• Cholangiocarcinoma
• Liver transplantation
• Perihilar cholangiocarcinomas
• Recurrence
• Resection
• Survival

• Humans
• Klatskin Tumor/surgery
• Klatskin Tumor/pathology
• Bile Duct Neoplasms/surgery
• Liver Transplantation
• Cholangiocarcinoma/surgery
• Cholangiocarcinoma/diagnosis
• Bile Ducts, Intrahepatic/pathology

• biliary drainage
• bilirubin
• hilar cholangiocarcinoma
• morbidity
• mortality
• prediction

Dickkopf-1 (DKK1) is involved in tumorigenesis and the invasion of several tumors. However, its biological function in human hilar cholangiocarcinoma (HCCA) has not yet been documented. This study was designed to investigate the clinical significance and biological function of DKK1 in HCCA. The expression of DKK1 was investigated in thirty-seven human HCCA biopsy samples by immunohistochemistry. To further explore the biological effects of DKK1 in HCCA, transient and stable knockdown of DKK1 in two human HCCA cells (QBC939 and FRH0201) were established using small interfering or short hairpin RNA expression vector. In the present study, immunohistochemistry revealed that DKK1 was up-regulated in human HCCA tissues (24/37, 64.9%). High levels of DKK1 in human HCCA correlated with metastasis to the hilar lymph nodes (P=0.038). Genetic depletion of DKK1 in HCCA cells resulted in significantly inhibited proliferation, colony formation and migration compared with controls. Most importantly, DKK1 down-regulation impaired tumor formation capacity of HCCA cells in vivo. Subsequent investigations revealed that β-catenin is an important target of DKK1 and DKK1 exerts its pro-invasion function at least in part through the β-catenin/ matrix metalloproteinase-7 (MMP-7) signaling pathway. Consistently, in human HCCA tissues, DKK1 level was positively correlated with β-catenin and MMP-7 expression, as well as tumor hilar lymphatic metastasis. Taken together, our findings indicate that DKK1 may be a crucial regulator in the tumorigenicity and invasion of human HCCA, DKK1 exerts its pro-invasion function at least in part through the β-catenin/ MMP-7 signaling pathway, suggesting DKK1 as a potential therapeutic target for HCCA.

• DKK1
• HCCA
• lymphatic metastasis
• tumorigenesis

To assess the feasibility and safety of percutaneous intraductal radiofrequency ablation (RFA) for unresectable Bismuth types III and IV hilar cholangiocarcinoma.

Percutaneous intraductal RFA combined with metal stent placement was successful in all patients without any technical problems; the technical success rate was 100%. Chemotherapy was administered to two patients. After treatment, serum direct bilirubin levels were notably decreased. Six patients died during the follow-up period. Median stent patency from the time of the first RFA and survival from the time of diagnosis were 100 days (95% confidence interval (CI), 85–115 days) and 5.3 months (95% CI, 2.5–8.1 months), respectively. No acute pancreatitis, bile duct bleeding and perforation, bile leakage, or other severe complications occurred. Four cases of procedure-related cholangitis, three cases of postoperative abdominal pain, and five cases of asymptomatic transient increase in serum amylase were observed. One patient who presented with stent blockage 252 days' post-procedure underwent repeat ablation.

Between September 2013 and May 2015, nine patients with unresectable Bismuth types III and IV hilar cholangiocarcinoma who were treated with percutaneous intraductal RFA combined with metal stent placement after the percutaneous transhepatic cholangial drainage were included in the retrospective analysis. Procedure-related complications, stent patency, and survival after treatment were investigated.

Percutaneous intraductal RFA combined with metal stent placement is a technically safe and feasible therapeutic option for the palliative treatment of unresectable Bismuth types III and IV hilar cholangiocarcinoma. Its long-term efficacy and safety is promising, but needs further study via randomized and prospective trials that include a greater number of patients.

