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Extra-Hepatic Bile duct cancer (cholangiocarcinoma)

The bile duct is the tube that collects bile from the liver, which is fed into the small intestine to digest food. 'extra-hepatic' means outside the liver. Cancer starting in the part of the bile duct outside the liver tends to be treated differently than cancer starting in the bile duct inside the liver.

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  • PubMed search for publications about Bile Duct Cancer - Limit search to: [Reviews]

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    MeSH term: Bile Duct Neoplasms
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Serrano PE, Kim D, Kim PT, et al.
Effect of Pancreatic Fistula on Recurrence and Long-Term Prognosis of Periampullary Adenocarcinomas after Pancreaticoduodenectomy.
Am Surg. 2016; 82(12):1187-1195 [PubMed] Related Publications
Pancreatic fistula (PF) is common after pancreaticoduodenectomy (PD). Its effect on recurrence and survival is not known. Retrospective study of patients undergoing PD for periampullary adenocarcinomas (2000-2012). Standard statistical analyses were performed to determine the impact of PF on disease-free survival (DFS) and overall survival (OS). There were 634 PDs (pancreatic adenocarcinoma: 347, other periampullary adenocarcinomas: 287). Any-grade PF developed in 81/634 (13%). Perioperative mortality rate was 1.7 per cent (11/634), higher in patients with PF (10 vs 0.5%, P < 0.001). In multivariable analysis, PF significantly reduced DFS in pancreatic [hazard ratio (HR) = 1.6, 95% confidence-interval (CI): 1.1-2.6, P = 0.043] but not in other periampullary adenocarcinomas [HR = 1.3 (95% CI: 0.8-2.2), P = 0.45]. Positive lymph nodes, margins, and high-grade histology were associated with decreased DFS and OS. Adjuvant therapy was associated with improved OS in pancreatic [HR = 0.7 (95% CI: 0.5-0.9), P = 0.02] but not in other periampullary adenocarcinomas [HR = 1.14 (95% CI: 0.8-1.7), P = 0.49]. PF did not alter OS in either group. After PD, PF is associated with decreased DFS in pancreatic but not in other periampullary adenocarcinomas. This decrease DFS did not alter OS. Tumor grade, lymph nodes, and resection margin status are associated with DFS and OS.

Dover LL, Jacob R, Wang TN, et al.
Improved Postoperative Survival for Intraductal-Growth Subtype of Intrahepatic Cholangiocarcinoma.
Am Surg. 2016; 82(11):1133-1139 [PubMed] Related Publications
Intrahepatic cholangiocarcinoma (ICC) is classified according to the following subtypes: massforming (MF), periductal infiltrating (PI), and intraductal growth (IG). The aim of this study is to measure the association between ICC subtypes and patient survival after surgical resection. Data were abstracted on all patients treated with definitive resections of ICC at a single institution between 2000 and 2011 with at least three years follow-up. Survival estimates were quantified using Kaplan-Meier curves and compared using the log-rank test. There were 37 patients with ICC treated with definitive partial hepatectomies with a median survival of 33.5 months. Tumor stage (P < 0.0001), satellitosis (P < 0.001), lymphovascular space invasion (P = 0.003), and macroscopic subtype (P = 0.003) were predictive of postoperative survival. Disease-free survivals for MF, PI, and IG subtypes, respectively, were 30 per cent, 0 per cent, and 57 per cent (P = 0.017). Overall survivals among ICC macroscopic subtypes were as follows: MF 37 per cent, PI 0 per cent, and IG 71 per cent (P = 0.003). Although limited by the small sample size of this rare cancer, this study demonstrates significant differences among macroscopic subtypes of ICC in both disease-free survivals and overall survivals after definitive partial hepatectomy.

Zhou YM, Sui CJ, Zhang XF, et al.
Influence of cirrhosis on long-term prognosis after surgery in patients with combined hepatocellular-cholangiocarcinoma.
BMC Gastroenterol. 2017; 17(1):25 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Little is known about the prognostic impact of cirrhosis on long-term survival of patients with combined hepatocellular-cholangiocarcinoma (cHCC-CC) after hepatic resection. The aim of this study was to elucidate the long-term outcome of hepatectomy in cHCC-CC patients with cirrhosis.
METHODS: A total of 144 patients who underwent curative hepatectomy for cHCC-CC were divided into two groups: cirrhotic group (n = 91) and noncirrhotic group (n = 53). Long-term postoperative outcomes were compared between the two groups.
RESULTS: Patients with cirrhosis had worse preoperative liver function, higher frequency of HBV infection, and smaller tumor size in comparison to those without cirrhosis. The 5-year overall survival rate in cirrhotic group was significantly lower than that in non-cirrhotic group (34.5% versus 54.1%, P = 0.032). The cancer recurrence-related death rate was similar between the two groups (46.2% versus 39.6%, P = 0.446), while the hepatic insufficiency-related death rate was higher in cirrhotic group (12.1% versus 1.9%, P = 0.033). Multivariate analysis indicated that cirrhosis was an independent prognostic factor of poor overall survival (hazard ratio 2.072, 95% confidence interval 1.041-4.123; P = 0.038).
CONCLUSIONS: The presence of cirrhosis is significantly associated with poor prognosis in cHCC-CC patietns after surgical resection, possibly due to decreased liver function.

Tian Q, Wang G, Zhang Y, et al.
Endoscopic radiofrequency ablation combined with fully covered self-expandable metal stent for inoperable periampullary carcinoma in a liver transplant patient: A case report.
Medicine (Baltimore). 2017; 96(5):e5790 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Postliver transplant periampullary carcinoma is an extremely uncommon disease.
PATIENT CONCERNS: Cutaneous jaundice in a patient who had received a liver transplant 4 years earlier.
DIAGNOSIS: Periampullary carcinoma.
INTERVENTIONS: Radiofrequency ablation plus fully covered self-expanding metal stents (FCSEMS).
OUTCOMES: The treatment of malignant neoplasm of the ampulla of Vater is the patient by radiofrequency ablation plus FCSEMS placement was successful. No complications occurred.
LESSONS: This is the first reported case of a liver transplant patient with inoperable periampullary carcinoma successfully treated by radiofrequency ablation plus FCSEMS placement. Our experience will be useful to other surgeons in managing similar patients in the future.

