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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).

Sato T, Hisaka T, Sakai H, et al.
Clinicopathological Study of Resections of Intraductal Papillary Neoplasm of the Bile Duct.
Anticancer Res. 2019; 39(8):4569-4573 [PubMed] Related Publications
BACKGROUND/AIM: The aim of this study was to examine the clinicopathological features of intraductal papillary neoplasm of the bile duct (IPNB) and investigate their relationships with intraductal papillary mucinous neoplasm (IPMN).
PATIENTS AND METHODS: Our study included 104 patients who underwent resection of tumors that showed papillary growth within the bile duct and pancreas.
RESULTS: Comparisons were performed based on subtypes and histological grades. The presence of various histological grades was confirmed in both the IPNB group and the IPMN group, and statistical significance was found in the between-group comparisons of subtypes and histological grades. It was shown that while all patients who underwent IPNB resection did not match the classifications proposed by Nakanuma et al., they did reflect classification characteristics.
CONCLUSION: IPNB and IPMN have common clinical histological features. Common features between IPNB subtype classifications were also identified, which may provide novel diagnostics.

Yang YH, Deng Q, Yang TB, et al.
A case report of cholangiocarcinoma combined with moderately differentiated gastric adenocarcinoma.
Medicine (Baltimore). 2019; 98(30):e16332 [PubMed] Related Publications
RATIONALE: Multiple primary carcinoma (MPM) refers to simultaneous or successive occurrence of ≥2 types of primary malignant tumors in a single organ or in different organs of the same individual. It is rarely seen in clinical practice. Among the various types of MPM, hilar cholangiocarcinoma combined with gastric cancer is extremely rare.
PATIENT CONCERNS: The patient was a 61-year-old man who was admitted to our hospital due to upper abdominal discomfort and yellow-stained skin mucosa for 9 days.
DIAGNOSES: Preoperative diagnosis: Considering the typical preoperative painless jaundice as well as his clinical imaging report, the patient received the following preoperative diagnosis: obstructive jaundice, type IV hilar cholangiocarcinoma based on Bismuth-Corlette classification, and no intrahepatic distant metastasis. Intraoperative diagnosis: The results of intraoperative snap freezing and laboratory examination indicated gastric adenocarcinoma. Therefore, the patient received an intraoperative diagnosis of obstructive jaundice, hilar cholangiocarcinoma, and gastric cancer. Postoperative pathological diagnosis: Postoperative pathological examination of the gastric lesion revealed the following results: ulcerative, moderately differentiated gastric adenocarcinoma and intestinal type in the Lauren classification of stomach cancer; moderately differentiated adenocarcinoma of the bile duct.
INTERVENTIONS: Surgical resection operation was carried out and the patient received chemotherapy after operation. But we could not strictly follow the relevant clinical guidelines to perform standardized operations and provide comprehensive treatment because of his economic situation, psychological factors, and the current medical environment in China.
OUTCOMES: The patient did not receive standardized postoperative therapy. Although he lived and worked normally for 8 months after the operation, he died 10 months after surgery.
LESSONS: This report reminds us to pay close attention to the likelihood of MPM and other low-incidence diseases. The physicians and imaging clinicians should explore all clinical possibilities to avoid misdiagnosis of this rare disease and formulate effective treatment plans to maximize the therapeutic benefits for the patient.

Zhou M, Ling W, Luo Y
Intrahepatic mass-forming cholangiocarcinoma growing in a giant hepatic hemangioma: A case report.
Medicine (Baltimore). 2019; 98(27):e16410 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Hepatic hemangioma (HH) is a common benign tumor with a high number of normal or abnormal blood vessels. Intrahepatic cholangiocarcinoma (ICC) is a relatively common malignant primary hepatic carcinoma (10%-15%) with high incidence rate and high fatality, yet low discovery rate in the early stages. Ultrasonography (US), computed tomography, and magnetic resonance imaging (MRI) are frequently used and indispensable imaging techniques for the diagnosis of hepatic lesions. It is possible to differentiate a liver lesion from HH with high accuracy owing to their different patterns and hemodynamic characteristics.
PATIENT CONCERNS: A 59-year-old Asian woman was referred to hospital for a hepatic mass, which was 9.0 × 6.5 cm in size, The patient was tested positive for hepatitis B antigen but negative for serum alpha-fetoprotein and carbohydrate antigen 199 and had a slightly elevated carcinoembryonic antigen level (3.56 ng/ml).
DIAGNOSIS: Liver US and MRI were performed. Grey-scale US revealed a huge heterogeneous mass on the right lobe with a point and line-like blood flow signal on Doppler US. Dynamic contrast-enhanced MRI showed heterogeneous annular nodular enhancement in the arterial phase. An initial diagnosis of HH was made based on the clinical history and imaging results; however, histopathologic examination of the liver lesions revealed modest to severe atypical hyperplasia of intrahepatic bile duct epithelium, cancerization, and mid to high differentiated mass-forming type cholangiocarcinoma combined with focal organized hemangioma.
INTERVENTIONS: The intrahepatic mass-forming cholangiocarcinoma (IMCC) lesion was considered a focal organization of hemangioma during operation and was surgically removed. No routine chemotherapy was performed after the operation.
OUTCOMES: The IMCC recurred 23 months after surgery, with elevated serum CA19-9 and CA125. Liver damage was evident, and the patient developed jaundice. The patient was discharged without active treatment and died in 4 months.
LESSONS: Although preoperative imaging of focal hepatic lesions is indispensable, intraoperative frozen section analysis and histopathological examination remain essential for definitive diagnosis. This is particularly important for high-risk patients and those with suspected malignancy.