• hilar cholangiocarcinoma
• metal stent
• percutaneous transhepatic cholangial drainage
• radiofrequency ablation

• Benign
• Biliary drainage
• Biliary stricture
• Controversy
• Hilar stricture
• Malignant
• Preoperative
• Primary sclerosing cholangitis

• Bile Duct Neoplasms/complications
• Bile Duct Neoplasms/surgery
• Bile Ducts/pathology
• Bile Ducts/surgery
• Bile Ducts, Intrahepatic/surgery
• Cholangiopancreatography, Endoscopic Retrograde/adverse effects
• Cholangitis, Sclerosing/complications
• Cholestasis/etiology
• Constriction, Pathologic/therapy
• Drainage/adverse effects
• Endoscopy
• Humans
• Stents/adverse effects

• Cholangiocarcinoma
• Malignant biliary stricture
• Malignant obstructive jaundice
• Meta-analysis
• Pancreatic head cancer
• Pancreaticoduodenectomy
• Peri-ampullary malignancy
• Preoperative biliary drainage
• Systematic review

• Biliary Tract Neoplasms/complications
• Biliary Tract Neoplasms/mortality
• Biliary Tract Neoplasms/surgery
• Biliary Tract Surgical Procedures/adverse effects
• Biliary Tract Surgical Procedures/methods
• Drainage/adverse effects
• Drainage/methods
• Duodenal Neoplasms/complications
• Duodenal Neoplasms/mortality
• Duodenal Neoplasms/surgery
• Humans
• Jaundice, Obstructive/etiology
• Jaundice, Obstructive/surgery
• Length of Stay
• Odds Ratio
• Pancreatic Neoplasms/complications
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/surgery
• Postoperative Complications
• Preoperative Care/methods
• Randomized Controlled Trials as Topic

The incidence of Cholangiocellular Carcinoma (CCA) is increasing in the western world. The tumour has a high proportion of desmoplastic stroma and is correlated with a worse prognosis when cancer associated myofibroblasts (CAFs) are present. Recent studies showed promising results after liver transplantation (LTx) in non-resectable early stage CCA. Mycophenolic acid (MPA) and the mTor inhibitor Everolimus are used to prevent organ rejection but recently were shown to exhibit an antiproliferative effect on CCA-cells. Little is known about the influence of immunosuppressive drugs on tumour cell proliferation and migration after paracrine stimulation by CAFs. Moreover, it is still unknown, which signaling pathways are activated following these specific cell-cell interactions.

CCA cell lines HuCCT1 and TFK1 were utilized for the study. CAFs were derived from resected CCA cancer tissue. Cell viability was measured by the crystal violet assay and tumour cell invasion was quantified using a modified co-culture transmigration assay. Semiquantitative cytokine-expression was measured using a cytokine-array. Protein expression and phosphorylation of ERK, STAT3 and AKT was determined by Western-blot analysis.

CCA cells treated with MPA exhibited a dose related decrease in cell viability in contrast to Cyclosporine A (CSA) treatment which had no effect on cell viability. Everolimus significantly inhibited proliferation at very low concentrations. The pro-invasive effect of CAFs in co-culture transmigration assay was significantly reduced by Everolimus at a concentration of 1nM (p = 0.047). In contrast, MPA and CSA showed no effect on tumour cell invasion. Treatment of CAFs with 1nM Everolimus showed a significant reduction in the expression of IL 8, IL 13, MCP1, MIF and Serpin E1. CCA-cells showed significant increases in phosphorylation of ERK, STAT3 and AKT under the influence of conditioned CAF-media. This effect was suppressed by Everolimus.

The secretion of proinflammatory cytokines by CAFs may lead to increased activation of JAK/STAT3-, ERK- and AKT-signaling and increased migration of CCA-cells. Everolimus abrogates this effect and inhibits proliferation of CCA-cells even at low concentrations.