Jung DH, Hwang S, Song GW, et al.
Clinicopathological Features and Prognosis of Intrahepatic Cholangiocarcinoma After Liver Transplantation and Resection.
Ann Transplant. 2017; 22:42-52 [PubMed] Related Publications
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) can be incidentally diagnosed after liver transplantation (LT). We investigated the clinicopathological features of LT recipients with ICC and compared prognosis with that of the control group. MATERIAL AND METHODS We identified 16 recipients with ICC in our institutional database. The propensity score-matched control group comprised 100 ICC patients who underwent hepatic resection (HR). RESULTS ICC incidence was 0.5% in all adult LT patients and 1.2% in adult recipients with primary liver cancer. Mean age was 58.0±4.8 years and 15 were male. All ICCs were diagnosed incidentally in the explanted livers. Mean ICC tumor diameter was 2.5±1.1 cm and 14 recipients had a single tumor. Tumor stages were I in 9, II in 5, and IV in 2. Concurrent second primary liver cancer was detected as hepatocellular carcinoma in 7 and combined hepatocellular carcinoma-cholangiocarcinoma in 1. Tumor recurrence and patient survival rates were 56.2% and 81.3% at 1 year and 78.1% and 52.4% at 5 years, respectively. Presence of second cancer did not affect tumor recurrence (p=0.959) or patient survival (p=0.737). All 3 patients with very early ICC did not show ICC recurrence. Compared with the control group, the tumor recurrence rate was higher after LT (p=0.024), but this difference disappeared after analysis was confined to recipients with ICC alone (p=0.121). Post-recurrence survival was not different after HR and LT (p=0.082). CONCLUSIONS ICC is rarely diagnosed after LT and half of such patients have second liver cancer. Post-transplant prognosis of ICC is poor except for very early ICC; thus, strict surveillance is mandatory.

Doherty B, Nambudiri VE, Palmer WC
Update on the Diagnosis and Treatment of Cholangiocarcinoma.
Curr Gastroenterol Rep. 2017; 19(1):2 [PubMed] Related Publications
PURPOSE OF REVIEW: Cholangiocarcinoma is a rare biliary adenocarcinoma associated with poor outcomes. Cholangiocarcinoma is subdivided into extrahepatic and intrahepatic variants. Intrahepatic cholangiocarcinoma is then further differentiated into (1) peripheral mass-forming tumors and (2) central periductal infiltrating tumors. We aimed to review the currently known risk factors, diagnostic tools, and treatment options, as well as highlight the need for further clinical trials and research to improve overall survival rates.
RECENT FINDINGS: Cholangiocarcinoma has seen significant increase in incidence rates over the last several decades. Most patients do not carry the documented risk factors, which include infections and inflammatory conditions, but cholangiocarcinoma typically forms in the setting of cholestasis and chronic inflammation. Management strategies include multispecialty treatments, with consideration of surgical resection, systemic chemotherapy, and targeted radiation therapy. Surgically resectable disease is the only curable treatment option, which may involve liver transplantation in certain selected cases. Referrals to centers of excellence, along with enrollment in novel clinical trials are recommended for patients with unresectable or recurrent disease. This article provides an overview of cholangiocarcinoma and discusses the current diagnosis and treatment options. While incidence is increasing and more risk factors are being discovered, much more work remains to improve outcomes of this ominous disease.

Zhang S, Jia J, Bi X, et al.
Sarcomatoid carcinoma of the common bile duct: A case report.
Medicine (Baltimore). 2017; 96(3):e5751 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Sarcomatoid carcinoma is an extremely rare lesion in the common bile duct (CBD).
PATIENT CONCERNS: We present a case of sarcomatoid carcinoma of the distal CBD in a 51-year-old woman who presented with jaundice and abdominal pain. Whipple's operation was performed successfully. Microscopically, the tumor was a poorly differentiated carcinoma containing a component of sarcoma-like differentiation. The tumor cells displayed spindle-shaped nuclei with occasional mitotic figures. Cytokeratin (CK) 7, CK19, CK18, and pan-CK (AE1/AE3) staining was positive on immunohistochemistry. Vimentin and carcinoembryonic antigen (CEA) staining were also positive.
DIAGNOSES: Sarcomatoid carcinoma of the distal CBD.
INTERVENTIONS: The patient received three cycles of chemotherapy after surgery.
OUTCOMES: The patient has experienced no adverse events in the 3 years post-surgery.
LESSONS: We present here a case report of sarcomatoid carcinoma of the distal CBD. The patient received chemotherapy after surgery, and was event-free for 3 years post-surgery, suggesting a relatively better prognosis, despite the infiltrative pattern of the tumor.

Treeprasertsuk S, Poovorawan K, Soonthornworasiri N, et al.
A significant cancer burden and high mortality of intrahepatic cholangiocarcinoma in Thailand: a nationwide database study.
BMC Gastroenterol. 2017; 17(1):3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We aimed to examine the burden of intrahepatic cholangiocarcinoma (ICC) in Thailand and identify the prognostic factors for all-causes of death.
METHODS: We conducted a population-based study of ICC patients admitted during 2009-2013 using the Nationwide Hospital Admission Database, the National Health Security Office (NHSO). There was an average of 1,051,146 patients/year with diagnosis of gastrointestinal diseases (GI). All patients with a diagnosis of ICC (ICD10- C221) were included from a total of 72,479 admissions from 858 hospitals. The surgical resection procedures such as the radical pancreaticoduodenectomy, subtotal and partial hepatectomy were analyzed. Data for all patients were censored 1 year post-study or death, whichever came first.
RESULTS: A total of 34,325 patients with ICC during a 5-year study period (on average, 6865 patients/year, with the incidence rate of 14.6 per 100,000 population, per year. The ICC patients had a mean age of 63.8+/-11.6 years and 63% were males. The mean length of hospital stay was 6.4+/-7.3 days with a mean+/-SD cost of hospitalization of $595+/-$1160 USD per admission. There were 659 patients (1.9%) underwent surgical resection. The overall survival of ICC patients with surgery was significantly better than those patients without surgery. Hazard ratio of death for patients without surgery was 2.5 (95% CI of 2.3-2.7). Approximately 14% of the ICC patients died during hospitalization. The median overall survival of all patients after the first admission was 53 +/-0.6 days. From the multivariate analysis, factors related to all-causes of death were: patients' age >60 years (OR = 1.2, 95% CI; 1.1-1.3), length of hospital stay of >7 days (OR = 1.1, 95% CI; 1.02-1.2), male (OR = 1.3, 95% CI; 1.2-1.4), living in the northern part of Thailand (OR = 1.5, 95% CI; 1.3-1.8) and presence of complications during admission (OR = 1.3, 95% CI; 1.1-1.5).
CONCLUSION: The disease burden of patients with ICC in Thailand is significant with the incidence rate of 14.6 per 100,000 population, per year during 2009-2013 and showed high mortality rate of 14%.

