seung Tae; Ahn, Soomin; Jang, Kee-Taek; Park, Young Suk; Park, Woong-Yang; Lee, Jeeyun; Heo, Jin Seok; Park, Joon Oh

    2016-01-01

    Background: Biliary tract cancers (BTCs) are rare and heterogeneous group of tumors classified anatomically into intrahepatic and extrahepatic bile ducts and gallbladder adenocarcinomas. Patient-derived tumor cell (PDC) models with genome analysis can be a valuable platform to develop a method to overcome the clinical barrier on BTCs. Material and Methods: Between January 2012 and June 2015, 40 BTC patients’ samples were collected. PDCs were isolated and cultured from surgical specimens, biopsy tissues, or malignant effusions including ascites and pleural fluid. Genome analysis using targeted panel sequencing as well as digital multiplexed gene analysis was applied to PDCs as well as primary tumors. Results: Extrahepatic cholangiocarcinoma (N = 15, 37.5%), intrahepatic cholangiocarcinoma (N = 10, 25.0%), gallbladder cancer (N = 14, 35.0%), and ampulla of Vater cancer (N = 1, 2.5%) were included. We identified 15 mutations with diverse genetic alterations in 19 cases of BTC from primary tumor specimens. The most common molecular alterations were in TP53 (8/19, 42.1%), including missense mutations such as C242Y, E285K, G112S, P19T, R148T, R248Q, and R273L. We also detected two NRAS mutations (G12C and Q61L), two KRAS mutations (G12A and G12S), two ERBB2 mutations (V777L and pM774delinsMA) and amplification, and three PIK3CA mutations (N345K, E545K, and E521K). PDC models were successfully established in 27 of 40 samples (67.5%), including 22/24 from body fluids (91.7%) and 5/16 from tissue specimens (31.3%). Conclusions: PDC models are promising tools for uncovering driver mutations and identifying rational therapeutic strategies in BTC. Application of this model is expected to inform clinical trials of drugs for molecular-based targeted therapy.

  8. Bile acid accelerates erbB2-induced pro-tumorigenic activities in biliary tract cancer.

    PubMed

    Kitamura, Takuya; Srivastava, Jaya; DiGiovanni, John; Kiguchi, Kaoru

    2015-06-01

    Although very few studies have addressed the molecular and cellular mechanisms underlying the development of biliary tract cancer (BTC), several lines of evidence suggest a role for the erbB receptor family. Overexpression and activation of erbB2 has been reported in a significant percentage of human BTC. Further, we previously reported that overexpression of erbB2 basal epithelial cells of the biliary tract (BK5.erbB2 mouse) led to the development of BTC. However, the mechanisms by which erbB2 overexpression led to the spontaneous development of tumors specifically in the biliary tract are not completely understood. The goals of the current study were to (1) determine whether a cooperative relationship between bile acid exposure and erbB2 activation exists during biliary tract carcinogenesis and (2) to characterize the mechanism(s) underlying bile acid-mediated biliary tract carcinogenesis in cells with activated erbB2. In this study, we demonstrated that the secondary conjugated bile acid, taurochenodeoxycholic acid (TCDC), increased proliferation of primary cultured gallbladder epithelial cells from BK5.erbB2 mice and human BTC cells. TCDC treatment activated EGFR/erbB2 and downstream signaling molecules in both primary cultured cells and human BTC cells. TCDC also increased the expression of epidermal growth factor receptor (EGFR) ligands and TACE activity in human BTC cells. Inhibition of src activation led to attenuation of bile-induced upregulation of TACE activity as well as signaling through the EGFR/erbB2, suggesting that during the development of BTC erbB2 overexpression/activation accelerates the bile acid-induced signaling cascade: bile acid → src → TACE → EGFR/erbB2 → downstream signaling. We also provide direct evidence that bile acids possess tumor promoting capacity in epithelial cells overexpressing erbB2 using the two-stage skin carcinogenesis model. Collectively these findings suggest cooperative roles for bile acid and

  9. Circulating MicroRNAs as Biomarkers in Biliary Tract Cancers

    PubMed Central

    Letelier, Pablo; Riquelme, Ismael; Hernández, Alfonso H.; Guzmán, Neftalí; Farías, Jorge G.; Roa, Juan Carlos

    2016-01-01

    Biliary tract cancers (BTCs) are a group of highly aggressive malignant tumors with a poor prognosis. The current diagnosis is based mainly on imaging and intraoperative exploration due to brush cytology havinga low sensitivity and the standard markers, such as carcinoembryonic antigen (CEA) and carbohydrate 19-9 (CA19-9), not having enough sensitivity nor specificity to be used in a differential diagnosis and early stage detection. Thus, better non-invasive methods that can distinguish between normal and pathological tissue are needed. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules of ~20–22 nucleotides that regulate relevant physiological mechanisms and can also be involved in carcinogenesis. Recent studies have demonstrated that miRNAs are detectable in multiple body fluids, showing great stability, either free or trapped in circulating microvesicles, such as exosomes. miRNAs are ideal biomarkers that may be used in screening and prognosis in biliary tract cancers, aiding also in the clinical decisions at different stages of cancer treatment. This review highlights the progress in the analysis of circulating miRNAs in serum, plasma and bile as potential diagnostic and prognostic markers of BTCs. PMID:27223281

  10. Circulating MicroRNAs as Biomarkers in Biliary Tract Cancers.

    PubMed

    Letelier, Pablo; Riquelme, Ismael; Hernández, Alfonso H; Guzmán, Neftalí; Farías, Jorge G; Roa, Juan Carlos

    2016-01-01

    Biliary tract cancers (BTCs) are a group of highly aggressive malignant tumors with a poor prognosis. The current diagnosis is based mainly on imaging and intraoperative exploration due to brush cytology havinga low sensitivity and the standard markers, such as carcinoembryonic antigen (CEA) and carbohydrate 19-9 (CA19-9), not having enough sensitivity nor specificity to be used in a differential diagnosis and early stage detection. Thus, better non-invasive methods that can distinguish between normal and pathological tissue are needed. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules of ~20-22 nucleotides that regulate relevant physiological mechanisms and can also be involved in carcinogenesis. Recent studies have demonstrated that miRNAs are detectable in multiple body fluids, showing great stability, either free or trapped in circulating microvesicles, such as exosomes. miRNAs are ideal biomarkers that may be used in screening and prognosis in biliary tract cancers, aiding also in the clinical decisions at different stages of cancer treatment. This review highlights the progress in the analysis of circulating miRNAs in serum, plasma and bile as potential diagnostic and prognostic markers of BTCs. PMID:27223281

  11. Recognition of Major Histocompatibility Complex Antigens on Cultured Human Biliary Epithelial Cells by Alloreactive Lymphocytes

    PubMed Central

    Saidman, Susan L.; Duquesnoy, Rene J.; Zeevi, Adriana; Fung, John J.; Starzl, Thomas E.; Demetris, A. Jake

    2010-01-01

    We have developed an in vitro system to study the interactions between biliary epithelium and lymphocytes using cultured human biliary epithelial cells. No class II antigens were detected by immunoperoxidase staining of the normal biliary epithelial cells, but alloactivated lymphocyte culture supernatants were able to induce class II expression. The activity of the supernatants was blocked with an anti-γ-interferon monoclonal antibody. In addition, recombinant human γ-interferon alone induced the expression of class II antigens and increased the intensity of class I staining of cultured biliary epithelial cells. Biliary epithelial cell–induced proliferation of alloreactive T lymphocytes demonstrated that the major histocompatibility complex molecules carry functional lymphocyte-activating determinants. The recognition of major histocompatibility complex determinants was confirmed by monoclonal antibody–blocking studies and by stimulation of an alloreactive T-cell clone. However, the biliary epithelial cells were much less potent stimulators than arterial endothelial cells tested in the same assay system. PMID:1704868

  12. Concurrent biliary drainage and portal vein embolization in preparation for extended hepatectomy in patients with biliary cancer

    PubMed Central

    Nilsson, Jan; Eriksson, Sam; Nørgaard Larsen, Peter; Keussen, Inger; Christiansen Frevert, Susanne; Lindell, Gert

    2015-01-01

    Background Patients with perihilar cholangiocarcinoma and gallbladder cancer extending into the hilum often present with jaundice and a small future liver remnant (FLR). If resectable, preoperative biliary drainage and portal vein embolization (PVE) are indicated. Classically, these measures have been performed sequentially, separated by 4–6 weeks. Purpose To report on a new regime where percutaneous transhepatic biliary drainage (PTBD) and PVE are performed simultaneously, shortening the preoperative process. Material and Methods Six patients were treated with concurrent PTBD and PVE under general anesthesia. Results Surgical exploration followed the combined procedure after 35 days (range, 28–51 days). The FLR ratio increased from 22% to 32%. Three patients developed cholangitis after the procedure. Conclusion The combined approach of PTBD and PVE seems feasible, but more studies on morbidity are warranted. PMID:25992300

  13. MicroRNA Markers for the Diagnosis of Pancreatic and Biliary-Tract Cancers

    PubMed Central

    Kojima, Motohiro; Sudo, Hiroko; Kawauchi, Junpei; Takizawa, Satoko; Kondou, Satoshi; Nobumasa, Hitoshi; Ochiai, Atsushi

    2015-01-01

    It is difficult to detect pancreatic cancer or biliary-tract cancer at an early stage using current diagnostic technology. Utilizing microRNA (miRNA) markers that are stably present in peripheral blood, we aimed to identify pancreatic and biliary-tract cancers in patients. With “3D-Gene”, a highly sensitive microarray, we examined comprehensive miRNA expression profiles in 571 serum samples obtained from healthy patients, patients with pancreatic, biliary-tract, or other digestive cancers, and patients with non-malignant abnormalities in the pancreas or biliary tract. The samples were randomly divided into training and test cohorts, and candidate miRNA markers were independently evaluated. We found 81 miRNAs for pancreatic cancer and 66 miRNAs for biliary-tract cancer that showed statistically different expression compared with healthy controls. Among those markers, 55 miRNAs were common in both the pancreatic and biliary-tract cancer samples. The previously reported miR-125a-3p was one of the common markers; however, it was also expressed in other types of digestive-tract cancers, suggesting that it is not specific to cancer types. In order to discriminate the pancreato-biliary cancers from all other clinical conditions including the healthy controls, non-malignant abnormalities, and other types of cancers, we developed a diagnostic index using expression profiles of the 10 most significant miRNAs. A combination of eight miRNAs (miR-6075, miR-4294, miR-6880-5p, miR-6799-5p, miR-125a-3p, miR-4530, miR-6836-3p, and miR-4476) achieved a sensitivity, specificity, accuracy and AUC of 80.3%, 97.6%, 91.6% and 0.953, respectively. In contrast, CA19-9 and CEA gave sensitivities of 65.6% and 40.0%, specificities of 92.9% and 88.6%, and accuracies of 82.1% and 71.8%, respectively, in the same test cohort. This diagnostic index identified 18/21 operable pancreatic cancers and 38/48 operable biliary-tract cancers in the entire cohort. Our results suggest that the

  14. Mononuclear cell complement receptor blockade in primary biliary cirrhosis.

    PubMed Central

    Al-Aghbar, M N; Neuberger, J; Williams, R; Eddleston, A L

    1985-01-01

    Peripheral blood monocyte and lymphocyte receptors for Fc and C3b fragments were examined in vitro in patients with primary biliary cirrhosis and other chronic liver diseases using sheep red blood cells coated with anti-SRBC IgG1 (to detect Fc receptors) and with anti-SRBC IgM and complement (to detect C3b receptors). The number of C3b receptors detected on 100 monocytes was significantly lower in patients with primary biliary cirrhosis (23.0 +/- 12.0, mean +/- 1 SD) compared with normal controls (57.4 +/- 16.9) and other chronic liver disease (HBsAg negative chronic active hepatitis 62.0 +/- 17.0, alcoholic cirrhosis 50.9 +/- 4.0), while the number of Fc receptors detected on 100 monocytes was not significantly different in all the groups (primary biliary cirrhosis 72.8 +/- 28.6, chronic active hepatitis 74.7 +/- 14.0, alcoholic cirrhosis 58.0 +/- 13.5 and normal controls 69.6 +/- 19.9). When mononuclear cells isolated from normal individuals were pre-incubated with serum from patients with primary biliary cirrhosis before testing their receptor function there was a significant reduction in the number of C3b receptors detected per 100 monocytes (27.6 +/- 10.8) compared with pre-incubation with normal serum (72.0 +/- 18.0). This reduction in C3b-receptor function was again observed when the serum used for pre-incubation was depleted of circulating immune complexes; but when complement was further depleted from these sera, the number of C3b-receptors detected after pre-incubation was similar to normal values (64.0 +/- 11.8). Lymphocyte receptors showed a similar pattern of results. This implies a specific C3b receptor blockade on monocytes and lymphocytes from patients with primary biliary cirrhosis which appears to be because of blocking by serum factor(s) including complement fragments. PMID:3155513

  15. Preoperative Biliary Drainage in Cases of Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Chemotherapy and Surgery

    PubMed Central

    Tsuboi, Tomofumi; Sasaki, Tamito; Serikawa, Masahiro; Ishii, Yasutaka; Mouri, Teruo; Shimizu, Akinori; Kurihara, Keisuke; Tatsukawa, Yumiko; Miyaki, Eisuke; Kawamura, Ryota; Tsushima, Ken; Murakami, Yoshiaki; Uemura, Kenichiro; Chayama, Kazuaki

    2016-01-01

    Objective. To elucidate the optimum preoperative biliary drainage method for patients with pancreatic cancer treated with neoadjuvant chemotherapy (NAC). Material and Methods. From January 2010 through December 2014, 20 patients with borderline resectable pancreatic cancer underwent preoperative biliary drainage and NAC with a plastic or metallic stent and received NAC at Hiroshima University Hospital. We retrospectively analyzed delayed NAC and complication rates due to biliary drainage, effect of stent type on perioperative factors, and hospitalization costs from diagnosis to surgery. Results. There were 11 cases of preoperative biliary drainage with plastic stents and nine metallic stents. The median age was 64.5 years; delayed NAC occurred in 9 cases with plastic stent and 1 case with metallic stent (p = 0.01). The complication rates due to biliary drainage were 0% (0/9) with metallic stents and 72.7% (8/11) with plastic stents (p = 0.01). Cumulative rates of complications determined with the Kaplan-Meier method on day 90 were 60% with plastic stents and 0% with metallic stents (log-rank test, p = 0.012). There were no significant differences between group in perioperative factors or hospitalization costs from diagnosis to surgery. Conclusions. Metallic stent implantation may be effective for preoperative biliary drainage for pancreatic cancer treated with NAC. PMID:26880897

  16. Investigation of Spatial Clustering of Biliary Tract Cancer Incidence in Osaka, Japan: Neighborhood Effect of a Printing Factory

    PubMed Central

    Ito, Yuri; Nakaya, Tomoki; Ioka, Akiko; Nakayama, Tomio; Tsukuma, Hideaki; Uehara, Shinichiro; Kogawa Sato, Kyoko; Endo, Ginji; Hayashi, Tomoshige

    2016-01-01

    Background In 2013, an unusually high incidence of biliary tract cancer among current or former workers of the offset color proof printing department of a printing company in Osaka, Japan, was reported. The purpose of this study was to examine whether distance from the printing factory was associated with incidence of biliary tract cancer and whether incident biliary tract cancer cases clustered around the printing factory in Osaka using population-based cancer registry data. Methods We estimated the age-standardized incidence ratio of biliary tract cancer according to distance from this printing factory. We also searched for clusters of biliary tract cancer incidence using spatial scan statistics. Results We did not observe statistically significantly high or low standardized incidence ratios for residents in each area categorized by distance from the printing factory for the entire sample or for either sex. The scan statistics did not show any statistically significant clustering of biliary tract cancer incidence anywhere in Osaka prefecture in 2004–2007. Conclusions There was no statistically significant clustering of biliary tract cancer incidence around the printing factory or in any other areas in Osaka, Japan, between 2004 and 2007. To date, even if some substances have diffused outside this source factory, they do not appear to have influenced the incidence of biliary tract cancer in neighboring residents. PMID:26902168

  17. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling.

    PubMed

    Kamimoto, Kenji; Kaneko, Kota; Kok, Cindy Yuet-Yin; Okada, Hajime; Miyajima, Atsushi; Itoh, Tohru

    2016-01-01

    Dynamic remodeling of the intrahepatic biliary epithelial tissue plays key roles in liver regeneration, yet the cellular basis for this process remains unclear. We took an unbiased approach based on in vivo clonal labeling and tracking of biliary epithelial cells in the three-dimensional landscape, in combination with mathematical simulation, to understand their mode of proliferation in a mouse liver injury model where the nascent biliary structure formed in a tissue-intrinsic manner. An apparent heterogeneity among biliary epithelial cells was observed: whereas most of the responders that entered the cell cycle upon injury exhibited a limited and tapering growth potential, a select population continued to proliferate, making a major contribution in sustaining the biliary expansion. Our study has highlighted a unique mode of epithelial tissue dynamics, which depends not on a hierarchical system driven by fixated stem cells, but rather, on a stochastically maintained progenitor population with persistent proliferative activity. PMID:27431614

  18. Androgen deprivation therapy for prostate cancer is associated in increased risk for biliary disease

    PubMed Central

    Saylor, Philip J.; Smith, Matthew R.; O'Malley, A. James; Keating, Nancy L.

    2013-01-01

    Background Androgen deprivation therapy (ADT) for prostate cancer produces benefits in several clinical situations but has adverse metabolic effects including obesity, increased abdominal girth, increased triglycerides, and insulin resistance. Each of these is a risk factor for gallstone disease. ADT with a gonadotropin releasing hormone (GnRH) agonist was recently shown in metabolomic analyses to increase plasma levels of some bile acids. We assessed whether ADT is associated with an increased incidence of biliary disease. Methods We studied 249,977 men aged >65 living in Surveillance, Epidemiology, and End Results regions who were diagnosed with prostate cancer during 1992-2007 and followed through 2009. We calculated incidence rates for biliary disease during treatment with GnRH agonists, orchiectomy, or no therapy. We used Cox proportional hazard models to assess the association of ADT with biliary disease. Results Among 185,106 men with local/regional prostate cancer, 47.8% received GnRH agonist treatment and 2.2% underwent bilateral orchiectomy during follow-up. GnRH agonist treatment was associated with significantly higher incidence of biliary disease compared with no treatment (14.46 vs. 12.44 cases per 1,000 person years; P<0.001). In adjusted analyses GnRH agonist use was associated with risk of biliary disease (adjusted hazard ratio=1.09, 95% confidence interval 1.04–1.14; P <0.001). Orchiectomy was not significantly associated with biliary disease. Conclusions GnRH agonist treatment may be associated with an increased risk of incident biliary disease. This potential risk must be weighed against the potential benefits of therapy. PMID:23428068

  19. Incidental biliary cystadenoma mimicking liver metastasis in a gastric cancer patient

    PubMed Central

    Yazıcı, Pınar; Aydın, Ünal

    2016-01-01

    Biliary cystadenoma represents a rare benign cystic hepatic neoplasm with premalignant potential. The diagnosis is usually difficult, and imaging methods may not be possible to clarify the pathology. It can be hard to determine, particularly in patients with a previous cancer history that has high metastatic potential in the liver. We presented a 53-year-old man with a newly diagnosed liver mass that was suspicious for metastasis 2 years after gastric cancer surgery and histological analysis confirmed the diagnosis of biliary cystadenoma. PMID:27528806

  20. Activated hedgehog pathway is a potential target for pharmacological intervention in biliary tract cancer.

    PubMed

    Kiesslich, Tobias; Mayr, Christian; Wachter, Julia; Bach, Doris; Fuereder, Julia; Wagner, Andrej; Alinger, Beate; Pichler, Martin; Di Fazio, Pietro; Ocker, Matthias; Berr, Frieder; Neureiter, Daniel

    2014-11-01

    Hedgehog (Hh) signalling contributes to carcinogenesis and represents a valid druggable target in human cancers, possibly also in biliary tract cancer (BTC). We analysed the expression of Hh components in BTC using eight heterogeneously differentiated cell lines, xenograft tumours and a human tissue microarray. The dose-, time- and cell line-dependent effects of two Hh inhibitors (cyclopamine and Gant-61) were analysed in vitro for survival, apoptosis, cell cycle distribution and possible synergism with conventional chemotherapeutic agents. In human BTC samples, the sonic Hh ligand and the Gli1 transcription factor showed increased expression in tumours compared to normal adjacent tissue and were significantly associated with high tumour grade and positive lymph node status. In BTC cell lines, we could confirm the Hh component expression at varying extent within the employed cell lines in vitro and in vivo indicating non-canonical signalling. Both Hh inhibitors showed dose-dependent cytotoxicity above 5 µM with a stronger effect for Gant-61 inducing apoptosis whereas cyclopamine rather inhibited proliferation. Cytotoxicity was associated with low cytokeratin expression and higher mesenchymal marker expression such as vimentin. Additionally, drug combinations of Gant-61 with conventional chemotherapy (cisplatin) exerted synergistic effects. In conclusion, Hh pathway is significantly activated in human BTC tissue compared to normal adjacent tissue. The current data demonstrate for the first time an effective anticancer activity of especially Gant-61 in BTC and suggest second generation Hh pathway inhibitors as a potential novel treatment strategy in BTC. PMID:25064451

  1. Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer

    PubMed Central

    Zuo, M; Rashid, A; Churi, C; Vauthey, J-N; Chang, P; Li, Y; Hung, M-C; Li, D; Javle, M

    2015-01-01

    Background: Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs). Methods: Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs. Results: Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment. Conclusions: Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy. PMID:25742482

  2. Mutant IDH inhibits HNF4α to block hepatocyte differentiation and promote biliary cancer

    PubMed Central

    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; Straley, Kim; Travins, Jeremy; Popovici-Muller, Janeta; Gliser, Camelia; Ferrone, Cristina R.; Apte, Udayan; Llovet, Josep M.; Wong, Kwok-Kin; Ramaswamy, Sridhar; Bardeesy, Nabeel

    2015-01-01

    Mutations in Isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer1–5. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alpha-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 maturation6–10. 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 HNF4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models (GEMMs) expressing mutant IDH in the adult liver show aberrant response to hepatic injury, characterized by HNF4α silencing, impaired hepatocyte differentiation and markedly elevated levels of cell proliferation. Moreover, mutant IDH and activated Kras, genetic alterations that co-exist in a subset of human IHCCs4,5, 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 GEMM of IDH-driven malignancy. PMID:25043045

  3. Septin 2 accelerates the progression of biliary tract cancer and is negatively regulated by mir-140-5p.

    PubMed

    Yu, Jianhua; Zhang, Weiguang; Tang, Haijun; Qian, Hongwei; Yang, Jianhui; Zhu, Zhiyang; Ren, Peitu; Lu, Baochun

    2016-09-01

    Aberrant expression of septin family members (SEPTs) has been noticed in various carcinomas; however, few studies have been conducted to determine their function in biliary tract cancer (BTC). In this study, we identified SEPT2 as a tumor-promoting gene that is regulated by miR-140-5p in BTC. Although miR-140-5p has been reported to be an anti-oncomiR for several types of cancer, this has not previously been shown for BTC. We found that the expression levels of SEPT2 and miR-140-5p were inversely correlated; SEPT2 was aberrantly upregulated in both primary tumor specimens and cell lines whereas miR-140-5p was significantly downregulated. Ectopic expression of miR-140-5p markedly decreased SEPT2 protein concentration in BTC cells and suppressed cell proliferation and colony formation in vitro. Interaction between miR-140-5p and the 3'UTR of SEPT2 was confirmed by luciferase assays and rescue experiments. Furthermore, overexpression of SEPT2 and low expression of miR-140-5p were associated with increased invasion of BTC as indicated by clinical parameters and confirmed by invasion assays in vitro. Xenografts formation assay also showed that SEPT2 overexpression significantly facilitated the growth of tumor in vivo. This finding may provide a novel therapeutic strategy for the treatment of biliary tract cancer. PMID:27155525

  4. Gemcitabine, Oxaliplatin, Tarceva &/or Cisplatin in HCC & Biliary Tree Cancers

    ClinicalTrials.gov

    2016-03-15

    Hepatocellular Carcinoma; Cholangiocellular Carcinoma; Cholangiocarcinoma of the Extrahepatic Bile Duct; Bile Duct Cancer; Periampullary Adenocarcinoma; Gallbladder Cancer; Extrahepatic Bile Duct Cancer

  5. MicroRNA 141 Expression Is a Potential Prognostic Marker of Biliary Tract Cancers

    PubMed Central

    Kim, Jaihwan; Ryu, Ji Kon; Lee, Sang Hyub; Kim, Yong-Tae

    2016-01-01

    Background/Aims In recent years, a large number of micro-ribonucleic acids (miRNAs) have been identified as putative prognostic biomarkers for solid cancers because of their role in controlling the expression of oncogenes and tumor suppressor genes. The aim of this study was to verify the utility of miRNA 141 as a prognostic biomarker of biliary tract cancers. Methods From June 2010 to June 2012, common bile duct cancer tissue samples and matched noncancerous tissues from the ampulla of Vater were obtained from patients with biliary tract cancer undergoing endoscopic retrograde cholangiopancreatography. Using quantitative real-time polymerase chain reaction assays, we measured the mean relative expression levels of miRNA 141 in both groups of tissues. Overexpression of miRNA 141 was defined as a greater than 2-fold increase in expression levels as determined by the 2−ΔΔCt method. Results In a cohort of 38 patients with biliary tract cancers (seven gallbladder, 13 hilar, and 18 distal bile duct cancers), 26 patients (68.4%) were male, and the median age was 69.5 (52 to 85) years. Nineteen patients (50%) had undergone R0 resection procedures, including three Whipple operations, seven pylorus-preserving pancreaticoduodenectomies, six bile duct resections, and three extended lobectomies. Among the patients who had undergone R0 resection, the overexpression of miRNA 141 was significantly associated with shorter disease-free survival and a greater risk of angiolymphatic invasion. Among the patients who did not undergo R0 resection, miRNA 141 overexpression was significantly associated with reduced overall survival. Conclusions Overexpression of miRNA 141 is an indicator of a poor prognosis in patients with biliary tract cancer, suggesting that miRNA 141 may be a valuable prognostic biomarker of this disease. PMID:27172928

  6. The association between biliary tract inflammation and risk of digestive system cancers

    PubMed Central

    Tsai, Tsung-Yu; Lin, Che-Chen; Peng, Cheng-Yuan; Huang, Wen-Hsin; Su, Wen-Pang; Lai, Shih-Wei; Chen, Hsuan-Ju; Lai, Hsueh-Chou

    2016-01-01

    Abstract The relationship between biliary tract inflammation (BTI) and digestive system cancers is unclear. This study aimed to evaluate the association between BTI and the risks of digestive system cancers. Using the Taiwan National Health Insurance claims data, information on a cohort of patients diagnosed with BTI (n = 4398) between 2000 and 2009 was collected. A comparison cohort of sex-, age-, and index year-matched persons without BTI (n = 17,592) was selected from the same database. The disease was defined by the ICD-9-CM. Both cohorts were followed until the end of 2010 and incidences of digestive system cancers were calculated. The results revealed an increase in adjusted hazard ratio (aHR) of biliary tract cancer (24.45; 95% confidence interval [CI]: 9.20–65.02), primary liver cancer (1.53; 95% CI: 1.07–2.18), and pancreatic cancer (3.10; 95% CI: 1.20–8.03) in patients with both gallbladder and BTI. The aHR of stomach cancer was also found to be increased (2.73; 95% CI: 1.28–5.81) in patients with gallbladder inflammation only. There were no differences in esophageal cancer (aHR: 0.82; 95% CI: 0.23–2.87) and colorectal cancer (aHR: 0.92; 95% CI: 0.59–1.45). The aHR for digestive system cancers increased by 3.66 times (95% CI: 2.50–5.35) and 12.20 times (95% CI: 8.66–17.17) in BTI visits frequency averaged 2 to 4 visits per year and frequency averaged ≥5 visits per year, respectively. Patients with BTI have significantly higher risk of digestive system cancers, particularly biliary tract, pancreatic, and primary liver cancers, compared with those who are without it. PMID:27495065

  7. Biliary tract obstruction secondary to cancer: management guidelines and selected literature review.

    PubMed

    Lokich, J J; Kane, R A; Harrison, D A; McDermott, W V

    1987-06-01

    Malignant biliary tract obstruction (MBTO) due to either primary biliary tract cancer or metastasis to the porta hepatis is a common clinical problem. The most common metastatic tumors causing MBTO in order of frequency are gastric, colon, breast, and lung cancers. Radiographic diagnostic procedures should proceed in a cost-effective sequence from ultrasonography, computerized tomography (CT), percutaneous transhepatic cholangiography (PTHC), and endoscopic retrograde pancreatography with the goal of establishing the site of the biliary tract obstruction. The identification of the site of obstruction could be established by ultrasound 70% to 80%, CT scan 80% to 90%, PTHC 100%, and endoscopic retrograde cholangiography (ERCP) 85%. Therapeutic intervention by radiographic decompression (PTHC or endoscopic prosthesis), surgical bypass, or radiation therapy with or without chemotherapy may be selectively used based on (1) the site of obstruction; (2) the type of primary tumor; and (3) the presence of specific symptoms related to the obstruction. ("Prophylactic" biliary tract decompression to prevent ascending cholangitis is not supported by the literature in that the frequency of sepsis in the face of malignant obstruction is small (in contrast to sepsis associated with stone disease). Furthermore, PTHC with drainage as a long-term procedure is associated with a substantial frequency of sepsis and is unnecessary and possibly problematic as a preoperative procedure simply to reduce the bilirubin level. The use of radiation therapy in conjunction with chemotherapy for patients not deemed suitable for a surgical bypass because of the presence of proximal obstruction is an important alternative to PTHC. PMID:3295131

  8. Predictive Factors of Biliary Tract Cancer in Anomalous Union of the Pancreaticobiliary Duct

    PubMed Central

    Park, Jin-Seok; Song, Tae Jun; Park, Tae Young; Oh, Dongwook; Lee, Hyun Kyo; Park, Do Hyun; Lee, Sang Soo; Seo, Dong Wan; Lee, Sung Koo; Kim, Myung-Hwan

    2016-01-01

    Abstract The assessment of malignancies associated with anomalous union of the pancreaticobiliary duct (AUPBD) is essential for the design of appropriate treatment strategies. The aim of the present study is to measure the incidence of AUPBD-related pancreaticobiliary malignancy and to identify predictive factors. This retrospective cohort study included cases of 229 patients with AUPBD between January 1999 and December 2013. The impact of bile duct dilatation on the incidence of AUPBD-related pancreaticobiliary disease was measured, and predictive factors were evaluated. Among 229 patients with AUPBD, 152 had common bile duct dilatation (≥10 mm) (dilated group) and 77 did not (<10 mm) (nondilated group). Intrahepatic cholangiocarcinoma occurred more frequently in the nondilated group than in the dilated group (3.9% vs 0%; P < 0.05). By contrast, no significant difference in the incidence of extrahepatic cholangiocarcinoma was observed between the 2 groups (1.3% vs 3.9%; P = 0.271). By univariate analysis, age, type of AUPBD, and the level of pancreatic enzymes refluxed in the bile duct were associated with occurrence of biliary tract cancers. In multivariate analysis, age ≥45 years (odds ratio [OR] 1.042, 95% confidence interval [CI] 1.011–1.073, P < 0.05), P-C type (OR 3.327, 95% CI 1.031–10.740, P < 0.05), and a high level of biliary lipase (OR 4.132, 95% CI 1.420–12.021, P < 0.05) showed a significant association with AUPBD-related biliary tract cancer. Intrahepatic cholangiocarcinoma may occur more frequently in AUPBD patients without bile duct dilatation. Age ≥45 years, P-C type, and biliary lipase level ≥45,000 IU/L are significantly associated with AUPBD-related biliary tract cancer. PMID:27196455

  9. Predictive Factors of Biliary Tract Cancer in Anomalous Union of the Pancreaticobiliary Duct.

    PubMed

    Park, Jin-Seok; Song, Tae Jun; Park, Tae Young; Oh, Dongwook; Lee, Hyun Kyo; Park, Do Hyun; Lee, Sang Soo; Seo, Dong Wan; Lee, Sung Koo; Kim, Myung-Hwan

    2016-05-01

    The assessment of malignancies associated with anomalous union of the pancreaticobiliary duct (AUPBD) is essential for the design of appropriate treatment strategies. The aim of the present study is to measure the incidence of AUPBD-related pancreaticobiliary malignancy and to identify predictive factors. This retrospective cohort study included cases of 229 patients with AUPBD between January 1999 and December 2013. The impact of bile duct dilatation on the incidence of AUPBD-related pancreaticobiliary disease was measured, and predictive factors were evaluated.Among 229 patients with AUPBD, 152 had common bile duct dilatation (≥10 mm) (dilated group) and 77 did not (<10 mm) (nondilated group). Intrahepatic cholangiocarcinoma occurred more frequently in the nondilated group than in the dilated group (3.9% vs 0%; P < 0.05). By contrast, no significant difference in the incidence of extrahepatic cholangiocarcinoma was observed between the 2 groups (1.3% vs 3.9%; P = 0.271). By univariate analysis, age, type of AUPBD, and the level of pancreatic enzymes refluxed in the bile duct were associated with occurrence of biliary tract cancers. In multivariate analysis, age ≥45 years (odds ratio [OR] 1.042, 95% confidence interval [CI] 1.011-1.073, P < 0.05), P-C type (OR 3.327, 95% CI 1.031-10.740, P < 0.05), and a high level of biliary lipase (OR 4.132, 95% CI 1.420-12.021, P < 0.05) showed a significant association with AUPBD-related biliary tract cancer.Intrahepatic cholangiocarcinoma may occur more frequently in AUPBD patients without bile duct dilatation. Age ≥45 years, P-C type, and biliary lipase level ≥45,000 IU/L are significantly associated with AUPBD-related biliary tract cancer. PMID:27196455

  10. Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1

    PubMed Central

    Jeffery, Hannah C.; van Wilgenburg, Bonnie; Kurioka, Ayako; Parekh, Krishan; Stirling, Kathryn; Roberts, Sheree; Dutton, Emma E.; Hunter, Stuart; Geh, Daniel; Braitch, Manjit K.; Rajanayagam, Jeremy; Iqbal, Tariq; Pinkney, Thomas; Brown, Rachel; Withers, David R.; Adams, David H.; Klenerman, Paul; Oo, Ye H.