LTx for non-resectable early stage CCA is currently performed in several clinical studies. Consistent with a role for common immunosuppressants in inhibiting tumour cell-proliferation and -invasion, our study indicates that a combination of standard therapies with Everolimus and MPA is a promising therapy option to treat CCA following LTx.

• AKT-pathway
• Cancer associated fibroblast
• Cholangiocarcinoma
• Cytokine expression
• ERK-pathway
• JAK/STAT-pathway
• Liver transplantation
• Mycophenolic acid
• Tumour growth
• Tumour migration
• Tumour proliferation
• mTOR-inhibitor

AIM: To explore the curative effect of surgery in the treatment of hilar cholangiocarcinoma (HC).

METHODS: A retrospective analysis was performed of the clinical data for 41 HC patients treated from October 2007 to March 2010 in Affiliated Hospital of Zunyi Medical College.

RESULTS: In the 41 patients, the incidence of postoperative complications was 36.59%, including incision infection in 2 cases, pulmonary infection in 3 cases, bile leakage in 3 cases, and pleural effusion in 7 cases. After radical resection, the 1-, 3-, and 5-year survival rates were 78.6%, 42.9% and 21.4%, respectively. After palliative resection, the 1-, 3-, and 5-year survival rates were 41.7%, 16.7% and 0.0%, respectively. In the conservative treatment (jaundice control) group, the 1-, 3-, and 5-year survival rates were 25.0%, 8.3% and 0.0%, respectively.

CONCLUSION: Radical resection can obviously improve the survival of HC patients.

• Hilar cholangiocarcinoma
• Radical resection
• Survival rate

• Disease spectrum
• hilar cholangiocarcinoma
• magnetic resonance cholangiopancreatography
• multi-detector computed tomography

• borderline resectable pancreatic cancer
• cholangiocarcinoma
• neoadjuvant therapy
• pancreatic cancer
• preoperative biliary drainage

• Cholangiocarcinoma
• Klatskin tumour
• Liver surgery
• Liver transplantation
• Primary sclerosing cholangitis

• Bile Duct Neoplasms/mortality
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/surgery
• Bile Ducts, Intrahepatic/pathology
• Bile Ducts, Intrahepatic/surgery
• Chemotherapy, Adjuvant
• Cholangiocarcinoma/mortality
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/surgery
• Hepatic Duct, Common/pathology
• Hepatic Duct, Common/surgery
• Humans
• Klatskin Tumor/mortality
• Klatskin Tumor/pathology
• Klatskin Tumor/surgery
• Liver Transplantation/adverse effects
• Liver Transplantation/mortality
• Living Donors
• Neoadjuvant Therapy
• Neoplasm Staging
• Radiotherapy, Adjuvant
• Risk Factors
• Time Factors
• Treatment Outcome
• Waiting Lists

AIM: To investigate the effect of preoperative biliary drainage (PBD) in jaundiced patients with hilar cholangiocarcinoma (HCCA) undergoing major liver resections.

METHODS: An observational study was carried out by reviewing a prospectively maintained database of HCCA patients who underwent major liver resection for curative therapy from January 2002 to December 2012. Patients were divided into two groups based on whether PBD was performed: a drained group and an undrained group. Patient baseline characteristics, preoperative factors, perioperative and short-term postoperative outcomes were compared between the two groups. Risk factors for postoperative complications were also analyzed by logistic regression test with calculating OR and 95%CI.