Waseem D, Tushar P
 Intrahepatic, perihilar and distal cholangiocarcinoma: Management and outcomes.
Ann Hepatol. 2017 Jan-Feb 2017; 16(1):133-139 [PubMed] Related Publications
 Introduction and aims. Cholangiocarcinomas are a heterogeneous group of tumors that can be classified into three clinically distinct types of cancers, intrahepatic, perihilar and distal cholangiocarcinoma. The inconsistent use of nomenclature for these cancers has obscured a true knowledge of the epidemiology, natural history and response to therapy of these cancers. Our aims were to define demographic characteristics, management and outcomes of these three distinct cancer types.
MATERIALS AND METHODS: A retrospective study of patients enrolled in an institutional cancer registry from 1992 to 2010. Median survival was compared between different treatment modalities over three time periods for the three types of cholangiocarcinoma at different stages of the disease using Kaplan Meyer analysis.
RESULTS: 242 patients were identified. All cases were reviewed and classified into intrahepatic (90 patients), distal (48 patients) or perihilar (104 patients) cholangiocarcinomas. These cancers differed in median age of onset, gender distribution, median survival and stage. 13.8% of patients presented with stage I, 5.8% with stage II, 9.6% with stage III, 28% with stage IV, with 41.8% having unknown stage. The overall median survival was 15.8 months, and was 23, 25, 14, and 4.5 months for stages I, II, III, and IV respectively. Surgery improved survival in both early and advanced stages. Multimodality therapies further improved outcomes, particularly for perihilar cholangiocarcinoma.
CONCLUSION: Perihilar, distal and intrahepatic cholangiocarcinoma vary in their presentation, natural history and therapeutic approach to management. A consistently applied classification is essential for meaningful interpretation of studies of these cancers.

Miura T, Yoshizawa T, Hirai H, et al.
Prognostic Impact of CD163+ Macrophages in Tumor Stroma and CD8+ T-Cells in Cancer Cell Nests in Invasive Extrahepatic Bile Duct Cancer.
Anticancer Res. 2017; 37(1):183-190 [PubMed] Related Publications
AIM: The aim of this study was to examine the clinicopathological influence of tumor-infiltrating cluster of differentiation (CD) 163(+) macrophages and CD8(+) T-cells, and to clarify the prognostic effects of these cells in patients with invasive extrahepatic bile duct cancer (EHBC).
MATERIALS AND METHODS: The numbers of CD8(+) T-cells in cancer cell nests and CD163(+) macrophages in tumor stroma were evaluated using immunohistochemistry in 101 resected EHBC specimens. Correlations with clinicopathological variables and overall survival were analyzed.
RESULTS: Perihilar EHBC and perineural invasion were significantly associated with a low number of tumor-infiltrating CD8(+) T-cells. Poorly- differentiated histology and nodal metastasis were significantly associated with a high number of tumor-infiltrating CD163(+) macrophages. A combination of high number of CD8(+) T-cells and low number of CD163(+) macrophages was independently related to better overall survival in the whole patient cohort (hazard ratio=0.127, p<0.001) and in patients treated with adjuvant chemotherapy (hazard ratio=0.139, p=0.021).
CONCLUSION: Infiltrating CD163(+) macrophages in tumor stroma and CD8(+) T-cells in cancer cell nests have a prognostic impact in patients with EHBC following resection and also after adjuvant chemotherapy.

Saengboonmee C, Seubwai W, Cha'on U, et al.
Metformin Exerts Antiproliferative and Anti-metastatic Effects Against Cholangiocarcinoma Cells by Targeting STAT3 and NF-ĸB.
Anticancer Res. 2017; 37(1):115-123 [PubMed] Related Publications
BACKGROUND/AIM: Cholangiocarcinoma (CCA) is an aggressive cancer for which standard treatments are still ineffective. This study demonstrated the antiproliferative and anti-metastatic activity of metformin, an anti-diabetic drug, in CCA cells.
MATERIALS AND METHODS: Cell proliferation, migration/invasion and anoikis resistance were determined. The underlying mechanisms were identified using western blotting and immunocytofluorescence.
RESULTS: Metformin significantly suppressed proliferation of CCA cells in a dose- and time-dependent manner, regardless of glucose present in the medium. A low dose of metformin significantly increased anoikis and inhibited migration/ invasion of CCA cells that was in concert with the decrease of vimentin, matrix metalloproteinase (MMP)-2 and -7. Activation of 5' adenosine monophosphate-activated protein kinase (AMPK) by phosphorylation together with suppression of nuclear translocation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-ĸB) were the underlying mechanisms for these effects.
CONCLUSION: Metformin is a potent antiproliferative and anti-metastatic agent against human CCA cells. These findings encourage the repurposing of metformin in clinical trials to improve CCA treatment.