    2016-01-01

    Background & Aims Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells characterised by the invariant TCR-chain, Vα7.2-Jα33, and are restricted by MR1, which presents bacterial vitamin B metabolites. They are important for antibacterial immunity at mucosal sites; however, detailed characteristics of liver-infiltrating MAIT (LI-MAIT) and their role in biliary immune surveillance remain unexplored. Methods The phenotype and intrahepatic localisation of human LI-MAIT cells was examined in diseased and normal livers. MAIT cell activation in response to E. coli-exposed macrophages, biliary epithelial cells (BEC) and liver B cells was assessed with/without anti-MR1. Results Intrahepatic MAIT cells predominantly localised to bile ducts in the portal tracts. Consistent with this distribution, they expressed biliary tropic chemokine receptors CCR6, CXCR6, and integrin αEβ7. LI-MAIT cells were also present in the hepatic sinusoids and possessed tissue-homing chemokine receptor CXCR3 and integrins LFA-1 and VLA-4, suggesting their recruitment via hepatic sinusoids. LI-MAIT cells were enriched in the parenchyma of acute liver failure livers compared to chronic diseased livers. LI-MAIT cells had an activated, effector memory phenotype, expressed α4β7 and receptors for IL-12, IL-18, and IL-23. Importantly, in response to E. coli-exposed macrophages, liver B cells and BEC, MAIT cells upregulated IFN-γ and CD40 Ligand and degranulated in an MR1-dependent, cytokine-independent manner. In addition, diseased liver MAIT cells expressed T-bet and RORγt and the cytokines IFN-γ, TNF-α, and IL-17. Conclusions Our findings provide the first evidence of an immune surveillance effector response for MAIT cells towards BEC in human liver; thus they could be manipulated for treatment of biliary disease in the future. PMID:26743076

  11. Early Gastric Cancer Recurrence Following Curative Resection Presenting as Biliary Tract Dilatation, Pancreatic Duct Dilatation and Intestinal Wall Thickening.

    PubMed

    Kato, Hiroyuki; Ito, Yukiko; Tanaka, Eri; Noguchi, Kensaku; Yamamoto, Shinzo; Taniguchi, Hiroyoshi; Yoshida, Hideo; Kumasaka, Toshio; Nakata, Ryo

    2016-01-01

    Early gastric cancer, especially cancer confined to the mucosa (stage T1a), is known to have a high cure rate with rare recurrence. We herein report the case of a 40-year-old female who initially presented with biliary tract dilatation, pancreatic duct dilatation and intestinal wall thickening 3 years after curative resection of pT1aN0 stage gastric cancer. The intestinal resection specimen revealed tumor cells spreading through the subserosa to the submucosa sparing mucosal membrane, which made exploratory laparotomy the only approach to confirm the diagnosis. It is always important to be aware of malignancy recurrence and clinicians should not hesitate to choose exploratory laparotomy to avoid any delay in the diagnosis and treatment. PMID:27041158

  12. [Human papillomavirus, neonatal giant cell hepatitis and biliary duct atresia].

    PubMed

    Drut, R; Gómez, M A; Drut, R M; Cueto, R E; Lojo, M

    1998-01-01

    We previously recognized the presence of HPV-DNA in cases of idiopathic neonatal giant cell hepatitis (INGCH) and extrahepatic biliary duct atresia (EBDA) in archivated tissue using the PCR technique. In order to investigate a possible vertical transmission we looked for the presence of HPV-DNA in cervical swabs in the mothers along with formalin-fixed paraffin-embedded hepatic tissue from 3 infants with INGCH and 4 patients with EBDA by nested-PCR. Cervical smears showed koilocytosis consistent with HPV infection in 2 cases. Delivery was vaginal except for one that was by cesarean section. All infants were males. Amplification of HPV-DNA was demonstrated in all cases, the types being concordant in infants and mothers. Although this is a small group, the findings appear in line with previous data. The presence of the same type of HPV-DNA in the infants' livers and their mothers' cervical swabs is another argument supporting the possibility of vertical transmission of the virus. PMID:9607071

  13. Phase I clinical trial of multiple-peptide vaccination for patients with advanced biliary tract cancer

    PubMed Central

    2014-01-01

    Background The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and only a few standard treatments are available for this condition. We performed a phase I trial to investigate the safety, immune response and anti-tumor effect of vaccination with three peptides derived from cancer-testis antigens. Methods This study was conducted as a phase I trial. Nine patients with advanced BTC who had unresectable tumors and were refractory to standard chemotherapy were enrolled. Three HLA-A*2402 restricted epitope peptides-cell division cycle associated 1 (CDCA1), cadherin 3 (CDH3) and kinesin family member 20A (KIF20A)-were administered subcutaneously, and the adverse events and immune response were assessed. The clinical effects observed were the tumor response, progression-free survival (PFS) and overall survival (OS). Results The three-peptide vaccination was well-tolerated up to a dose of 3 mg per peptide (9 mg total). No grade 3 or 4 adverse events were observed after vaccination. Peptide-specific T cell immune responses were observed in all patients and stable disease was observed in 5 of 9 patients. The median PFS and OS were 3.4 and 9.7 months. The Grade 2 injection site reaction and continuous vaccination after PD judgment appeared to be prognostic of OS. Conclusions Multiple-peptide vaccination was well tolerated and induced peptide-specific T-cell responses. Trial registration This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR000003229). PMID:24606884

  14. Methylated Bone Morphogenetic Protein 3 (BMP3) Gene: Evaluation of Tumor Suppressor Function and Biomarker Potential in Biliary Cancer

    PubMed Central

    Kisiel, John B; Li, Jia; Zou, Hongzhi; Oseini, Abdul M; Strauss, Benjamin B; Gulaid, Kadra H.; Moser, Catherine D; Aderca, Ileana; Ahlquist, David A; Roberts, Lewis R; Shire, Abdirashid M

    2014-01-01

    Background Although cholangiocarcinoma (CC) is an uncommon and highly lethal malignancy, early detection enables the application of potentially curative therapies and improves survival. Consequently, tools to improve the early diagnosis of CC are urgently needed. During a screen for genes epigenetically suppressed by methylation in CC that might serve as methylation markers for CC, we found that the BMP3 gene is methylated in CC cell lines, but the potential diagnostic value and the function of BMP3 in CC are unknown. Methods We aimed to quantitatively assess BMP3 methylation in resected CC tumor specimens using methylation specific PCR and evaluate the tumor suppressor role of BMP3 in biliary cancer cell lines in comparison to an immortalized normal cholangiocyte cell line. Expression of BMP3 was quantified by mRNA levels before and after treatment with 5-Aza-2’-deoxycytidine and trichostatin A. After transfection with a BMP3-containing plasmid, cell viability was measured using the bromodeoxyuridine incorporation assay and apoptosis quantified by caspase assay. Results In primary CC tumor tissue specimens significantly more methylated BMP3 copies were found when compared to matched benign bile duct epithelium from the same patient, with high specificity. BMP3 expression was absent in cell lines with BMP3 methylation; this suppression of BMP3 expression was reversed by treatment with a DNA demethylating agent and histone de-acetylase inhibitor. Transfection of a BMP3-expressing construct into a BMP3-negative biliary cancer cell line restored BMP3 mRNA expression and reduced cell proliferation and cell viability while increasing the rate of apoptosis. Conclusion These findings strongly support a tumor suppressor role for BMP3 in CC and suggest that BMP3 methylation may be a new biomarker for early detection of CCs. of the peptidome are also involved. PMID:25077038

  15. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling

    PubMed Central

    Kamimoto, Kenji; Kaneko, Kota; Kok, Cindy Yuet-Yin; Okada, Hajime; Miyajima, Atsushi; Itoh, Tohru

    2016-01-01

    Dynamic remodeling of the intrahepatic biliary epithelial tissue plays key roles in liver regeneration, yet the cellular basis for this process remains unclear. We took an unbiased approach based on in vivo clonal labeling and tracking of biliary epithelial cells in the three-dimensional landscape, in combination with mathematical simulation, to understand their mode of proliferation in a mouse liver injury model where the nascent biliary structure formed in a tissue-intrinsic manner. An apparent heterogeneity among biliary epithelial cells was observed: whereas most of the responders that entered the cell cycle upon injury exhibited a limited and tapering growth potential, a select population continued to proliferate, making a major contribution in sustaining the biliary expansion. Our study has highlighted a unique mode of epithelial tissue dynamics, which depends not on a hierarchical system driven by fixated stem cells, but rather, on a stochastically maintained progenitor population with persistent proliferative activity. DOI: http://dx.doi.org/10.7554/eLife.15034.001 PMID:27431614

  16. Notch Signaling Coordinates Progenitor Cell-Mediated Biliary Regeneration Following Partial Hepatectomy

    PubMed Central

    Lu, Jie; Zhou, Yingqun; Hu, Tianyuan; Zhang, Hui; Shen, Miao; Cheng, Ping; Dai, Weiqi; Wang, Fan; Chen, Kan; Zhang, Yan; Wang, Chengfeng; Li, Jingjing; Zheng, Yuanyuan; Yang, Jing; Zhu, Rong; Wang, Jianrong; Lu, Wenxia; Zhang, Huawei; Wang, Junshan; Xia, Yujing; De Assuncao, Thiago M.; Jalan-Sakrikar, Nidhi; Huebert, Robert C.; Bin Zhou; Guo, Chuanyong

    2016-01-01

    Aberrant transcriptional regulation contributes to the pathogenesis of both congenital and adult forms of liver disease. Although the transcription factor RBPJ is essential for liver morphogenesis and biliary development, its specific function in the differentiation of hepatic progenitor cells (HPC) has not been investigated, and little is known about its role in adult liver regeneration. HPCs are bipotent liver stem cells that can self-replicate and differentiate into hepatocytes or cholangiocytes in vitro. HPCs are thought to play an important role in liver regeneration and repair responses. While the coordinated repopulation of both hepatocyte and cholangiocyte compartment is pivotal to the structure and function of the liver after regeneration, the mechanisms coordinating biliary regeneration remain vastly understudied. Here, we utilized complex genetic manipulations to drive liver-specific deletion of the Rbpj gene in conjunction with lineage tracing techniques to delineate the precise functions of RBPJ during biliary development and HPC-associated biliary regeneration after hepatectomy. Furthermore, we demonstrate that RBPJ promotes HPC differentiation toward cholangiocytes in vitro and blocks hepatocyte differentiation through mechanisms involving Hippo-Notch crosstalk. Overall, this study demonstrates that the Notch-RBPJ signaling axis critically regulates biliary regeneration by coordinating the fate decision of HPC and clarifies the molecular mechanisms involved. PMID:26951801

  17. Biliary intraepithelial neoplasia (BilIN) is frequently found in surgical margins of biliary tract cancer resection specimens but has no clinical implications.

    PubMed

    Matthaei, Hanno; Lingohr, Philipp; Strässer, Anke; Dietrich, Dimo; Rostamzadeh, Babak; Glees, Simone; Roering, Martin; Möhring, Pauline; Scheerbaum, Martin; Stoffels, Burkhard; Kalff, Jörg C; Schäfer, Nico; Kristiansen, Glen

    2015-02-01

    Biliary tract cancers are aggressive tumors of which the incidence seems to increase. Resection with cancer-free margins is crucial for curative therapy. However, how often biliary intraepithelial neoplasia (BilIN) occurs in resection margins and what its clinical and therapeutic implications might be is largely unknown. We reexamined margins of resection specimens of adenocarcinoma of the biliary tree including the gallbladder for the presence of BilIN. When present, it was graded. The findings were correlated with clinicopathological parameters and overall survival. Complete examination of the resection margin could be performed on 55 of 78 specimens (71%). BilIN was detected in the margin in 29 specimens (53%) and was mainly low-grade (BilIN-1; N = 14 of 29; 48%). In resection specimens of extrahepatic cholangiocarcinoma, BilIN was most frequent (N = 6 of 8; 75%). BilIN was found in the resection margin more frequently in extrahepatic cholangiocarcinomas (P = 0.007) and in large primary tumors (P = 0.001) with lymphovascular (P = 0.006) and perineural invasion (P = 0.049). Patients with cancer in the resection margin (R1) had a significantly shorter overall survival than those with resection margins free of tumor (R0) irrespective of the presence of BilIN (R0 vs R1; P < 0.001) or BilIN grade (BilIN-positive vs BilIN-negative, P = 0.6, and BilIN-1 + 2 vs BilIN-3, P = 0.58). BilIN is frequently found in the surgical margin of resection specimens of adenocarcinoma of the biliary tract. Hepatopancreatobiliary surgeons will be confronted with this recently defined entity when an intraoperative frozen section of a resection margin is requested. However, this diagnosis does not require additional resection and in the intraoperative evaluation of resection, the emphasis should remain on the detection of residual invasive tumor. PMID:25425476

  18. Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration

    PubMed Central

    Carpino, Guido; Renzi, Anastasia; Franchitto, Antonio; Cardinale, Vincenzo; Onori, Paolo; Reid, Lola; Alvaro, Domenico; Gaudio, Eugenio

    2016-01-01

    Niches containing stem/progenitor cells are present in different anatomical locations along the human biliary tree and within liver acini. The most primitive stem/progenitors, biliary tree stem/progenitor cells (BTSCs), reside within peribiliary glands located throughout large extrahepatic and intrahepatic bile ducts. BTSCs are multipotent and can differentiate towards hepatic and pancreatic cell fates. These niches' matrix chemistry and other characteristics are undefined. Canals of Hering (bile ductules) are found periportally and contain hepatic stem/progenitor cells (HpSCs), participating in the renewal of small intrahepatic bile ducts and being precursors to hepatocytes and cholangiocytes. The niches also contain precursors to hepatic stellate cells and endothelia, macrophages, and have a matrix chemistry rich in hyaluronans, minimally sulfated proteoglycans, fetal collagens, and laminin. The microenvironment furnishes key signals driving HpSC activation and differentiation. Newly discovered third niches are pericentral within hepatic acini, contain Axin2+ unipotent hepatocytic progenitors linked on their lateral borders to endothelia forming the central vein, and contribute to normal turnover of mature hepatocytes. Their relationship to the other stem/progenitors is undefined. Stem/progenitor niches have important implications in regenerative medicine for the liver and biliary tree and in pathogenic processes leading to diseases of these tissues. PMID:26880956

  19. The association between biliary tract inflammation and risk of digestive system cancers: A population-based cohort study.

    PubMed

    Tsai, Tsung-Yu; Lin, Che-Chen; Peng, Cheng-Yuan; Huang, Wen-Hsin; Su, Wen-Pang; Lai, Shih-Wei; Chen, Hsuan-Ju; Lai, Hsueh-Chou

    2016-08-01

    The relationship between biliary tract inflammation (BTI) and digestive system cancers is unclear. This study aimed to evaluate the association between BTI and the risks of digestive system cancers.Using the Taiwan National Health Insurance claims data, information on a cohort of patients diagnosed with BTI (n = 4398) between 2000 and 2009 was collected. A comparison cohort of sex-, age-, and index year-matched persons without BTI (n = 17,592) was selected from the same database. The disease was defined by the ICD-9-CM. Both cohorts were followed until the end of 2010 and incidences of digestive system cancers were calculated.The results revealed an increase in adjusted hazard ratio (aHR) of biliary tract cancer (24.45; 95% confidence interval [CI]: 9.20-65.02), primary liver cancer (1.53; 95% CI: 1.07-2.18), and pancreatic cancer (3.10; 95% CI: 1.20-8.03) in patients with both gallbladder and BTI. The aHR of stomach cancer was also found to be increased (2.73; 95% CI: 1.28-5.81) in patients with gallbladder inflammation only. There were no differences in esophageal cancer (aHR: 0.82; 95% CI: 0.23-2.87) and colorectal cancer (aHR: 0.92; 95% CI: 0.59-1.45). The aHR for digestive system cancers increased by 3.66 times (95% CI: 2.50-5.35) and 12.20 times (95% CI: 8.66-17.17) in BTI visits frequency averaged 2 to 4 visits per year and frequency averaged ≥5 visits per year, respectively.Patients with BTI have significantly higher risk of digestive system cancers, particularly biliary tract, pancreatic, and primary liver cancers, compared with those who are without it. PMID:27495065

  20. Pharmacokinetic Study of Adjuvant Gemcitabine Therapy for Biliary Tract Cancer following Major Hepatectomy (KHBO1101)

    PubMed Central

    Fujiwara, Yutaka; Kobayashi, Shogo; Nagano, Hiroaki; Kanai, Masashi; Hatano, Etsuo; Toyoda, Masanori; Ajiki, Tetsuo; Takashima, Yuki; Yoshimura, Kenichi; Hamada, Akinobu; Minami, Hironobu; Ioka, Tatsuya

    2015-01-01

    Background Biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy cannot tolerate the standard gemcitabine regimen (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks) due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy for biliary tract cancer following major hepatectomy determined that the recommended dose is 1,000 mg/m2 on days 1 and 15 every 4 weeks. Here, we evaluate the pharmacokinetics and pharmacodynamics of gemcitabine in these subjects. Methods We evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by gemcitabine therapy. A pharmacokinetic evaluation of gemcitabine and its main metabolite, 2′,2′-difluorodeoxyuridine (dFdU), was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800–1,000 mg/m2. Physical examination and adverse events were monitored for 12 weeks. Results Thirteen patients were enrolled from August 2011 to January 2013, with 12 ultimately completing the pharmacokinetic study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had superficial spreading type cholangiocarcinoma. The median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43–83 days). We observed the following toxicities: neutropenia (n = 11, 91.7%), leukopenia (n = 10, 83.3%), thrombocytopenia (n = 6, 50.0%), and infection (n = 5, 41.7%). Grade 3 or 4 neutropenia was observed in 25% (n = 3) of patients. There were differences in clearance of gemcitabine and dFdU between our subjects and the subjects who had not undergone hepatectomy. Conclusion Major hepatectomy did not affect the pharmacokinetics of gemcitabine or dFdU. Trial Registration UMIN-CTR in (JPRN) UMIN000005109 PMID:26633034

  1. Novel management of acute or secondary biliary liver conditions using hepatically differentiated human dental pulp cells.

    PubMed

    Ishkitiev, Nikolay; Yaegaki, Ken; Imai, Toshio; Tanaka, Tomoko; Fushimi, Naho; Mitev, Vanyo; Okada, Mio; Tominaga, Noriko; Ono, Sachie; Ishikawa, Hiroshi

    2015-02-01

    The current definitive treatment for acute or chronic liver condition, that is, cirrhosis, is liver transplantation from a limited number of donors, which might cause complications after donation. Hence, bone marrow stem cell transplantation has been developed, but the risk of carcinogenesis remains. We have recently developed a protocol for hepatic differentiation of CD117(+) stem cells from human exfoliated deciduous teeth (SHED). In the present study, we examine whether SHED hepatically differentiated (hd) in vitro could be used to treat acute liver injury (ALI) and secondary biliary cirrhosis. The CD117(+) cell fraction was magnetically separated from SHED and then differentiated into hepatocyte-like cells in vitro. The cells were transplanted into rats with either ALI or induced secondary biliary cirrhosis. Engraftment of human liver cells was determined immunohistochemically and by in situ hybridization. Recovery of liver function was examined by means of histochemical and serological tests. Livers of transplanted animals were strongly positive for human immunohistochemical factors, and in situ hybridization confirmed engraftment of human hepatocytes. The tests for recovery of liver function confirmed the presence of human hepatic markers in the animals' blood serum and lack of fibrosis and functional integration of transplanted human cells into livers. No evidence of malignancy was found. We show that in vitro hdSHED engraft morphologically and functionally into the livers of rats having acute injury or secondary biliary cirrhosis. SHED are readily accessible adult stem cells, capable of proliferating in large numbers before differentiating in vitro. This makes SHED an appropriate and safe stem cell source for regenerative medicine. PMID:25234861

  2. Triple bypass for advanced pancreatic head cancer associated with biliary stricture, duodenal stenosis, and recurrent obstructive pancreatitis.

    PubMed

    Kudo, Yuzan; Sato, Norihiro; Tamura, Toshihisa; Hirata, Keiji

    2016-12-01

    Bypass surgery for cancer of the pancreatic head is usually done to palliate the obstructive symptoms in the biliary and/or digestive system. However, it is uncommon for patients to require pancreatic duct drainage for recurrent obstructive pancreatitis. In this article, we report a surgical technique of triple bypass consisting of Roux-en-Y hepaticojejunostomy, gastrojejunostomy, and pancreaticojejunostomy for advanced pancreatic cancer. A 76-year-old male patient with locally advanced and metastatic pancreatic head cancer was referred to our department for biliary stricture, duodenal stenosis, and recurrent obstructive pancreatitis associated with persistent pancreatic pseudocyst. In an attempt to resolve all these problems simultaneously, a triple bypass was performed. The patient survived and continued to receive chemotherapy for almost 1 year after surgery without any serious complications. Thus, triple bypass is a useful surgical technique that could relief symptoms and offer better quality of life to patients with advanced pancreatic cancer presenting with biliary stricture, duodenal stenosis, and severe obstructive pancreatitis difficult to treat by medication or endoscopic procedures. PMID:27495991

  3. Lung cancer - small cell

    MedlinePlus

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC ...

  4. Lung cancer - small cell

    MedlinePlus

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC are ...

  5. Diagnosis of Cancer Spread Using Percutaneous Transhepatic Biliary Cholangioscopy-guided Ultrasonography for Malignant Bile Duct Stenosis

    PubMed Central

    2001-01-01

    The characteristics of sites of intramural cancer spread were examined by comparing the intraductal ultrasonography (IDUS) and wall thickening findings at sites of intramural cancer spread and non-spread, in patients with malignant bile duct stenosis who had undergone percutaneous transhepatic biliary drainage (PTBD). The subjects were ten patients with extrahepatic bile duct cancer, two with pancreatic cancer, one with cancer of the gallbladder, and one with cancer of the papilla of Vater who underwent preoperative IDUS. From these patients, 50 IDUS slices were examined with a congruent relationship with the histologic section of resected tissue. The maximum thickening, minimum thickening, maximum/minimum thickening ratio, and form factor of the medial and lateral margins of the medial hypoechoic layer were determined using diagnostic imaging, and the results were compared at sites of cancer spread and non-spread. Twelve slices were obtained from the site of stenosis, 14 from sites of cancer spread, and 24 from non-spread sites. The maximum thickening, minimum thickening, and maximum/minimum thickening ratio differed significantly between the sites of spread and the non-spread. The absolute values for wall thickening are useful for diagnosing the presence of intramural spread in patients with malignant biliary duct stenosis. PMID:18493560

  6. SHOTGUN PROTEOMICS: IDENTIFICATION OF UNIQUE PROTEIN PROFILES OF APOPTOTIC BODIES FROM BILIARY EPITHELIAL CELLS

    PubMed Central

    Lleo, Ana; Zhang, Weici; McDonald, W. Hayes; Seeley, Erin H.; Leung, Patrick S.C.; Coppel, Ross L.; Ansari, Aftab A.; Adams, David H.; Afford, Simon; Invernizzi, Pietro; Gershwin, M. Eric

    2014-01-01

    Shotgun proteomics is a powerful analytic method to characterize complex protein mixtures in combination with multi-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS). We have used this platform for proteomic characterization of apoptotic bodies in efforts to define the complex protein mixtures found in primary cultures of human intrahepatic biliary epithelial cells (HiBEC), human renal proximal tubular epithelial cells, human bronchial epithelial cells, isolated intrahepatic biliary epithelial cells from explanted primary biliary cirrhosis (PBC) and control liver, using a total of 24 individual samples. Further, as additional controls and for purposes of comparison, proteomic signatures were also obtained from intact cells and apoptotic bodies. The data obtained from LC-MS/MS, combined with database searches and protein assembly algorithms, allowed us to address significant differences in protein spectral counts and identify unique pathways that may be a component to the induction of the signature inflammatory cytokine response against BECs, including the Notch signaling pathway, IL8, IL6, CXCR2 and integrin signaling. Indeed there are 11 proteins that localize specifically to apoptotic bodies of HiBEC and 8 proteins that were specifically absent in HiBEC apoptotic bodies. In conclusion, proteomic analysis of BECs from PBC liver compared to normal liver are significantly different, suggesting that an immunological attack affects the repertoire of proteins expressed and that such cells should be thought of as living in an environment undergoing continuous selection secondary to an innate and adaptive immune response, reflecting an almost “Darwinian” bias. PMID:24841946

  7. A meta-analysis of gemcitabine biomarkers in patients with pancreatico-biliary cancers

    PubMed Central

    Wei, Christina H.; Gorgan, Tristan R.; Elashoff, David A.; Hines, O. Joe; Farrell, James J.; Donahue, Timothy R.

    2013-01-01

    Objectives To summarize all clinical studies evaluating the prognostic role of gemcitabine metabolic genes in pancreatico-biliary (PB) cancer patients receiving gemcitabine (GEM) therapy in the neoadjuvant, adjuvant or palliative settings. Methods Meta-analyses were performed to calculate the pooled hazard rations (HRs) for each gene by each clinical outcome (overall, disease free, and progression free survivals) using a random-effects approach. Results The search strategy identified 16 eligible studies, comprised of 632 PB patients total, with moderate quality. Compared to low expression, pooled hazards ratios for OS of hENT1, dCK, RRM1, RRM2, and DPD were 0.37 (95%CI, 0.28–0.47), 0.40 (95%CI, 0.20-0.80), 2.21 (95%CI, 1.12-4.36), 2.13 (95%CI, 1.00-4.52), and 1.91 (95%CI, 1.16-3.17), respectively. A similar trend was observed for each of these biomarkers in DFS and PFS prognostication. Subgroup analyses for hENT1 showed a comparable survival correlation in the adjuvant and palliative settings. Conclusions High expression of hENT1 in PB cancer patients receiving GEM-based adjuvant therapy is associated with improved OS and DFS and may be the best examined prognostic marker to date. Evidence for other biomarkers is limited by a small number of publications investigating these markers. PMID:24152955

  8. Efficacy and safety of gemcitabine-based chemotherapies in biliary tract cancer: A meta-analysis

    PubMed Central

    Liu, Heng; Zhang, Qi-Di; Li, Zheng-Hong; Zhang, Qing-Qing; Lu, Lun-Gen

    2014-01-01

    AIM: To investigate the efficacy and safety of gemcitabine (Gem)-based combination chemotherapies for the treatment of advanced biliary tract cancer. METHODS: Clinical trials were identified by searching scientific literature databases (PubMed, EMBASE and the Cochrane Library) for studies published between 1975 and 2013. Two reviewers independently evaluated the relevant studies and manually searched references from these reports to locate additional eligible studies. The disease response and control rates, progression-free and overall survivals, and the grade 3-4 toxicities were evaluated by a meta-analysis. Odds-ratios (ORs) of the disease response and control rates and grade 3-4 toxicities, and the mean difference (MD) of both progression-free and overall survivals were calculated and used for statistical analysis. RESULTS: Seven randomized trials with a total of 858 patients were selected and included in the final analysis. The studies were divided into subgroups based on the chemotherapy regimens, including Gem-based and non-Gem-based chemotherapies. The overall analyses revealed that the patients treated with Gem-based combination chemotherapy had significantly higher disease response rates [OR = 1.69, 95% confidence interval (CI): 1.17-2.43; P = 0.01], a longer progression-free survival (MD = 1.95, 95%CI: 0.90-3.00; P = 0.00) and a longer overall survival (MD = 1.85, 95%CI: 0.26-3.44; P = 0.02). A higher incidence of grade 3-4 hematological toxicities, including leukopenia (OR = 2.98, 95%CI: 1.44-6.20; P = 0.00), anemia (OR = 2.96, 95%CI: 1.79-4.92; P = 0.00) and neutropenia (OR = 2.80, 95%CI: 1.39-5.64; P = 0.00) was found in the Gem-based combination chemotherapy group compared with the Gem monotherapy and non-Gem-based chemotherapy groups. CONCLUSION: Gem-based combination chemotherapy is a potential first-line treatment for advanced biliary tract cancer as a result of improved survival, though with additional toxicity. PMID:25548500

  9. Immunohistochemical analyses of cell cycle progression and gene expression of biliary epithelial cells during liver regeneration after partial hepatectomy of the mouse

    PubMed Central

    Fukuda, Tatsuya; Fukuchi, Tomokazu; Yagi, Shinomi; Shiojiri, Nobuyoshi

    2015-01-01

    The liver has a remarkable regeneration capacity, and, after surgical removal of its mass, the remaining tissue undergoes rapid regeneration through compensatory growth of its constituent cells. Although hepatocytes synchronously proliferate under the control of various signaling molecules from neighboring cells, there have been few detailed analyses on how biliary cells regenerate for their cell population after liver resection. The present study was undertaken to clarify how biliary cells regenerate after partial hepatectomy of mice through extensive analyses of their cell cycle progression and gene expression using immunohistochemical and RT-PCR techniques. When expression of PCNA, Ki67 antigen, topoisomerase IIα and phosphorylated histone H3, which are cell cycle markers, was immunohistochemically examined during liver regeneration, hepatocytes had a peak of the S phase and M phase at 48–72 h after resection. By contrast, biliary epithelial cells had much lower proliferative activity than that of hepatocytes, and their peak of the S phase was delayed. Mitotic figures were rarely detectable in biliary cells. RT-PCR analyses of gene expression of biliary markers such as Spp1 (osteopontin), Epcam and Hnf1b demonstrated that they were upregulated during liver regeneration. Periportal hepatocytes expressed some of biliary markers, including Spp1 mRNA and protein. Some periportal hepatocytes had downregulated expression of HNF4α and HNF1α. Gene expression of Notch signaling molecules responsible for cell fate decision of hepatoblasts to biliary cells during development was upregulated during liver regeneration. Notch signaling may be involved in biliary regeneration. PMID:26633692

  10. Squamous cell skin cancer

    MedlinePlus

    ... cell; NMSC - squamous cell; Squamous cell skin cancer; Squamous cell carcinoma of the skin ... squamous cell cancer is called Bowen disease (or squamous cell carcinoma in situ). This type does not spread to ...