RESULTS: In total, 78 jaundiced patients with HCCA underwent major liver resection: 32 had PBD prior to operation while 46 did not have PBD. The two groups were comparable with respect to age, sex, body mass index and co-morbidities. Furthermore, there was no significant difference in the total bilirubin (TBIL) levels between the drained group and the undrained group at admission (294.2 ± 135.7 vs 254.0 ± 63.5, P = 0.126). PBD significantly improved liver function, reducing not only the bilirubin levels but also other liver enzymes. The preoperative TBIL level was significantly lower in the drained group as compared to the undrained group (108.1 ± 60.6 vs 265.7 ± 69.1, P = 0.000). The rate of overall postoperative complications (53.1% vs 58.7%, P = 0.626), reoperation rate (6.3% vs 6.5%, P = 1.000), postoperative hospital stay (16.5 vs 15.0, P = 0.221) and mortality (9.4% vs 4.3%, P = 0.673) were similar between the two groups. In addition, there was no significant difference in infectious complications (40.6% vs 23.9%, P = 0.116) and noninfectious complications (31.3% vs 47.8%, P = 0.143) between the two groups. Univariate and multivariate analyses revealed that preoperative TBIL > 170 μmol/L (OR = 13.690, 95%CI: 1.275-147.028, P = 0.031), Bismuth-Corlette classification (OR = 0.013, 95%CI: 0.001-0.166, P = 0.001) and extended liver resection (OR = 14.010, 95%CI: 1.130-173.646, P = 0.040) were independent risk factors for postoperative complications.

CONCLUSION: Overall postoperative morbidity and mortality rates after major liver resection are not improved by PBD in HCCA patients with jaundice. Preoperative TBIL > 170 μmol/L, Bismuth-Corlette classification and extended liver resection are independent risk factors linked to postoperative complications.

• Obstructive jaundice
• Hilar cholangiocarcinoma
• Preoperative biliary drainage
• Major hepatectomy
• Surgical outcome

• Aged
• Bile Duct Neoplasms/complications
• Bile Duct Neoplasms/mortality
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/surgery
• Bile Ducts, Intrahepatic/pathology
• Bile Ducts, Intrahepatic/surgery
• Chi-Square Distribution
• Cholangiocarcinoma/complications
• Cholangiocarcinoma/mortality
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/surgery
• Drainage/adverse effects
• Drainage/mortality
• Female
• Hepatectomy/adverse effects
• Hepatectomy/mortality
• Humans
• Jaundice, Obstructive/diagnosis
• Jaundice, Obstructive/etiology
• Jaundice, Obstructive/mortality
• Jaundice, Obstructive/therapy
• Length of Stay
• Logistic Models
• Male
• Middle Aged
• Multivariate Analysis
• Odds Ratio
• Postoperative Complications/mortality
• Postoperative Complications/surgery
• Preoperative Care
• Reoperation
• Retrospective Studies
• Risk Factors
• Treatment Outcome

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

Hilar cholangiocarcinoma (HC) is a rare tumor that causes devastating disease. In the late stages, this carcinoma primarily invades the portal vein and metastasizes to the hepatic lobes; it is associated with a poor prognosis. HC is diagnosed by its clinical manifestation and results of imaging techniques such as ultrasound, computed tomography, magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiography, and percutaneous transhepatic cholangiography. Preoperative hepatic bile drainage can improve symptoms associated with insufficient liver and kidney function, coagulopathy, and jaundice. Surgical margin-negative (R0) resection, including major liver resection, is the most effective and potentially curative treatment for HC. If the tumor is not resected, then liver transplantation with adjuvant management can improve survival. We conducted a systematic review of developments in imaging studies and major surgical hepatectomy for HC with positive outcomes regarding quality of life.

• Adult
• Aged
• Aged, 80 and over
• Bile Duct Neoplasms/mortality
• Bile Duct Neoplasms/therapy
• Bile Ducts/surgery
• Chemoradiotherapy, Adjuvant/mortality
• Cholangiocarcinoma/mortality
• Cholangiocarcinoma/therapy
• Female
• Germany/epidemiology
• Hepatectomy/mortality
• Humans
• Male
• Middle Aged
• Neoplasm Recurrence, Local/mortality
• Neoplasm Recurrence, Local/prevention & control
• Postoperative Care/mortality
• Prevalence
• Risk Factors
• Survival Analysis
• Survival Rate
• Treatment Outcome

AIM: To investigate the clinical features and survival of patients treated for cholangiocarcinoma in our institution and to analyze the factors affecting their survival.