Zhang H, Zhu B, Zhang H, et al.
HBV Infection Status and the Risk of Cholangiocarcinoma in Asia: A Meta-Analysis.
Biomed Res Int. 2016; 2016:3417976 [PubMed] Free Access to Full Article Related Publications
Background. The inconsistent finding was between hepatitis B virus (HBV) infections and cholangiocarcinoma (CCA). This meta-analysis is to explore this relationship in Asia. Methods. A literature search was performed using PubMed, Web of Science, and Cochrane Library to October 30, 2015. Pooled incidence rate and OR with 95% CI were calculated using STATA 11.0. Results. Thirty-nine studies were included. The pooled incidence rate of CCA patients with HBV infection was 31% (95% CI 22%-39%). The pooled OR showed increased risk of CCA incidence with HBV infection (OR = 2.72, 95% CI 1.90-3.88), especially in ICC (OR = 3.184, 95% CI 2.356-4.302), while it showed no risk in ECC (OR = 1.407, 95% CI 0.925-2.141). Also, the pooled OR showed increased risk of ICC and ECC incidence (OR = 6.857, 95% CI 4.421-10.633 and OR = 1.740, 95% CI 1.260-2.404) in patients with HBsAg+/HBcAb+. The pooled OR showed increased risk of ICC incidence (OR = 1.410, 95% CI 1.095-1.816) in patients with HBsAg-/HBcAb+. Conclusion. It is suggested that HBV infection is associated with an increased risk of CCA in Asia. Two HBV infection models (HBsAg+/HBcAb+ and HBsAg-/HBcAb+) increase the risk of CCA, and patients with HBsAg-/HBcAb+ also had a risk of ICC. This trial is registered with PROSPERO CRD42015029264.

Wirth TC, Vogel A
Surveillance in cholangiocellular carcinoma.
Best Pract Res Clin Gastroenterol. 2016; 30(6):987-999 [PubMed] Related Publications
Cholangiocellular carcinoma is the most frequent malignant neoplasm originating from the epithelium of intra- or extrahepatic bile ducts. In the past decades, the incidence of cholangiocarcinoma has been shown to increase while overall mortality has remained high with an approximate 5-year overall survival below 20%. Surgery remains the only curative option while systemic treatment is limited to palliative chemotherapy. Therefore, surveillance strategies for patients at risk of developing cholangiocarcinoma are urgently needed, particularly in patients with primary sclerosing cholangitis and patients infected with liver flukes. Here we summarize the currently available data on surveillance of risk populations and methods for the detection of cholangiocarcinoma.

Yamashita YI, Wang H, Kurihara T, et al.
Clinical Significances of Preoperative Classification of Intrahepatic Cholangiocarcinoma: Different Characteristics of Perihilar vs. Peripheral ICC.
Anticancer Res. 2016; 36(12):6563-6569 [PubMed] Related Publications
BACKGROUND: The aim of this study was to evaluate the clinical significance of preoperative classification of intrahepatic cholangiocarcinoma (ICC) into perihilar and peripheral types using dynamic computed tomography (CT).
PATIENTS AND METHODS: A retrospective cohort study was performed to analyze the differences in clinical characteristics between perihilar and peripheral ICC samples from patients between 1990-2014.
RESULTS: A total of 87 patients were divided into three ICC subtypes; perihilar (n=34), peripheral (n=44), and unclassifiable ICC (n=9). The positive rates of pathological lymphatic infiltration (ly) (p=0.02) and perineural invasion (pn) (p<0.0001) were significantly higher in perihilar ICC. There was no significant difference in the disease-free survival rate (p=0.2268); however, the overall survival rate of perihilar ICC was significantly worse (p=0.0031). The rate of systemic recurrence (>3 nodules) was significantly higher in perihilar ICC (p=0.0135).
CONCLUSION: In perihilar ICC, the local tumor invasions such as ly and pn were more frequent. Therefore, it is important in such cases to attempt to achieve a sufficient tumor margin. Systemic recurrences were more frequent in perihilar ICC, so perioperative chemotherapy should be conducted as well.

Vasilieva L, Papadhimitriou SI, Alexopoulou A, et al.
Clinical presentation, diagnosis, and survival in cholangiocarcinoma: A prospective study.
Arab J Gastroenterol. 2016; 17(4):181-184 [PubMed] Related Publications
BACKGROUND AND STUDY AIMS: The diagnosis of cholangiocarcinoma (CCA) is difficult. The present study aimed to assess the clinical features, diagnosis, and survival in CCA.
PATIENTS AND METHODS: This is a prospective study on 46 patients with CCA who underwent endoscopic retrograde cholangiopancreatography (ERCP) or surgical resection and 20 controls with a clinical and ERCP suspicion for CCA in whom surgical biopsy and/or 4-year follow-up showed a benign biliary stricture.
RESULTS: The median age at presentation was 71years (range 44-88). Thirty-four patients (73.9%) presented with painless jaundice. Median CA 19-9 value was 188IU/L (range 1-49,138), with a level of <100IU/L in 13 patients (28%). Total bilirubin was 11.9 (0.6-36.3)mg/dL. The tumour was intrahepatic in 3 (6.5%), hilar (Klatskin) in 25 (54.3%), and located in the lower third of the bile duct in 18 (39.1%) patients. The diagnosis was confirmed by positive cytology in 10 (21.7%), biopsy in 20 (43.5%), cholangioscopy in five (10.9%), and imaging and clinical grounds in 11 (23.9%) patients. Cytology was feasible in 36 patients; it was positive in 10 and "highly indicative" in two patients (33.3% sensitivity). Twenty-two patients (47.8%) were treated by surgical resection, and the rest were offered palliative biliary drainage. Mean estimated survival for the entire group of CCA patients was 21.5±3.3months. Survival was slightly longer in patients who underwent surgical resection than those who had palliative treatment; the estimated mean survival rates were 26.2±4.2 vs. 17.1±3.3months, respectively, but the difference was not statistically significant (p=0.115).
CONCLUSION: The diagnosis of CCA is difficult and often delayed. The outcome is generally poor.