  11. Transcatheter arterial chemoembolization with gemcitabine and oxaliplatin for the treatment of advanced biliary tract cancer

    PubMed Central

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

    2015-01-01

    Background The aim of this study was to determine the therapeutic efficacy and safety of transarterial chemoembolization (TACE) with gemcitabine and oxaliplatin in patients with advanced biliary tract cancer (BTC). Methods We retrospectively analyzed the outcomes for 65 patients with advanced BTC treated by TACE with gemcitabine 1,000 mg/m2 and oxaliplatin 100 mg/m2. Follow-up laboratory tests and computed tomography or magnetic resonance imaging were performed routinely to evaluate the response of the tumor to treatment. All patients were assessed for adverse effects. Results Of the 65 patients, 19 (29.2%) achieved a partial response, 36 (55.4%) showed stable disease, and ten (15.4%) showed progressive disease. The overall response rate was 29.2%. At the end of this study, five patients were still alive. The median overall survival was 12.0 months (95% confidence interval 8.5–15.5). There were no serious complications after TACE. Conclusion The disease control rate and overall survival in this retrospective study were consistent with those in previous reports. TACE with gemcitabine and oxaliplatin was well tolerated and highly effective in patients with advanced BTC. PMID:25792843

  12. Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice

    PubMed Central

    Firrincieli, Delphine; Zúñiga, Silvia; Rey, Colette; Wendum, Dominique; Lasnier, Elisabeth; Rainteau, Dominique; Braescu, Thomas; Falguières, Thomas; Boissan, Mathieu; Cadoret, Axelle; Housset, Chantal; Chignard, Nicolas

    2013-01-01

    Alterations in apical junctional complexes (AJCs) have been reported in genetic or acquired biliary diseases. The vitamin D nuclear receptor (VDR), predominantly expressed in biliary epithelial cells in the liver, has been shown to regulate AJCs. The aim of our study was thus to investigate the role of VDR in the maintenance of bile duct integrity in mice challenged with biliary-type liver injury. Vdr−/− mice subjected to bile duct ligation (BDL) displayed increased liver damage compared to wildtype BDL mice. Adaptation to cholestasis, ascertained by expression of genes involved in bile acid metabolism and tissue repair, was limited in Vdr−/− BDL mice. Furthermore, evaluation of Vdr−/− BDL mouse liver tissue sections indicated altered E-cadherin staining associated with increased bile duct rupture. Total liver protein analysis revealed that a truncated form of E-cadherin was present in higher amounts in Vdr−/− mice subjected to BDL compared to wildtype BDL mice. Truncated E-cadherin was also associated with loss of cell adhesion in biliary epithelial cells silenced for VDR. In these cells, E-cadherin cleavage occurred together with calpain 1 activation and was prevented by the silencing of calpain 1. Furthermore, VDR deficiency led to the activation of the epidermal growth factor receptor (EGFR) pathway, while EGFR activation by EGF induced both calpain 1 activation and E-cadherin cleavage in these cells. Finally, truncation of E-cadherin was blunted when EGFR signaling was inhibited in VDR-silenced cells. Conclusion: Biliary-type liver injury is exacerbated in Vdr−/− mice by limited adaptive response and increased bile duct rupture. These results indicate that loss of VDR restricts the adaptation to cholestasis and diminishes bile duct integrity in the setting of biliary-type liver injury. (Hepatology 2013;58:1401–1412) PMID:23696511

  13. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer

    PubMed Central

    Aleksandrova, Krasimira; Boeing, Heiner; Nöthlings, Ute; Jenab, Mazda; Fedirko, Veronika; Kaaks, Rudolf; Lukanova, Annekatrin; Trichopoulou, Antonia; Trichopoulos, Dimitrios; Boffetta, Paolo; Trepo, Elisabeth; Westhpal, Sabine; Duarte-Salles, Talita; Stepien, Magdalena; Overvad, Kim; Tjønneland, Anne; Halkjær, Jytte; Boutron-Ruault, Marie-Christine; Dossus, Laure; Racine, Antoine; Lagiou, Pagona; Bamia, Christina; Benetou, Vassiliki; Agnoli, Claudia; Palli, Domenico; Panico, Salvatore; Tumino, Rosario; Vineis, Paolo; Bueno-de-Mesquita, Bas; Peeters, Petra H; Gram, Inger Torhild; Lund, Eiliv; Weiderpass, Elisabete; Quirós, J Ramón; Agudo, Antonio; Sánchez, María-José; Gavrila, Diana; Barricarte, Aurelio; Dorronsoro, Miren; Ohlsson, Bodil; Lindkvist, Björn; Johansson, Anders; Sund, Malin; Khaw, Kay-Tee; Wareham, Nicholas; Travis, Ruth C; Riboli, Elio; Pischon, Tobias

    2014-01-01

    Obesity and associated metabolic disorders have been implicated in liver carcinogenesis; however, there are little data on the role of obesity-related biomarkers on liver cancer risk. We studied prospectively the association of inflammatory and metabolic biomarkers with risks of hepatocellular carcinoma (HCC), intrahepatic bile duct (IBD), and gallbladder and biliary tract cancers outside of the liver (GBTC) in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Over an average of 7.7 years, 296 participants developed HCC (n = 125), GBTC (n = 137), or IBD (n = 34). Using risk-set sampling, controls were selected in a 2:1 ratio and matched for recruitment center, age, sex, fasting status, and time of blood collection. Baseline serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), C-peptide, total high-molecular-weight (HMW) adiponectin, leptin, fetuin-a, and glutamatdehydrogenase (GLDH) were measured, and incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for lifestyle factors, diabetes, hepatitis infection, and adiposity measures, higher concentrations of CRP, IL-6, C-peptide, and non-HMW adiponectin were associated with higher risk of HCC (IRR per doubling of concentrations = 1.22; 95% CI = 1.02-1.46; P = 0.03; 1.90; 95% CI = 1.30-2.77; P = 0.001; 2.25; 95% CI = 1.43-3.54; P = 0.0005; and 2.09; 95% CI = 1.19-3.67; P = 0.01, respectively). CRP was associated also with risk of GBTC (IRR = 1.22; 95% CI = 1.05-1.42; P = 0.01). GLDH was associated with risks of HCC (IRR = 1.62; 95% CI = 1.25-2.11; P = 0.0003) and IBD (IRR = 10.5; 95% CI = 2.20-50.90; P = 0.003). The continuous net reclassification index was 0.63 for CRP, IL-6, C-peptide, and non-HMW adiponectin and 0.46 for GLDH, indicating good predictive ability of these biomarkers. Conclusion: Elevated levels of

  14. Limited Role for Biliary Stent as Surrogate Fiducial Marker in Pancreatic Cancer: Stent and Intratumoral Fiducials Compared

    SciTech Connect

    Horst, Astrid van der; Lens, Eelco; Wognum, Silvia; Jong, Rianne de; Hooft, Jeanin E. van; Tienhoven, Geertjan van; Bel, Arjan

    2014-07-01

    Purpose: Because of low soft-tissue contrast of cone beam computed tomography (CBCT), fiducial markers are often used for radiation therapy patient setup verification. For pancreatic cancer patients, biliary stents have been suggested as surrogate fiducials. Using intratumoral fiducials as standard for tumor position, this study aims to quantify the suitability of biliary stents for measuring interfractional and respiratory-induced position variations of pancreatic tumors. Methods and Materials: Eleven pancreatic cancer patients with intratumoral fiducials and a biliary stent were included in this study. Daily CBCT scans (243 in total) were registered with a reference CT scan, based on bony anatomy, on fiducial markers, and on the biliary stent, respectively. We analyzed the differences in tumor position (ie, markers center-of-mass position) among these 3 registrations. In addition, we measured for 9 patients the magnitude of respiratory-induced motion (MM) of the markers and of the stent on 4-dimensional CT (4DCT) and determined the difference between these 2 magnitudes (ΔMM). Results: The stent indicated tumor position better than bony anatomy in 67% of fractions; the absolute difference between the markers and stent registration was >5 mm in 46% of fractions and >10 mm in 20% of fractions. Large PTV margins (superior-inferior direction, >19 mm) would be needed to account for this interfractional position variability. On 4DCT, we found in superior-inferior direction a mean ΔMM of 0.5 mm (range, –2.6 to 4.2 mm). Conclusions: For respiratory-induced motion, the mean ΔMM is small, but for individual patients the absolute difference can be >4 mm. For interfractional position variations, a stent is, on average, a better surrogate fiducial than bony anatomy, but large PTV margins would still be required. Therefore, intratumoral fiducials are recommended for online setup verification for all pancreatic patients scheduled for radiation therapy, including

  15. Cisplatin/gemcitabine or oxaliplatin/gemcitabine in the treatment of advanced biliary tract cancer: a systematic review

    PubMed Central

    Fiteni, Frédéric; Nguyen, Thierry; Vernerey, Dewi; Paillard, Marie-Justine; Kim, Stefano; Demarchi, Martin; Fein, Francine; Borg, Christophe; Bonnetain, Franck; Pivot, Xavier

    2014-01-01

    Cisplatin/gemcitabine association has been a standard of care for first-line regimen in advanced biliary tract cancer nevertheless oxaliplatin/gemcitabine regimen is frequently preferred. Because comparative effectiveness in clinical outcomes of cisplatin- versus oxaliplatin-containing chemotherapy is not available, a systematic review of studies assessing cisplatin/gemcitabine or oxaliplatin/gemcitabine chemotherapies in advanced biliary tract cancer was performed. Published studies evaluating cisplatin/gemcitabine or oxaliplatin/gemcitabine in advanced biliary tract cancer were included. Each study was weighted according to the number of patients included. The primary objective was to assess weighted median of medians overall survival (mOS) reported for both regimens. Secondary goals were to assess weighted median of medians progression-free survival (mPFS) and toxic effects were pooled and compared within each arm. Thirty-three studies involving 1470 patients were analyzed. In total, 771 and 699 patients were treated by cisplatin/gemcitabine and oxaliplatin/gemcitabine, respectively. Weighted median of mOS was 9.7 months in cisplatin group and 9.5 months in oxaliplatin group. Cisplatin-based chemotherapy was significantly associated with more grade 3 and 4 asthenia, diarrhea, liver toxicity, and hematological toxicity. Sensitivity analysis including only the studies with the standard regimen of cisplatin (25–35 mg/m2 administered on days 1 and 8) showed that the weighted median of mOS increased from 9.7 to 11.7 months but Gem/CDDP regimen remained more toxic than Gemox regimen. These results suggest that the Gem/CDDP regimen with cisplatin (25–35 mg/m2) administered on days 1 and 8 is associated with survival advantage than Gemox regimen but with addition of toxicity. PMID:25111859

  16. Gemcitabine Plus Cisplatin for Advanced Biliary Tract Cancer: A Systematic Review

    PubMed Central

    Park, Joon Oh; Oh, Do-Youn; Hsu, Chiun; Chen, Jen-Shi; Chen, Li-Tzong; Orlando, Mauro; Kim, Jong Seok; Lim, Ho Yeong

    2015-01-01

    Evidence suggests that combined gemcitabine-cisplatin chemotherapy extends survival in patients with advanced biliary tract cancer (BTC). We conducted a systematic review in order to collate this evidence and assess whether gemcitabine-cisplatin efficacy is influenced by primary tumor site, disease stage, or geographic region, and whether associated toxicities are related to regimen. MEDLINE (1946-search date), EMBASE (1966-search date), ClinicalTrials. gov (2008-search date), and abstracts from major oncology conferences (2009- search date) were searched (5 Dec 2013) using terms for BTC, gemcitabine, and cisplatin. All study types reporting efficacy (survival, response rates) or safety (toxicities) outcomes of gemcitabine-cisplatin in BTC were eligible for inclusion; efficacy data were extracted from prospective studies only. Evidence retrieved from one meta-analysis (abstract), four randomized controlled trials, 12 nonrandomized prospective studies, and three retrospective studies supported the efficacy and safety of gemcitabine-cisplatin for BTC. Median overall survival ranged from 4.6 to 11.7 months, and response rate ranged from 17.1% to 36.6%. Toxicities were generally acceptable and manageable. Heterogeneity in study designs and data collected prevented formal meta-analysis, however exploratory assessments suggested that efficacy did not vary with primary tumor site (gallbladder vs. others), disease stage (metastatic vs. locally advanced), or geographic origin (Asia vs. other). Incidence of grade 3/4 toxicities was not related to gemcitabine dose or cisplatin frequency. Despite individual variation in study designs, the evidence presented suggests that gemcitabine-cisplatin is effective in patients from a diverse range of countries and with heterogeneous disease characteristics. No substantial differences in toxicity were observed among the different dosing schedules of gemcitabine and cisplatin. PMID:25989801

  17. Whole-exome tumor sequencing study in biliary cancer patients with a response to MEK inhibitors

    PubMed Central

    Ahn, Daniel H.; Ozer, Hatice Gulcin; Hancioglu, Baris; Lesinski, Gregory B.; Timmers, Cynthia; Bekaii-Saab, Tanios

    2016-01-01

    We previously conducted a phase-II study with selumetinib (AZD6244), a small molecule inhibitor of MEK1/2, in advanced biliary tract cancers (BTC), where the primary endpoint was response rate. Several patients experienced objective response. These findings were confirmed with MEK162 in a similar patient population. To assess for tumor-specific genetic variants that mediate sensitivity to MEK inhibition in BTC, we performed whole-exome sequencing in patients with an objective response to selumetinib. Normal and tumor DNA from FFPE tissue from two patients who experienced an objective response underwent whole-exome sequencing. Raw sequence reads were processed with GATK workflow and tumor specific variants were identified using MuTect and VarScan2. Ensemble Variant Effect Predictor was used to determine functional consequences of these variants. Copy number changes and potential gene fusion events were also screened. Findings were compared to assess for any commonality between the two tumor samples, and whether the identified variants were intrinsic to the MAPK pathway. 1169 and 628 tumor-specific variants were identified in the two samples. Further analysis demonstrated 60 and 53 functional and novel variants, respectively. Of the identified tumor-specific variants, fusion events or copy number changes, no commonality was seen. Several variants in genes associated with ERK signaling were present in each tumor sample. Although there were no common tumor-specific variants in the two patients who exhibited an objective response to selumetinib, several genes associated with ERK signaling were identified. Confirmatory studies investigating the role of the identified genes and other potential tumor independent factors need further investigation. PMID:26683364

  18. [Long-Term Multidisciplinary Therapy for Multiple Liver Metastases from Colorectal Cancer with Biliary Drainage for Occlusive Jaundice--A Case Report].

    PubMed

    Okamura, Shu; Mikami, Koji; Murata, Kohei; Nushijima, Yoichirou; Okada, Kazuyuki; Yanagisawa, Tetsu; Fukuchi, Nariaki; Ebisui, Chikara; Yokouchi, Hideoki; Kinuta, Masakatsu

    2015-11-01

    Here, we report the case of a 43-year-old man who was diagnosed with sigmoid colon cancer with synchronous multiple liver metastases following resection of a primary lesion. Subsequent mFOLFOX+BV therapy elicited a marked response in the liver metastases, which led to the patient undergoing hepatic (S7) radiofrequency ablation (RFA), hepatic resection (lateral segmentectomy and partial [S5] resection), and cholecystectomy. Six months later, transluminal RFA was repeated because liver (S7) metastasis recurred, and 8 courses of XELOX plus BV therapy were administered. As obstructive jaundice due to recurrence of the liver metastases developed after a 6 months hiatus in chemotherapy, we endoscopically inserted a biliary stent. Despite reducing IRIS plus BV therapy, obstructive jaundice developed again, and 3 intrahepatic biliary stents were inserted with percutaneous transhepatic biliary drainage. To date, the patient has been alive for 4 years since the initial resection of the primary lesion after undergoing consecutive systemic chemotherapy with different regimens. Some studies have shown that in cases of obstructive jaundice caused by advanced gastrointestinal cancer, longer survival could be expected by reducing the severity of jaundice, suggesting that resuming chemotherapy as well as improving the severity of jaundice could contribute to better outcomes. The patient in the present case was successfully treated twice with biliary drainage for occlusive jaundice and chemotherapy, suggesting that a combination of multidisciplinary therapy and adequate local therapy such as biliary drainage could be important for the treatment of metastatic liver cancer. PMID:26805157

  19. Lipopolysaccharide (LPS)-Induced Biliary Epithelial Cell NRas Activation Requires Epidermal Growth Factor Receptor (EGFR)

    PubMed Central

    Trussoni, Christy E.; Tabibian, James H.; Splinter, Patrick L.; O’Hara, Steven P.

    2015-01-01

    Cholangiocytes (biliary epithelial cells) actively participate in microbe-induced proinflammatory responses in the liver and contribute to inflammatory and infectious cholangiopathies. We previously demonstrated that cholangiocyte TLR-dependent NRas activation contributes to proinflammatory/ proliferative responses. We test the hypothesis that LPS-induced activation of NRas requires the EGFR. SV40-transformed human cholangiocytes (H69 cells), or low passage normal human cholangiocytes (NHC), were treated with LPS in the presence or absence of EGFR or ADAM metallopeptidase domain 17 (TACE) inhibitors. Ras activation assays, quantitative RT-PCR, and proliferation assays were performed in cells cultured with or without inhibitors or an siRNA to Grb2. Immunofluorescence for phospho-EGFR was performed on LPS-treated mouse samples and specimens from patients with primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis C, and normal livers. LPS-treatment induced an association between the TLR/MyD88 and EGFR/Grb2 signaling apparatus, NRas activation, and EGFR phosphorylation. NRas activation was sensitive to EGFR and TACE inhibitors and correlated with EGFR phosphorylation. The TACE inhibitor and Grb2 depletion prevented LPS-induced IL6 expression (p<0.05) and proliferation (p<0.01). Additionally, cholangiocytes from LPS-treated mouse livers and human primary sclerosing cholangitis (PSC) livers exhibited increased phospho-EGFR (p<0.01). Moreover, LPS-induced mouse cholangiocyte proliferation was inhibited by concurrent treatment with the EGFR inhibitor, Erlotinib. Our results suggest that EGFR is essential for LPS-induced, TLR4/MyD88-mediated NRas activation and induction of a robust proinflammatory cholangiocyte response. These findings have implications not only for revealing the signaling potential of TLRs, but also implicate EGFR as an integral component of cholangiocyte TLR-induced proinflammatory processes. PMID:25915403

  20. Lipopolysaccharide (LPS)-Induced Biliary Epithelial Cell NRas Activation Requires Epidermal Growth Factor Receptor (EGFR).

    PubMed

    Trussoni, Christy E; Tabibian, James H; Splinter, Patrick L; O'Hara, Steven P

    2015-01-01

    Cholangiocytes (biliary epithelial cells) actively participate in microbe-induced proinflammatory responses in the liver and contribute to inflammatory and infectious cholangiopathies. We previously demonstrated that cholangiocyte TLR-dependent NRas activation contributes to proinflammatory/ proliferative responses. We test the hypothesis that LPS-induced activation of NRas requires the EGFR. SV40-transformed human cholangiocytes (H69 cells), or low passage normal human cholangiocytes (NHC), were treated with LPS in the presence or absence of EGFR or ADAM metallopeptidase domain 17 (TACE) inhibitors. Ras activation assays, quantitative RT-PCR, and proliferation assays were performed in cells cultured with or without inhibitors or an siRNA to Grb2. Immunofluorescence for phospho-EGFR was performed on LPS-treated mouse samples and specimens from patients with primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis C, and normal livers. LPS-treatment induced an association between the TLR/MyD88 and EGFR/Grb2 signaling apparatus, NRas activation, and EGFR phosphorylation. NRas activation was sensitive to EGFR and TACE inhibitors and correlated with EGFR phosphorylation. The TACE inhibitor and Grb2 depletion prevented LPS-induced IL6 expression (p<0.05) and proliferation (p<0.01). Additionally, cholangiocytes from LPS-treated mouse livers and human primary sclerosing cholangitis (PSC) livers exhibited increased phospho-EGFR (p<0.01). Moreover, LPS-induced mouse cholangiocyte proliferation was inhibited by concurrent treatment with the EGFR inhibitor, Erlotinib. Our results suggest that EGFR is essential for LPS-induced, TLR4/MyD88-mediated NRas activation and induction of a robust proinflammatory cholangiocyte response. These findings have implications not only for revealing the signaling potential of TLRs, but also implicate EGFR as an integral component of cholangiocyte TLR-induced proinflammatory processes. PMID:25915403

  1. Optimal dose of gemcitabine for the treatment of biliary tract or pancreatic cancer in patients with liver dysfunction.

    PubMed

    Shibata, Takashi; Ebata, Tomoki; Fujita, Ken-ichi; Shimokata, Tomoya; Maeda, Osamu; Mitsuma, Ayako; Sasaki, Yasutsuna; Nagino, Masato; Ando, Yuichi

    2016-02-01

    A clear consensus does not exist about whether the initial dose of gemcitabine, an essential anticancer antimetabolite, should be reduced in patients with liver dysfunction. Adult patients with biliary tract or pancreatic cancer were divided into three groups according to whether they had mild, moderate, or severe liver dysfunction, evaluated on the basis of serum bilirubin and liver transaminase levels at baseline. As anticancer treatment, gemcitabine at a dose of 800 or 1000 mg/m(2) was given as an i.v. infusion once weekly for 3 weeks of a 4-week cycle. The patients were prospectively evaluated for adverse events during the first cycle, and the pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine, were studied to determine the optimal initial dose of gemcitabine as monotherapy according to the severity of liver dysfunction. A total of 15 patients were studied. Liver dysfunction was mild in one patient, moderate in six, and severe in eight. All 15 patients had been undergoing biliary drainage for obstructive jaundice when they received gemcitabine. Grade 3 cholangitis developed in one patient with moderate liver dysfunction who received gemcitabine at the dose level of 1000 mg/m(2). No other patients had severe treatment-related adverse events resulting in the omission or discontinuation of gemcitabine treatment. The plasma concentrations of gemcitabine and difluorodeoxyuridine were similar among the groups. An initial dose reduction of gemcitabine as monotherapy for the treatment of biliary tract or pancreatic cancers is not necessary for patients with hyperbilirubinemia, provided that obstructive jaundice is well managed. (Clinical trial registration no. UMIN000005363.) PMID:26595259

  2. Lapatinib Ditosylate in Treating Patients With Unresectable Liver or Biliary Tract Cancer

    ClinicalTrials.gov

    2015-04-08

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  3. Chemical coding and chemosensory properties of cholinergic brush cells in the mouse gastrointestinal and biliary tract

    PubMed Central

    Schütz, Burkhard; Jurastow, Innokentij; Bader, Sandra; Ringer, Cornelia; von Engelhardt, Jakob; Chubanov, Vladimir; Gudermann, Thomas; Diener, Martin; Kummer, Wolfgang; Krasteva-Christ, Gabriela; Weihe, Eberhard

    2015-01-01

    The mouse gastro-intestinal and biliary tract mucosal epithelia harbor choline acetyltransferase (ChAT)-positive brush cells with taste cell-like traits. With the aid of two transgenic mouse lines that express green fluorescent protein (EGFP) under the control of the ChAT promoter (EGFPChAT) and by using in situ hybridization and immunohistochemistry we found that EGFPChAT cells were clustered in the epithelium lining the gastric groove. EGFPChAT cells were numerous in the gall bladder and bile duct, and found scattered as solitary cells along the small and large intestine. While all EGFPChAT cells were also ChAT-positive, expression of the high-affinity choline transporter (ChT1) was never detected. Except for the proximal colon, EGFPChAT cells also lacked detectable expression of the vesicular acetylcholine transporter (VAChT). EGFPChAT cells were found to be separate from enteroendocrine cells, however they were all immunoreactive for cytokeratin 18 (CK18), transient receptor potential melastatin-like subtype 5 channel (TRPM5), and for cyclooxygenases 1 (COX1) and 2 (COX2). The ex vivo stimulation of colonic EGFPChAT cells with the bitter substance denatonium resulted in a strong increase in intracellular calcium, while in other epithelial cells such an increase was significantly weaker and also timely delayed. Subsequent stimulation with cycloheximide was ineffective in both cell populations. Given their chemical coding and chemosensory properties, EGFPChAT brush cells thus may have integrative functions and participate in induction of protective reflexes and inflammatory events by utilizing ACh and prostaglandins for paracrine signaling. PMID:25852573

  4. Chemical coding and chemosensory properties of cholinergic brush cells in the mouse gastrointestinal and biliary tract.

    PubMed

    Schütz, Burkhard; Jurastow, Innokentij; Bader, Sandra; Ringer, Cornelia; von Engelhardt, Jakob; Chubanov, Vladimir; Gudermann, Thomas; Diener, Martin; Kummer, Wolfgang; Krasteva-Christ, Gabriela; Weihe, Eberhard

    2015-01-01

    The mouse gastro-intestinal and biliary tract mucosal epithelia harbor choline acetyltransferase (ChAT)-positive brush cells with taste cell-like traits. With the aid of two transgenic mouse lines that express green fluorescent protein (EGFP) under the control of the ChAT promoter (EGFP (ChAT) ) and by using in situ hybridization and immunohistochemistry we found that EGFP (ChAT) cells were clustered in the epithelium lining the gastric groove. EGFP (ChAT) cells were numerous in the gall bladder and bile duct, and found scattered as solitary cells along the small and large intestine. While all EGFP (ChAT) cells were also ChAT-positive, expression of the high-affinity choline transporter (ChT1) was never detected. Except for the proximal colon, EGFP (ChAT) cells also lacked detectable expression of the vesicular acetylcholine transporter (VAChT). EGFP (ChAT) cells were found to be separate from enteroendocrine cells, however they were all immunoreactive for cytokeratin 18 (CK18), transient receptor potential melastatin-like subtype 5 channel (TRPM5), and for cyclooxygenases 1 (COX1) and 2 (COX2). The ex vivo stimulation of colonic EGFP (ChAT) cells with the bitter substance denatonium resulted in a strong increase in intracellular calcium, while in other epithelial cells such an increase was significantly weaker and also timely delayed. Subsequent stimulation with cycloheximide was ineffective in both cell populations. Given their chemical coding and chemosensory properties, EGFP (ChAT) brush cells thus may have integrative functions and participate in induction of protective reflexes and inflammatory events by utilizing ACh and prostaglandins for paracrine signaling. PMID:25852573

  5. Primary Biliary Cirrhosis

    MedlinePlus

    ... liver cancer every 6 to 12 months. Health care providers use blood tests, ultrasound, or both to check for signs of ... the diagnosis of primary biliary cirrhosis. A health care provider uses the test selectively when he or she is concerned that ...

  6. A novel keratin18 promoter that drives reporter gene expression in the intrahepatic and extrahepatic biliary system allows isolation of cell-type specific transcripts from zebrafish liver

    PubMed Central

    Wilkins, Benjamin J.; Gong, Weilong; Pack, Michael

    2015-01-01

    Heritable and acquired biliary disorders are an important cause of acute and chronic human liver disease. Biliary development and physiology have been studied extensively in rodent models and more recently, zebrafish have been used to uncover pathogenic mechanisms and potential therapies for these conditions. Here we report development of novel transgenic lines labeling the intrahepatic and extrahepatic biliary system of zebrafish larvae that can be used for lineage tracing and isolation of biliary-specific RNAs from mixed populations of liver cells. We show that GFP expression driven by a 4.4 kilobase promoter fragment from the zebrafish keratin18 (krt18) gene allows visualization of all components of the developing biliary system as early as 3 days post-fertilization. In addition, expression of a ribosomal fusion protein (EGFP-Rpl10a) in krt18:TRAP transgenic fish allows for enrichment of translated biliary cell mRNAs via translating ribosome affinity purification (TRAP). Future studies utilizing these reagents will enhance our understanding of the morphologic and molecular processes involved in biliary development and disease. PMID:24394404

  7. [Malignant biliary obstruction].

    PubMed

    Hucl, Tomáš

    2016-01-01

    Pancreatic cancer and cholangiocarcinoma are the most common causes of malignant biliary obstruction. They are diseases of increasing incidence and unfavorable prognosis. Only patients with localized disease indicated for surgery have a chance of long-term survival. These patients represent less than 20 % of all patients, despite the progress in our diagnostic abilities.Locally advanced and metastatic tumors are treated with palliative chemotherapy or chemoradiotherapy; the results of such treatments are unsatisfactory. The average survival of patients with unresectable disease is 6 months and only 5-10 % of patients survive 5 years.Biliary drainage is an integral part of palliative treatment. Endoscopically or percutaneosly placed stents improve quality of life, decrease cholestasis and pruritus, but do not significantly improve survival. Biliary stents get occluded over time, possibly resulting in acute cholangitis and require repeated replacement.Photodynamic therapy and radiofrequency ablation, locally active endoscopic methods, have been increasingly used in recent years in palliative treatment of patients with malignant biliary obstruction. In photodynamic therapy, photosensitizer accumulates in tumor tissue and is activated 48 hours later by light of a specific wave length. Application of low voltage high frequency current during radiofrequency ablation results in tissue destruction by heat. Local ablation techniques can have a significant impact in a large group of patients with malignant biliary obstruction, leading to improved prognosis, quality of life and stent patency. PMID:26898789

  8. Cell phones and cancer

    MedlinePlus

    Cancer and cell phones; Do cell phones cause cancer? ... Several major studies show no link between cell phones and cancer at this time. However, since the information available is based on short-term studies, the impact of many years of ...

  9. Cell phones and cancer

    MedlinePlus

    Cancer and cell phones; Do cell phones cause cancer? ... Several major studies show no link between cell phones and cancer at this time. However, since the information available is based on short-term studies, the impact of many years of exposure ...

  10. Biliary stricture

    MedlinePlus

    ... to a gallstone in the bile duct Pancreatitis Primary sclerosing cholangitis Risk factors include: Gallstones Injury to ... Inflammation and narrowing of the biliary duct may return in some ... remain for a long period can lead to liver damage ( cirrhosis ).

  11. Biliary stricture

    MedlinePlus

    ... help reveal a problem with the biliary system . Alkaline phosphatase (ALP) is higher than normal. Bilirubin level ... the small intestine. In some cases, a tiny metal or plastic mesh tube ( stent ) is placed across ...

  12. Glycemic index, glycemic load, dietary carbohydrate, and dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans

    PubMed Central

    Fedirko, V.; Lukanova, A.; Bamia, C.; Trichopolou, A.; Trepo, E.; Nöthlings, U.; Schlesinger, S.; Aleksandrova, K.; Boffetta, P.; Tjønneland, A.; Johnsen, N. F.; Overvad, K.; Fagherazzi, G.; Racine, A.; Boutron-Ruault, M. C.; Grote, V.; Kaaks, R.; Boeing, H.; Naska, A.; Adarakis, G.; Valanou, E.; Palli, D.; Sieri, S.; Tumino, R.; Vineis, P.; Panico, S.; Bueno-de-Mesquita, H. B(as).; Siersema, P. D.; Peeters, P. H.; Weiderpass, E.; Skeie, G.; Engeset, D.; Quirós, J. R.; Zamora-Ros, R.; Sánchez, M. J.; Amiano, P.; Huerta, J. M.; Barricarte, A.; Johansen, D.; Lindkvist, B.; Sund, M.; Werner, M.; Crowe, F.; Khaw, K. T.; Ferrari, P.; Romieu, I.; Chuang, S. C.; Riboli, E.; Jenab, M.

    2013-01-01

    Background The type and quantity of dietary carbohydrate as quantified by glycemic index (GI) and glycemic load (GL), and dietary fiber may influence the risk of liver and biliary tract cancers, but convincing evidence is lacking. Patients and methods The association between dietary GI/GL and carbohydrate intake with hepatocellular carcinoma (HCC; N = 191), intrahepatic bile duct (IBD; N = 66), and biliary tract (N = 236) cancer risk was investigated in 477 206 participants of the European Prospective Investigation into Cancer and Nutrition cohort. Dietary intake was assessed by country-specific, validated dietary questionnaires. Hazard ratios and 95% confidence intervals were estimated from proportional hazard models. HBV/HCV status was measured in a nested case–control subset. Results Higher dietary GI, GL, or increased intake of total carbohydrate was not associated with liver or biliary tract cancer risk. For HCC, divergent risk estimates were observed for total sugar = 1.43 (1.17–1.74) per 50 g/day, total starch = 0.70 (0.55–0.90) per 50 g/day, and total dietary fiber = 0.70 (0.52–0.93) per 10 g/day. The findings for dietary fiber were confirmed among HBV/HCV-free participants [0.48 (0.23–1.01)]. Similar associations were observed for IBD [dietary fiber = 0.59 (0.37–0.99) per 10 g/day], but not biliary tract cancer. Conclusions Findings suggest that higher consumption of dietary fiber and lower consumption of total sugars are associated with lower HCC risk. In addition, high dietary fiber intake could be associated with lower IBD cancer risk. PMID:23123507

  13. High Rates of Recurrent Biliary Tract Obstruction in Children with Sickle Cell Disease

    PubMed Central

    Amoako, Martha O.; Casella, James F.; Strouse, John J.

    2014-01-01

    BACKGROUND Individuals with sickle cell disease (SCD) have an increased risk of cholelithiasis from bilirubin stones. Symptomatic biliary tract disease (BTD) includes acute and chronic cholecystitis, obstruction of the common bile duct (CBD), cholangitis, and gallstone pancreatitis. Cholecystectomy is the main treatment strategy for symptomatic patients; however, the prevalence of recurrent BTD following cholecystectomy has not been systematically evaluated. We conducted a retrospective cohort study to describe the recurrence of BTD after cholecystectomy and characterize risk factors for recurrent disease. PROCEDURE We identified patients <22 years of age who presented to the Johns Hopkins Children Center with symptomatic BTD from July 1993 to June 2008. RESULTS We identified 56 patients with a total of 76 episodes of symptomatic BTD (median age at first event 15.9, range 4.6 to 21.5 years). Eleven of the 56 patients (19.6%) had at least one episode of recurrent symptomatic BTD (median follow-up of 5.3 years). Baseline characteristics were similar between the patients with a single episode of BTD and those with recurrent BTD. CONCLUSIONS These results demonstrate that recurrent BTD is a frequent complication of SCD (20% by age 4 years) and often presents as CBD obstruction by stone, despite cholecystectomy. In our cohort, recurrence was not associated with age at first episode, baseline total bilirubin, gender, or genotype of SCD. PMID:23255346

  14. Cross-Activating Invariant NKT Cells and Kupffer Cells Suppress Cholestatic Liver Injury in a Mouse Model of Biliary Obstruction

    PubMed Central

    Duwaerts, Caroline C.; Sun, Eric P.; Cheng, Chao-Wen; van Rooijen, Nico; Gregory, Stephen H.