METHODS: This retrospective cohort study assessed patients diagnosed with cholangiocarcinoma between January 1997 and December 2007 at the University Malaya Medical Centre in Malaysia. The clinical data and associated outcomes were collected using a structured proforma.

RESULTS: Of the 69 patients diagnosed with cholangiocarcinoma, 38 (55%) were male; mean patient age was 61 years. Twelve patients (17%) had intrahepatic, 38 (55%) had perihilar and 19 (28%) had distal tumors. Only 12 patients underwent curative surgery, including seven R0 resections. Only one patient died within 30 d after surgery. The overall median survival was 4 mo, whereas the median survival of R0 resected patients was 16 mo. The overall 1-, 2- and 3-year cumulative survival rates were 67%, 17% and 17%, respectively. Survival rates were significantly associated with curative resection (P = 0.002), intrahepatic tumor (P = 0.003), negative margin status (P = 0.013), early tumor stage (P = 0.016), higher tumor differentiation (P = 0.032) and absence of jaundice (P = 0.038). Multivariate analysis showed that tumor location was a significant independent predictor of patient survival.

CONCLUSION: Curative, margin-negative resection of early stage, well-differentiated intrahepatic tumors is associated with improved patient survival.

• Cholangiocarcinoma
• Bile duct tumor
• Surgery
• Malaysia

• biliary tract carcinoma
• cholangiocarcinoma
• gall bladder carcinoma
• surgery
• neo-adjuvant therapy
• adjuvant therapy

Cholangiocarcinoma is the primary malignancy arising from the biliary epithelium. The disease is marked by jaundice, cholestasis, and cholangitis. Over 50 percent of patients present with advanced stage disease, precluding curative surgical resection as an option of treatment. Prognosis is poor, and survival has been limited even after biliary decompression. Palliative management has become the standard of care for unresectable disease and has evolved to include an endoscopic approach. Photodynamic therapy (PDT) consists of administration of a photosensitizer followed by local irradiation with laser therapy. Several studies conducted in Europe and the United States have shown a marked improvement in the symptoms of cholestasis, survival, and quality of life. This article summarizes the published experience regarding PDT for cholangiocarcinoma and the steps required to administer this therapy safely.

• Cholangiocarcinoma
• Cholestasis
• Jaundice
• Neoplasia
• Palliation
• Photodynamic therapy
• Photofrin

• Biliary cancer
• Cholangiocarcinoma
• Photodynamic therapy

• Adult
• Aged
• Aged, 80 and over
• Bile Duct Neoplasms/mortality
• Bile Duct Neoplasms/surgery
• Female
• Hepatic Duct, Common
• Humans
• Klatskin Tumor/mortality
• Klatskin Tumor/surgery
• Liver Transplantation
• Male
• Middle Aged
• Survival Rate

AIM: To study the outcome and prognostic factors in a series of patients with extrahepatic cholangiocarcinoma and determine the impact of comorbidity on survival.

METHODS: A retrospective analysis of 68 patients with extrahepatic cholangiocarcinoma (perihilar, n = 37; distal, n = 31) seen at a single tertiary-care institution during the period 1999-2003 was performed. Data on presentation, management, and outcome were assessed by chart review. Pathologic confirmation was obtained in 37 cases (54.4%). Comorbidity was evaluated by using the Charlson comorbidity index (CCI).