Cloyd JM, Tran Cao HS, Petzel MQ, et al.
Impact of pancreatectomy on long-term patient-reported symptoms and quality of life in recurrence-free survivors of pancreatic and periampullary neoplasms.
J Surg Oncol. 2017; 115(2):144-150 [PubMed] Related Publications
BACKGROUND: Long term patient-reported symptoms and quality of life (QOL) are important outcome metrics following cancer operations, but have been poorly described in patients who have previously undergone pancreatectomy.
METHODS: We conducted a cross-sectional survey of recurrence-free survivors of pancreatic ductal adenocarcinoma, periampullary carcinomas, and pancreatic neuroendocrine tumors who had undergone prior pancreatectomy. QOL and symptom burden were measured using the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire, and psychosocial distress was measured using the Hospital Anxiety and Depression Scale.
RESULTS: Of 331 eligible patients surveyed, 217 (66%) participated at a median of 53.3 (range, 7.6-214.8) months following pancreatoduodenectomy (PD, n = 165) or distal pancreatectomy (DP, n = 52). Among all patients, overall QOL scores were favorable and influenced by race, histology, and type of surgery. The most common significant symptoms reported were fatigue (82%), back pain (32%), and difficulty with digestion (31%). In general, PD survivors reported better QOL, lower levels of anxiety/depression, greater levels of diarrhea, and improved appetite, constipation, fatigue, anxiety, and depression (P < 0.05) than DP survivors. On both univariate and multivariate regression analysis, DP was negatively associated with QOL.
CONCLUSIONS: Most disease-free survivors of pancreatic neoplasms report favorable QOL, but gastrointestinal and psychosocial symptoms may exist long after pancreatectomy. J. Surg. Oncol. 2017;115:144-150. © 2016 Wiley Periodicals, Inc.

Bruhnding A, Notch D, Beard A
Anti-Yo positive paraneoplastic cerebellar degeneration in the setting of cholangiocarcinoma.
J Clin Neurosci. 2017; 36:71-72 [PubMed] Related Publications
Paraneoplastic neurological syndromes are a rare complication of malignancy. Subacute cerebellar ataxia, or paraneoplastic cerebellar degeneration, usually presents in women with a subcate onset of gait instability, followed by progressive limb and trunk ataxia, dysarthria, diplopia, and dysphagia that occurs in the setting of, or precedes the diagnosis of, a gynecologic or breast malignancy and clinically stabilizes within six months. The most common autoantibody associated with PCD is purkinje cell cytoplasmic antibody type 1, also known as anti-Yo. Here we describe the first reported case of a man with anti-Yo positive paraneoplastic cerebellar degeneration in the setting of occult cholangiocarcinoma.

Maki H, Kawaguchi Y, Arita J, et al.
Real-time confocal laser endomicroscopic evaluation of primary liver cancer based on human liver autofluorescence.
J Surg Oncol. 2017; 115(2):151-157 [PubMed] Related Publications
BACKGROUND: Confocal laser endomicroscopy (CLE) is available for real-time microscopic examination. This study aims to evaluate the usefulness of intraoperative CLE examination as a modality to evaluate surgical margins in surgery for primary liver cancer.
METHODS: A probe-based CLE system (Cellvizio 100, Mauna Kea Technologies, Paris, France) was used. The subjects comprised seven specimens obtained from six patients with primary liver cancer in November 2015. The probe was manually attached to the surfaces of specimens, and images were collected without external fluorophores. CLE images were compared with hematoxylin and eosin-stained slides. Fluorescence intensity (FI) values of the CLE images were assessed using luminance-analyzing software.
RESULTS: CLE examination visualized non-cancerous regions in the background liver as regular structures with high fluorescence because of human liver autofluorescence. Conversely, hepatocellular carcinoma and intrahepatic cholangiocarcinoma were depicted as irregular structures with low fluorescence. The median FI values of the non-cancerous regions and the cancerous regions were 104 (79.8-156) and 74.9 (60.6-106), respectively, and were significantly different (P = 0.031).
CONCLUSIONS: The probe-based CLE enables real-time differentiation of cancerous regions from non-cancerous tissues in surgical specimens because of human liver autofluorescence. CLE can be used to confirm negative surgical margins in the operating room. J. Surg. Oncol. 2017;115:151-157. © 2016 Wiley Periodicals, Inc.

Likhitrattanapisal S, Tipanee J, Janvilisri T
Meta-analysis of gene expression profiles identifies differential biomarkers for hepatocellular carcinoma and cholangiocarcinoma.
Tumour Biol. 2016; 37(9):12755-12766 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the members of hepatobiliary diseases. Both types of cancer often exert high levels of similarity in terms of phenotypic characteristics, thus leading to difficulties in HCC and CCA differential diagnoses. In this study, a transcriptome meta-analysis was performed on HCC and CCA microarray data to identify differential transcriptome networks and potential biomarkers for HCC and CCA. Raw data from nine gene expression profiling datasets, consisting of 1,185 samples in total, were methodologically compiled and analyzed. To evaluate differentially expressed (DE) genes in HCC and CCA, the levels of gene expression were compared between cancer and its normal counterparts (i.e., HCC versus normal liver and CCA versus normal bile duct) using t test (P < 0.05) and k-fold validation. A total of 226 DE genes were specific to HCC, 249 DE genes specific to CCA, and 41 DE genes in both HCC and CCA. Gene ontology and pathway enrichment analyses revealed different patterns between functional transcriptome networks of HCC and CCA. Cell cycle and glycolysis/gluconeogenesis pathways were exclusively dysregulated in HCC whereas complement and coagulation cascades as well as glycine, serine, and threonine metabolism were prodominantly differentially expressed in CCA. Our meta-analysis revealed distinct dysregulation in transcriptome networks between HCC and CCA. Certain genes in these networks were discussed in the context of HCC and CCA transition, unique characteristics of HCC and CCA, and their potentials as HCC and CCA differential biomarkers.