    2013-01-01

    Both Kupffer cells and invariant natural killer T (iNKT) cells suppress neutrophil-dependent liver injury in a mouse model of biliary obstruction. We hypothesize that these roles are interdependent and require iNKT cell-Kupffer cell cross-activation. Female, wild-type and iNKT cell-deficient C57Bl/6 mice were injected with magnetic beads 3 days prior to bile duct ligation (BDL) in order to facilitate subsequent Kupffer cell isolation. On day three post-BDL, the animals were euthanized and the livers dissected. Necrosis was scored; Kupffer cells were isolated and cell surface marker expression (flow cytometry), mRNA expression (qtPCR), nitric oxide (NO.) production (Griess reaction), and protein secretion (cytometric bead-array or ELISAs) were determined. To address the potential role of NO. in suppressing neutrophil accumulation, a group of WT mice received 1400W, a specific inducible nitric oxide synthase (iNOS) inhibitor, prior to BDL. To clarify the mechanisms underlying Kupffer cell-iNKT cell cross-activation, WT animals were administered anti-IFN-γ or anti-lymphocyte function-associated antigen (LFA)-1 antibody prior to BDL. Compared to their WT counterparts, Kupffer cells obtained from BDL iNKT cell-deficient mice expressed lower iNOS mRNA levels, produced less NO., and secreted more neutrophil chemoattractants. Both iNOS inhibition and IFN-γ neutralization increased neutrophil accumulation in the livers of BDL WT mice. Anti-LFA-1 pre-treatment reduced iNKT cell accumulation in these same animals. These data indicate that the LFA-1-dependent cross-activation of iNKT cells and Kupffer cells inhibits neutrophil accumulation and cholestatic liver injury. PMID:24260285

  15. Cross-activating invariant NKT cells and kupffer cells suppress cholestatic liver injury in a mouse model of biliary obstruction.

    PubMed

    Duwaerts, Caroline C; Sun, Eric P; Cheng, Chao-Wen; van Rooijen, Nico; Gregory, Stephen H

    2013-01-01

    Both Kupffer cells and invariant natural killer T (iNKT) cells suppress neutrophil-dependent liver injury in a mouse model of biliary obstruction. We hypothesize that these roles are interdependent and require iNKT cell-Kupffer cell cross-activation. Female, wild-type and iNKT cell-deficient C57Bl/6 mice were injected with magnetic beads 3 days prior to bile duct ligation (BDL) in order to facilitate subsequent Kupffer cell isolation. On day three post-BDL, the animals were euthanized and the livers dissected. Necrosis was scored; Kupffer cells were isolated and cell surface marker expression (flow cytometry), mRNA expression (qtPCR), nitric oxide (NO (.) ) production (Griess reaction), and protein secretion (cytometric bead-array or ELISAs) were determined. To address the potential role of NO (.) in suppressing neutrophil accumulation, a group of WT mice received 1400W, a specific inducible nitric oxide synthase (iNOS) inhibitor, prior to BDL. To clarify the mechanisms underlying Kupffer cell-iNKT cell cross-activation, WT animals were administered anti-IFN-γ or anti-lymphocyte function-associated antigen (LFA)-1 antibody prior to BDL. Compared to their WT counterparts, Kupffer cells obtained from BDL iNKT cell-deficient mice expressed lower iNOS mRNA levels, produced less NO (.) , and secreted more neutrophil chemoattractants. Both iNOS inhibition and IFN-γ neutralization increased neutrophil accumulation in the livers of BDL WT mice. Anti-LFA-1 pre-treatment reduced iNKT cell accumulation in these same animals. These data indicate that the LFA-1-dependent cross-activation of iNKT cells and Kupffer cells inhibits neutrophil accumulation and cholestatic liver injury. PMID:24260285

  16. Rhesus rotavirus VP4 sequence-specific activation of mononuclear cells is associated with cholangiopathy in murine biliary atresia.

    PubMed

    Walther, Ashley; Mohanty, Sujit K; Donnelly, Bryan; Coots, Abigail; Lages, Celine S; Lobeck, Inna; Dupree, Phylicia; Meller, Jaroslaw; McNeal, Monica; Sestak, Karol; Tiao, Greg

    2015-09-15

    Biliary atresia (BA), a neonatal obstructive cholangiopathy, remains the most common indication for pediatric liver transplantation in the United States. In the murine model of BA, Rhesus rotavirus (RRV) VP4 surface protein determines biliary duct tropism. In this study, we investigated how VP4 governs induction of murine BA. Newborn mice were injected with 16 strains of rotavirus and observed for clinical symptoms of BA and mortality. Cholangiograms were performed to confirm bile duct obstruction. Livers and bile ducts were harvested 7 days postinfection for virus titers and histology. Flow cytometry assessed mononuclear cell activation in harvested cell populations from the liver. Cytotoxic NK cell activity was determined by the ability of NK cells to kill noninfected cholangiocytes. Of the 16 strains investigated, the 6 with the highest homology to the RRV VP4 (>87%) were capable of infecting bile ducts in vivo. Although the strain Ro1845 replicated to a titer similar to RRV in vivo, it caused no symptoms or mortality. A Ro1845 reassortant containing the RRV VP4 induced all BA symptoms, with a mortality rate of 89%. Flow cytometry revealed that NK cell activation was significantly increased in the disease-inducing strains and these NK cells demonstrated a significantly higher percentage of cytotoxicity against noninfected cholangiocytes. Rotavirus strains with >87% homology to RRV's VP4 were capable of infecting murine bile ducts in vivo. Development of murine BA was mediated by RRV VP4-specific activation of mononuclear cells, independent of viral titers. PMID:26206856

  17. PET-CT in Determining the Radioembolization Dose Delivered to Patients With Liver Metastasis, Primary Liver Cancer, or Biliary Cancer

    ClinicalTrials.gov

    2016-03-01

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Stage D Adult Primary Liver Cancer (BCLC); Unspecified Adult Solid Tumor, Protocol Specific

  18. Association of Endoscopic Sphincterotomy or Papillary Balloon Dilatation and Biliary Cancer

    PubMed Central

    Peng, Yen-Chun; Lin, Cheng-Li; Hsu, Wan-Yun; Chow, Wai-Keung; Lee, Show-Wu; Yeh, Hong-Zen; Chang, Chi-Sen; Kao, Chia-Hung

    2015-01-01

    Abstract Endoscopic sphincterotomy (EST) and endoscopic papillary balloon dilatation (EPBD) have become the main therapeutic procedures in the treatment of biliary and pancreas disease. The risk of cholangiocarcinoma (CCA) is not well investigated among post-EST/EPBD patients with benign diseases, particularly in Asia population. A retrospective nationwide cohort study using data from Taiwan's National Health Insurance Research Database (from January 1, 1998 through December 31, 2010) was conducted. Among patients with history of biliary stone with cholangitis, there were 17,503 patients in the EST/EPBD cohort and 69,998 subjects in the comparison. The incidence rate ratio was calculated using the Poisson regression model. Multivariable Cox proportional hazard models, adjusted for potential confounding factors, were used to assess the risk of developing CCA associated with endoscopic EST/EPBD. The cumulative incidences of CCA in the 2 cohorts were calculated using Kaplan–Meier analyses, and differences between the survival curves of the 2 cohorts were analyzed using a log-rank test. The overall incidence of CCA in the EST/EPBD cohort was higher than in the controls (1.36 vs 7.37 per 1000 person-years, IRR = 5.40, 95% CI = 5.15–5.67), with an adjusted HR of 4.41 (95% CI = 3.86–5.04). There were no CCA occurrences among patients receiving EST over the follow-up period 3 year after EST performed. The cumulative incidence of extrahepatic CCA seemed to be little growing in patients receiving EPBD. The cumulative incidence of intrahepatic CCA was also steady increasing in patients treated with EPBD and was more than patients receiving EST 10 years after EPBD by Kaplan–Meier analysis. In the population-based cohort study, EST is not associated with a long-term risk of intrahepatic and extrahepatic CCA. The risk of CCA for EPBD needs further investigation. PMID:26061315

  19. Presence of CCK-A, B receptors and effect of gastrin and cholecystokinin on growth of pancreatobiliary cancer cell lines

    PubMed Central

    Jang, Jin-Young; Kim, Sun-Whe; Ku, Ja-Lok; Park, Yong-Hyun; Park, Jae-Gahb

    2005-01-01

    AIM: To investigate the effects of gastrin and cholecystokinin (CCK) and their specific antagonists on the growth of pancreatic and biliary tract cancer cell lines. METHODS: Five pancreatic and 6 biliary cancer cell lines with 2 control cells were used in this study. Cell proliferation study was done using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) test and direct cell count method. Reverse transcription-polymerase chain reaction (RT-PCR) and slot blot hybridization were performed to examine and quantify the expression of hormonal receptors in these cell lines. RESULTS: SNU-308 showed a growth stimulating effect by gastrin-17, as did SNU-478 by both gastrin-17 and CCK-8. The trophic effect of these two hormones was completely blocked by specific antagonists (L-365, 260 for gastrin and L-364, 718 for CCK). Other cell lines did not respond to gastrin or CCK. In RT-PCR, the presence of CCK-A receptor and CCK-B/gastrin receptor mRNA was detected in all biliary and pancreatic cancer cell lines. In slot blot hybridization, compared to the cell lines which did not respond to hormones, those that responded to hormones showed high expression of receptor mRNA. CONCLUSION: Gastrin and CCK exert a trophic action on some of the biliary tract cancers. PMID:15682471

  20. Biliary cysts.

    PubMed Central

    Flanigan, P D

    1975-01-01

    This review brings the total number of biliary cysts reported in the world literature to 955. Eighty-one per cent of patients are females and 61% were discovered before age ten. The classical triad of right upper quadrant pain, right upper quandrant mass, and juandice is present in 38% of cases. The duration of symptoms prior to diagnosis ranged from less than one week to more than 40 years. The etiology is multifaceted and evidence of the existence of both acquired and congenital cysts is presented. The most useful diagnostic tool is fiberoptic endoscopy with retrograde contrast injection of the common bile duct and pancreatic duct. The incidence of biliary carcinoma in patients with biliary cysts is found to be 2.5%; 24 cases have been reported. Considerable controversy has existed concerning the best operative procedure for biliary cysts; no treatment or medical treatment yielding a 97% mortality rate. In an analysis of 235 patients presented since 1968 with an average followup of 5.2 years, the best procedure appears to be excision with either choledochocholedocostomy or Roux-en-Y hepaticojejunostomy. The operative mortality for all procedures is now 3 to 4%. PMID:1103760

  1. Biliary atresia

    PubMed Central

    Chardot, Christophe

    2006-01-01

    Biliary atresia (BA) is a rare disease characterised by a biliary obstruction of unknown origin that presents in the neonatal period. It is the most frequent surgical cause of cholestatic jaundice in this age group. BA occurs in approximately 1/18,000 live births in Western Europe. In the world, the reported incidence varies from 5/100,000 to 32/100,000 live births, and is highest in Asia and the Pacific region. Females are affected slightly more often than males. The common histopathological picture is one of inflammatory damage to the intra- and extrahepatic bile ducts with sclerosis and narrowing or even obliteration of the biliary tree. Untreated, this condition leads to cirrhosis and death within the first years of life. BA is not known to be a hereditary condition. No primary medical treatment is relevant for the management of BA. Once BA suspected, surgical intervention (Kasai portoenterostomy) should be performed as soon as possible as operations performed early in life is more likely to be successful. Liver transplantation may be needed later if the Kasai operation fails to restore the biliary flow or if cirrhotic complications occur. At present, approximately 90% of BA patients survive and the majority have normal quality of life. PMID:16872500

  2. B CELLS PROMOTE HEPATIC INFLAMMATION, BILIARY CYST FORMATION, AND SALIVARY GLAND INFLAMMATION IN THE NOD.C3C4 MODEL OF AUTOIMMUNE CHOLANGITIS

    PubMed Central

    Moritoki, Yuki; Tsuda, Masanobu; Tsuneyama, Koichi; Zhang, Weici; Yoshida, Katsunori; Lian, Zhe-Xiong; Yang, Guo-Xiang; Ridgway, William M.; Wicker, Linda S.; Ansari, Aftab A.; Gershwin, M. Eric

    2011-01-01

    There are now several murine models of autoimmune cholangitis that have features both similar and distinct from human PBC. One such model, the NOD.c3c4 mouse, manifests portal cell infiltrates, anti-mitochondrial antibodies but also biliary cysts. The biliary cysts are not a component of PBC and not found in the other murine models. To address the immunopathology in these mice, we generated genetically B cell deficient Igμ−/− NOD.c3c4 mice and compared the immunopathology of these animals to control B cell sufficient NOD.c3c4 mice. B cell deficient mice demonstrated decreased number of non-B cells in the liver accompanied by reduced numbers of activated natural killer cells. The degree of granuloma formation and bile duct damage were comparable to NOD.c3c4 mice. In contrast, liver inflammation, biliary cyst formation and salivary gland inflammation was significantly attenuated in these B cell deficient mice. In conclusion, B cells play a critical role in promoting liver inflammation and also contribute to cyst formation as well as salivary gland pathology in autoimmune NOD.c3c4 mice, illustrating a critical role of B cells in modulating specific organ pathology and, in particular, in exacerbating both the biliary disease and the sialadenitis. PMID:21349500

  3. Biopsy - biliary tract

    MedlinePlus

    Cytology analysis - biliary tract; Biliary tract biopsy ... A sample for a biliary tract biopsy can be obtained in different ways. A needle biopsy can be done if you have a well-defined tumor. The biopsy site ...

  4. Influence of the Biliary System on Biliary Bacteria Revealed by Bacterial Communities of the Human Biliary and Upper Digestive Tracts

    PubMed Central

    Ye, Fuqiang; Shen, Hongzhang; Li, Zhen; Meng, Fei; Li, Lei; Yang, Jianfeng; Chen, Ying; Bo, Xiaochen; Zhang, Xiaofeng; Ni, Ming

    2016-01-01

    Biliary bacteria have been implicated in gallstone pathogenesis, though a clear understanding of their composition and source is lacking. Moreover, the effects of the biliary environment, which is known to be generally hostile to most bacteria, on biliary bacteria are unclear. Here, we investigated the bacterial communities of the biliary tract, duodenum, stomach, and oral cavity from six gallstone patients by using 16S rRNA amplicon sequencing. We found that all observed biliary bacteria were detectable in the upper digestive tract. The biliary microbiota had a comparatively higher similarity with the duodenal microbiota, versus those of the other regions, but with a reduced diversity. Although the majority of identified bacteria were greatly diminished in bile samples, three Enterobacteriaceae genera (Escherichia, Klebsiella, and an unclassified genus) and Pyramidobacter were abundant in bile. Predictive functional analysis indicated enhanced abilities of environmental information processing and cell motility of biliary bacteria. Our study provides evidence for the potential source of biliary bacteria, and illustrates the influence of the biliary system on biliary bacterial communities. PMID:26930491

  5. Fragmentation of cancer cells

    NASA Astrophysics Data System (ADS)

    Vanapalli, Siva; Kamyabi, Nabiollah

    Tumor cells have to travel through blood capillaries to be able to metastasize and colonize in distant organs. Among the numerous cells that are shed by the primary tumor, very few survive in circulation. In vivo studies have shown that tumor cells can undergo breakup at microcapillary junctions affecting their survival. It is currently unclear what hydrodynamic and biomechanical factors contribute to fragmentation and moreover how different are the breakup dynamics of highly and weakly metastatic cells. In this study, we use microfluidics to investigate flow-induced breakup of prostate and breast cancer cells. We observe several different modes of breakup of cancer cells, which have striking similarities with breakup of viscous drops. We quantify the breakup time and find that highly metastatic cancer cells take longer to breakup than lowly metastatic cells suggesting that tumor cells may dynamically modify their deformability to avoid fragmentation. We also identify the role that cytoskeleton and membrane plays in the breakup process. Our study highlights the important role that tumor cell fragmentation plays in cancer metastasis. Cancer Prevention and Research Institute of Texas.

  6. Preneoplastic conditions underlying bile duct cancer

    PubMed Central

    Sibulesky, Lena; Nguyen, Justin; Patel, Tushar

    2012-01-01

    Background Malignancies arising from the biliary tract can arise from the epithelial lining of the biliary tract and surrounding tissues. Conditions that predispose to malignancy as well as preneoplastic changes in biliary tract epithelia have been identified. In this overview, we discuss preneoplastic conditions of the biliary tract and emphasize their clinical relevance. Results Chronic biliary tract inflammation predisposes to cancer in the biliary tract. Biliary tract carcinogenesis involves a multistep process as a consequence of chronic biliary epithelial injury or inflammation. Reminiscent of other gastrointestinal epithelial malignancies such as gastric, colon, and pancreatic cancer, biliary tract cancers may evolve via a multistep progression from epithelial hyperplasia and dysplasia to malignant transformation. The potential role of initiating cells is also becoming recognized. Conclusions In spite of improved risk factor recognition, and advances in diagnostic tools, the early diagnosis of pre-malignant or malignant biliary tract conditions is extremely challenging, and there is a paucity of evidence on which to base their management. As a result, the role of pre-emptive surgery remains largely undefined. PMID:22391777

  7. Basal cell cancer (image)

    MedlinePlus

    ... is needed to prove the diagnosis of basal cell carcinoma. Treatment varies depending on the size, depth, and location of the cancer. Early treatment by a dermatologist may result in a cure rate of more than 95%, but regular examination ...

  8. Comparative proteomics reveals novel components at the plasma membrane of differentiated HepaRG cells and different distribution in hepatocyte- and biliary-like cells.

    PubMed

    Petrareanu, Catalina; Macovei, Alina; Sokolowska, Izabela; Woods, Alisa G; Lazar, Catalin; Radu, Gabriel L; Darie, Costel C; Branza-Nichita, Norica

    2013-01-01

    Hepatitis B virus (HBV) is a human pathogen causing severe liver disease and eventually death. Despite important progress in deciphering HBV internalization, the early virus-cell interactions leading to infection are not known. HepaRG is a human bipotent liver cell line bearing the unique ability to differentiate towards a mixture of hepatocyte- and biliary-like cells. In addition to expressing metabolic functions normally found in liver, differentiated HepaRG cells support HBV infection in vitro, thus resembling cultured primary hepatocytes more than other hepatoma cells. Therefore, extensive characterization of the plasma membrane proteome from HepaRG cells would allow the identification of new cellular factors potentially involved in infection. Here we analyzed the plasma membranes of non-differentiated and differentiated HepaRG cells using nanoliquid chromatography-tandem mass spectrometry to identify the differences between the proteomes and the changes that lead to differentiation of these cells. We followed up on differentially-regulated proteins in hepatocytes- and biliary-like cells, focusing on Cathepsins D and K, Cyclophilin A, Annexin 1/A1, PDI and PDI A4/ERp72. Major differences between the two proteomes were found, including differentially regulated proteins, protein-protein interactions and intracellular localizations following differentiation. The results advance our current understanding of HepaRG differentiation and the unique properties of these cells. PMID:23977166

  9. The correlation between LDH serum levels and clinical outcome in advanced biliary tract cancer patients treated with first line chemotherapy

    PubMed Central

    Faloppi, Luca; Del Prete, Michela; Gardini, Andrea Casadei; Santini, Daniele; Silvestris, Nicola; Bianconi, Maristella; Giampieri, Riccardo; Valgiusti, Martina; Brunetti, Oronzo; Bittoni, Alessandro; Andrikou, Kalliopi; Lai, Eleonora; Dessì, Alessandra; Cascinu, Stefano; Scartozzi, Mario

    2016-01-01

    LDH may represent an indirect marker of neo-angiogenesis and worse prognosis in many tumour types. We assessed the correlation between LDH and clinical outcome for biliary tract cancer (BTC) patients treated with first-line chemotherapy. Overall, 114 advanced BTC patients treated with first-line gemcitabine and cisplatin were included. Patients were divided into two groups (low vs. high LDH), according to pre-treatment LDH values. Patients were also classified according to pre- and post-treatment variation in LDH serum levels (increased vs. decreased). Median progression free survival (PFS) was 5.0 and 2.6 months respectively in patients with low and high pre-treatment LDH levels (p = 0.0042, HR = 0.56, 95% CI: 0.37–0.87). Median overall survival (OS) was 7.7 and 5.6 months (low vs. high LDH) (p = 0.324, HR = 0.81, 95% CI: 0.54–1.24). DCR was 71% vs. 43% (low vs. high LDH) (p = 0.002). In 38 patients with decreased LDH values after treatment, PFS and OS were respectively 6.2 and 12.1 months, whereas in 76 patients with post-treatment increased LDH levels, PFS and OS were respectively 3.0 and 5.1 months (PFS: p = 0.0009; HR = 0.49; 95% IC: 0.33–0.74; OS: p < 0.0001; HR = 0.42; 95% IC: 0.27–0.63). Our data seem to suggest that LDH serum level may predict clinical outcome in BTC patients receiving first-line chemotherapy. PMID:27063994

  10. Chemotherapy targeting cancer stem cells

    PubMed Central

    Liu, Haiguang; Lv, Lin; Yang, Kai

    2015-01-01

    Conventional chemotherapy is the main treatment for cancer and benefits patients in the form of decreased relapse and metastasis and longer overall survival. However, as the target therapy drugs and delivery systems are not wholly precise, it also results in quite a few side effects, and is less efficient in many cancers due to the spared cancer stem cells, which are considered the reason for chemotherapy resistance, relapse, and metastasis. Conventional chemotherapy limitations and the cancer stem cell hypothesis inspired our search for a novel chemotherapy targeting cancer stem cells. In this review, we summarize cancer stem cell enrichment methods, the search for new efficient drugs, and the delivery of drugs targeting cancer stem cells. We also discuss cancer stem cell hierarchy complexity and the corresponding combination therapy for both cancer stem and non-stem cells. Learning from cancer stem cells may reveal novel strategies for chemotherapy in the future. PMID:26045975

  11. Cancer Stem Cells in Pancreatic Cancer

    PubMed Central

    Bao, Qi; Zhao, Yue; Renner, Andrea; Niess, Hanno; Seeliger, Hendrik; Jauch, Karl-Walter; Bruns, Christiane J.

    2010-01-01

    Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer. PMID:24281178

  12. Impact of Intraluminal Brachytherapy on Survival Outcome for Radiation Therapy for Unresectable Biliary Tract Cancer: A Propensity-Score Matched-Pair Analysis

    SciTech Connect

    Yoshioka, Yasuo; Ogawa, Kazuhiko; Oikawa, Hirobumi; Onishi, Hiroshi; Kanesaka, Naoto; Tamamoto, Tetsuro; Kosugi, Takashi; Hatano, Kazuo; Kobayashi, Masao; Ito, Yoshinori; Takayama, Makoto; Takemoto, Mitsuhiro; Karasawa, Katsuyuki; Nagakura, Hisayasu; Imai, Michiko; Kosaka, Yasuhiro; Yamazaki, Hideya; Isohashi, Fumiaki; Nemoto, Kenji; Nishimura, Yasumasa

    2014-07-15

    Purpose: To determine whether adding intraluminal brachytherapy (ILBT) to definitive radiation therapy (RT) for unresectable biliary tract cancer has a positive impact on survival outcome. Methods and Materials: The original cohort comprised 209 patients, including 153 who underwent external beam RT (EBRT) alone and 56 who received both ILBT and EBRT. By matching propensity scores, 56 pairs (112 patients) consisting of 1 patient with and 1 patient without ILBT were selected. They were well balanced in terms of sex, age, performance status, clinical stage, jaundice, and addition of chemotherapy. The impact of ILBT on overall survival (OS), disease-specific survival (DSS), and local control (LC) was investigated. Results: The 2-year OS rates were 31% for the ILBT+ group and 40% for theILBT– group (P=.862). The 2-year DSS rates were 42% for the ILBT+ group and 41% for the ILBT– group (P=.288). The 2-year LC rates were 65% for the ILBT+ group and 35% for the ILBT– group (P=.094). Three of the 4 sensitivity analyses showed a significantly better LC for the ILBT+ group (P=.010, .025, .049), and another showed a marginally better LC (P=.068), and none of the sensitivity analyses showed any statistically significant differences in OS or DSS. Conclusions: In the treatment for unresectable biliary tract cancer, the addition of ILBT to RT has no impact on OS or DSS but is associated with better LC. Therefore, the role of ILBT should be addressed by other measures than survival benefit, for example, by less toxicity, prolonged biliary tract patency decreasing the need for further palliative interventions, or patient quality of life.

  13. Low white blood cell count and cancer

    MedlinePlus

    Neutropenia and cancer; Absolute neutrophil count and cancer; ANC and cancer ... A person with cancer can get a low white blood cell count from the cancer or from treatment for the cancer. Cancer may ...

  14. Lapatinib in Treating Patients With Locally Advanced or Metastatic Biliary Tract or Liver Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2014-12-18

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  15. Interventional Endoscopy Database for Pancreatico-biliary, Gastrointestinal and Esophageal Disorders

    ClinicalTrials.gov

    2015-06-01

    Ampullary Cancer; Duodenal Cancer; Bile Duct Cancer; Bile Duct Disorders; Gallstones; Obstructive Jaundice; Pancreatic Disorders (Noncancerous); Colorectal Cancer; Esophageal Cancer; Barrett's Esophagus; Gastric Malignancies; Pancreatic Cancer; Pediatric Gastroenterology; Cholangiocarcinoma; Pancreatic Pseudocysts; Acute and Chronic Pancreatitis; Recurrent Pancreatitis; Cholangitis; Bile Leak; Biliary Strictures; Pancreatic Divisum; Biliary and Pancreatic Stones; Choledocholithiasis

  16. Rotavirus Infects Human Biliary Epithelial Cells and Stimulates Secretion of Cytokines IL-6 and IL-8 via MAPK Pathway

    PubMed Central

    Clemente, Maria Grazia; Patton, John T.; Anders, Robert A.; Yolken, Robert H.; Schwarz, Kathleen B.

    2015-01-01

    Biliary atresia (BA) is an infantile inflammatory cholangiopathy of unknown etiology although epidemiologic studies and animal models utilizing rotavirus (RV) have suggested a role for viral infection. Proinflammatory and profibrotic cytokines have been detected in infants with BA. The purpose of our study was to investigate the susceptibility of human cholangiocytes (H69 cells) to infection with RRV and to determine if this infection resulted in cytokine secretion. Infection of H69 cells by RRV was noncytolytic and resulted in a time-dependent increase in the release of both infectious virions and cytokines IL-6 and IL-8 into the supernate. The greatest difference in cytokine supernatant levels between infected and mock-infected cells was noted at 24 hours postinfection (h p.i.) for IL-8, 556 ± 111 versus 77 ± 68 pg/mL (p < 0.0001), and at 48 h p.i. for IL-6, 459 ± 64 versus 67 ± 2 pg/mL (p < 0.0001). Production of both cytokines following RRV infection was significantly reduced by pretreating the H69 cells with inhibitors of mitogen-activated protein kinase (MAPK). Conclusion. RRV can infect human cholangiocytes resulting in the production of proinflammatory and profibrotic cytokines via the MAPK pathway. RRV-infected H69 cells could be a useful model system for investigating the viral hypothesis of BA. PMID:26247025

  17. Establishment and characterization of novel xenograft models of human biliary tract carcinomas.

    PubMed

    Emura, Fabian; Kamma, Hiroshi; Ghosh, Mila; Koike, Naoto; Kawamoto, Toru; Saijo, Kaoru; Ohno, Tadao; Ohkohchi, Nobuhiro; Todoroki, Takeshi

    2003-11-01

    In order to develop new therapeutic regimens for biliary tract cancers, which carry dismal prognoses, the establishment of a human biliary tract cancer xenograft model is essential. Herein, we report the successful establishment and characterization of two xenograft models of human biliary tract cancers. An adenosquamous gallbladder cancer cell line (TGBC-44) and a bile duct adenocarcinoma cell line (TGBC-47) were obtained from fresh surgical specimens in our department and subcutaneously inoculated into nude mice. The overall tumor take rate was 100% and solid tumors grew measurable after 5 and 7 days for TGBC-44 and TGBC-47, respectively. Tumor doubling time was 3.9+/-1.1 and 4.1+/-0.5 days in the exponential growth phase in TGBC-44 and TGBC-47 xenografts, respectively. Isozyme test and karyotype analysis confirmed the human origin. Histopathology analysis revealed that the TGBC-44 xenograft retained both the squamous and the adenocarcinoma components, and the TGBC-47 xenograft exhibited poorly differentiated adenocarcinoma as in the corresponding original tumors. Immunohistochemistry and Western blotting studies revealed positive and similar expression of platelet derived endothelial growth factor/thymidine phosphorylase (PDGF/TP), thymidylate synthase (TS), and cyclooxygenase-2 (COX-2) in both original tumors and xenograft models. No macroscopic metastases were found at the time of sacrifice. We have successfully established two models of human biliary tract cancer, gallbladder and bile duct cancer. Models retained the morphological and biochemical characteristics of the original tumor and demonstrated constant biological behavior in all transplanted mice. These models could be useful tools for developing new diagnostic and therapeutic strategies against biliary tract cancers. PMID:14532968

  18. Extragonadal Germ Cell Cancer (EGC)

    MedlinePlus

    ... Testicular Cancer Resource Center Extragonadal Germ Cell Cancer (EGC) 95% of all testicular tumors are germ cell ... seen in young adults. Patients with mediastinal nonseminomatous EGC are typically classed as poor risk patients because ...

  19. Pancreatic small cell cancer.

    PubMed

    El Rassy, Elie; Tabchi, Samer; Kourie, Hampig Raphael; Assi, Tarek; Chebib, Ralph; Farhat, Fadi; Kattan, Joseph

    2016-06-01

    Small cell carcinoma (SCC) is most commonly associated with lung cancer. Extra-pulmonary SCC can originate in virtually any organ system, with the gastrointestinal tract being the most common site of involvement. We review the clinical presentation, pathogenesis, histology, imaging modalities and optimal therapeutic management of PSCC in light of available evidence. PMID:26566245

  20. Membrane in cancer cells

    SciTech Connect

    Galeotti, T.; Cittadini, A.; Neri, G.; Scarpa, A.

    1988-01-01

    This book contains papers presented at a conference on membranes in cancer cells. Topics covered include Oncogenies, hormones, and free-radical processes in malignant transformation in vitro and Superoxide onion may trigger DNA strand breaks in human granulorytes by acting as a membrane target.

  1. Nonsmall cell lung cancer.

    PubMed

    Sculier, Jean-Paul

    2013-03-01

    The objective of this review is to report the Clinical Year in Review proceedings in the field of nonsmall cell lung cancer that were presented at the 2012 European Respiratory Society Congress in Vienna, Austria. Various topics were reviewed, including epidemiology, screening, diagnosis, treatment, prognosis, and palliative and end of life care. PMID:23457162

  2. Phase I trial of vandetanib in combination with gemcitabine and capecitabine in patients with advanced solid tumors with an expanded cohort in pancreatic and biliary cancers.

