Long-term Survival after resection for perihilar cholangiocarcinoma: Impact of UICC staging and surgical procedure.

Background/aims: Perihilar cholangiocarcinoma is a rare disease with unfavorable prognosis resulting in low survival rates. This study aims to retrospectively assess the beneficial histopathological features and surgical procedures in long-term survivors (i.e.

Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma.

Background & Aims: In cholangiocarcinoma, early metastatic spread via lymphatic vessels often precludes curative therapies. Cholangiocarcinoma invasiveness is fostered by an extensive stromal reaction, enriched in cancer-associated fibroblasts (CAFs) and lymphatic endothelial cells (LECs). Cholangiocarcinoma cells recruit and activate CAFs by secreting PDGF-D.

Comparison of the sixth and the seventh editions of the UICC classification for intrahepatic cholangiocarcinoma.

Background: The current seventh edition of the TNM classification for intrahepatic cholangiocarcinoma (ICC) includes tumor number, vascular invasion, lymph node involvement but no longer the tumor size as compared to the sixth edition. The impact of the seventh edition on stage-based prognostic prediction for patients with ICC was evaluated.

Methods: Between 03/2001 and 02/2013, 98 patients with the diagnosis of an ICC were surgically treated at our center.

[CA19-9 in intrahepatic cholangiocarcinoma : A diagnostic and prognostic armamentarium?].

Background: Intrahepatic cholangiocarcinomas are the second most common malignant tumors of the liver with an unfavorable prognosis. The role of CA19-9 in terms of patient prognosis is still under debate in the literature.

Objective: The aim of the present study was to investigate the prognostic value of preoperatively assessed CA19-9 levels in patients with intrahepatic cholangiocarcinoma after surgery.

Liver Regeneration-Related Cytokine Profiles in Donors and Recipients Before and After Living-Donor Liver Transplant.

Objectives: The liver's capability to completely regenerate after injury is a unique phenomenon in which cytokines are of particular interest. Here, we aimed to assess the release patterns and prognostic relevance of liver regeneration-related cytokines in the setting of living-donor liver transplant.

Materials And Methods: Eleven cytokines related to liver regeneration (hepatocyte growth factor, interleukin 6, insulin-like growth factor-1, tumor necrosis factor alpha, transforming growth factor beta, granulocyte colony-stimulating factor, stem cell factor, chemokine (C-X-C motif) ligand 12, angiogenin, fibroblast growth factor-2, and vascular endothelial growth factor) were compared in 13 living-donor liver transplant recipients and their corresponding donors before and daily (10 days) after transplant.

Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2 ) mice.

Unlabelled: Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASFs), which are drivers of fibrosis. The activated phenotype of ASFs is characterized by an increased sensitivity to apoptotic stimuli.

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

Aim: To examine the influence on apoptotic mechanisms following inhibition of polo-like kinases as therapeutically approach for cholangiocellular cancer treatment.

Methods: As most cholangiocarcinomas are chemotherapy-resistant due to mechanisms preventing tumor cell death, we investigated the effect of Cisplatin on cholangiocellular carcinoma (CCA) cell lines KMCH-1 and Mz-Ch-1. Polo-like kinases (PLK) are important regulators of the cell cycle and their inhibition is discussed as a potential therapy while PLK inhibition can regulate apoptotic mediators.

Annexin A10 optimally differentiates between intrahepatic cholangiocarcinoma and hepatic metastases of pancreatic ductal adenocarcinoma: a comparative study of immunohistochemical markers and panels.

Discriminating intrahepatic cholangiocarcinoma (ICC) from hepatic metastases of pancreatic ductal adenocarcinoma (mPDAC) can be challenging. While pathologists might depend on clinical information regarding a primary tumor, their diagnosis will lead the patient either to potentially curative surgery (for ICC) or to palliation (for mPDAC). Beyond the validation of recently published potential biomarkers for PDAC (primary or metastatic) in a large cohort, we assessed diagnostic performance of the most promising candidates in the challenging task of discriminating metastatic PDAC (mPDAC) from ICC.

[Klatskin tumor: long-term survival following surgery].

Background: Perihilar cholangiocarcinoma (Klatskin tumor) is a rare tumor entity with an unfavorable prognosis despite optimal treatment.

Objectives: The aim of the study is to investigate beneficial histopathological features and recommendations for surgery in perihilar cholangiocarcinoma to improve patients' long term survival.

Material And Methods: 192 patients suffering from perihilar cholangiocarcinoma underwent attempted tumor resection between 1998 and 2008 at our clinic.

Novel immunohistochemical markers differentiate intrahepatic cholangiocarcinoma from benign bile duct lesions.