RESULTS: Mean age at diagnosis was 73.4 ± 11.5 years. Jaundice was the most common symptom presented (86.8%). Median CCI score was 1 (range, 0 to 4). Nineteen patients (27.9%) underwent tumor resection. Palliative biliary drainage was performed in 39 patients (57.4%), and 6 patients (8.8%) received only best supportive care. Tumor-free margin status (R0) was achieved in 15 cases (78.9% of resection group). Baseline serum carbohydrate antigen 19-9 (CA 19-9) level was revealed to be an independent predictor of surgical treatment (P = 0.026). Overall median survival was 3.1 ± 0.9 mo, with 1- and 2-year survival rates of 21% and 7%, respectively. In the univariate analysis, tumor resection, CCI score, and serum CA 19-9 levels correlated significantly with outcome. In the multivariate analysis, only resection (HR 0.10; 95% CI, 0.02-0.51, P = 0.005) and a CCI score ≥ 2 (HR 3.36; 95% CI, 1.0-10.9, P = 0.045) were found to independently predict survival.

CONCLUSION: Tumor resection and comorbidity emerged as significant prognostic variables in extrahepatic cholangiocarcinoma. Comorbidity evaluation instruments should be applied in the clinical management of such patients.

• Charlson index
• Cholangiocarcinoma
• Comorbidity
• Prognosis
• Survival

Several advances in diagnosis, treatment and palliation of cholangiocarcinoma (CC) have occurred in the last decades. A multidisciplinary approach to this disease is therefore recommended. CC is a relatively rare tumor and the main risk factors are: chronic inflammation, genetic predisposition and congenital abnormalities of the biliary tree. While the incidence of intra-hepatic CC is increasing, the incidence of extra-hepatic CC is trending down. The only curative treatment for CC is surgical resection with negative margins. Liver transplantation has been proposed only for selected patients with hilar CC that cannot be resected who have no metastatic disease after a period of neoadjuvant chemo-radiation therapy. Magnetic resonance imaging/magnetic resonance cholangiopancreatography, positron emission tomography scan, endoscopic ultrasound and computed tomography scans are the most frequently used modalities for diagnosis and tumor staging. Adjuvant therapy, palliative chemotherapy and radiotherapy have been relatively ineffective for inoperable CC. For most of these patients biliary stenting provides effective palliation. Photodynamic therapy is an emerging palliative treatment that seems to provide pain relief, improve biliary patency and increase survival. The clinical utility of other emerging therapies such as transarterial chemoembolization, hepatic arterial chemoinfusion and high intensity intraductal ultrasound needs further study.

• Cholangiocarcinoma
• Epidemiology
• Diagnosis
• Therapy
• Palliation
• Systematic review

• Cholangiocarcinoma
• lymph nodes
• prognostic factors
• resection margin
• survival

Diagnostic methods for biliary tract carcinoma and the efficacy of these methods are discussed. Neither definite methods for early diagnosis nor specific markers are available in this disease. When this disease is suspected on the basis of clinical symptoms and risk factors, hemato-biochemical examination and abdominal ultrasonography are performed and, where appropriate, enhanced computed tomography (CT) and/or magnetic resonance cholangiopancreatography (MRCP) is carried out. Diagnoses of extrahepatic bile duct cancer and ampullary carcinoma are often made based on the presence of obstructive jaundice. Although rare, abdominal pain and pyrexia, as well as abnormal findings of the hepatobiliary system detected by hemato-biochemical examination, serve as a clue to making a diagnosis of these diseases. On the other hand, the early diagnosis of gallbladder cancer is scarcely possible on the basis of clinical symptoms, so when this cancer is found with the onset of abdominal pain and jaundice, it is already advanced at the time of detection, thus making a cure difficult. When gallbladder cancer is suspected, enhanced CT is carried out. Multidetector computed tomography (MDCT), in particular — one of the methods of enhanced CT — is useful for decision of surgical criteria, because MDCT shows findings such as localization and extension of the tumor, and the presence or absence of remote metastasis. Procedures such as magnetic resonance imaging, endoscopic ultrasonography, bile duct biopsy, and cholangioscopy should be carried out taking into account indications for these procedures in individual patients. However, direct biliary tract imaging is necessary for making a precise diagnosis of the horizontal extension of bile duct cancer.

• Cholangiocarcinoma
• biliary drainage
• major hepatectomy