Sîrbu MP, Baicu AM, Bacalbaşa N, et al.
The Role of Histopathology and Immunohistochemistry in the Diagnosis of Neuroendocrine Biliary Duct Tumor.
Chirurgia (Bucur). 2019 May-Jun; 114(3):401-408 [PubMed] Related Publications
Neuroendocrine tumors of the biliary tract are rare entities developed form Kulchitsky cells which undergo a process of malignant transformation. However, the differential diagnostic between neuroendocrine tumors of the biliary tract and hilar cholangiocarcinoma is very difficult to be established during the preoperative workup; therefore, most patients are submitted to surgery with radical intent and the final diagnostic remains to be confirmed through histopathological and immunohistochemistry studies of the specimen of resection. We present the case of a 60 year old patient who was submitted to en bloc extended right hepatectomy (including segment IV and caudate lobe) with extra hepatic biliary tree resection and left hepatic duct preservation, left cholangiojejunostomy (Roux-En-Y technique), celiac and common hepatic arteries lymphadenectomy and segmental portal vein resection with end-to-end anastomosis for a tumor of the biliary carrefour extended to the right biliary duct and invading the portal vein. The histopathological and immunohistochemistry studies confirmed the presence of a grade 1 neuroendocrine tumor, the staining being positive for Chromogranin A, Neuron-Specific Enolase (NSE) and Ki-67 (1% nuclear positive). At 24 months follow-up the patient is free of recurrent disease.

Dumitraşcu T, Ionescu MI
Caudate Lobectomy for Perihilar Cholangiocarcinoma - Current Evidence.
Chirurgia (Bucur). 2019 May-Jun; 114(3):317-325 [PubMed] Related Publications
At the moment, surgery is considered the only therapeutic approach offering a chance of long-term survival in patients diagnosed with perihilar cholangiocarcinoma (PHC). Curative intent surgery for PHC has experienced significant technical improvements over the years, from simple bile duct resection to complex surgical procedures including lymph nodes dissection, major hepatectomies and, sometimes, vascular resections. The modern surgical approach of PHC is associated with significantly improved survival rates, albeit with increased postoperative morbidity. The initial Western experience with major hepatectomies for PHC was not encouraging, as it was associated with unacceptably high mortality rates. Currently the mortality rates after surgery for PHC have significantly decreased, but it appears that the mortality rates in Western centres still remain higher, compared with the East Asian centres. The differences of outcomes between East Asian and Western centres are explained not only by the management of PHC but also by patient characteristics. En bloc caudate lobectomy as part of radical resections for PHC has been reported in clinical practice nearly three decades ago. The rationale of en bloc caudate lobectomy is based on the pattern of tumour spread in PHC, taking in consideration the fact that caudate lobe invasion appears to be a frequent event in patients resected for PHC. While en bloc caudate lobectomy in the context of curative intent surgery for PHC has been discussed in a host of publications so far, the currently available literature reached conflicting results regarding its overall impact on the patient. Therefore, the aim of this paper is to review the current relevant literature pertaining to the impact of en bloc caudate lobectomy in the context of curative intent surgery for PHC.