    PubMed

    Kessler, Elizabeth R; Eckhardt, S Gail; Pitts, Todd M; Bradshaw-Pierce, Erica L; O'byrant, Cindy L; Messersmith, Wells A; Nallapreddy, Sujatha; Weekes, Colin; Spratlin, Jennifer; Lieu, Christopher H; Kane, Madeleine A; Eppers, Sarah; Freas, Elizabeth; Leong, Stephen

    2016-04-01

    Background Vandetanib is a multitargeted tyrosine kinase inhibitor that affects vascular endothelial growth factor receptor (VEGF), epidermal growth factor (EGF), and rearranged during transfection (RET) mediated receptors which are important for growth and invasion of biliary and pancreatic cancers. This phase I study evaluated the safety profile of vandetanib in combination with standard doses of gemcitabine and capecitabine in order to determine the maximum tolerated dose (MTD). Methods In this single center phase I trial, patients received gemcitabine intravenously (IV) at 1000 mg/m2 days 1, 8, 15 in a 28 day cycle, capecitabine orally at 850 mg/m2 twice daily on days 1-21, and escalating doses of vandetanib (200 or 300 mg orally daily). Once the MTD was defined, an expansion cohort of patients with advanced biliary cancers and locally advanced or metastatic pancreatic cancer was enrolled. Blood samples were also collected at predetermined time points for biomarker analysis. Results Twenty-three patients were enrolled: 9 in the dose escalation and 14 in the dose expansion cohort. One dose limiting toxicity (DLT), of grade 4 neutropenia, occurred in the 200 mg vandetanib cohort. The most common adverse effects were diarrhea (39 %), nausea and vomiting (34 %), and rash (33 %). There were 3 partial responses and stable disease of >2 months (range 2-45, median 5) was observed in 15/23 patients. There was no association between changes in biomarker analytes and disease response. Conclusion The combination of gemcitabine, capecitabine and vandetanib is well tolerated at the recommended phase II dose of gemcitabine 1000 mg/m2 weekly for three consecutive weeks, capecitabine 850 mg/m2 BID days 1-21, and vandetanib 300 mg daily, every 28 days. This combination demonstrated promising activity in pancreaticobiliary cancers and further evaluation is warranted in these diseases. NCT00551096. PMID:26715573

  3. Relationship between UGT1A1*6/*28 polymorphisms and severe toxicities in Chinese patients with pancreatic or biliary tract cancer treated with irinotecan-containing regimens

    PubMed Central

    Yang, Chen; Liu, Ying; Xi, Wen-qi; Zhou, Chen-fei; Jiang, Jin-ling; Ma, Tao; Ye, Zheng-bao; Zhang, Jun; Zhu, Zheng-gang

    2015-01-01

    Purpose The aim of this retrospective study was to investigate the relationship between UGT1A1 polymorphisms and toxicities in Chinese patients with pancreatic or biliary tract cancer receiving irinotecan-containing regimens as the second- or third-line chemotherapy. Patients and methods A total of 36 patients with unresectable pancreatic cancer and 12 patients with unresectable biliary tract cancer were included. Approximately 33 patients were treated with FOLFIRI regimen, a chemotherapy regimen, where FOL stands for folinic acid, F for fluorouracil, and IRI for irinotecan (irinotecan 180 mg/m2 at day 1, CF 200 mg/m2 at day 1–2, 5-FU 400 mg/m2 at day 1–2, followed by continuous infusion of 5-FU 600 mg/m2 for 22 hours at day 1–2, every 2 weeks). The other 15 patients were treated with irinotecan monotherapy (180 mg/m2, every 2 weeks). UGT1A1*6/*28 polymorphisms were detected by direct sequencing. Results The frequencies of GG, GA, AA genotypes for UGT1A1*6 were 70.8% (n=34), 25.0% (n=12), and 4.2% (n=2), respectively. And those of TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 were 79.2% (n=38), 18.8% (n=9), and 2.0% (n=1), respectively. A total of 22 patients (45.8%) had grade III–IV neutropenia, and six patients (12.5%) experienced grade III–IV diarrhea. The incidence of grade III–IV neutropenia in patients with UGT1A1*6 GA or AA genotype was 71.4%, which was significantly higher than that with GG genotype (35.3%, P=0.022). No relationship was found between grade III–IV neutropenia and UGT1A1*28 polymorphism. The statistical analysis between grade III–IV diarrhea and UGT1A1*6/*28 polymorphisms was not conducted in view of the limited number of patients. Conclusion In Chinese patients with pancreatic or biliary tract cancer administered irinotecan-containing regimens, those with UGT1A1*6 variant may have a high risk of severe neutropenia. PMID:26229432

  4. Primary biliary cirrhosis

    MedlinePlus

    Primary biliary cirrhosis is irritation and swelling (inflammation) of the bile ducts of the liver. This blocks the flow ... ducts in the liver is not known. However, primary biliary cirrhosis is an autoimmune disorder. That means your body's ...

  5. Irradiation of biliary carcinoma

    SciTech Connect

    Herskovic, A.; Heaston, D.; Engler, M.J.; Fishburn, R.I.; Jones, R.S.; Noell, K.T.

    1981-04-01

    External and interstitial irradiation have effected the disappearance of biliary lesions. The use of indwelling catheters in the biliary tract makes the technique more appealing. Iridium 192 implants were used.

  6. Small Cell Lung Cancer

    PubMed Central

    Kalemkerian, Gregory P.; Akerley, Wallace; Bogner, Paul; Borghaei, Hossein; Chow, Laura QM; Downey, Robert J.; Gandhi, Leena; Ganti, Apar Kishor P.; Govindan, Ramaswamy; Grecula, John C.; Hayman, James; Heist, Rebecca Suk; Horn, Leora; Jahan, Thierry; Koczywas, Marianna; Loo, Billy W.; Merritt, Robert E.; Moran, Cesar A.; Niell, Harvey B.; O’Malley, Janis; Patel, Jyoti D.; Ready, Neal; Rudin, Charles M.; Williams, Charles C.; Gregory, Kristina; Hughes, Miranda

    2013-01-01

    Neuroendocrine tumors account for approximately 20% of lung cancers; most (≈15%) are small cell lung cancer (SCLC). These NCCN Clinical Practice Guidelines in Oncology for SCLC focus on extensive-stage SCLC because it occurs more frequently than limited-stage disease. SCLC is highly sensitive to initial therapy; however, most patients eventually die of recurrent disease. In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. Most cases of SCLC are attributable to cigarette smoking; therefore, smoking cessation should be strongly promoted. PMID:23307984

  7. Safety and Immune Response to a Multi-component Immune Based Therapy (MKC1106-PP) for Patients With Advanced Cancer.

    ClinicalTrials.gov

    2010-08-02

    Ovarian; Melanoma; Renal; Prostate; Colorectal; Endometrial Carcinoma; Cervical Carcinoma; Testicular Cancer; Thyroid Cancer; Small Cell Lung Carcinoma; Mesothelioma; Breast Carcinoma; Esophageal Carcinoma; Gastric Cancer; Pancreatic Carcinoma; Neuroendocrine Cancer; Liver Cancer; Gallbladder Cancer; Biliary Tract Cancer; Anal Carcinoma; Bone Sarcomas; Soft Tissue Sarcomas; Carcinoma of Unknown Origin, Primary

  8. [Radiotherapy of cancers of the pancreas and extrahepatic biliary tree. Gross tumor volume (GTV). Clinical target volume (CTV)].

    PubMed

    Atlan, D; Mornex, F

    2001-10-01

    Anatomical data of pancreas, biliary tree, regional lymph nodes is required to define GTV and CTV. In case of postoperative irradiation, CTV is designed in collaboration with radiation oncologist and surgeon oncologist. For exclusive radiotherapy, endodigestive ultrasonography, CT scan and MRI could help radiation oncologist defining GTV. Although, accuracy of all the imaging techniques in past years remains poor. Currently, no available literature is published regarding security margins for the definition of CTV. Therefore, recommendations according to clinical experience are proposed. PMID:11715305

  9. The Distribution and the Fibrotic Role of Elevated Inflammatory Th17 Cells in Patients With Primary Biliary Cirrhosis

    PubMed Central

    Shi, TianYan; Zhang, Ting; Zhang, LiNa; Yang, YunJiao; Zhang, HaoZe; Zhang, FengChun

    2015-01-01

    Abstract T helper (Th) 17 cells were reported to have the property of proinflammation and profibrosis. We first investigate the levels of Th17 cells in primary biliary cirrhosis (PBC) patients, and then explore their distribution and fibrotic role in the disease. We compared the circulating Th17 and hepatic interleukin (IL)-17-positive cells between patients and healthy controls (HCs) at different disease stages by flow cytometry and immunohistochemistry, respectively. The levels of chemokine (c-c motif) ligand (CCL) 20 were then measured. For exploration of the reason why Th17 cells increased, CD4+CD161+ populations were sorted and cultured with IL-23 and IL-1β to analyze their proliferation and IL-17 secretions. The serum IL-23 and IL-1β were tested by enzyme-linked immunosorbent assay. The proliferation and expressions of α-smooth muscle actin and IL-8 of hepatic stellate cells (HSCs) were identified after stimulated by different concentrations of IL-17. Circulating and hepatic Th17 cells were elevated in PBC patients compared with HCs. Early PBC patients presented with more Th17 cells in periphery blood and less in the liver than advanced PBC patients. Accordingly, the levels of both serum and hepatic CCL20 for Th17 cells were higher, especially in those with advanced disease. The progenitor of Th17, CD4+CD161+ cell was increased in PBC. Moreover, the percentage of Th17 cells was positively related with CD4+CD161+ cell. After stimulation with IL-23 and IL-1β which were improved in PBC patients, CD4+CD161+ cells from PBC patients expressed more IL-17, although their proliferation were not different between 2 groups. IL-17 can promote the proliferation of HSCs at a dose-dependent method, and also increase the IL-8 expression in a dose/time-dependent way. Anti-IL-17 can neutralize the above reactions. CD4+CD161+ cells are a source of increased Th17 in PBC patients. With disease progression, Th17 population decreased in the circulation, accompanied by greater

  10. Stochastic elimination of cancer cells.

    PubMed Central

    Michor, Franziska; Nowak, Martin A; Frank, Steven A; Iwasa, Yoh

    2003-01-01

    Tissues of multicellular organisms consist of stem cells and differentiated cells. Stem cells divide to produce new stem cells or differentiated cells. Differentiated cells divide to produce new differentiated cells. We show that such a tissue design can reduce the rate of fixation of mutations that increase the net proliferation rate of cells. It has, however, no consequence for the rate of fixation of neutral mutations. We calculate the optimum relative abundance of stem cells that minimizes the rate of generating cancer cells. There is a critical fraction of stem cell divisions that is required for a stochastic elimination ('wash out') of cancer cells. PMID:14561289

  11. Altered expression of miR-92a correlates with Th17 cell frequency in patients with primary biliary cirrhosis

    PubMed Central

    LIANG, DONG-YU; HOU, YAN-QIANG; LUO, LI-JUN; AO, LI

    2016-01-01

    MicroRNAs (miRNAs or miRs) are small, non-coding RNA molecules that play significant roles in numerous diseases. However, there is limited information regarding the plasma expression of miRNAs in patients with primary biliary cirrhosis (PBC) as well as the potential role of miRNAs in the development of PBC. miRNA microarray analysis was performed using plasma obtaind from three patients with PBC and three healthy controls. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to confirm the differential expression of miRNAs in the plasma and peripheral blood mononuclear cells (PBMCs) isolated from 20 patients with PBC, 20 patients with chronic hepatitis B (CHB) and 20 healthy controls. These miRNAs in PBMCs and plasma were validated by linear regression analyses. The T cell subset frequency was analyzed by flow cytometry. Correlations between altered miRNA expression and the frequency of the T cell subsets were determined by linear regression analyses. The co-expression of miRNAs and IL-17A was examined using fluorescence in situ hybridization (FISH) and immunohistochemistry. The microarray analysis identified sixteen miRNAs that were differentially expressed. Four miRNAs were validated by RT-qPCR. The expression pattern of miR-572 and miR-92a in the PBMCs correlated with the expression pattern in plasma. We also found that miR-92a expression closely correlated with the frequency of a subset of IL-17-producing T helper cells (Th17), and that miR-92a was co-expressed with IL-17A in patients with PBC. Taken together, these findings revealed that plasma from patients with PBC has a unique miRNA expression profile. Moreover, miR-92a may play an important role in the pathogenesis of PBC by regulating Th17 cell differentiation. PMID:27246196

  12. Increased IL-23 and IL-17 expression by peripheral blood cells of patients with primary biliary cirrhosis.

    PubMed

    Qian, Cheng; Jiang, Tingwang; Zhang, Weiwei; Ren, Chuanlu; Wang, Qianqian; Qin, Qin; Chen, Jie; Deng, Anmei; Zhong, Renqian

    2013-10-01

    Primary biliary cirrhosis (PBC) is a typical autoimmune disease for which the pathogenesis remains unclear. IL-23 and IL-17 are pro-inflammatory cytokines of the "IL-23/IL-17 axis," which may play a key role in the pathogenesis of autoimmune diseases. In this study, we investigated the expression of IL-23 and IL-17 in the peripheral blood of patients with PBC and its clinical significance. We used quantitative PCR to determine mRNA expressions of IL-23, IL-23 receptor, and IL-17 in peripheral blood mononuclear cells (PBMC) from PBC patients. ELISA's were used to determine patients' serum levels of IL-23 and IL-17. IL-23- and IL-17-producing cells in liver biopsis were also analyzed. Compared to a healthy control group, the mRNA expression levels of IL-23 p19, its corresponding receptor, IL-23R, and IL-17 in PBMC's from PBC patients were significantly increased, and these levels were correlated with PBC disease stages. PBC patients' serum levels of IL-23 and IL-17 were higher than those in a post-hepatic cirrhosis group and a healthy group, and were significantly higher in the early PBC disease stages than in the advanced PBC stages. There were significantly more IL23+ and IL-17+ mononuclear cells in portal areas of liver tissues in advanced stages of this disease than in the early stages. The serum levels of IL-23 and IL-17 in PBC patients were positively correlated with serum GGT levels. Thus, IL-23 and IL-17 may play an important role in the pathogenesis of PBC by promoting inflammation. Because the IL-23 and IL-17 levels in the peripheral blood of PBC patients were increased and were correlated with clinical stages, they may be indices that could be used to clinically monitor PBC. PMID:23910013

  13. Targeting Breast Cancer Stem Cells

    PubMed Central

    Liu, Suling; Wicha, Max S.

    2010-01-01

    There is increasing evidence that many cancers, including breast cancer, contain populations of cells that display stem-cell properties. These breast cancer stem cells, by virtue of their relative resistance to radiation and cytotoxic chemotherapy, may contribute to treatment resistance and relapse. The elucidation of pathways that regulate these cells has led to the identification of potential therapeutic targets. A number of agents capable of targeting breast cancer stem cells in preclinical models are currently entering clinical trials. Assessment of the efficacy of the agents will require development of innovative clinical trial designs with appropriate biologic and clinical end points. The effective targeting of breast cancer stem cells has the potential to significantly improve outcome for women with both early-stage and advanced breast cancer. PMID:20498387

  14. Treatment Option Overview (Small Cell Lung Cancer)

    MedlinePlus

    ... Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points ...

  15. Stages of Small Cell Lung Cancer

    MedlinePlus

    ... Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points ...

  16. Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury

    PubMed Central

    Chen, Ya-Hui; Chen, Hui-Ling; Chien, Chin-Sung; Wu, Shang-Hsin; Ho, Yi-Tian; Yu, Chun-Hsien; Chang, Mei-Hwei

    2015-01-01

    Whether hepatocytes can convert into biliary epithelial cells (BECs) during biliary injury is much debated. To test this concept, we traced the fate of genetically labeled [dipeptidyl peptidase IV (DPPIV)-positive] hepatocytes in hepatocyte transplantation model following acute hepato-biliary injury induced by 4,4’-methylene-dianiline (DAPM) and D-galactosamine (DAPM+D-gal) and in DPPIV-chimeric liver model subjected to acute (DAPM+D-gal) or chronic biliary injury caused by DAPM and bile duct ligation (DAPM+BDL). In both models before biliary injury, BECs are uniformly DPPIV-deficient and proliferation of DPPIV-deficient hepatocytes is restricted by retrorsine. We found that mature hepatocytes underwent a stepwise conversion into BECs after biliary injury. In the hepatocyte transplantation model, DPPIV-positive hepatocytes entrapped periportally proliferated, and formed two-layered plates along portal veins. Within the two-layered plates, the hepatocytes gradually lost their hepatocytic identity, proceeded through an intermediate state, acquired a biliary phenotype, and subsequently formed bile ducts along the hilum-to-periphery axis. In DPPIV-chimeric liver model, periportal hepatocytes expressing hepatocyte nuclear factor-1β (HNF-1β) were exclusively DPPIV-positive and were in continuity to DPPIV-positives bile ducts. Inhibition of hepatocyte proliferation by additional doses of retrorsine in DPPIV-chimeric livers prevented the appearance of DPPIV-positive BECs after biliary injury. Moreover, enriched DPPIV-positive BEC/hepatic oval cell transplantation produced DPPIV-positive BECs or bile ducts in unexpectedly low frequency and in mid-lobular regions. These results together suggest that mature hepatocytes but not contaminating BECs/hepatic oval cells are the sources of periportal DPPIV-positive BECs. We conclude that mature hepatocytes contribute to biliary regeneration in the environment of acute and chronic biliary injury through a ductal plate

  17. Pediatric Biliary Interventions.

    PubMed

    Atchie, Benjamin; Kalva, Sanjeeva; Josephs, Shellie

    2015-12-01

    An interventional radiologist is frequently called to evaluate and treat biliary diseases in children; a tailored approach specific to this population is required. Imaging with an emphasis on minimizing ionizing radiation is used not only in the initial workup but also to guide interventions. The most common form of intervention generally consists of transhepatic biliary drainage to treat either biliary obstruction or bile leakage, a scenario frequently encountered after pediatric liver transplantation. Other pathologies referred for evaluation and management include biliary atresia and, rarely, symptomatic choledochal cysts. Biliary complications caused by an underlying malignancy are not a frequently encountered problem in the pediatric population. The initial evaluation, role of preprocedural imaging, and interventional management with an emphasis on technique are discussed regarding these common biliary pathologies in children. PMID:26615168

  18. Altered expression of miR-92a correlates with Th17 cell frequency in patients with primary biliary cirrhosis.

    PubMed

    Liang, Dong-Yu; Hou, Yan-Qiang; Luo, Li-Jun; Ao, Li

    2016-07-01

    MicroRNAs (miRNAs or miRs) are small, non-coding RNA molecules that play significant roles in numerous diseases. However, there is limited information regarding the plasma expression of miRNAs in patients with primary biliary cirrhosis (PBC) as well as the potential role of miRNAs in the development of PBC. miRNA microarray analysis was performed using plasma obtaind from three patients with PBC and three healthy controls. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to confirm the differential expression of miRNAs in the plasma and peripheral blood mononuclear cells (PBMCs) isolated from 20 patients with PBC, 20 patients with chronic hepatitis B (CHB) and 20 healthy controls. These miRNAs in PBMCs and plasma were validated by linear regression analyses. The T cell subset frequency was analyzed by flow cytometry. Correlations between altered miRNA expression and the frequency of the T cell subsets were determined by linear regression analyses. The co-expression of miRNAs and IL-17A was examined using fluorescence in situ hybridization (FISH) and immunohistochemistry. The microarray analysis identified sixteen miRNAs that were differentially expressed. Four miRNAs were validated by RT-qPCR. The expression pattern of miR-572 and miR-92a in the PBMCs correlated with the expression pattern in plasma. We also found that miR-92a expression closely correlated with the frequency of a subset of IL-17-producing T helper cells (Th17), and that miR-92a was co-expressed with IL-17A in patients with PBC. Taken together, these findings revealed that plasma from patients with PBC has a unique miRNA expression profile. Moreover, miR-92a may play an important role in the pathogenesis of PBC by regulating Th17 cell differentiation. PMID:27246196

  19. Lung cancer - non-small cell

    MedlinePlus

    Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Smoking causes most cases (around 90%) of lung cancer. The risk depends on the number of cigarettes ...

  20. Role of stents and laser therapy in biliary strictures

    NASA Astrophysics Data System (ADS)

    Chennupati, Raja S.; Trowers, Eugene A.

    2001-05-01

    The most frequent primary cancers causing malignant obstructive jaundice were pancreatic cancer (57%), hilar biliary cancer (19% including metastatic disease), nonhilar biliary cancer (14%) and papillary cancer (10%). Endoscopic stenting has widely replaced palliative surgery for malignant biliary obstruction because of its lower risk and cost. Self-expandable metal stents are the preferred mode of palliation for hilar malignancies. Plastic stents have a major role in benign biliary strictures. Major complications and disadvantages associated with metallic stents include high cost, cholangitis. malposition, migration, unextractability, and breakage of the stents, pancreatitis and stent dysfunction. Dysfunction due to tumor ingrowth can be relieved by thermal methods (argon plasma coagulator therapy). We present a concise review of the efficacy of metallic stents for palliation of malignant strictures.

  1. Contemporary Renal Cell Cancer Epidemiology

    PubMed Central

    Chow, Wong-Ho; Devesa, Susan S.

    2010-01-01

    We analyzed renal cell cancer incidence patterns in the United States and reviewed recent epidemiologic evidence with regard to environmental and host genetic determinants of renal cell cancer risk. Renal cell cancer incidence rates continued to rise among all racial/ethnic groups in the United States, across all age groups, and for all tumor sizes, with the most rapid increases for localized stage disease and small tumors. Recent cohort studies confirmed the association of smoking, excess body weight, and hypertension with an elevated risk of renal cell cancer, and suggested that these factors can be modified to reduce the risk. There is increasing evidence for an inverse association between renal cell cancer risk and physical activity and moderate intake of alcohol. Occupational exposure to TCE has been positively associated with renal cell cancer risk in several recent studies, but its link with somatic mutations of the VHL gene has not been confirmed. Studies of genetic polymorphisms in relation to renal cell cancer risk have produced mixed results, but genome-wide association studies with larger sample size and a more comprehensive approach are underway. Few epidemiologic studies have evaluated risk factors by subtypes of renal cell cancer defined by somatic mutations and other tumor markers. PMID:18836333

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

    PubMed Central

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

    2016-01-01

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

  3. Adult Human Biliary Tree Stem Cells Differentiate to β-Pancreatic Islet Cells by Treatment with a Recombinant Human Pdx1 Peptide

    PubMed Central

    Scafetta, Gaia; Renzi, Anastasia; De Canio, Michele; Sicilia, Francesca; Nevi, Lorenzo; Casa, Domenico; Panetta, Rocco; Berloco, Pasquale Bartolomeo; Reid, Lola M.; Federici, Giorgio; Gaudio, Eugenio; Maroder, Marella; Alvaro, Domenico

    2015-01-01

    Generation of β-pancreatic cells represents a major goal in research. The aim of this study was to explore a protein-based strategy to induce differentiation of human biliary tree stem cells (hBTSCs) towards β-pancreatic cells. A plasmid containing the sequence of the human pancreatic and duodenal homeobox 1 (PDX1) has been expressed in E. coli. Epithelial-Cell-Adhesion-Molecule positive hBTSCs or mature human hepatocyte cell line, HepG2, were grown in medium to which Pdx1 peptide was added. Differentiation toward pancreatic islet cells were evaluated by the expression of the β-cell transcription factors, Pdx1 and musculoapo-neurotic fibrosarcoma oncogene homolog A, and of the pancreatic hormones, insulin, glucagon, and somatostatin, investigated by real time polymerase chain reaction, western blot, light microscopy and immunofluorescence. C-peptide secretion in response to high glucose was also measured. Results indicated how purified Pdx1 protein corresponding to the primary structure of the human Pdx1 by mass spectroscopy was efficiently produced in bacteria, and transduced into hBTSCs. Pdx1 exposure triggered the expression of both intermediate and mature stage β-cell differentiation markers only in hBTSCs but not in HepG2 cell line. Furthermore, hBTSCs exposed to Pdx1 showed up-regulation of insulin, glucagon and somatostatin genes and formation of 3-dimensional islet-like structures intensely positive for insulin and glucagon. Finally, Pdx1-induced islet-like structures exhibited glucose-regulated C-peptide secretion. In conclusion, the human Pdx1 is highly effective in triggering hBTSC differentiation toward functional β-pancreatic cells. PMID:26252949

  4. Adult Human Biliary Tree Stem Cells Differentiate to β-Pancreatic Islet Cells by Treatment with a Recombinant Human Pdx1 Peptide.

    PubMed

    Cardinale, Vincenzo; Puca, Rosa; Carpino, Guido; Scafetta, Gaia; Renzi, Anastasia; De Canio, Michele; Sicilia, Francesca; Nevi, Lorenzo; Casa, Domenico; Panetta, Rocco; Berloco, Pasquale Bartolomeo; Reid, Lola M; Federici, Giorgio; Gaudio, Eugenio; Maroder, Marella; Alvaro, Domenico

    2015-01-01

    Generation of β-pancreatic cells represents a major goal in research. The aim of this study was to explore a protein-based strategy to induce differentiation of human biliary tree stem cells (hBTSCs) towards β-pancreatic cells. A plasmid containing the sequence of the human pancreatic and duodenal homeobox 1 (PDX1) has been expressed in E. coli. Epithelial-Cell-Adhesion-Molecule positive hBTSCs or mature human hepatocyte cell line, HepG2, were grown in medium to which Pdx1 peptide was added. Differentiation toward pancreatic islet cells were evaluated by the expression of the β-cell transcription factors, Pdx1 and musculoapo-neurotic fibrosarcoma oncogene homolog A, and of the pancreatic hormones, insulin, glucagon, and somatostatin, investigated by real time polymerase chain reaction, western blot, light microscopy and immunofluorescence. C-peptide secretion in response to high glucose was also measured. Results indicated how purified Pdx1 protein corresponding to the primary structure of the human Pdx1 by mass spectroscopy was efficiently produced in bacteria, and transduced into hBTSCs. Pdx1 exposure triggered the expression of both intermediate and mature stage β-cell differentiation markers only in hBTSCs but not in HepG2 cell line. Furthermore, hBTSCs exposed to Pdx1 showed up-regulation of insulin, glucagon and somatostatin genes and formation of 3-dimensional islet-like structures intensely positive for insulin and glucagon. Finally, Pdx1-induced islet-like structures exhibited glucose-regulated C-peptide secretion. In conclusion, the human Pdx1 is highly effective in triggering hBTSC differentiation toward functional β-pancreatic cells. PMID:26252949

  5. Molecular genetics and targeted therapeutics in biliary tract carcinoma

    PubMed Central

    Marks, Eric I; Yee, Nelson S

    2016-01-01

    The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract. PMID:26819503

  6. Preoperative biliary drainage.

    PubMed

    Saxena, Payal; Kumbhari, Vivek; Zein, Mohamad E L; Khashab, Mouen A

    2015-01-01

    The role of preoperative biliary drainage (PBD) in patients with distal or proximal biliary obstruction secondary to resectable tumors has been a matter for debate. A review of the literature using Medline, Embase and Cochrane databases was undertaken for studies evaluating routes of drainage (endoscopic or percutaneous) and stent types (plastic or metal) in patients with resectable disease. Preoperative biliary drainage is indicated for relief of symptomatic jaundice, cholangitis, patients undergoing neoadjuvant therapy or those patients where surgery may be delayed. Endoscopic methods are preferred over percutaneous methods because of lower complication rates. In patients with proximal biliary obstruction, PBD should be guided by imaging studies to aid in selective biliary cannulation for unilateral drainage in order to reduce the risk of cholangitis in undrained liver segments. PMID:25293587

  7. Acute Biliary Septic Shock

    PubMed Central

    1990-01-01

    Forty-seven cases of biliary tract infection with septic shock are presented. The sepsis was caused by empyema of the gallbladder in 23 cases and by cholangitis in the remainder. Gallstones were most frequently the cause of the sepsis. An appropriate diagnostic description of the syndrome of biliary tract infection and septic shock should therefore include a description of the underlying biliary disease as well as the term acute biliary shock. In this series, emergency surgical management by removal of gallstones and drainage of suppuration was felt to be the most appropriate treatment. There was a high incidence of gallbladder rupture (10.6%) and intrahepatic stones (53.2%). Of the 13 patients who died, 8 might have survived if early operation had been performed after the diagnosis of acute biliary septic shock was established. PMID:2278914

  8. Autophagy, cell death, and cancer

    PubMed Central

    Lin, Lin; Baehrecke, Eric H

    2015-01-01

    Autophagy is an evolutionarily conserved intracellular catabolic process that is used by all cells to degrade dysfunctional or unnecessary cytoplasmic components through delivery to the lysosome. Increasing evidence reveals that autophagic dysfunction is associated with human diseases, such as cancer. Paradoxically, although autophagy is well recognized as a cell survival process that promotes tumor development, it can also participate in a caspase-independent form of programmed cell death. Induction of autophagic cell death by some anticancer agents highlights the potential of this process as a cancer treatment modality. Here, we review our current understanding of the molecular mechanism of autophagy and the potential roles of autophagy in cell death, cancer development, and cancer treatment. PMID:27308466

  9. Drugs Approved for Kidney (Renal Cell) Cancer

    MedlinePlus

    ... Ask about Your Treatment Research Drugs Approved for Kidney (Renal Cell) Cancer This page lists cancer drugs ... that are not listed here. Drugs Approved for Kidney (Renal Cell) Cancer Afinitor (Everolimus) Aldesleukin Avastin (Bevacizumab) ...