Zhang T, Su ZZ, Wang P, et al.
Double contrast-enhanced ultrasonography in the detection of periampullary cancer: Comparison with B-mode ultrasonography and MR imaging.
Eur J Radiol. 2016; 85(11):1993-2000 [PubMed] Related Publications
PURPOSE: To investigate the value of double contrast-enhanced ultrasonography (DCEUS) in the detection of periampullary cancer.
MATERIALS AND METHODS: Ninety-nine patients with surgery or biopsy-proven periampullary cancer who underwent both DCEUS and magnetic resonance imaging (MRI) examinations before operation were enrolled in our study. DCEUS in which intravenous microbubbles were used in combination with oral contrast agent and MRI were performed preoperatively to make a detection diagnosis of periampullary cancer. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of DCEUS, B-mode ultrasonography (BUS) and MRI were calculated and compared. Receiver operating characteristic (ROC) curves were used to evaluate the accuracy of BUS, DCEUS and MRI in the detection. Stratified analyses were performed for different pathological types and different sizes of periampullary lesions. The inter- and intra-observer reliability of DCEUS for cancer detection was also investigated.
RESULT: There were no significant differences in sensitivity, specificity, PPV, NPV or accuracy between DCEUS and MRI (all P>0.05). ROC analysis showed that the accuracy of DCEUS or MRI was higher than that of BUS (P<0.001), while no significant differences were noted in the accuracy between DCEUS and MR. In the 76 cases of periampullary cancer, DCEUS appeared to be superior to BUS for ampullary carcinoma, duodenum carcinoma and for lesions with an average diameter of less than 3cm. DCEUS appeared equal to BUS in other groups. No significant differences were noted between DCEUS and MRI in the stratified analysis. A considerably well agreement between DCEUS and MRI was obtained using Kappa analysis (k=0.649, P<0.001). The intra- and inter-observer reproducibility were both good for detection of periampullary cancer by DCEUS, with a Kappa values of 0.783 (P<0.01) and 0.732 (P<0.01), respectively.
CONCLUSION: DCEUS provides an available and useful imaging modality in the detection of periampullary cancer. This technique can aid in displaying the invisible periampullary region in BUS and may also become an effective supplemental method to MRI.

Huang XQ, Shu J, Luo L, et al.
Differentiation grade for extrahepatic bile duct adenocarcinoma: Assessed by diffusion-weighted imaging at 3.0-T MR.
Eur J Radiol. 2016; 85(11):1980-1986 [PubMed] Related Publications
PURPOSE-: To assess the pathological differentiation grade in the patients with extrahepatic bile duct adenocarcinoma (EBDA) using diffusion-weighted imaging (DWI) at 3.0-T MR.
METHODS-: Sixty-eight patients who were clinically and histologically diagnosed with EBDA underwent abdominal DWI within 2 weeks before surgery. The lesion signal intensity, signal intensity ratio of the lesion and hepar (SIR-LH) value, and apparent diffusion coefficient (ADC) value in patients with EBDA were retrospectively analysed.
RESULTS: -In the 68 patients, 22 well-differentiated, 36 moderately-differentiated, and 10 poorly-differentiated EBDAs were histopathological confirmed. These EBDAs exhibited hyper-intensity on DWI in 95.59% of patients. Hyper-intensity lesions were found in 90.91% of patients with good-differentiation, in 97.22% with moderate-differentiation and in 100% with poor-differentiation. There showed no statistical difference for the lesion signal intensity (P=0.426) and SIR-LH value (P=0.766) on DWI among three groups. The median ADC value of the well-differentiated, moderately-differentiated and poorly-differentiated EBDAs were 1.506×10(-3)mm(2)/s, 1.275×10(-3)mm(2)/s and 1.154×10(-3)mm(2)/s, respectively. As the pathological differentiation grade decreased, the lesion ADC value of EBDA gradually declined (x(2)=51.220, P=0.000). The ADC value <1.184×10(-3)mm(2)/s can predict the poorly-differentiated EBDA with a sensitivity of 100% and a specificity of 94.83%. The ADC value >1.316×10(-3)mm(2)/s can forecast the well-differentiated EBDA with a sensitivity of 100% and a specificity of 84.78%.
CONCLUSIONS-: The histopathological differentiation grade of EBDA can be detected non-invasively using DWI at 3.0-T MR.

Lu Z, Liu S, Yi Y, et al.
Serum gamma-glutamyl transferase levels affect the prognosis of patients with intrahepatic cholangiocarcinoma who receive postoperative adjuvant transcatheter arterial chemoembolization: A propensity score matching study.
Int J Surg. 2017; 37:24-28 [PubMed] Related Publications
BACKGROUND: The postoperative prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is far from satisfactory. Whether postoperative adjuvant transcatheter arterial chemoembolization (TACE) is effective for patients with ICC after R0 liver resection remains controversial.
MATERIALS AND METHODS: We retrospectively reviewed the data of 272 patients with ICC who received a radical hepatectomy at our center between 2000 and 2011. After the propensity score of postoperative TACE was calculated, 75 patients who received TACE were matched at a 1:2 ratios with 150 patients who did not receive TACE. Univariate and multivariate Cox analyses were performed to identify the independent predictors of overall survival.
RESULTS: The postoperative protective effect of adjuvant TACE was significantly influenced by serum gamma-glutamyl transferase (GGT) levels (P for interaction = 0.026). Postoperative TACE was not a significant predictor of overall survival (hazard ratio = 0.89, P = 0.704) in patients with GGT levels ≤ 54 U/L. Postoperative TACE was a significant predictor of overall survival in patients with GGT levels >54 U/L (hazard ratio = 0.44, P = 0.001). Regarding short-term outcomes, a total of 74 patients (32.9%) had varying degrees of complications, and the majority of these complications were grade I (18.7%) or II (10.2%).
CONCLUSION: The safety of postoperative TACE was validated, and the results suggest that only patients with elevated serum GGT levels will benefit from this treatment following curative liver resection for ICC.