Aims: The distinction between intrahepatic cholangiocarcinoma (ICC) and benign bile duct lesions can be challenging. Using our previously identified potential biomarkers for ICC, we examined whether these are useful for the differential diagnosis of ICC, bile duct adenoma and reactive bile duct proliferations in an immunohistochemical approach and identified a diagnostic marker panel including known biomarkers.

Methods: Subjects included samples from 77 patients with ICC, 33 patients with bile duct adenoma and 47 patients with ductular reactions in liver cirrhosis.

Mycophenolic acid induces apoptosis of hepatic stellate cells in an in vitro model of HCV.

Introduction: Hepatitis C virus (HCV) infection is an important risk factor for the development of liver fibrosis and progression to cirrhosis. Liver transplantation as terminal treatment option for liver disease requires life-long immunosuppression. However, immunomodulatory therapy may promote reinfection and renewed fibrogenesis.

Polo-like kinase 3 is associated with improved overall survival in cholangiocarcinoma.

Background & Aims: Cholangiocarcinomas (CCA) paradoxically express the death ligand TRAIL and thus, are dependent on effective survival signals to circumvent apoptosis. Hedgehog signalling exerts major survival signals in CCA by regulating serine/threonine kinase polo-like kinase (PLK)2. We here aimed to examine the role of PLK1/2/3 expression for CCA tumour biology.

TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess.

Background & Aims: Low-grade chronic inflammation is a cardinal feature of the metabolic syndrome, yet its pathogenesis is not well defined. The purpose of this study was to examine the role of TRAIL receptor (TR) signaling in the pathogenesis of obesity-associated inflammation using mice with the genetic deletion of TR.

Methods: TR knockout (TR(-/-)) mice and their littermate wild-type (WT) mice were fed a diet high in saturated fat, cholesterol and fructose (FFC) or chow.

Endoscopic management is the treatment of choice for bile leaks after liver resection.

Background: Despite improvements in surgical techniques and postoperative patient care, bile leaks still occur postoperatively in as many as 15% of liver resections (LRs) and are associated with high mortality. There is a paucity of outcome data on endoscopic treatment of complex bile leaks.

Objective: The aim of this retrospective study was to evaluate the efficacy of interventional endoscopy in the treatment of bile leaks after LR.

Vascular and nerval damage after intraoperative radiation therapy of the liver hilum in a large animal model.

It has been demonstrated that intraoperative radiotherapy is a therapeutic option for patients suffering from perihilar cholangiocarcinoma. Aim of our study was to investigate vascular and nerve damages after irradiation of the liver hilum in a pig model. Twenty-four pigs underwent central bile duct resection followed by biliodigestive anastomosis.

Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma.

Unlabelled: Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2).

Expression of apoptosis- and vitamin D pathway-related genes in hepatocellular carcinoma.

Background/aims: Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and therapeutic options are scarce. As they might represent future targets for cancer therapy, the expression of apoptosis-related genes in HCC is of particular interest. In this pilot study, we further examined apoptosis-related genes in human HCC and also focused on vitamin D signaling as this might be a regulator of HCC cell apoptosis.

Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma.

Cancer-associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAFs are "activated" and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma as a desmoplastic tumor model, we investigated the sensitivity of liver CAFs to the cytotoxic drug navitoclax, a BH3 mimetic.

Tumor growth effects of rapamycin on human biliary tract cancer cells.

Background: Liver transplantation is an important treatment option for patients with liver-originated tumors including biliary tract carcinomas (BTCs). Post-transplant tumor recurrence remains a limiting factor for long-term survival. The mammalian target of rapamycin-targeting immunosuppressive drug rapamycin could be helpful in lowering BTC recurrence rates.

Targeting PDGFR-β in Cholangiocarcinoma.

Background: Cholangiocarcinomas (CCAs) are highly desmoplastic neoplasms with a tumour microenvironment plentiful in myofibroblasts (MFBs). MFB-derived PDGF-BB survival signalling is a mediator of CCA cell resistance to apoptotic stimuli. This raises the concept that targeting PDGFR-β, a cognate receptor of PDGF-BB, represents a potential strategy for the treatment of human CCA.

Role of stress-induced NKG2D ligands in liver diseases.

Cell death by apoptosis is a prominent feature in a variety of liver diseases. It is likely that apoptosis is the initial cellular response to hepatocyte and biliary injury, which then leads to the initiation of cellular and cytokine cascades culminating in hepatocyte death with subsequent fibrosis and cirrhosis. This sequence of events is of paramount clinical importance.

Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells.

Unlabelled: Cholangiocarcinoma (CCA) cells paradoxically express the death ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and, therefore, are dependent upon potent survival signals to circumvent TRAIL cytotoxicity. CCAs are also highly desmoplastic cancers with a tumor microenvironment rich in myofibroblasts (MFBs). Herein, we examine a role for MFB-derived CCA survival signals.