  10. Myofibroblastic cell activation and neovascularization predict native liver survival and development of esophageal varices in biliary atresia

    PubMed Central

    Suominen, Janne S; Lampela, Hanna; Heikkilä, Päivi; Lohi, Jouko; Jalanko, Hannu; Pakarinen, Mikko P

    2014-01-01

    AIM: To study the relation between collagen 1, α-smooth muscle actin (α-SMA) and CD34 expression and the most essential portoenterostomy (PE) outcomes. METHODS: Liver specimens were obtained at PE from 33 biliary atresia (BA) patients for immunohistochemical analysis of collagen 1, α-SMA and CD34. Liver biopsies from 35 organ donors were used as controls. Expression patterns were related to clinical data including age at PE, serum total and conjugated bilirubin concentration at the time of PE and during follow-up, incidence of esophageal varices in follow-up upper gastrointestinal endoscopies, and native liver survival as well as to detailed histopathological findings. RESULTS: Collagen 1 (16.4% vs 4.5%, P < 0.0001), α-SMA (17.9% vs 4.6%, P < 0.0001) and CD34 (4.9% vs 3.8%, P = 0.017) were markedly overexpressed in BA patients compared with controls. Patients who underwent liver transplantation by age of two years had significantly higher expression of collagen 1 (18.6% vs 13.7%, P = 0.024), α-SMA (20.4% vs 15.4%, P = 0.009) and CD34 (5.9% vs 4.0%, P = 0.029) at PE compared with native liver survivors. CD34-positive microvessels were identified in the centrizonal region close to central vein in every BA patient. In majority of BA cases (56%) neovascularization was frequent as CD34-positive microvessels were observed in over half of the hepatic lobules. In controls, the CD34-positive microvessels were rare as they were completely absent in 40 % and were found in less than 5 % of the hepatic lobules in the rest. The difference between BA patients and controls was significant (P < 0.0001). Patients who developed esophageal varices by two years had significantly higher expression of CD34 at PE compared with patients without varices (5.6% vs 4.0%, P = 0.019). Expression of α-SMA (r = 0.758, P < 0.0001) and collagen 1 (r = 0.474, P = 0.016), and the amount of CD34-positive microvessels (r = 0.356, P = 0.047) were related to patient age at PE. CONCLUSION: Hepatic

  11. Red Blood Cell Distribution Width to Platelet Ratio is Related to Histologic Severity of Primary Biliary Cirrhosis.

    PubMed

    Wang, Huan; Xu, Hongqin; Wang, Xiaomei; Wu, Ruihong; Gao, Xiuzhu; Jin, Qinglong; Niu, Junqi

    2016-03-01

    We aimed to investigate whether red blood cell distribution width (RDW) and RDW to platelet ratio (RPR) were related to the histologic severity of primary biliary cirrhosis (PBC).Seventy-three treatment-naïve PBC patients who had undergone a liver biopsy between January 2010 and January 2015 were enrolled in our study. The patients' histological stages were based on the classifications of Ludwig and Scheuer. The patients were divided into early stage (Stage I) and advanced stage (Stage II, III, and IV) hepatic fibrosis according to their histological stage. All common patient demographics, clinical characteristics, hematological parameters, liver biochemistry, and antimitochondrial M2 antibody levels (AMA-M2) were retrospectively analyzed, and RDW, RPR, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis index based on the 4 factors (FIB-4) were calculated.A total of 28 (38.4%) patients had early stage PBC, whereas 45 (62.6%) were classified as advanced stage. Regarding age, no significant differences between the early and advanced stages were observed. Patients with advanced stage PBC had significantly higher RDW (13.6 vs 14.4; P = 0.019), conjugated bilirubin (10.1 vs 23.4; P = 0.029), and significantly lower cholinesterase (7901.1 vs 6060.8; P = 0.001) and platelets (212.6 vs 167.0; P = 0.006). However, no significant differences (P > 0.05) in other routine parameters previously evaluated in PBC, including aspartate aminotransferase (AST) and mean platelet volume, were found between the groups. The sensitivity and specificity of RDW were 33.3% and 92.9%, respectively, and the area under the receiver-operating characteristic curve (AUROC) was 0.66. However, the sensitivity and specificity of RPR were 46.7% and 96.4%, respectively, and the corresponding AUROC was 0.74 (P < 0.001). Hence, compared with preexisting indicators, RPR showed a higher AUROC than APRI (0.648; P = 0.035) and FIB-4 (0.682; P = 0.009).RDW

  12. Red Blood Cell Distribution Width to Platelet Ratio is Related to Histologic Severity of Primary Biliary Cirrhosis

    PubMed Central

    Wang, Huan; Xu, Hongqin; Wang, Xiaomei; Wu, Ruihong; Gao, Xiuzhu; Jin, Qinglong; Niu, Junqi

    2016-01-01

    Abstract We aimed to investigate whether red blood cell distribution width (RDW) and RDW to platelet ratio (RPR) were related to the histologic severity of primary biliary cirrhosis (PBC). Seventy-three treatment-naïve PBC patients who had undergone a liver biopsy between January 2010 and January 2015 were enrolled in our study. The patients’ histological stages were based on the classifications of Ludwig and Scheuer. The patients were divided into early stage (Stage I) and advanced stage (Stage II, III, and IV) hepatic fibrosis according to their histological stage. All common patient demographics, clinical characteristics, hematological parameters, liver biochemistry, and antimitochondrial M2 antibody levels (AMA-M2) were retrospectively analyzed, and RDW, RPR, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis index based on the 4 factors (FIB-4) were calculated. A total of 28 (38.4%) patients had early stage PBC, whereas 45 (62.6%) were classified as advanced stage. Regarding age, no significant differences between the early and advanced stages were observed. Patients with advanced stage PBC had significantly higher RDW (13.6 vs 14.4; P = 0.019), conjugated bilirubin (10.1 vs 23.4; P = 0.029), and significantly lower cholinesterase (7901.1 vs 6060.8; P = 0.001) and platelets (212.6 vs 167.0; P = 0.006). However, no significant differences (P > 0.05) in other routine parameters previously evaluated in PBC, including aspartate aminotransferase (AST) and mean platelet volume, were found between the groups. The sensitivity and specificity of RDW were 33.3% and 92.9%, respectively, and the area under the receiver-operating characteristic curve (AUROC) was 0.66. However, the sensitivity and specificity of RPR were 46.7% and 96.4%, respectively, and the corresponding AUROC was 0.74 (P < 0.001). Hence, compared with preexisting indicators, RPR showed a higher AUROC than APRI (0.648; P = 0.035) and FIB-4 (0.682; P

  13. Invasive cancer cells and metastasis

    NASA Astrophysics Data System (ADS)

    Mierke, Claudia Tanja

    2013-12-01

    The physics of cancer is a relatively new emerging field of cancer research. In the last decade it has become a focus of biophysical research as well as becoming a novel focus for classical cancer research. This special section of Physical Biology focusing on invasive cancer cells and metastasis (physical oncology) will give greater insight into the different subfields where physical approaches are being applied to cancer research. This focus on the physical aspects of cancer is necessary because novel approaches in the field of genomics and proteomics have not altered the field of cancer research dramatically, due to the fact that few breakthroughs have been made. It is still not understood why some primary tumors metastasize and thus have a worse outcome compared to others that do not metastasize. As biophysicists, we and others suggest that the mechanical properties of the cancer cells, which possess the ability to transmigrate, are quite different compared to non-metastatic and non-invasive cancer cells. Furthermore, we hypothesize that these cancer cells undergo a selection process within the primary tumor that enables them to weaken their cell-cell adhesions and to alter their cell-matrix adhesions in order to be able to cross the outermost boundary of the primary tumor, as well as the surrounding basement membrane, and to invade the connective tissue. This prerequisite may also help the cancer cells to enter blood or lymph vessels, get transported with the vessel flow and form secondary tumors either within the vessel, directly on the endothelium, or in a different organ after crossing the endothelial lining a second time. This special section begins with a paper by Mark F Coughlin and Jeffrey J Fredberg on the changes in cytoskeletal dynamics and nonlinear rheology due to the metastatic capability of cancer cells from different cancer tissue types such as skin, bladder, prostate and kidney [1]. The hypothesis was that the metastatic outcome is impacted by

  14. History of biliary surgery.

    PubMed

    Spirou, Yannos; Yannos, Spirou; Petrou, Athanasios; Athanasios, Petrou; Christoforides, Christos; Christos, Christoforides; Felekouras, Evangelos; Evangelos, Felekouras

    2013-05-01

    Since ancient times biliary surgery has been one of the major interests of doctors and other scientists around the world. From the ancient Greeks and Egyptians to the greatest scientists of modern times biliary surgery has advanced remarkably. Especially during the last century huge progress has been made in this field. Minimally invasive surgical techniques have been developed and combined with general anesthesia and antisepsis that have made biliary surgery particularly safe for every patient and have made cholecystectomy one of the most common operations in the world today. PMID:23430002

  15. Characterization of acute biliary hyperplasia in Fisher 344 Rats administered the Indole-3-Carbinol Analog, NSC-743380

    SciTech Connect

    Eldridge, Sandy R.; Covey, Joseph; Morris, Joel; Fang, Bingliang; Horn, Thomas L.; Elsass, Karen E.; Hamre, John R.; McCormick, David L.; Davis, Myrtle A.

    2014-12-15

    NSC-743380 (1-[(3-chlorophenyl)-methyl]-1H-indole-3-carbinol) is in early stages of development as an anticancer agent. Two metabolites reflect sequential conversion of the carbinol functionality to a carboxaldehyde and the major metabolite, 1-[(3-chlorophenyl)-methyl]-1H-indole-3-carboxylic acid. In an exploratory toxicity study in rats, NSC-743380 induced elevations in liver-associated serum enzymes and biliary hyperplasia. Biliary hyperplasia was observed 2 days after dosing orally for 2 consecutive days at 100 mg/kg/day. Notably, hepatotoxicity and biliary hyperplasia were observed after oral administration of the parent compound, but not when major metabolites were administered. The toxicities of a structurally similar but pharmacologically inactive molecule and a structurally diverse molecule with a similar efficacy profile in killing cancer cells in vitro were compared to NSC-743380 to explore scaffold versus target-mediated toxicity. Following two oral doses of 100 mg/kg/day given once daily on two consecutive days, the structurally unrelated active compound produced hepatic toxicity similar to NSC-743380. The structurally similar inactive compound did not, but, lower exposures were achieved. The weight of evidence implies that the hepatotoxicity associated with NSC-743380 is related to the anticancer activity of the parent molecule. Furthermore, because biliary hyperplasia represents an unmanageable and non-monitorable adverse effect in clinical settings, this model may provide an opportunity for investigators to use a short-duration study design to explore biomarkers of biliary hyperplasia. - Highlights: • NSC-743380 induced biliary hyperplasia in rats. • Toxicity of NSC-743380 appears to be related to its anticancer activity. • The model provides an opportunity to explore biomarkers of biliary hyperplasia.

  16. Multicenter study of endoscopic preoperative biliary drainage for malignant distal biliary obstruction

    PubMed Central

    Sasahira, Naoki; Hamada, Tsuyoshi; Togawa, Osamu; Yamamoto, Ryuichi; Iwai, Tomohisa; Tamada, Kiichi; Kawaguchi, Yoshiaki; Shimura, Kenji; Koike, Takero; Yoshida, Yu; Sugimori, Kazuya; Ryozawa, Shomei; Kakimoto, Toshiharu; Nishikawa, Ko; Kitamura, Katsuya; Imamura, Tsunao; Mizuide, Masafumi; Toda, Nobuo; Maetani, Iruru; Sakai, Yuji; Itoi, Takao; Nagahama, Masatsugu; Nakai, Yousuke; Isayama, Hiroyuki

    2016-01-01

    AIM: To determine the optimal method of endoscopic preoperative biliary drainage for malignant distal biliary obstruction. METHODS: Multicenter retrospective study was conducted in patients who underwent plastic stent (PS) or nasobiliary catheter (NBC) placement for resectable malignant distal biliary obstruction followed by surgery between January 2010 and March 2012. Procedure-related adverse events, stent/catheter dysfunction (occlusion or migration of PS/NBC, development of cholangitis, or other conditions that required repeat endoscopic biliary intervention), and jaundice resolution (bilirubin level < 3.0 mg/dL) were evaluated. Cumulative incidence of jaundice resolution and dysfunction of PS/NBC were estimated using competing risk analysis. Patient characteristics and preoperative biliary drainage were also evaluated for association with the time to jaundice resolution and PS/NBC dysfunction using competing risk regression analysis. RESULTS: In total, 419 patients were included in the study (PS, 253 and NBC, 166). Primary cancers included pancreatic cancer in 194 patients (46%), bile duct cancer in 172 (41%), gallbladder cancer in three (1%), and ampullary cancer in 50 (12%). The median serum total bilirubin was 7.8 mg/dL and 324 patients (77%) had ≥ 3.0 mg/dL. During the median time to surgery of 29 d [interquartile range (IQR), 30-39 d]. PS/NBC dysfunction rate was 35% for PS and 18% for NBC [Subdistribution hazard ratio (SHR) = 4.76; 95%CI: 2.44-10.0, P < 0.001]; the pig-tailed tip was a risk factor for PS dysfunction. Jaundice resolution was achieved in 85% of patients and did not depend on the drainage method (PS or NBC). CONCLUSION: PS has insufficient patency for preoperative biliary drainage. Given the drawbacks of external drainage via NBC, an alternative method of internal drainage should be explored. PMID:27076764

  17. Salivary Gland Cancer Stem Cells

    PubMed Central

    Adams, April; Warner, Kristy; Nör, Jacques E.

    2013-01-01

    Emerging evidence suggests the existence of a tumorigenic population of cancer cells that demonstrate stem cell-like properties such as self-renewal and multipotency. These cells, termed cancer stem cells (CSC), are able to both initiate and maintain tumor formation and progression. Studies have shown that CSC are resistant to traditional chemotherapy treatments preventing complete eradication of the tumor cell population. Following treatment, CSC are able to re-initiate tumor growth leading to patient relapse. Salivary gland cancers are relatively rare but constitute a highly significant public health issue due to the lack of effective treatments. In particular, patients with mucoepidermoid carcinoma or adenoid cystic carcinoma, the two most common salivary malignancies, have low long-term survival rates due to the lack of response to current therapies. Considering the role of CSC in resistance to therapy in other tumor types, it is possible that this unique sub-population of cells is involved in resistance of salivary gland tumors to treatment. Characterization of CSC can lead to better understanding of the pathobiology of salivary gland malignancies as well as to the development of more effective therapies. Here, we make a brief overview of the state-of-the-science in salivary gland cancer, and discuss possible implications of the cancer stem cell hypothesis to the treatment of salivary gland malignancies. PMID:23810400

  18. Imaging of malignancies of the biliary tract- an update

    PubMed Central

    2014-01-01

    Malignancies of the biliary tract include cholangiocarcinoma, gallbladder cancers and carcinoma of the ampulla of Vater. Biliary tract adenocarcinomas are the second most common primary hepatobiliary cancer. Due to their slow growing nature, non-specific and late symptomatology, these malignancies are often diagnosed in advanced stages with poor prognosis. Apart from incidental discovery of gall bladder carcinoma upon cholecystectomy, early stage biliary tract cancers are now detected with computed tomography (CT) and magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP). Accurate characterization and staging of these indolent cancers will determine outcome as majority of the patients’ are inoperable at the time of presentation. Ultrasound is useful for initial evaluation of the biliary tract and gallbladder masses and in determining the next suitable modality for further evaluation. Multimodality imaging plays an integral role in the management of the biliary tract malignancies. The imaging techniques most useful are MRI with MRCP, endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasound (EUS) and positron emission tomography (PET). In this review we will discuss epidemiology and the role of imaging in detection, characterization and management of the biliary tract malignancies under the three broad categories of cholangiocarcinomas (intra- and extrahepatic), gallbladder cancers and ampullary carcinomas. PMID:25608662

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

    PubMed

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

    2016-01-01

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

  20. Successful endoscopic ultrasound-guided overstenting biliary drainage through a pre-existing proximal migrated metal biliary stent.

    PubMed

    Artifon, E L A; Takada, J; Okawa, L; Ferreira, F; Santos, M; Moura, E G H; Otoch, J P; Sakai, P

    2011-01-01

    Biliary endoscopic drainage using metallic self-expanded stents has become a well-established method for palliative treatment of malignant biliary obstruction. However, its occlusion, mainly by tumor overgrowth, is still the main complication without a standard treatment. We here describe a new method of treatment for biliary metallic stent occlusion, through the echo guided biliary drainage. We present a 68-year-old patient with metastatic pancreatic cancer previously treated for jaundice with ERCP and self-expandable metallic stent insertion. Four weeks later, the patient developed jaundice and symptoms of gastric outlet obstruction. A new ERCP confirmed obstruction of the second portion of the duodenum, due to diffuse tumor growth. EUS was performed, and the previous metal biliary stent was seen occluded at the distal portion in the common bile duct. A EUS-guided choledocododenostomy was performed and then, an overlapping self-expanding metal enteral stent was placed through the malignant obstruction. There were no early complications and the procedure was also clinically effective in relieving jaundice and gastric outlet obstruction symptoms. If ERCP fails in the management of occluded biliary metallic stents, EUS biliary drain can provide effective biliary decompression and should be considered an alternative to other endoscopic techniques. PMID:22041320

  1. Basal cell skin cancer

    MedlinePlus

    ... occur on skin that is regularly exposed to sunlight or other ultraviolet radiation. This type of skin ... skin cancer is to reduce your exposure to sunlight . Always use sunscreen: Apply sunscreen with sun protection ...

  2. Squamous cell skin cancer

    MedlinePlus

    ... occur on skin that is regularly exposed to sunlight or other ultraviolet radiation. The earliest form of ... skin cancer is to reduce your exposure to sunlight . Always use sunscreen: Apply sunscreen with sun protection ...

  3. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment

    PubMed Central

    Mu, Xueru; Español-Suñer, Regina; Mederacke, Ingmar; Affò, Silvia; Manco, Rita; Sempoux, Christine; Lemaigre, Frédéric P.; Adili, Arlind; Yuan, Detian; Weber, Achim; Unger, Kristian; Heikenwälder, Mathias; Leclercq, Isabelle A.; Schwabe, Robert F.

    2015-01-01

    In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19–, A6- and α-fetoprotein–positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells. PMID:26348897

  4. Schwann cells induce cancer cell dispersion and invasion

    PubMed Central

    Deborde, Sylvie; Lyubchik, Anna; Zhou, Yi; He, Shizhi; McNamara, William F.; Chernichenko, Natalya; Lee, Sei-Young; Barajas, Fernando; Chen, Chun-Hao; Bakst, Richard L.; Vakiani, Efsevia; He, Shuangba; Hall, Alan; Wong, Richard J.

    2016-01-01

    Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression. PMID:26999607

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

    PubMed Central

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

    2016-01-01

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

  6. Stenting in Malignant Biliary Obstruction.

    PubMed

    Almadi, Majid A; Barkun, Jeffrey S; Barkun, Alan N

    2015-10-01

    Decompression of the biliary system in patients with malignant biliary obstruction has been widely accepted and implemented as part of the care. Despite a wealth of literature, there remains a significant amount of uncertainty as to which approach would be most appropriate in different clinical settings. This review covers stenting of the biliary system in cases of resectable or palliative malignant biliary obstruction, potential candidates for biliary drainage, technical aspects of the procedure, as well as management of biliary stent dysfunction. Furthermore, periprocedural considerations including proper mapping of the location of obstruction and the use of antibiotics are addressed. PMID:26431598

  7. Innate Lymphoid Cells in Cancer.

    PubMed

    Vallentin, Blandine; Barlogis, Vincent; Piperoglou, Christelle; Cypowyj, Sophie; Zucchini, Nicolas; Chéné, Matthieu; Navarro, Florent; Farnarier, Catherine; Vivier, Eric; Vély, Frédéric

    2015-10-01

    The world of lymphocytes has recently expanded. A group of cells, innate lymphoid cells (ILC), has been defined. It includes lymphoid cells that have been known for decades, such as natural killer (NK) cells and lymphoid tissue-inducer (LTi) cells. NK cells recognize a vast array of tumor cells, which they help to eliminate through cytotoxicity and the production of cytokines, such as IFNγ. Advances in our understanding of NK-cell biology have led to a growing interest in the clinical manipulation of these cells in cancer. The other ILCs are found mostly in the mucosae and mucosal-associated lymphoid tissues, where they rapidly initiate immune responses to pathogens without the need for specific sensitization. Here, we outline the basic features of ILCs and review the role of ILCs other than NK cells in cancer. Much of the role of these ILCs in cancer remains unknown, but several findings should lead to further efforts to dissect the contribution of different ILC subsets to the promotion, maintenance, or elimination of tumors at various anatomic sites. This will require the development of standardized reagents and protocols for monitoring the presence and function of ILCs in human blood and tissue samples. PMID:26438443

  8. Cancer stem cell signaling pathways.

    PubMed

    Matsui, William H

    2016-09-01

    Tissue development and homeostasis are governed by the actions of stem cells. Multipotent cells are capable of self-renewal during the course of one's lifetime. The accurate and appropriate regulation of stem cell functions is absolutely critical for normal biological activity. Several key developmental or signaling pathways have been shown to play essential roles in this regulatory capacity. Specifically, the Janus-activated kinase/signal transducer and activator of transcription, Hedgehog, Wnt, Notch, phosphatidylinositol 3-kinase/phosphatase and tensin homolog, and nuclear factor-κB signaling pathways have all been shown experimentally to mediate various stem cell properties, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation. Unsurprisingly, many of these crucial signaling pathways are dysregulated in cancer. Growing evidence suggests that overactive or abnormal signaling within and among these pathways may contribute to the survival of cancer stem cells (CSCs). CSCs are a relatively rare population of cancer cells capable of self-renewal, differentiation, and generation of serially transplantable heterogeneous tumors of several types of cancer. PMID:27611937

  9. Nanomechanical analysis of cells from cancer patients

    NASA Astrophysics Data System (ADS)

    Cross, Sarah E.; Jin, Yu-Sheng; Rao, Jianyu; Gimzewski, James K.

    2007-12-01

    Change in cell stiffness is a new characteristic of cancer cells that affects the way they spread. Despite several studies on architectural changes in cultured cell lines, no ex vivo mechanical analyses of cancer cells obtained from patients have been reported. Using atomic force microscopy, we report the stiffness of live metastatic cancer cells taken from the body (pleural) fluids of patients with suspected lung, breast and pancreas cancer. Within the same sample, we find that the cell stiffness of metastatic cancer cells is more than 70% softer, with a standard deviation over five times narrower, than the benign cells that line the body cavity. Different cancer types were found to display a common stiffness. Our work shows that mechanical analysis can distinguish cancerous cells from normal ones even when they show similar shapes. These results show that nanomechanical analysis correlates well with immunohistochemical testing currently used for detecting cancer.

  10. General Information about Small Cell Lung Cancer

    MedlinePlus

    ... Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  11. General Information about Renal Cell Cancer

    MedlinePlus

    ... Renal Cell Cancer Treatment (PDQ®)–Patient Version General Information About Renal Cell Cancer Go to Health Professional ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  12. Invasive cancer cells and metastasis

    NASA Astrophysics Data System (ADS)

    Mierke, Claudia Tanja

    2013-12-01

    The physics of cancer is a relatively new emerging field of cancer research. In the last decade it has become a focus of biophysical research as well as becoming a novel focus for classical cancer research. This special section of Physical Biology focusing on invasive cancer cells and metastasis (physical oncology) will give greater insight into the different subfields where physical approaches are being applied to cancer research. This focus on the physical aspects of cancer is necessary because novel approaches in the field of genomics and proteomics have not altered the field of cancer research dramatically, due to the fact that few breakthroughs have been made. It is still not understood why some primary tumors metastasize and thus have a worse outcome compared to others that do not metastasize. As biophysicists, we and others suggest that the mechanical properties of the cancer cells, which possess the ability to transmigrate, are quite different compared to non-metastatic and non-invasive cancer cells. Furthermore, we hypothesize that these cancer cells undergo a selection process within the primary tumor that enables them to weaken their cell-cell adhesions and to alter their cell-matrix adhesions in order to be able to cross the outermost boundary of the primary tumor, as well as the surrounding basement membrane, and to invade the connective tissue. This prerequisite may also help the cancer cells to enter blood or lymph vessels, get transported with the vessel flow and form secondary tumors either within the vessel, directly on the endothelium, or in a different organ after crossing the endothelial lining a second time. This special section begins with a paper by Mark F Coughlin and Jeffrey J Fredberg on the changes in cytoskeletal dynamics and nonlinear rheology due to the metastatic capability of cancer cells from different cancer tissue types such as skin, bladder, prostate and kidney [1]. The hypothesis was that the metastatic outcome is impacted by

  13. Immunotherapeutic approaches in biliary tract carcinoma: Current status and emerging strategies

    PubMed Central

    Marks, Eric I; Yee, Nelson S

    2015-01-01

    For biliary tract carcinoma (BTC), complete surgical resection of tumor is only feasible in a minority of patients, and the treatment options for patients with unresectable or metastatic disease are limited. Advances in cancer immunology have led to identification of tumor-infiltrating immune cells as indicators of prognosis and response to treatment in BTC. This has also facilitated development of immunotherapy that focuses on enhancing the immune system against biliary tumors. This includes peptide- and dendritic cell-based vaccines that stimulate in-vivo immune responses against tumor-specific antigens. Adoptive immunotherapy, which entails the ex-vivo expansion of tumor-infiltrating immune cells for subsequent reintroduction, and cytokine-based therapies have been developed in BTC. Clinical studies indicate that this type of therapy is generally well tolerated. Combination therapy with dendritic cell-based vaccines and adoptive immunotherapy has shown particularly good potential. Emerging strategies through discovery of novel antigen targets and by reversal of tumor-associated immunosuppression are expected to improve the efficacy of immunotherapy in BTC. Collaborative efforts by integration of targeted immunotherapeutics with molecular profiling of biliary tumor will hopefully make a positive impact on advancing towards the goal of developing precision treatment of patients with this highly lethal disease. PMID:26600933

  14. Histochemical Analyses of Biliary Development During Metamorphosis of Xenopus laevis Tadpoles.

    PubMed

    Ueno, Tomoya; Ishihara, Akinori; Yagi, Shinomi; Koike, Toru; Yamauchi, Kiyoshi; Shiojiri, Nobuyoshi

    2015-01-01

    In mammalian liver development, intrahepatic biliary morphogenesis takes place in periportal, but not in pericentral, regions. Liver progenitor cells transiently form epithelial plate structures and then intrahepatic bile ducts around the portal veins under the influence of the mesenchyme. The present study was undertaken to histochemically examine normal biliary development and its dependence on the action of the thyroid hormone triiodothyronine (T3) in Xenopus laevis tadpoles. In these tadpoles, the development of hepatic ducts and intrahepatic biliary ducts commenced along the portal veins at NF stages 48-50 and stages 50-52, respectively, when the blood concentration of thyroid hormone may be still low. Some periportal hepatocytes expressed carbamoylphosphate synthase I and SOX9, which are hepatocyte and biliary cell markers, respectively, suggesting that periportal hepatocytes give rise to biliary epithelial cells. Periportal biliary cells did not form ductal plates, nor was the periportal mesenchyme well developed as seen in fetal mouse livers. jag1 mRNA was moderately expressed in cells of portal veins and biliary epithelial cells, and notch1 and notch2 mRNAs were weakly detectable in biliary epithelial cells during metamorphosis as seen in developing mammalian livers. These results suggest that Notch signaling plays a decisive role in biliary cell differentiation and morphogenesis of Xenopus tadpoles. Anti-thyroid agent treatment of the tadpoles resulted in delayed biliary morphogenesis, suggesting that biliary development may depend on T3. However, T3 treatment of the tadpoles did not enhance biliary development. Thus, T3 may act positively on biliary development at a very low concentration. PMID:25660701

  15. A Comparison of Preoperative Biliary Drainage Methods for Perihilar Cholangiocarcinoma: Endoscopic versus Percutaneous Transhepatic Biliary Drainage

    PubMed Central

    Kim, Kwang Min; Park, Ji Won; Lee, Jong Kyun; Lee, Kwang Hyuck; Lee, Kyu Taek; Shim, Sang Goon

    2015-01-01

    Background/Aims Controversy remains over the optimal approach to preoperative biliary drainage in patients with resectable perihilar cholangiocarcinoma. We compared the clinical outcomes of endoscopic biliary drainage (EBD) with those of percutaneous transhepatic biliary drainage (PTBD) in patients undergoing preoperative biliary drainage for perihilar cholangiocarcinoma. Methods A total of 106 consecutive patients who underwent biliary drainage before surgical treatment were divided into two groups: the PTBD group (n=62) and the EBD group (n=44). Results Successful drainage on the first attempt was achieved in 36 of 62 patients (58.1%) with PTBD, and in 25 of 44 patients (56.8%) with EBD. There were no significant differences in predrainage patient demographics and decompression periods between the two groups. Procedure-related complications, especially cholangitis and pancreatitis, were significantly more frequent in the EBD group than the PTBD group (PTBD vs EBD: 22.6% vs 54.5%, p<0.001). Two patients (3.8%) in the PTBD group experienced catheter tract implantation metastasis after curative resection during the follow-up period. Conclusions EBD was associated with a higher risk of procedure-related complications than PTBD. These complications were managed properly without severe morbidity; however, in the PTBD group, there were two cases of cancer dissemination along the catheter tract. PMID:26087784

  16. Targeting the Checkpoint to Kill Cancer Cells

    PubMed Central

    Benada, Jan; Macurek, Libor

    2015-01-01

    Cancer treatments such as radiotherapy and most of the chemotherapies act by damaging DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Inhibiting the checkpoint allows entry to mitosis despite the presence of DNA damage and can lead to cell death. Importantly, as cancer cells exhibit increased levels of endogenous DNA damage due to an excessive replication stress, inhibiting the checkpoint kinases alone could act as a directed anti-cancer therapy. Here, we review the current status of inhibitors targeted towards the checkpoint effectors and discuss mechanisms of their actions in killing of cancer cells. PMID:26295265

  17. Lung cancer - non-small cell

    MedlinePlus

    Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Smoking causes most cases (around 90%) of lung cancer. The risk ... day and for how long you have smoked. Being around the smoke ...

  18. On the Stem Cell Origin of Cancer

    PubMed Central

    Sell, Stewart

    2010-01-01

    In each major theory of the origin of cancer—field theory, chemical carcinogenesis, infection, mutation, or epigenetic change—the tissue stem cell is involved in the generation of cancer. Although the cancer type is identified by the more highly differentiated cells in the cancer cell lineage or hierarchy (transit-amplifying cells), the property of malignancy and the molecular lesion of the cancer exist in the cancer stem cell. In the case of teratocarcinomas, normal germinal stem cells have the potential to become cancers if placed in an environment that allows expression of the cancer phenotype (field theory). In cancers due to chemically induced mutations, viral infections, somatic and inherited mutations, or epigenetic changes, the molecular lesion or infection usually first occurs in the tissue stem cells. Cancer stem cells then give rise to transit-amplifying cells and terminally differentiated cells, similar to what happens in normal tissue renewal. However, the major difference between cancer growth and normal tissue renewal is that whereas normal transit amplifying cells usually differentiate and die, at various levels of differentiation, the cancer transit-amplifying cells fail to differentiate normally and instead accumulate (ie, they undergo maturation arrest), resulting in cancer growth. PMID:20431026

  19. Cancer stem cells and exosome signaling.

    PubMed

    Hannafon, Bethany N; Ding, Wei-Qun

    2015-01-01

    Exosomes have been recognized as mediators of intercellular communication among different cell populations in various biological model systems. By transfer of signaling molecules such as proteins, lipids, and RNAs between different cell types, exosomes are implicated in both physiological and pathological processes. The tumor microenvironment consists of multiple types of cells including adult stem cells, cancer stem cells, and stromal cells. These cells are known to intercommunicate with each other thereby modulating tumor progression. Recent studies have provided evidence demonstrating that exosomes mediate the interactions among different types of cells within the tumor microenvironment, providing new insight into how these cells interact with each other through exosome signaling. This review is focused on recent studies that have examined exosome-mediated intercommunication among cancer stem cells, adult stem cells, cancer cells, and stromal cells within the tumor microenvironment. Based on the current literature, it seems clear that adult stem cells and cancer stem cells secret exosomes that can be transferred to their surrounding cells thereby modulating cancer progression. Likewise, cancer cells and stromal cells also release exosomes that can be taken up by cancer stem cells or adult stem cells, leading to alterations to their phenotype. The molecular mechanisms and biological consequences of the exosome-mediated interactions of these cells remain to be further elucidated. A better understanding of how exosomes mediate intercellular communication in the tumor microenvironment and the specific biological consequences of these interactions will likely offer new opportunities in the development of diagnostic or therapeutic strategies against cancer. PMID:27358879

  20. Cancer stem cells and exosome signaling

    PubMed Central

    Hannafon, Bethany N.

    2015-01-01

    Exosomes have been recognized as mediators of intercellular communication among different cell populations in various biological model systems. By transfer of signaling molecules such as proteins, lipids, and RNAs between different cell types, exosomes are implicated in both physiological and pathological processes. The tumor microenvironment consists of multiple types of cells including adult stem cells, cancer stem cells, and stromal cells. These cells are known to intercommunicate with each other thereby modulating tumor progression. Recent studies have provided evidence demonstrating that exosomes mediate the interactions among different types of cells within the tumor microenvironment, providing new insight into how these cells interact with each other through exosome signaling. This review is focused on recent studies that have examined exosome-mediated intercommunication among cancer stem cells, adult stem cells, cancer cells, and stromal cells within the tumor microenvironment. Based on the current literature, it seems clear that adult stem cells and cancer stem cells secret exosomes that can be transferred to their surrounding cells thereby modulating cancer progression. Likewise, cancer cells and stromal cells also release exosomes that can be taken up by cancer stem cells or adult stem cells, leading to alterations to their phenotype. The molecular mechanisms and biological consequences of the exosome-mediated interactions of these cells remain to be further elucidated. A better understanding of how exosomes mediate intercellular communication in the tumor microenvironment and the specific biological consequences of these interactions will likely offer new opportunities in the development of diagnostic or therapeutic strategies against cancer.

  1. Basal cell skin cancer

    MedlinePlus

    ... occur in younger people who have had extensive sun exposure. You are more likely to get basal cell ... severe sunburns early in life Long-term daily sun exposure (such as the sun exposure received by people ...

  2. Regulation of intrahepatic biliary duct morphogenesis by Claudin 15-like b

    PubMed Central

    Cheung, Isla D.; Bagnat, Michel; Ma, Taylur P.; Datta, Anirban; Evason, Kimberley; Moore, John C.; Lawson, Nathan; Mostov, Keith E.; Moens, Cecilia B.; Stainier, Didier Y.R.

    2011-01-01

    The intrahepatic biliary ducts transport bile produced by the hepatocytes out of the liver. Defects in biliary cell differentiation and biliary duct remodeling cause a variety of congenital diseases including Alagille Syndrome and polycystic liver disease. While the molecular pathways regulating biliary cell differentiation have received increasing attention (Lemaigre, 2010), less is known about the cellular behavior underlying biliary duct remodeling. Here, we have identified a novel gene, claudin 15-like b (cldn15lb), which exhibits a unique and dynamic expression pattern in the hepatocytes and biliary epithelial cells in zebrafish. Claudins are tight junction proteins that have been implicated in maintaining epithelial polarity, regulating paracellular transport, and providing barrier function. In zebrafish cldn15lb mutant livers, tight junctions are observed between hepatocytes, but these cells show polarization defects as well as canalicular malformations. Furthermore, cldn15lb mutants show abnormalities in biliary duct morphogenesis whereby biliary epithelial cells remain clustered together and form a disorganized network. Our data suggest that Cldn15lb plays an important role in the remodeling process during biliary duct morphogenesis. Thus, cldn15lb mutants provide a novel in vivo model to study the role of tight junction proteins in the remodeling of the biliary network and hereditary cholestasis. PMID:22020048

  3. Biliary Elimination of Pemetrexed Is Dependent on Mrp2 in Rats: Potential Mechanism of Variable Response in Nonalcoholic Steatohepatitis.