Venturini M, Sallemi C, Agostini G, et al.
Chemoembolization with drug eluting beads preloaded with irinotecan (DEBIRI) vs doxorubicin (DEBDOX) as a second line treatment for liver metastases from cholangiocarcinoma: a preliminary study.
Br J Radiol. 2016; 89(1067):20160247 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
OBJECTIVE: The aim of our preliminary study was to compare the efficacy of drug-eluting beads preloaded with irinotecan (DEBIRI) vs drug-eluting beads preloaded with doxorubicin (DEBDOX) as second-line treatment of unresectable liver metastases from cholangiocarcinoma (CCA).
METHODS: In 2013, 10 patients affected by multiple liver metastases from CCA, resistant to the first-line chemotherapy regimen, were enrolled: 5 patients were submitted to lobar/segmental transarterial chemoembolization (TACE) with DEBIRI (100-mg irinotecan/1 vial) and 5 patients with DEBDOX (50-mg doxorubicin/1 vial), performed every 3 weeks. Patients treated with DEBIRI received antipain premedication consisting of 30-mg of morphine and 3-4 ml of intra-arterial lidocaine. Complications and efficacy were assessed (response evaluation criteria in solid tumour 1.1).
RESULTS: A total of 32 TACE were performed (mean: 3.2 TACE/patient), all well tolerated, with only 1 case of asymptomatic cholecystitis spontaneously recovered. Response rates of patients treated with DEBDOX and DEBIRI were: 4/5 progressive disease and 1/5 partial response vs 2/5 partial response, 2/5 stable disease and 1/5 progressive disease, respectively, with the appearance of variable necrosis percentage. Progression-free survival from the first procedure and progressive disease were 12.67 weeks for DEBIRI and 15.78 weeks for DEBDOX, respectively. Overall survival from time of primary diagnosis was 176 weeks for DEBIRI and 125 weeks for DEBDOX, respectively.
CONCLUSION: In our preliminary experience, DEBIRI was more effective than DEBDOX as a second-line treatment for hepatic metastases from CCA. Antipain drug administration and the use of the microcatheter led to a good treatment tolerability and a low complication rate. Advances in knowledge: In our preliminary experience, DEBIRI was more effective than DEBDOX as a second-line treatment of hepatic metastases from CCA; further studies involving a larger cohort of patients are needed.

Sun K, Xu S, Wei J, et al.
Clinicopathological features of 11 Epstein-Barr virus-associated intrahepatic cholangiocarcinoma at a single center in China.
Medicine (Baltimore). 2016; 95(40):e5069 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
To date, only 20 cases of Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinomas (IHCCs) have been reported in the literature.Pathology records of IHCC from January 1, 2007 to December 31, 2013 were retrieved from our hospital. Clinical information related to EBV-associated IHCC were also obtained, including gender, age at initial diagnosis, tumor size, tumor-node-metastasis stage, and follow-up duration. Surgically resected stage-matched EBV-negative IHCCs with full follow-up were selected for comparison. All liver specimens were fixed in 10% neutral-buffered formalin and paraffin-embedded tissue blocks containing cholangiocarcinoma and nonneoplastic liver tissue. Hematoxylin and eosin-stained sections were present in all cases.Among 329 primary IHCC patients, intranuclear expression of EBV was only found in 11 patients (3.3%), with an age range of 30 to 67 years (mean, 53.2 years; median, 54 years). The group consisted of 4 male and 7 female patients (M:F ratio 1:1.8). Histopathological analysis showed 1 case (9.1%) belonged to the typical lymphoepithelioma-like carcinoma (LELC), primarily composed of undifferentiated tumor cells intimately admixed with abundant lymphoplasmacytic cells. Two cases (18.2%) belonged to the conventional-type IHCCs, showing irregularly shaped neoplastic glands and scattered lymphoplasmacytic infiltration. The remaining 8 cases (72.7%) belonged to the lymphoepithelioma-like cholangiocarcinomas (LELCCs), showing varied glandular differentiation and dense lymphoplasmacytic infiltration. The overall survival of EBV-positive IHCCs was not significantly different from that of EBV-negative IHCCs (P = 0.512).Our data demonstrate that EBV-associated IHCC is very rare and may be subclassified into 3 different pathological types including LELC, conventional-type IHCC and LELCC on the basis of the tumor cellular differentiation, and host cellular immune responses in the tumors. The etiological, clinical, pathological, and molecular features are needed to be future studied by multicentric efforts in recruiting more EBV-associated IHCC patients.

Lee KB
Histopathology of a benign bile duct lesion in the liver: Morphologic mimicker or precursor of intrahepatic cholangiocarcinoma.
Clin Mol Hepatol. 2016; 22(3):400-405 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
A bile duct lesion originating from intrahepatic bile ducts is generally regarded as an incidental pathologic finding in liver specimens. However, a recent study on the molecular classification of intrahepatic cholangiocarcinoma has focused on the heterogeneity of this carcinoma and has suggested that the cells of different origins present in the biliary tree may have a major role in the mechanism of oncogenesis. In this review, benign intrahepatic bile duct lesions-regarded in the past as reactive changes or remnant developmental anomalies and now noted to have potential for developing precursor lesions of intrahepatic cholangiocarcinoma-are discussed by focusing on the histopathologic features and its implications in clinical practice.

Nagayoshi Y, Yamamoto K, Hashimoto S, et al.
An Autopsy Case of Lepidic Pulmonary Metastasis from Cholangiocarcinoma.
Intern Med. 2016; 55(19):2849-2853 [PubMed] Article available free on PMC after 01/11/2017 Related Publications
We herein report the first case of pulmonary metastasis with lepidic growth that originated from cholangiocarcinoma. A 77-year-old man was admitted to our hospital due to exertional dyspnea and liver dysfunction. Computed tomography showed widespread infiltration and a ground-glass opacity in the lung and dilation of the intrahepatic bile duct. The pulmonary lesion progressed rapidly, and the patient died of respiratory failure. Cholangiocarcinoma and lepidic pulmonary metastasis were pathologically diagnosed by an autopsy. Lepidic pulmonary growth is an atypical pattern of metastasis, and immunopathological staining is useful to distinguish pulmonary metastasis from extrapulmonary cancer and primary pulmonary adenocarcinoma.