    PubMed

    Dzierlenga, Anika L; Clarke, John D; Klein, David M; Anumol, Tarun; Snyder, Shane A; Li, HongYu; Cherrington, Nathan J

    2016-08-01

    Hepatic multidrug resistance-associated protein 2 (MRP2) provides the biliary elimination pathway for many xenobiotics. Disruption of this pathway contributes to retention of these compounds and may ultimately lead to adverse drug reactions. MRP2 mislocalization from the canalicular membrane has been observed in nonalcoholic steatohepatitis (NASH), the late stage of nonalcoholic fatty liver disease, which is characterized by fat accumulation, oxidative stress, inflammation, and fibrosis. MRP2/Mrp2 mislocalization is observed in both human NASH and the rodent methionine and choline-deficient (MCD) diet model, but the extent to which it impacts overall transport capacity of MRP2 is unknown. Pemetrexed is an antifolate chemotherapeutic indicated for non-small cell lung cancer, yet its hepatobiliary elimination pathway has yet to be determined. The purpose of this study was to quantify the loss of Mrp2 function in NASH using an obligate Mrp2 transport substrate. To determine whether pemetrexed is an obligate Mrp2 substrate, its cumulative biliary elimination was compared between wild-type and Mrp2(-/-) rats. No pemetrexed was detected in the bile of Mrp2(-/-) rats, indicating pemetrexed is completely reliant on Mrp2 function for biliary elimination. Comparing the biliary elimination of pemetrexed between MCD and control animals identified a transporter-dependent decrease in biliary excretion of 60% in NASH. This study identifies Mrp2 as the exclusive biliary elimination mechanism for pemetrexed, making it a useful in vivo probe substrate for Mrp2 function, and quantifying the loss of function in NASH. This mechanistic feature may provide useful insight into the impact of NASH on interindividual variability in response to pemetrexed. PMID:27233293

  4. [Dendritic cells in cancer immunotherapy].

    PubMed

    Gato, M; Liechtenstein, T; Blanco-Luquín, I; Zudaire, M I; Kochan, G; Escors, D

    2015-01-01

    Since the beginning of the 20th century, biomedical scientists have tried to take advantage of the natural anti-cancer activities of the immune system. However, all the scientific and medical efforts dedicated to this have not resulted in the expected success. In fact, classical antineoplastic treatments such as surgery, radio and chemotherapy are still first line treatments. Even so, there is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anti-cancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen presenting cells such as DC. Although there are a number of strategies to strengthen antigen presentation by DC, anti-cancer immunotherapy is not as effective as we would expect according to preclinical data accumulated in recent decades. We do not aim to make an exhaustive review of DC immunotherapy here, which is an extensive research subject already dealt with in many specialised reviews. Instead, we present the experimental approaches undertaken by our group over the last decade, by modifying DC to improve their anti-tumour capacities. PMID:26486534

  5. MicroRNA-98 and let-7 Regulate Expression of Suppressor of Cytokine Signaling-4 in Biliary Epithelial Cells in Response to Cryptosporidium parvum Infection

    PubMed Central

    Hu, Guoku; Zhou, Rui; Liu, Jun; Gong, Ai-Yu; Chen, Xian-Ming

    2010-01-01

    Expression of the cytokine-inducible Src homology 2 protein (CIS) and suppressors of cytokine signaling proteins (SOCS) represents an important element of host cell reactions in response to pathogen infection. We previously demonstrated that Cryptosporidium parvum infection downregulates miR-98 and let-7 to induce CIS expression in biliary epithelial cells. We reported here that downregulation of miR-98 and let-7 also coordinates epithelial expression of SOCS4 following C. parvum infection. Targeting of SOCS4 3'-untranslated region by miR-98 or let-7 resulted in translational repression. Functional manipulation of miR-98 caused reciprocal alterations in SOCS4 protein expression. Transfection of miR-98 precursor abolished C. parvum-stimulated SOCS4 upregulation. Moreover, expression of SOCS4 in epithelial cells showed an inhibitory effect on phosphorylation of signal transducers and activators of transcription proteins induced by C. parvum. These data suggest an important role for miRNAs in the coordinated regulation of CIS/SOCS expression in epithelial cells in response to C. parvum infection. PMID:20486857

  6. Percutaneous Palliation of Pancreatic Head Cancer: Randomized Comparison of ePTFE/FEP-Covered Versus Uncovered Nitinol Biliary Stents

    SciTech Connect

    Krokidis, Miltiadis; Fanelli, Fabrizio; Orgera, Gianluigi; Tsetis, Dimitrios; Mouzas, Ioannis; Bezzi, Mario; Kouroumalis, Elias; Pasariello, Roberto; Hatzidakis, Adam

    2011-04-15

    The purpose of this study was to compare the clinical effectiveness of expanded polytetrafluoroethylene/fluorinated-ethylene-propylene (ePTFE/FEP)-covered stents with that of uncovered nitinol stents for the palliation of malignant jaundice caused by inoperable pancreatic head cancer. Eighty patients were enrolled in a prospective randomized study. Bare nitinol stents were used in half of the patients, and ePTFE/FEP-covered stents were used in the remaining patients. Patency, survival, complications, and mean cost were calculated in both groups. Mean patency was 166.0 {+-} 13.11 days for the bare-stent group and 234.0 {+-} 20.87 days for the covered-stent group (p = 0.007). Primary patency rates at 3, 6, and 12 months were 77.5, 69.8, and 69.8% for the bare-stent group and 97.5, 92.2, and 87.6% for the covered-stent group, respectively. Mean secondary patency was 123.7 {+-} 22.5 days for the bare-stent group and 130.3 {+-} 21.4 days for the covered-stent group. Tumour ingrowth occurred exclusively in the bare-stent group in 27.5% of cases (p = 0.002). Median survival was 203.2 {+-} 11.8 days for the bare-stent group and 247.0 {+-} 20 days for the covered-stent group (p = 0.06). Complications and mean cost were similar in both groups. Regarding primary patency and ingrowth rate, ePTFE/FEP-covered stents have shown to be significantly superior to bare nitinol stents for the palliation of malignant jaundice caused by inoperable pancreatic head cancer and pose comparable cost and complications. Use of a covered stent does not significantly influence overall survival rate; nevertheless, the covered endoprosthesis seems to offer result in fewer reinterventions and better quality of patient life.

  7. Prostate Cancer Stem Cells: Research Advances

    PubMed Central

    Jaworska, Dagmara; Król, Wojciech; Szliszka, Ewelina

    2015-01-01

    Cancer stem cells have been defined as cells within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. Experimental evidence showed that these highly tumorigenic cells might be responsible for initiation and progression of cancer into invasive and metastatic disease. Eradicating prostate cancer stem cells, the root of the problem, has been considered as a promising target in prostate cancer treatment to improve the prognosis for patients with advanced stages of the disease. PMID:26593898

  8. [The biliary intestinal obstruction].

    PubMed

    Demetrashvili, Z M; Asatiani, G A; Nemsadze, G Sh; Kenchadze, G Z

    2012-01-01

    The successful experience of treatment of 3 patients with biliary intestinal obstruction is depicted. The most informative means of diagnostics was the multispiral computed tomography. Authors state, that the volume of the operation should include only the liquidation of the intestinal obstruction. The simultaneous biliodigestive fistulae closure should be performed only in rare situations. PMID:22678540

  9. Reversing breast cancer stem cell into breast somatic stem cell.

    PubMed

    Wijaya, L; Agustina, D; Lizandi, A O; Kartawinata, M M; Sandra, F

    2011-02-01

    Stem cells have an important role in cell biology, allowing tissues to be renewed by freshly created cells throughout their lifetime. The specific micro-environment of stem cells is called stem cell niche; this environment influences the development of stem cells from quiescence through stages of differentiation. Recent advance researches have improved the understanding of the cellular and molecular components of the micro-environment--or niche--that regulates stem cells. We point out an important trend to the study of niche activity in breast cancers. Breast cancer has long been known to conserve a heterogeneous population of cells. While the majority of cells that make up tumors are destined to differentiate and eventually stop dividing, only minority populations of cells, termed cancer stem cell, possess extensive self renewal capability. These cancer stem cells possess characteristics of both stem cells and cancer cells. Breast cancer stem cells reversal to breast somatic stem cells offer a new therapy, that not only can stop the spread of breast cancer cells, but also can differentiate breast cancer stem cells into normal breast somatic stem cells. These can replace damaged breast tissue. Nevertheless, the complexity of realizing this therapy approach needs further research. PMID:21044008

  10. Cancer stem cells in small cell lung cancer

    PubMed Central

    Verlicchi, Alberto; Rosell, Rafael

    2016-01-01

    Small cell lung cancer (SCLC) is one of the most aggressive lung tumors, with poor survival rates. Although patients may initially respond to treatment, this is followed by rapid development of drug resistance and disease progression. SCLC patients often present with metastasis at time of diagnosis, ruling out surgery as a treatment option. Currently, treatment options for this disease remain limited and platinum-based chemotherapy is the treatment of choice. A better understanding of the biology of SCLC could allow us to identify new therapeutic targets. Cancer stem cell (CSC) theory is currently crucial in cancer research and could provide a viable explanation for the heterogeneity, drug resistance, recurrence and metastasis of several types of tumors. Some characteristics of SCLC, such as aggressiveness, suggest that this kind of tumor could be enriched in CSCs, and drug resistance in SCLC could be attributable to the existence of a CSC subpopulation in SCLC. Herein we summarize current understanding of CSC in SCLC, including the evidence for CSC markers and signaling pathways involved in stemness. We also discuss potential ongoing strategies and areas of active research in SCLC, such as immunotherapy, that focus on inhibition of signaling pathways and targeting molecules driving stemness. Understanding of signaling pathways and the discovery of new therapeutic markers specific to CSCs will lead to new advances in therapy and improvements in prognosis of SCLC patients. Therefore, evaluation of these CSC-specific molecules and pathways may become a routine part of SCLC diagnosis and therapy. PMID:26958490

  11. Multiple Myeloma Cancer Stem Cells

    PubMed Central

    Huff, Carol Ann; Matsui, William

    2008-01-01

    Multiple myeloma is characterized by the clonal expansion of neoplastic plasma cells within the bone marrow, elevated serum immunoglobulin, and osteolytic bone disease. The disease is highly responsive to a wide variety of anticancer treatments including conventional cytotoxic chemotherapy, corticosteroids, radiation therapy, and a growing number of agents with novel mechanisms of action. However, few if any patients are cured with these modalities and relapse remains a critical issue. A better understanding of clonogenic multiple myleoma cells is essential to ultimately improving long-term outcomes, but the nature of the cells responsible for myeloma regrowth and disease relapse is unclear. We review evidence that functional heterogeneity exists in multiple myeloma and discuss potential strategies and clinical implications of the stem-cell model of cancer in this disease. PMID:18539970

  12. Biliary Ascariasis Mimicking Colonic Tumor Infiltration of the Biliary System.

    PubMed

    Sundriyal, Deepak; Mittal, Gyanendra; Kumar, Sushil; Manjunath, Suraj; Sharma, Navneet; Gupta, Mahesh

    2015-09-01

    Ascariasis is a common problem in developing countries with poor hygiene and sanitation. It is endemic in India and usually seen in the northern states. Biliary ascariasis is an uncommon cause of obstructive jaundice. We present a case of carcinoma of hepatic flexure of colon in which the patient developed biliary ascariasis and posed a diagnostic challenge as it mimicked tumor infiltration of the biliary system. PMID:27217679

  13. Head and Neck Cancer Stem Cells

    PubMed Central

    Krishnamurthy, S.; Nör, J.E.

    2012-01-01

    Most cancers contain a small sub-population of cells that are endowed with self-renewal, multipotency, and a unique potential for tumor initiation. These properties are considered hallmarks of cancer stem cells. Here, we provide an overview of the field of cancer stem cells with a focus on head and neck cancers. Cancer stem cells are located in the invasive fronts of head and neck squamous cell carcinomas (HNSCC) close to blood vessels (perivascular niche). Endothelial cell-initiated signaling events are critical for the survival and self-renewal of these stem cells. Markers such as aldehyde dehydrogenase (ALDH), CD133, and CD44 have been successfully used to identify highly tumorigenic cancer stem cells in HNSCC. This review briefly describes the orosphere assay, a method for in vitro culture of undifferentiated head and neck cancer stem cells under low attachment conditions. Notably, recent evidence suggests that cancer stem cells are exquisitely resistant to conventional therapy and are the “drivers” of local recurrence and metastatic spread. The emerging understanding of the role of cancer stem cells in the pathobiology of head and neck squamous cell carcinomas might have a profound impact on the treatment paradigms for this malignancy. PMID:21933937

  14. Head and neck cancer stem cells.

    PubMed

    Krishnamurthy, S; Nör, J E

    2012-04-01

    Most cancers contain a small sub-population of cells that are endowed with self-renewal, multipotency, and a unique potential for tumor initiation. These properties are considered hallmarks of cancer stem cells. Here, we provide an overview of the field of cancer stem cells with a focus on head and neck cancers. Cancer stem cells are located in the invasive fronts of head and neck squamous cell carcinomas (HNSCC) close to blood vessels (perivascular niche). Endothelial cell-initiated signaling events are critical for the survival and self-renewal of these stem cells. Markers such as aldehyde dehydrogenase (ALDH), CD133, and CD44 have been successfully used to identify highly tumorigenic cancer stem cells in HNSCC. This review briefly describes the orosphere assay, a method for in vitro culture of undifferentiated head and neck cancer stem cells under low attachment conditions. Notably, recent evidence suggests that cancer stem cells are exquisitely resistant to conventional therapy and are the "drivers" of local recurrence and metastatic spread. The emerging understanding of the role of cancer stem cells in the pathobiology of head and neck squamous cell carcinomas might have a profound impact on the treatment paradigms for this malignancy. PMID:21933937

  15. How cell death shapes cancer

    PubMed Central

    Labi, V; Erlacher, M

    2015-01-01

    Apoptosis has been established as a mechanism of anti-cancer defense. Members of the BCL-2 family are critical mediators of apoptotic cell death in health and disease, often found to be deregulated in cancer and believed to lead to the survival of malignant clones. However, over the years, a number of studies pointed out that a model in which cell death resistance unambiguously acts as a barrier against malignant disease might be too simple. This is based on paradoxical observations made in tumor patients as well as mouse models indicating that apoptosis can indeed drive tumor formation, at least under certain circumstances. One possible explanation for this phenomenon is that apoptosis can promote proliferation critically needed to compensate for cell loss, for example, upon therapy, and to restore tissue homeostasis. However, this, at the same time, can promote tumor development by allowing expansion of selected clones. Usually, tissue resident stem/progenitor cells are a major source for repopulation, some of them potentially carrying (age-, injury- or therapy-induced) genetic aberrations deleterious for the host. Thereby, apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage. Tumorigenesis initiated by repeated cell attrition and repopulation, as confirmed in different genetic models, has parallels in human cancers, exemplified in therapy-induced secondary malignancies and myelodysplastic syndromes in patients with congenital bone marrow failure syndromes. Here, we aim to review evidence in support of the oncogenic role of stress-induced apoptosis. PMID:25741600

  16. Adenocarcinoma of the extrahepatic biliary tree.

    PubMed Central

    Anderson, J. B.; Cooper, M. J.; Williamson, R. C.

    1985-01-01

    Increasing survival rates for carcinoma of the biliary tree could reflect the selection of patients for referral to a specialist centre as well as modern improvements in diagnosis and treatment. To determine the true incidence and outcome of biliary cancer, the records of 243 unselected Bristol patients were reviewed retrospectively over a 15-year period. Mean age was 64 years. Gallstones were associated in 38% of cases. Sixty-nine of 87 patients with gallbladder carcinoma were submitted to laparotomy. The operative (30-day) mortality rate was 56% and the one-year survival rate was 7%; one patient with an unexpected carcinoma is alive 7 years after cholecystectomy (1% five-year survival rate). Among 31 patients with carcinoma of the ampulla the operative mortality rate was 27%; one-year and five-year survival rates were 46% and 15%. Bile duct cancers (n = 125) arose proximal to the entry of the cystic duct (n = 63), distal to that point (n = 46) or diffusely (n = 16). For proximal cholangiocarcinoma the operative mortality rate was 38% and 1-year survival rate 17%; no patient lived for 2 years. For distal cholangiocarcinoma the operative mortality rate was 45% and one-year survival rate 26%; no patient lived for 3 years. Only palliative procedures were undertaken for diffuse cholangiocarcinoma; 2 patients survived 1 year (13%). Overall 5 patients with carcinoma of the extrahepatic biliary tree appear to have been cured (2%). PMID:2988399

  17. Extinction models for cancer stem cell therapy

    PubMed Central

    Sehl, Mary; Zhou, Hua; Sinsheimer, Janet S.; Lange, Kenneth L.

    2012-01-01

    Cells with stem cell-like properties are now viewed as initiating and sustaining many cancers. This suggests that cancer can be cured by driving these cancer stem cells to extinction. The problem with this strategy is that ordinary stem cells are apt to be killed in the process. This paper sets bounds on the killing differential (difference between death rates of cancer stem cells and normal stem cells) that must exist for the survival of an adequate number of normal stem cells. Our main tools are birth–death Markov chains in continuous time. In this framework, we investigate the extinction times of cancer stem cells and normal stem cells. Application of extreme value theory from mathematical statistics yields an accurate asymptotic distribution and corresponding moments for both extinction times. We compare these distributions for the two cell populations as a function of the killing rates. Perhaps a more telling comparison involves the number of normal stem cells NH at the extinction time of the cancer stem cells. Conditioning on the asymptotic time to extinction of the cancer stem cells allows us to calculate the asymptotic mean and variance of NH. The full distribution of NH can be retrieved by the finite Fourier transform and, in some parameter regimes, by an eigenfunction expansion. Finally, we discuss the impact of quiescence (the resting state) on stem cell dynamics. Quiescence can act as a sanctuary for cancer stem cells and imperils the proposed therapy. We approach the complication of quiescence via multitype branching process models and stochastic simulation. Improvements to the τ-leaping method of stochastic simulation make it a versatile tool in this context. We conclude that the proposed therapy must target quiescent cancer stem cells as well as actively dividing cancer stem cells. The current cancer models demonstrate the virtue of attacking the same quantitative questions from a variety of modeling, mathematical, and computational perspectives

  18. Colon Cancer Cell Separation by Dielectrophoresis

    NASA Astrophysics Data System (ADS)

    Yang, Fang; Yang, Xiaoming; Jiang, H.; Wood, P.; Hrushesky, W.; Wang, Guiren

    2009-11-01

    Separation of cancer cells from the other biological cells can be useful for clinical cancer diagnosis and cancer treatment. In this presentation, conventional dielectrophoresis (c-DEP) is used in a microfluidic chip to manipulate and collect colorectal cancer HCT116 cell, which is doped with Human Embryonic Kidney 293 cells (HEK 293). It is noticed that, the HCT116 cell are deflected to a side channel from a main channel clearly by apply electric field at particular AC frequency band. This motion caused by negative DEP can be used to separate the cancer cell from others. In this manuscript, chip design, flow condition, the DEP spectrum of the cancer cell are reported respectively, and the separation and collection efficiency are investigated as well. The sorter is microfabricated using plastic laminate technology. -/abstract- This work has been financially supported by the NSF RII funding (EP

  19. Endoscopic ultrasound-guided biliary drainage of hilar biliary obstruction.

    PubMed

    Park, Do Hyun

    2015-09-01

    Only 20-30% of patients with hilar cholangiocarcinoma (CC) are candidates for potentially curative resection. However, even after curative (R0) resection, these patients have a disease recurrence rate of up to 76%. The prognosis of hilar cholangiocarcinoma (CC) is limited by tumor spread along the biliary tree leading to obstructive jaundice, cholangitis, and liver failure. Therefore, palliative biliary drainage may be a major goal for patients with hilar CC. Endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is an established method for palliation of patients with malignant biliary obstruction. However, there are patients for whom endoscopic stent placement is not possible because of failed biliary cannulation or tumor infiltration that limits transpapillary access. In this situation, percutaneous transhepatic biliary drainage (PTBD) is an alternative method. However, PTBD has a relatively high rate of complications and is frequently associated with patient discomfort related to external drainage. Endoscopic ultrasound-guided biliary drainage has therefore been introduced as an alternative to PTBD in cases of biliary obstruction when ERCP is unsuccessful. In this review, the indications, technical tips, outcomes, and the future role of EUS-guided intrahepatic biliary drainage, such as hepaticogastrostomy or hepaticoduodenostomy, for hilar biliary obstruction will be summarized. PMID:26178753

  20. Future developments in biliary stenting

    PubMed Central

    Hair, Clark D; Sejpal, Divyesh V

    2013-01-01

    Biliary stenting has evolved dramatically over the past 30 years. Advancements in stent design have led to prolonged patency and improved efficacy. However, biliary stenting is still affected by occlusion, migration, anatomical difficulties, and the need for repeat procedures. Multiple novel plastic biliary stent designs have recently been introduced with the primary goals of reduced migration and improved ease of placement. Self-expandable bioabsorbable stents are currently being investigated in animal models. Although not US Food and Drug Administration approved for benign disease, fully covered self-expandable metal stents are increasingly being used in a variety of benign biliary conditions. In malignant disease, developments are being made to improve ease of placement and stent patency for both hilar and distal biliary strictures. The purpose of this review is to describe recent developments and future directions of biliary stenting. PMID:23837001

  1. Mitochondria, cholesterol and cancer cell metabolism.

    PubMed

    Ribas, Vicent; García-Ruiz, Carmen; Fernández-Checa, José C

    2016-12-01

    Given the role of mitochondria in oxygen consumption, metabolism and cell death regulation, alterations in mitochondrial function or dysregulation of cell death pathways contribute to the genesis and progression of cancer. Cancer cells exhibit an array of metabolic transformations induced by mutations leading to gain-of-function of oncogenes and loss-of-function of tumor suppressor genes that include increased glucose consumption, reduced mitochondrial respiration, increased reactive oxygen species generation and cell death resistance, all of which ensure cancer progression. Cholesterol metabolism is disturbed in cancer cells and supports uncontrolled cell growth. In particular, the accumulation of cholesterol in mitochondria emerges as a molecular component that orchestrates some of these metabolic alterations in cancer cells by impairing mitochondrial function. As a consequence, mitochondrial cholesterol loading in cancer cells may contribute, in part, to the Warburg effect stimulating aerobic glycolysis to meet the energetic demand of proliferating cells, while protecting cancer cells against mitochondrial apoptosis due to changes in mitochondrial membrane dynamics. Further understanding the complexity in the metabolic alterations of cancer cells, mediated largely through alterations in mitochondrial function, may pave the way to identify more efficient strategies for cancer treatment involving the use of small molecules targeting mitochondria, cholesterol homeostasis/trafficking and specific metabolic pathways. PMID:27455839

  2. Cancer stem cells and differentiation therapy.

    PubMed

    Sell, Stewart

    2006-01-01

    Cancers arise from stem cells in adult tissues and the cells that make up a cancer reflect the same stem cell --> progeny --> differentiation progression observed in normal tissues. All adult tissues are made up of lineages of cells consisting of tissue stem cells and their progeny (transit-amplifying cells and terminally differentiated cells); the number of new cells produced in normal tissue lineages roughly equals the number of old cells that die. Cancers result from maturation arrest of this process, resulting in continued proliferation of cells and a failure to differentiate and die. The biological behavior, morphological appearance, and clinical course of a cancer depend on the stage of maturation at which the genetic lesion is activated. This review makes a comparison of cancer cells to embryonic stem cells and to adult tis sue stem cells while addressing two basic questions: (1) Where do cancers come from?, and (2) How do cancers grow? The answers to these questions are critical to the development of approaches to the detection, prevention, and treatment of cancer. PMID:16557043

  3. Biliary ascariasis. A case report.

    PubMed

    Sarihan, H; Gürkök, S; Sari, A

    1995-01-01

    Ascaris lumbricoides is a worldwide intestinal infestation that may cause various complications. Biliary ascariasis, however, is a rare condition. We describe a child with biliary ascariasis. The patient's clinical symptoms were pain, vomiting and abdominal tenderness, and she was thought to have acute appendicitis. However, laboratory examination revealed high serum alkaline phosphatase and amylase levels, and ultrasonography and percutaneous cholangiography demonstrated biliary ascariasis. The patient was successfully treated with mebendazole and antispasmolytic drugs. PMID:8560608

  4. Mast cells, angiogenesis and cancer.

    PubMed

    Ribatti, Domenico; Crivellato, Enrico

    2011-01-01

    Mast cells (MCs) were first described by Paul Ehrlich 1 in his doctoral thesis. MCs have long been implicated in the pathogenesis of allergic reactions and certain protective responses to parasites. As most tumors contain inflammatory cell infiltrates, which often include plentiful MCs, the question as to the possible contribution of MCs to tumor development has progressively been emerging. In this chapter, the specific involvement of MCs in tumor biology and tumor fate will be considered, with particular emphasis on the capacity of these cells to stimulate tumor growth by promoting angiogenesis and lymphangiogenesis. Data from experimental carcinogenesis and from different tumor settings in human pathology will be summarized. Information to be presented will suggest that MCs may serve as a novel therapeutic target for cancer treatment. PMID:21713661

  5. Ouabain enhances lung cancer cell detachment.

    PubMed

    Ruanghirun, Thidarat; Pongrakhananon, Varisa; Chanvorachote, Pithi

    2014-05-01

    A human steroid hormone, ouabain, has been shown to play a role in several types of cancer cell behavior; however, its effects on cancer metastasis are largely unknown. Herein, we demonstrate that sub-toxic concentrations of ouabain facilitate cancer cell detachment from the extracellular matrix in human lung cancer cells. Ouabain at concentrations of 0-10 pM significantly enhanced cell detachment in dose- and time- dependent manners, while having minimal effect on cell viability. The detachment-inducing effect of ouabain was found to be mediated through focal-adhesion kinase and ATP-dependent tyrosine kinase pathways. Alpha-5 and beta-1 integrins were found to be down-regulated in response to ouabain treatment. Since detachment of cancer cells is a prerequisite process for metastasis to begin, these insights benefit our understanding over the molecular basis of cancer biology. PMID:24778025

  6. Endothelial cell metabolism: parallels and divergences with cancer cell metabolism

    PubMed Central

    2014-01-01

    The stromal vasculature in tumors is a vital conduit of nutrients and oxygen for cancer cells. To date, the vast majority of studies have focused on unraveling the genetic basis of vessel sprouting (also termed angiogenesis). In contrast to the widely studied changes in cancer cell metabolism, insight in the metabolic regulation of angiogenesis is only just emerging. These studies show that metabolic pathways in endothelial cells (ECs) importantly regulate angiogenesis in conjunction with genetic signals. In this review, we will highlight these emerging insights in EC metabolism and discuss them in perspective of cancer cell metabolism. While it is generally assumed that cancer cells have unique metabolic adaptations, not shared by healthy non-transformed cells, we will discuss parallels and highlight differences between endothelial and cancer cell metabolism and consider possible novel therapeutic opportunities arising from targeting both cancer and endothelial cells. PMID:25250177

  7. The biology of cancer stem cells.

    PubMed

    Lobo, Neethan A; Shimono, Yohei; Qian, Dalong; Clarke, Michael F

    2007-01-01

    Cancers originally develop from normal cells that gain the ability to proliferate aberrantly and eventually turn malignant. These cancerous cells then grow clonally into tumors and eventually have the potential to metastasize. A central question in cancer biology is, which cells can be transformed to form tumors? Recent studies elucidated the presence of cancer stem cells that have the exclusive ability to regenerate tumors. These cancer stem cells share many characteristics with normal stem cells, including self-renewal and differentiation. With the growing evidence that cancer stem cells exist in a wide array of tumors, it is becoming increasingly important to understand the molecular mechanisms that regulate self-renewal and differentiation because corruption of genes involved in these pathways likely participates in tumor growth. This new paradigm of oncogenesis has been validated in a growing list of tumors. Studies of normal and cancer stem cells from the same tissue have shed light on the ontogeny of tumors. That signaling pathways such as Bmi1 and Wnt have similar effects in normal and cancer stem cell self-renewal suggests that common molecular pathways regulate both populations. Understanding the biology of cancer stem cells will contribute to the identification of molecular targets important for future therapies. PMID:17645413

  8. Restoration of normal phenotype in cancer cells

    DOEpatents

    Bissell, Mina J.; Weaver, Valerie M.

    1998-01-01

    A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying .beta..sub.1 integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive.

  9. Restoration of normal phenotype in cancer cells

    DOEpatents

    Bissell, M.J.; Weaver, V.M.

    1998-12-08

    A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying {beta}{sub 1} integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive. 14 figs.

  10. Biliary Mucosal Barrier and Microbiome

    PubMed Central

    Verdier, Julien; Luedde, Tom; Sellge, Gernot

    2015-01-01

    Background The biliary system is in continuous contact with the complex microbiota of the intestine. Microbial products have recently been proposed as potential triggers for biliary diseases. Methods The aim of this review is to provide a summary of the current knowledge regarding the role of the biliary and intestinal microbiome in biliary inflammatory diseases. Results Previously, it was suggested that the healthy biliary system is a sterile organ, while acute cholangitis and cholecystitis may occur from ascending infections. Although non-inflammatory biliary colonization by certain bacteria such as Salmonella spp. has been already recognized since several decades, human and animal studies indicated only very recently that the gallbladder harbors a complex microbiota also under non-pathologic conditions. Novel findings suggested that – similar to the situation in the intestine – the biliary mucosa features a chemical, mechanical, and immunological barrier, ensuring immunological tolerance against commensals. However, microbial triggers might influence acute and chronic inflammatory disease of the biliary system and the whole liver. Conclusion Although yet undefined, dysbiosis of the biliary or intestinal microbiota rather than a single microorganism may influence disease progression. PMID:26468308

  11. Cancer

    MedlinePlus

    ... body. Cancerous cells are also called malignant cells. Causes Cancer grows out of cells in the body. Normal ... of many cancers remains unknown. The most common cause of cancer-related death is lung cancer. In the U.S., ...

  12. Deregulation of Cell Signaling in Cancer

    PubMed Central

    Giancotti, Filippo G.

    2014-01-01

    Summary Oncogenic mutations disrupt the regulatory circuits that govern cell function, enabling tumor cells to undergo de-regulated mitogenesis, to resist to proapoptotic insults, and to invade through tissue boundaries. Cancer cell biology has played a crucial role in elucidating the signaling mechanisms by which oncogenic mutations sustain these malignant behaviors and thereby in identifying rational targets for cancer drugs. The efficacy of such targeted therapies illustrate the power of a reductionist approach to the study of cancer. PMID:24561200

  13. Targeting Aldehyde Dehydrogenase Cancer Stem Cells in Ovarian Cancer

    PubMed Central

    Landen, Charles N.; Goodman, Blake; Katre, Ashwini A.; Steg, Adam D.; Nick, Alpa M.; Stone, Rebecca L.; Miller, Lance D.; Mejia, Pablo Vivas; Jennings, Nicolas B.; Gershenson, David M.; Bast, Robert C.; Coleman, Robert L.; Lopez-Berestein, Gabriel; Sood, Anil K.

    2010-01-01

    Aldehyde dehydrogenase-1A1 (ALDH1A1) expression characterizes a subpopulation of cells with tumor initiating or cancer stem cell properties in several malignancies. Our goal was to characterize the phenotype of ALDH1A1-positive ovarian cancer cells and examine the biological effects of ALDH1A1 gene silencing. In our analysis of multiple ovarian cancer cell lines, we found that ALDH1A1 expression and activity was significantly higher in taxane and platinum-resistant cell lines. In patient samples, 72.9% of ovarian cancers had ALDH1A1 expression, in whom the percent of ALDH1A1-positive cells correlated negatively with progression-free survival (6.05 v 13.81 months, p<0.035). Subpopulations of A2780cp20 cells with ALDH1A1 activity were isolated for orthotopic tumor initiating studies, where tumorigenicity was approximately 50-fold higher with ALDH1A1-positive cells. Interestingly, tumors derived from ALDH1A1-positive cells gave rise to both ALDH1A1-positive and ALDH1A1-negative populations, but ALDH1A1-negative cells could not generate ALDH1A1-positive cells. In an in vivo orthotopic mouse model of ovarian cancer, ALDH1A1 silencing using nanoliposomal siRNA sensitized both taxane- and platinum-resistant cell lines to chemotherapy, significantly reducing tumor growth in mice compared to chemotherapy alone (a 74–90% reduction, p<0.015). These data demonstrate that the ALDH1A1 subpopulation is associated with chemoresistance and outcome in ovarian cancer patients, and targeting ALDH1A1 sensitizes resistant cells to chemotherapy. ALDH1A1-positive cells have enhanced, but not absolute, tumorigenicity, but do have differentiation capacity lacking in ALDH1A1-negative cells. This enzyme may be important for identification and targeting of chemoresistant cell populations in ovarian cancer. PMID:20889728

  14. Role of stem cells in cancer therapy and cancer stem cells: a review

    PubMed Central

    Sagar, Jayesh; Chaib, Boussad; Sales, Kevin; Winslet, Marc; Seifalian, Alexander

    2007-01-01

    For over 30 years, stem cells have been used in the replenishment of blood and immune systems damaged by the cancer cells or during treatment of cancer by chemotherapy or radiotherapy. Apart from their use in the immuno-reconstitution, the stem cells have been reported to contribute in the tissue regeneration and as delivery vehicles in the cancer treatments. The recent concept of 'cancer stem cells' has directed scientific communities towards a different wide new area of research field and possible potential future treatment modalities for the cancer. Aim of this review is primarily focus on the recent developments in the use of the stem cells in the cancer treatments, then to discuss the cancer stem cells, now considered as backbone in the development of the cancer; and their role in carcinogenesis and their implications in the development of possible new cancer treatment options in future. PMID:17547749

  15. Treatment Options by Stage (Small Cell Lung Cancer)

    MedlinePlus

    ... Cancer Prevention Lung Cancer Screening Research Small Cell Lung Cancer Treatment (PDQ®)–Patient Version General Information About Small Cell Lung Cancer Go to Health Professional Version Key Points ...