Rayar M, Levi Sandri GB, Houssel-Debry P, et al.
Multimodal Therapy including Yttrium-90 Radioembolization as a Bridging Therapy to Liver Transplantation for a Huge and Locally Advanced Intrahepatic Cholangiocarcinoma.
J Gastrointestin Liver Dis. 2016; 25(3):401-4 [PubMed] Related Publications
Treatment of intrahepatic cholangiocarcinoma remains a major challenge. For an unresectable lesion without extrahepatic spread, liver transplantation could be a potential solution but it is still associated with poor oncologic results owing to the absence of effective neoadjuvant treatment. We report the case of a young man with locally advanced intrahepatic cholangiocarcinoma presenting with multiple intrahepatic metastases and vascular structure involvement. The lesion was significantly downstaged by a multimodal therapy including intra-arterial Yttrium-90 radioembolization, systemic chemotherapy and external radiotherapy, allowing liver transplantation. Three years after the procedure, oncologic outcome is excellent with no sign of recurrence. Multimodal therapy including Yttrium-90 radioembolization could be relevant as neoadjuvant treatment before liver transplantation for unresectable intrahepatic cholangiocarcinoma.

Wen F, Zhao X, Zhao Y, et al.
The anticancer effects of Resina Draconis extract on cholangiocarcinoma.
Tumour Biol. 2016; 37(11):15203-15210 [PubMed] Related Publications
Cholangiocarcinoma (CCA) is a relatively rare, heterogeneous malignant tumor with poor clinical outcomes. Because of high insensitivity to chemotherapy and radiotherapy, there are no effective treatment options. Efforts to identify and develop new agents for prevention and treatment of this deadly disease are urgent. Here, we assessed the apoptotic cytotoxicity of Resina Draconis extract (RDE) using in vitro and in vivo assays and identified the mechanisms underlying antitumor effects of RDE. RDE was obtained via vacuum distillation of Resina Draconis with 75 % ethanol. The ethanol extract could inhibit CCA cell proliferation and trigger apoptotic cell death in both QBC939 and HCCC9810 cell lines in a time- and concentration-dependent manner. RDE treatment resulted in intracellular caspase-8 and poly (ADP-ribose) polymerase protease activation. RDE significantly downregulated antiapoptotic protein survivin expression and upregulated proapoptotic protein Bak expression. RDE also inhibited CCA tumor growth in vivo. We observed that human CCA tissues had much higher survivin expression than did paired adjacent normal tissue. Taken together, the current data suggested that RDE has anticancer effects on CCA, and that RDE could function as a novel anticancer agent to benefit patients with CCA.

Wu X, Xia M, Chen D, et al.
Profiling of downregulated blood-circulating miR-150-5p as a novel tumor marker for cholangiocarcinoma.
Tumour Biol. 2016; 37(11):15019-15029 [PubMed] Related Publications
Altered microRNA (miRNA) expression plays a role in cholangiocarcinoma (CCA) development; thus, detection of blood-circulating miRNAs could be useful as CCA markers. This study profiled serum miRNA levels in patients with primary sclerosing cholangitis (PSC) and CCA and then assessed the role of miR-150-5p in CCA progression in vitro. Three samples were randomly selected from each of 50 sera of healthy controls, 30 PSC sera, and 28 CCA sera with matched bile samples for miRNA microarray profiling. The dysregulated miRNAs were confirmed using qRT-PCR, and miR-150-5p was selected for further in vitro and ex vivo studies. The miRNA microarray identified three dysregulated miRNAs in both CCA and PSC samples, while miR-150-5p level was consistently lower in CCA sera, bile, and tissues than in normal control and PSC sera (P < 0.05). Furthermore, levels of miR-150-5p were associated with serum carbohydrate antigen 19-9 (CA19-9) levels and CCA pathological grade. Bioinformatic Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses showed that miR-150-5p could regulate hand-full gene pathways, including cancer pathway (P < 0.01). However, overexpression of miR-150-5p inhibited proliferation, migration, and invasion capability of CCA cells (P < 0.05). Luciferase reporter assay showed that miR-150-5p bound to an oncogene Ets including gene-1 (ELK1), and Western blot data confirmed that miR-150-5p suppressed ELK1 expression in CCA cell lines. These results suggest that reduced miR-150-5p expression could contribute to CCA development and progression due to uncontrolled ELK1 expression. Thus, further study could evaluate miR-150-5p as a novel target and predictor for CCA prevention and treatment.

Tian Y, Liu L, Yeolkar NV, et al.
Diagnostic role of staging laparoscopy in a subset of biliary cancers: a meta-analysis.
ANZ J Surg. 2017; 87(1-2):22-27 [PubMed] Related Publications
BACKGROUND: Accurate preoperative radiological staging of biliary cancers remains difficult. Despite the improvement in imaging techniques, a number of patients with biliary cancers who undergo laparotomy are ultimately found to have unresectable diseases. The goals of staging laparoscopy (SL) are to rule out metastatic and locally advanced unresectable diseases and better define locally advanced unresectable diseases. This study evaluates the efficiency of SL in ruling out unresectable disease in a subset of biliary cancers.
METHODS: Literature published between January 2000 and December 2015 on the use of SL for patients with biliary cancers was retrieved from five electronic databases. Summary estimates of sensitivity, specificity and diagnostic odds ratio were calculated.
RESULTS: Eight studies were included in the meta-analysis. During the laparoscopy, unresectable disease was found in 316 of 1062 patients (29.8%), of whom 32.4% were patients with suspected hilar cholangiocarcinoma (HC) and 27.6% were patients with suspected gallbladder cancer (GBC). The sensitivities were 0.556 (95% confidence interval (CI): 0.495-0.616) for patients with HC and 0.642 (95% CI: 0.579-0.701) for patients with GBC. The pooled specificity for the SL was 100% (95% CI: 0.993-1.000) for all studies.
CONCLUSIONS: This meta-analysis revealed that 32.4% of patients with HC and 27.6% of patients with GBC may avoid unnecessary laparotomy with the use of SL. It is worthwhile to perform SL combined with an intraoperative ultrasound in patients with suspected GBC or HC.

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