  16. Percutaneous Transhepatic Biliary Drainage in the Management of Postsurgical Biliary Leaks in Patients with Nondilated Intrahepatic Bile Ducts

    SciTech Connect

    Cozzi, Guido Severini, Aldo; Civelli, Enrico; Milella, Marco; Pulvirenti, Andrea; Salvetti, Monica; Romito, Raffaele; Suman, Laura; Chiaraviglio, Francesca; Mazzaferro, Vincenzo

    2006-06-15

    Purpose. To assess the feasibility of percutaneous transhepatic biliary drainage (PTBD) for the treatment of postsurgical biliary leaks in patients with nondilated intrahepatic bile ducts, its efficacy in restoring the integrity of bile ducts, and technical procedures to reduce morbidity. Methods. Seventeen patients out of 936 undergoing PTBD over a 20-year period had a noncholestatic liver and were retrospectively reviewed. All patients underwent surgery for cancer and suffered a postsurgical biliary leak of 345 ml/day on average; 71% were in poor condition and required permanent nutritional support. An endoscopic approach failed or was excluded due to inaccessibility of the bile ducts. Results. Established biliary leaks and site of origin were diagnosed an average of 21 days (range 1-90 days) after surgery. In all cases percutaneous access to the biliary tree was achieved. An external (preleakage) drain was applied in 7 cases, 9 patients had an external-internal fistula bridging catheter, and 1 patient had a percutaneous hepatogastrostomy. Fistulas healed in an average of 31 days (range 3-118 days ) in 15 of 17 patients (88%) following PTBD. No major complications occurred after drainage. Post-PTBD cholangitis was observed in 6 of 17 patients (35%) and was related to biliary sludge formation occurring mostly when drainage lasted >30 days and was of the external-internal type. Median patient survival was 17.7 months and in all cases the repaired biliary leaks remained healed. Conclusions. PTBD is a feasible, effective, and safe procedure for the treatment of postsurgical biliary leaks. It is therefore a reliable alternative to surgical repair, which entails longer hospitalization and higher costs.

  17. Regulation of NANOG in cancer cells.

    PubMed

    Gong, Shuai; Li, Qiuhui; Jeter, Collene R; Fan, Qingxia; Tang, Dean G; Liu, Bigang

    2015-09-01

    As one of the key pluripotency transcription factors, NANOG plays a critical role in maintaining the self-renewal and pluripotency in normal embryonic stem cells. Recent data indicate that NANOG is expressed in a variety of cancers and its expression correlates with poor survival in cancer patients. Of interest, many studies suggest that NANOG enhances the defined characteristics of cancer stem cells and may thus function as an oncogene to promote carcinogenesis. Therefore, NANOG expression determines the cell fate not only in pluripotent cells but also in cancer cells. Although the regulation of NANOG in normal embryonic stem cells is reasonably well understood, the regulation of NANOG in cancer cells has only emerged recently. The current review provides a most updated summary on how NANOG expression is regulated during tumor development and progression. PMID:26013997

  18. Confocal Raman imaging for cancer cell classification

    NASA Astrophysics Data System (ADS)

    Mathieu, Evelien; Van Dorpe, Pol; Stakenborg, Tim; Liu, Chengxun; Lagae, Liesbet

    2014-05-01

    We propose confocal Raman imaging as a label-free single cell characterization method that can be used as an alternative for conventional cell identification techniques that typically require labels, long incubation times and complex sample preparation. In this study it is investigated whether cancer and blood cells can be distinguished based on their Raman spectra. 2D Raman scans are recorded of 114 single cells, i.e. 60 breast (MCF-7), 5 cervix (HeLa) and 39 prostate (LNCaP) cancer cells and 10 monocytes (from healthy donors). For each cell an average spectrum is calculated and principal component analysis is performed on all average cell spectra. The main features of these principal components indicate that the information for cell identification based on Raman spectra mainly comes from the fatty acid composition in the cell. Based on the second and third principal component, blood cells could be distinguished from cancer cells; and prostate cancer cells could be distinguished from breast and cervix cancer cells. However, it was not possible to distinguish breast and cervix cancer cells. The results obtained in this study, demonstrate the potential of confocal Raman imaging for cell type classification and identification purposes.

  19. Dendritic cell-based cancer therapeutic vaccines

    PubMed Central

    Palucka, Karolina; Banchereau, Jacques

    2013-01-01

    The past decade has seen tremendous developments in novel cancer therapies, through targeting of tumor cell-intrinsic pathways whose activity is linked to genetic alterations, as well as the targeting of tumor cell-extrinsic factors such as growth factors. Furthermore, immunotherapies are entering the clinic at an unprecedented speed following the demonstration that T cells can efficiently reject tumors and that their anti-tumor activity can be enhanced with antibodies against immune regulatory molecules (checkpoints blockade). Current immunotherapy strategies include monoclonal antibodies against tumor cells or immune regulatory molecules, cell-based therapies such as adoptive transfer of ex vivo activated T cells and natural killer (NK) cells, and cancer vaccines. Herein, we discuss the immunological basis for therapeutic cancer vaccines and how the current understanding of dendritic cell (DC) and T cell biology might enable development of next-generation curative therapies for patients with cancer. PMID:23890062

  20. Radiofrequency treatment alters cancer cell phenotype

    NASA Astrophysics Data System (ADS)

    Ware, Matthew J.; Tinger, Sophia; Colbert, Kevin L.; Corr, Stuart J.; Rees, Paul; Koshkina, Nadezhda; Curley, Steven; Summers, H. D.; Godin, Biana

    2015-07-01

    The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment.

  1. Radiofrequency treatment alters cancer cell phenotype

    PubMed Central

    Ware, Matthew J.; Tinger, Sophia; Colbert, Kevin L.; Corr, Stuart J.; Rees, Paul; Koshkina, Nadezhda; Curley, Steven; Summers, H. D.; Godin, Biana

    2015-01-01

    The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment. PMID:26165830

  2. Epigenetic targeting of ovarian cancer stem cells.

    PubMed

    Wang, Yinu; Cardenas, Horacio; Fang, Fang; Condello, Salvatore; Taverna, Pietro; Segar, Matthew; Liu, Yunlong; Nephew, Kenneth P; Matei, Daniela

    2014-09-01

    Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor-suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cells (OCSC). In this study, we tested the hypothesis that DNA-hypomethylating agents may be able to reset OCSC toward a differentiated phenotype by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH(+) ovarian cancer cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low-dose SGI-110 reduced the stem-like properties of ALDH(+) cells, including their tumor-initiating capacity, resensitized these OCSCs to platinum, and induced reexpression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by reprogramming residual cancer stem-like cells. Furthermore, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer. PMID:25035395

  3. Breast cancer cell lines: friend or foe?

    PubMed Central

    Burdall, Sarah E; Hanby, Andrew M; Lansdown, Mark RJ; Speirs, Valerie

    2003-01-01

    The majority of breast cancer research is conducted using established breast cancer cell lines as in vitro models. An alternative is to use cultures established from primary breast tumours. Here, we discuss the pros and cons of using both of these models in translational breast cancer research. PMID:12631387

  4. Cancer stem cell targeted therapy: progress amid controversies

    PubMed Central

    Wang, Tao; Shigdar, Sarah; Gantier, Michael P.; Hou, Yingchun; Wang, Li; Li, Yong; Shamaileh, Hadi Al; Yin, Wang; Zhou, Shu-Feng; Zhao, Xinhan; Duan, Wei

    2015-01-01

    Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy. PMID:26496035

  5. Turning Cancer Cells into Cancer Killers.

    PubMed

    2016-01-01

    Researchers have changed leukemia cells into natural killer cells by adding a specific antibody to bone marrow cells from patients with acute myeloblastic leukemia. The induced natural killer cells killed leukemia cells in culture. The antibody does not trigger the same conversion in bone marrow from healthy patients. PMID:26621762

  6. Cancer stem cells in glioblastoma

    PubMed Central

    Lathia, Justin D.; Mack, Stephen C.; Mulkearns-Hubert, Erin E.; Valentim, Claudia L.L.; Rich, Jeremy N.

    2015-01-01

    Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial. PMID:26109046

  7. Interfacial geometry dictates cancer cell tumorigenicity.

    PubMed

    Lee, Junmin; Abdeen, Amr A; Wycislo, Kathryn L; Fan, Timothy M; Kilian, Kristopher A

    2016-08-01

    Within the heterogeneous architecture of tumour tissue there exists an elusive population of stem-like cells that are implicated in both recurrence and metastasis. Here, by using engineered extracellular matrices, we show that geometric features at the perimeter of tumour tissue will prime a population of cells with a stem-cell-like phenotype. These cells show characteristics of cancer stem cells in vitro, as well as enhanced tumorigenicity in murine models of primary tumour growth and pulmonary metastases. We also show that interfacial geometry modulates cell shape, adhesion through integrin α5β1, MAPK and STAT activity, and initiation of pluripotency signalling. Our results for several human cancer cell lines suggest that interfacial geometry triggers a general mechanism for the regulation of cancer-cell state. Similar to how a growing tumour can co-opt normal soluble signalling pathways, our findings demonstrate how cancer can also exploit geometry to orchestrate oncogenesis. PMID:27043781

  8. Interfacial geometry dictates cancer cell tumorigenicity

    NASA Astrophysics Data System (ADS)

    Lee, Junmin; Abdeen, Amr A.; Wycislo, Kathryn L.; Fan, Timothy M.; Kilian, Kristopher A.

    2016-08-01

    Within the heterogeneous architecture of tumour tissue there exists an elusive population of stem-like cells that are implicated in both recurrence and metastasis. Here, by using engineered extracellular matrices, we show that geometric features at the perimeter of tumour tissue will prime a population of cells with a stem-cell-like phenotype. These cells show characteristics of cancer stem cells in vitro, as well as enhanced tumorigenicity in murine models of primary tumour growth and pulmonary metastases. We also show that interfacial geometry modulates cell shape, adhesion through integrin α5β1, MAPK and STAT activity, and initiation of pluripotency signalling. Our results for several human cancer cell lines suggest that interfacial geometry triggers a general mechanism for the regulation of cancer-cell state. Similar to how a growing tumour can co-opt normal soluble signalling pathways, our findings demonstrate how cancer can also exploit geometry to orchestrate oncogenesis.

  9. Biliary scintigraphy in acute pancreatitis

    SciTech Connect

    Serafini, A.N.; Al-Sheikh, W.; Barkin, J.S.; Hourani, M.; Sfakiankis, G.; Clarke, L.P.; Ashkar, F.S.

    1982-08-01

    A prospective study was carried out in 60 patients to determine the efficacy of /sup 99m/Tc-PIPIDA scintigraphy in differentiating biliary pancreatitis from nonbiliary pancreatitis. Forty patients were classified as having biliary pancreatitis and 20 patients as having the nonbiliary type. Scintigraphic scans were divided into five main types according to the time to visualization of the gallbladder and the time to excretion of /sup 99m/Tc-PIPIDA into the intestinal tract. Normal scans were obtained on 95% of patients (19/20) with nonbiliary pancreatitis; 22.5% of patients (9/40) with biliary pancreatitis had normal scans. It is concluded that elevated amylase levels together with an abnormal biliary scan, as defined by the criteria presented here, indicate biliary pancreatitis, while a normal scan largely excludes such diagnosis.

  10. Biliary scintigraphy in acute pancreatitis

    SciTech Connect

    Serafini, A.N.; Al-Sheikh, W.; Barkin, J.S.; Hourani, M.; Sfakiankis, G.; Clarke, L.P.; Ashkar, F.S.

    1982-08-01

    A prospective study was carried out in 60 patients to determine the efficacy of /sup 99//sup m/Tc-PIPIDA scintigraphy in differentiating biliary pancreatitis from nonbiliary pancreatitis. Forty patients were classified as having biliary pancreatitis and 20 patients as having the nonbiliary type. Scintigraphic scans were divided into five main types according to the time to visualization of the gallbladder and the time to excretion of /sup 99//sup m/Tc-PIPIDA into the intestinal tract. Normal scans were obtained in 95% of patients (19/20) with nonbiliary pancreatitis; 22.5% of patients (9/40) with biliary pancreatitis had normal scans. It is concluded that elevated amylase levels together with an abnormal biliary scan, as defined by the criteria presented here, indicate biliary pancreatitis, while a normal scan largely excludes such diagnosis.

  11. Cancer: The Transforming Power of Cell Competition.

    PubMed

    Gil, Jesus; Rodriguez, Tristan

    2016-02-22

    The tumour-host microenvironment plays key roles in cancer, but the mechanisms involved are not fully understood. Two new studies provide insight into this problem by showing that through cell competition, a fitness-sensing process that usually eliminates defective cells, pre-cancerous lesions signal the death of surrounding tissue that in turn promotes their neoplastic transformation. PMID:26906487

  12. Learning about Cancer by Studying Stem Cells

    MedlinePlus

    ... About Cancer by Studying Stem Cells Inside Life Science View All Articles | Inside Life Science Home Page Learning About Cancer by Studying Stem ... Once Upon a Stem Cell This Inside Life Science article also appears on LiveScience . Learn about related ...

  13. Biliary excretion of iron and ferritin in idiopathic hemochromatosis

    SciTech Connect

    Hultcrantz, R.; Angelin, B.; Bjoern-Rasmussen, E.E.; Ewerth, S.; Einarsson, K.

    1989-06-01

    The role of biliary excretion of iron and ferritin in iron overload was studied and evaluated. Ten patients with idiopathic hemochromatosis and two groups of controls (14 gallstone patients and 16 healthy subjects) were included. Liver tissue (obtained by percutaneous or operative biopsy) was investigated with light microscopy and transmission electron microscopy in combination with x-ray microanalysis. Fasting bile samples were obtained through duodenal aspiration or at cholecystectomy. Iron was determined in liver tissue and bile using atomic absorption spectroscopy, and ferritin was determined in serum and bile with a radioimmunoassay technique. All patients with hemochromatosis had iron-positive staining as seen in light microscopy. Electron microscopy showed iron-containing proteins in the lysosomes and cytosol of liver parenchymal cells, and this observation was supported by x-ray microanalysis. Hepatic iron concentration was increased about eightfold in the patients with hemochromatosis (p less than 0.001). Biliary iron concentration, expressed per millimole of bile acid, was increased about twofold (p less than 0.05) and biliary ferritin concentration about fivefold (p less than 0.001) in hemochromatosis. Four of the patients with hemochromatosis were reexamined after completed treatment with venesection; this resulted in normalized biliary concentrations of iron and ferritin. We conclude that biliary secretion of ferritin occurs in humans and that both iron and ferritin excretion are enhanced in hepatic iron overload. The apparently limited capacity of biliary iron excretion may be of importance for the hepatic iron accumulation in hemochromatosis.

  14. Proposed therapies in primary biliary cholangitis.

    PubMed

    Floreani, Annarosa; Sun, Ying; Zou, Zheng Sheng; Li, Baosen; Cazzagon, Nora; Bowlus, Christopher L; Gershwin, M Eric

    2016-03-01

    ABSTARCT Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response. PMID:26577047

  15. Excretion of biliary compounds during intrauterine life

    PubMed Central

    Macias, Rocio IR; Marin, Jose JG; Serrano, Maria A

    2009-01-01

    In adults, the hepatobiliary system, together with the kidney, constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine, respectively. However, during intrauterine life the biliary route of excretion for cholephilic compounds, such as bile acids and biliary pigments, is very poor. Although very early in pregnancy the fetal liver produces bile acids, bilirubin and biliverdin, these compounds cannot be efficiently eliminated by the fetal hepatobiliary system, owing to the immaturity of the excretory machinery in the fetal liver. Therefore, the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta. Owing to the presence of detoxifying enzymes and specific transport systems at different locations of the placental barrier, such as the endothelial cells of chorionic vessels and trophoblast cells, this organ plays an important role in the hepatobiliary-like function during intrauterine life. The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother. This may result in oxidative stress and apoptosis, mainly in the placenta and fetal liver, which might affect normal fetal development and challenge the fate of the pregnancy. The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem. PMID:19230042

  16. Response of Breast Cancer Cells and Cancer Stem Cells to Metformin and Hyperthermia Alone or Combined

    PubMed Central

    Lee, Hyemi; Park, Heon Joo; Park, Chang-Shin; Oh, Eun-Taex; Choi, Bo-Hwa; Williams, Brent; Lee, Chung K.; Song, Chang W.

    2014-01-01

    Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5–10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44high/CD24low cells of MCF-7 cells and, CD44high/CD24high cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia. PMID:24505341

  17. Wnt Signaling in Cancer Stem Cell Biology

    PubMed Central

    de Sousa e Melo, Felipe; Vermeulen, Louis

    2016-01-01

    Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer. PMID:27355964

  18. Breast cancer stem cells and radiation

    NASA Astrophysics Data System (ADS)

    Phillips, Tiffany Marie

    2007-12-01

    The present studies explore the response of breast cancer stem cells (BCSC's) to radiation and the implications for clinical cancer treatment. Current cancer therapy eliminates bulky tumor mass but may fail to eradicate a critical tumor initiating cell population termed "cancer stem cells". These cells are potentially responsible for tumor formation, metastasis, and recurrence. Recently cancer stem cells have been prospectively identified in various malignancies, including breast cancer. The breast cancer stem cell has been identified by the surface markers CD44+/CD24 -(low). In vitro mammosphere cultures allow for the enrichment of the cancer stem cell population and were utilized in order to study differential characteristics of BCSC's. Initial studies found that BCSC's display increased radiation resistance as compared to other non-stem tumor cells. This resistance was accompanied by decreased H2AX phosphorylation, decreased reactive oxygen species formation, and increased phosphorylation of the checkpoint protein Chk1. These studies suggest differential DNA damage and repair within the BCSC population. Studies then examined the consequences of fractionated radiation on the BCSC population and found a two-fold increase in BCSC's following 5 x 3Gy. This observation begins to tie cancer stem cell self-renewal to the clinical stem cell phenomenon of accelerated repopulation. Accelerated repopulation is observed when treatment gaps increase between sequential fractions of radiotherapy and may be due to cancer stem cell symmetric self-renewal. The balance between asymmetric and symmetric stem cell division is vital for proper maintenance; deregulation is likely linked to cancer initiation and progression. The developmental Notch-1 pathway was found to regulate BCSC division. Over-expressing the constitutively active Notch-1-ICD in MCF7 cells produced an increase in the BCSC population. Additionally, radiation was observed to increase the expression of the Notch-1

  19. Dendritic cell-based cancer immunotherapy for colorectal cancer

    PubMed Central

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Saito, Keisuke; Takami, Shinichiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-01-01

    Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients. PMID:27158196

  20. Wnt and the Cancer Niche: Paracrine Interactions with Gastrointestinal Cancer Cells Undergoing Asymmetric Cell Division

    PubMed Central

    Xin, Hong-Wu; Ambe, Chenwi M.; Ray, Satyajit; Kim, Bo-Kyu; Koizumi, Tomotake; Wiegand, Gordon W.; Hari, Danielle; Mullinax, John E.; Jaiswal, Kshama R.; Garfield, Susan H.; Stojadinovic, Alexander; Rudloff, Udo; Thorgeirsson, Snorri S.; Avital, Itzhak

    2013-01-01

    Objective: Stem-like cancer cells contribute to cancer initiation and maintenance. Stem cells can self-renew by asymmetric cell division (ACD). ACD with non-random chromosomal cosegregation (ACD-NRCC) is one possible self-renewal mechanism. There is a paucity of evidence supporting ACD-NRCC in human cancer. Our aim was to investigate ACD-NRCC and its potential interactions with the cancer niche (microenvironment) in gastrointestinal cancers. Design: We used DNA double and single labeling approaches with FACS to isolate live cells undergoing ACD-NRCC. Results: Gastrointestinal cancers contain rare subpopulations of cells capable of ACD-NRCC. ACD-NRCC was detected preferentially in subpopulations of cells previously suggested to be stem-like/tumor-initiating cancer cells. ACD-NRCC was independent of cell-to-cell contact, and was regulated by the cancer niche in a heat-sensitive paracrine fashion. Wnt pathway genes and proteins are differentially expressed in cells undergoing ACD-NRCC vs. symmetric cell division. Blocking the Wnt pathway with IWP2 (WNT antagonist) or siRNA-TCF4 resulted in suppression of ACD-NRCC. However, using a Wnt-agonist did not increase the relative proportion of cells undergoing ACD-NRCC. Conclusion: Gastrointestinal cancers contain subpopulations of cells capable of ACD-NRCC. Here we show for the first time that ACD-NRCC can be regulated by the Wnt pathway, and by the cancer niche in a paracrine fashion. However, whether ACD-NRCC is exclusively associated with stem-like cancer cells remains to be determined. Further study of these findings might generate novel insights into stem cell and cancer biology. Targeting the mechanism of ACD-NRCC might engender novel approaches for cancer therapy. PMID:23901343

  1. Interacting Alleles of the Coinhibitory Immunoreceptor Genes Cytotoxic T-Lymphocyte Antigen 4 and Programmed Cell-Death 1 Influence Risk and Features of Primary Biliary Cirrhosis

    PubMed Central

    Juran, Brian D.; Atkinson, Elizabeth J.; Schlicht, Erik M.; Fridley, Brooke L.; Petersen, Gloria M.; Lazaridis, Konstantinos N.

    2012-01-01

    Autoimmune diseases such as primary biliary cirrhosis (PBC) result from failure in the immune mechanisms that establish and maintain self-tolerance. Evidence suggests that these processes are shared among the spectrum of autoimmune syndromes and are likely genetically determined. Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell-death 1 (PDCD1) are two genes encoding coinhibitory immunoreceptors that harbor polymorphisms with demonstrated associations to multiple autoimmune disorders. We aimed to assess functional single nucleotide polymorphisms (SNPs) in these two genes for association with PBC. SNPs in CTLA4 and PDCD1 were genotyped in 351 PBC patients and 205 controls. Allele and genotype frequencies were evaluated for association with PBC and/or antimitochondrial antibody (AMA) positivity with logistic regression. Haplotypes were inferred with an expectation-maximization algorithm, and allelic interaction was analyzed by logistic regression modeling. Individual SNPs demonstrated no association to PBC. However, the GG genotype of CTLA4 49AG was significantly associated with AMA positivity among the PBC patients. Also, individual SNPs and a haplotype of CTLA4 as well as a rare genotype of the PDCD1 SNP PD1.3 were associated with orthotopic liver transplantation. As well, we identified the influence of an interaction between the putatively autoimmune-protective CTLA4 49AG:CT60 AA haplotype and autoimmune-risk PDCD1 PD1.3 A allele on development of PBC. Conclusion Our findings illustrate the complex nature of the genetically induced risk of PBC and emphasize the importance of considering definable subphenotypes of disease, such as AMA positivity, or definitive measures of disease severity/progression, like orthotopic liver transplantation, when genetic analyses are being performed. Comprehensive screening of genes involved with immune function will lead to a greater understanding of the genetic component of autoimmunity in PBC while furthering our

  2. A PDZ-Like Motif in the Biliary Transporter ABCB4 Interacts with the Scaffold Protein EBP50 and Regulates ABCB4 Cell Surface Expression.

    PubMed

    Venot, Quitterie; Delaunay, Jean-Louis; Fouassier, Laura; Delautier, Danièle; Falguières, Thomas; Housset, Chantal; Maurice, Michèle; Aït-Slimane, Tounsia

    2016-01-01

    ABCB4/MDR3, a member of the ABC superfamily, is an ATP-dependent phosphatidylcholine translocator expressed at the canalicular membrane of hepatocytes. Defects in the ABCB4 gene are associated with rare biliary diseases. It is essential to understand the mechanisms of its canalicular membrane expression in particular for the development of new therapies. The stability of several ABC transporters is regulated through their binding to PDZ (PSD95/DglA/ZO-1) domain-containing proteins. ABCB4 protein ends by the sequence glutamine-asparagine-leucine (QNL), which shows some similarity to PDZ-binding motifs. The aim of our study was to assess the potential role of the QNL motif on the surface expression of ABCB4 and to determine if PDZ domain-containing proteins are involved. We found that truncation of the QNL motif decreased the stability of ABCB4 in HepG2-transfected cells. The deleted mutant ABCB4-ΔQNL also displayed accelerated endocytosis. EBP50, a PDZ protein highly expressed in the liver, strongly colocalized and coimmunoprecipitated with ABCB4, and this interaction required the QNL motif. Down-regulation of EBP50 by siRNA or by expression of an EBP50 dominant-negative mutant caused a significant decrease in the level of ABCB4 protein expression, and in the amount of ABCB4 localized at the canalicular membrane. Interaction of ABCB4 with EBP50 through its PDZ-like motif plays a critical role in the regulation of ABCB4 expression and stability at the canalicular plasma membrane. PMID:26789121

  3. A PDZ-Like Motif in the Biliary Transporter ABCB4 Interacts with the Scaffold Protein EBP50 and Regulates ABCB4 Cell Surface Expression

    PubMed Central

    Venot, Quitterie; Delaunay, Jean-Louis; Fouassier, Laura; Delautier, Danièle; Falguières, Thomas; Housset, Chantal; Maurice, Michèle; Aït-Slimane, Tounsia

    2016-01-01

    ABCB4/MDR3, a member of the ABC superfamily, is an ATP-dependent phosphatidylcholine translocator expressed at the canalicular membrane of hepatocytes. Defects in the ABCB4 gene are associated with rare biliary diseases. It is essential to understand the mechanisms of its canalicular membrane expression in particular for the development of new therapies. The stability of several ABC transporters is regulated through their binding to PDZ (PSD95/DglA/ZO-1) domain-containing proteins. ABCB4 protein ends by the sequence glutamine-asparagine-leucine (QNL), which shows some similarity to PDZ-binding motifs. The aim of our study was to assess the potential role of the QNL motif on the surface expression of ABCB4 and to determine if PDZ domain-containing proteins are involved. We found that truncation of the QNL motif decreased the stability of ABCB4 in HepG2-transfected cells. The deleted mutant ABCB4-ΔQNL also displayed accelerated endocytosis. EBP50, a PDZ protein highly expressed in the liver, strongly colocalized and coimmunoprecipitated with ABCB4, and this interaction required the QNL motif. Down-regulation of EBP50 by siRNA or by expression of an EBP50 dominant-negative mutant caused a significant decrease in the level of ABCB4 protein expression, and in the amount of ABCB4 localized at the canalicular membrane. Interaction of ABCB4 with EBP50 through its PDZ-like motif plays a critical role in the regulation of ABCB4 expression and stability at the canalicular plasma membrane. PMID:26789121

  4. Overexpression Of Hepatocyte Nuclear Factor-1beta Predicting Poor Prognosis Is Associated With Biliary Phenotype In Patients With Hepatocellular Carcinoma

    PubMed Central

    Yu, Dan-Dan; Jing, Ying-Ying; Guo, Shi-Wei; Ye, Fei; Lu, Wen; Li, Quan; Dong, Yu-Long; Gao, Lu; Yang, Yu-Ting; Yang, Yang; Wu, Meng-Chao; Wei, Li-Xin

    2015-01-01

    Hepatocyte nuclear factor-1beta (HNF-1B) is involved in the hepatobiliary specification of hepatoblasts to cholangiocytes during liver development, and is strongly expressed throughout adult biliary epithelium. The aim of this study was to examine the expression of HNF-1B in different pathologic subtypes of primary liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (ICC), and the relationship between HNF-1B expression, clinicopathological features and prognosis. We retrospectively investigated 2 cohorts of patients, including 183 HCCs and 69 ICCs. The expression of HNF-1B was examined by immunohistochemistry. We found that HNF-1B expression was associated with pathological subtype of primary tumor, and HNF-1B expression in HCC tissue may be associated with the change of phenotype on recurrence. The HNF-1B expression was positively correlated with biliary/HPC (hepatic progenitor cell) markers expression. Further, multivariable analysis showed that HNF-1B expression was an independent prognostic factor for both overall survival and disease-free survival of HCC patients. However, no correlation between HNF-1B expression and survival was found in ICC patients. In summary, HCC with high HNF-1B expression displayed biliary phenotype and tended to show poorer prognosis. HNF-1B-positive malignant cells could be bipotential cells and give rise to both hepatocytic and cholangiocytic lineages during tumorigenesis. PMID:26311117

  5. Copper Cu 64 Anti-CEA Monoclonal Antibody M5A PET in Diagnosing Patients With CEA Positive Cancer

    ClinicalTrials.gov

    2016-09-12

    Breast Cancer; Colon Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Gastrointestinal Cancer; Liver and Intrahepatic Biliary Tract Cancer; Lung Cancer; Metastatic Cancer; Pancreatic Cancer; Rectal Cancer; Thyroid Gland Medullary Carcinoma; Unspecified Adult Solid Tumor, Protocol Specific

  6. Obstructive jaundice at the initial presentation in small-cell lung cancer

    PubMed Central

    Ochi, Nobuaki; Takigawa, Nagio; Yasugi, Masayuki; Ishida, Etsuji; Kawamoto, Hirofumi; Taniguchi, Akihiko; Harada, Daijiro; Hayashi, Eiko; Toda, Hiroko; Yanai, Hiroyuki; Tanimoto, Mitsune; Kiura, Katsuyuki

    2010-01-01

    Obstructive jaundice sometimes may develop in association with advanced small-cell lung cancer (SCLC); however, SCLC initially presenting with obstructive jaundice is rare. This report presents the cases of two SCLC patients with obstructive jaundice at the initial diagnosis. A 64-year-old male presented with obstructive jaundice due to a tumor at the head of the pancreas. He was diagnosed with SCLC by transbronchial biopsy from a lung tumor in the left upper lobe. Another 74-year-old male was admitted with jaundice due to a tumor in the porta hepatis. He was also diagnosed with SCLC by a fine-needle aspiration biopsy of a lung tumor in the left lower lobe. Both cases were successfully treated with systemic chemotherapy after endoscopic retrograde biliary drainage. PMID:23754881

  7. Newborn Screening for Biliary Atresia

    PubMed Central

    Wang, Kasper S.

    2016-01-01

    Biliary atresia is the most common cause of pediatric end-stage liver disease and the leading indication for pediatric liver transplantation. Affected infants exhibit evidence of biliary obstruction within the first few weeks after birth. Early diagnosis and successful surgical drainage of bile are associated with greater survival with the child’s native liver. Unfortunately, because noncholestatic jaundice is extremely common in early infancy, it is difficult to identify the rare infant with cholestatic jaundice who has biliary atresia. Hence, the need for timely diagnosis of this disease warrants a discussion of the feasibility of screening for biliary atresia to improve outcomes. Herein, newborn screening for biliary atresia in the United States is assessed by using criteria established by the Discretionary Advisory Committee on Heritable Disorders in Newborns and Children. Published analyses indicate that newborn screening for biliary atresia by using serum bilirubin concentrations or stool color cards is potentially life-saving and cost-effective. Further studies are necessary to evaluate the feasibility, effectiveness, and costs of potential screening strategies for early identification of biliary atresia in the United States. PMID:26620065

  8. Therapeutic strategies targeting cancer stem cells.

    PubMed

    Ning, Xiaoyan; Shu, Jianchang; Du, Yiqi; Ben, Qiwen; Li, Zhaoshen

    2013-04-01

    Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy. PMID:23358473

  9. Cancer Stem Cells in the Thyroid

    PubMed Central

    Nagayama, Yuji; Shimamura, Mika; Mitsutake, Norisato

    2016-01-01

    The cancer stem cell (CSC) model posits that CSCs are a small, biologically distinct subpopulation of cancer cells in each tumor that have self-renewal and multi-lineage potential, and are critical for cancer initiation, metastasis, recurrence, and therapy-resistance. Numerous studies have linked CSCs to thyroid biology, but the candidate markers and signal transduction pathways that drive thyroid CSC growth are controversial, the origin(s) of thyroid CSCs remain elusive, and it is unclear whether thyroid CSC biology is consistent with the original hierarchical CSC model or the more recent dynamic CSC model. Here, we critically review the thyroid CSC literature with an emphasis on research that confirmed the presence of thyroid CSCs by in vitro sphere formation or in vivo tumor formation assays with dispersed cells from thyroid cancer tissues or bona fide thyroid cancer cell lines. Future perspectives of thyroid CSC research are also discussed. PMID:26973599

  10. Therapeutic strategies targeting cancer stem cells

    PubMed Central

    Ning, Xiaoyan; Shu, Jianchang; Du, Yiqi; Ben, Qiwen; Li, Zhaoshen

    2013-01-01

    Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy. PMID:23358473