Guo LQ, Sun HW, Zhang CY, et al.
Efficacy of fluoxetine for anorexia nervosa caused by chemotherapy in patients with cholangiocarcinoma.
Medicine (Baltimore). 2019; 98(24):e15945 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Fluoxetine has been reported to treat anorexia nervosa (AN) caused by chemotherapy in patients with cholangiocarcinoma effectively. However, no study systematically investigated its efficacy and safety. Thus, this study will systematically assess its efficacy and safety for AN caused by chemotherapy in patients with cholangiocarcinoma.
METHODS: A comprehensive literature search for relevant studies will be conducted from the following databases from inception to the present: MEDILINE, EMBASE, Cochrane Library, Web of Science, PSYCINFO, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All randomized controlled trials on assessing the efficacy and safety of fluoxetine for AN caused by chemotherapy in patients with cholangiocarcinoma will be considered for inclusion in this study. RevMan V.5.3 software will be used for risk of bias assessment and statistical analysis.
RESULTS: This study will summarize the latest evidence of fluoxetine for AN caused by chemotherapy in patients with cholangiocarcinoma through assessing outcomes of weight, depression, anxiety, and quality of life. Additionally, any adverse events will also be analyzed.
CONCLUSION: The findings of this study will provide most recent evidence of fluoxetine for AN caused by chemotherapy in patients with cholangiocarcinoma.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019131583.

Sakata K, Yoshizumi T, Izumi T, et al.
The Role of DNA Repair Glycosylase OGG1 in Intrahepatic Cholangiocarcinoma.
Anticancer Res. 2019; 39(6):3241-3248 [PubMed] Related Publications
BACKGROUND/AIM: The effects of oxidative stress on various carcinomas were reported in previous studies, but those in intrahepatic cholangiocarcinoma (ICC) have not been fully elucidated. The purpose of this study was, thus, to reveal the effects of oxidative DNA damage and repair enzymes on ICC.
MATERIALS AND METHODS: The levels of 8-hydroxydeoxyguanosine (8-OHdG) and 8-OHdG DNA glycosylase (OGG1) were immunohistochemically evaluated in specimens resected from 63 patients with ICC.
RESULTS: Low OGG1 expression was related to tumour depth T4 (p=0.04), venous invasion (p=0.0005), lymphatic vessel invasion (p=0.03), and perineural invasion (p=0.03). Compared to the high-OGG1-expression group, patients with low OGG1 expression had a significantly poorer prognosis (overall survival: p=0.04, recurrence-free survival: p=0.02). Unlike for OGG1, the expression levels of 8-OHdG showed no association with prognosis.
CONCLUSION: Oxidative DNA damage and DNA repair enzymes may be closely related to ICC progression.

Bisello S, Buwenge M, Palloni A, et al.
Radiotherapy or Chemoradiation in Unresectable Biliary Cancer: A Retrospective Study.
Anticancer Res. 2019; 39(6):3095-3100 [PubMed] Related Publications
BACKGROUND/AIM: To retrospectively evaluate the outcome of patients with unresectable biliary cholangiocarcinoma (CC) treated with radiotherapy (RT) plus/minus chemotherapy (CHT).
MATERIALS AND METHODS: Data of patients with intrahepatic CC (ICC), Klatskin's tumor (KT), distal extrahepatic CC (ECC), and gallbladder cancer (GBC) diagnosed from 1991 to 2017 were retrospectively analyzed. The treatment was mainly based on RT plus concurrent CHT +/- brachytherapy (BRT) boost. The Kaplan-Meier method was used to calculate survival curves that were compared using the log-rank test.
RESULTS: Seventy-six patients were included in this analysis (males: 59%; females: 41%; median age: 66.5 years). A minority of patients (7.9%) were treated for disease recurrence after surgery. According to TNM, 78.5% of patients had T stage >3 and 77.6% of patients were treated with concurrent CHT-RT while 22.3% received RT followed by sequential CHT. Median RT dose was 50 Gy (range: 16-75 Gy) delivered with conventional fractionation. CHT was based on Gemcitabine or 5-fluorouracil. BRT was prescribed to 51.3% of patient with a median dose of 14 Gy. Reported Grade ≥3 acute GI and hematological toxicity were 13.2% and 8.1%, respectively. No other severe acute toxicities were reported. One- and 2-year overall survival (OS) were 58.1% and 25.8%, respectively (median: 13.5 months), while 1- and 2-year progression-free survival (PFS) were 43.4% and 9.4%, respectively. None of the following variables had a significant impact on OS and PFS: BRT boost, tumor site, concurrent CHT, and the drugs used in concurrent CHT. In contrast, patients receiving RT with 2D technique showed a PFS significantly higher compared to patients treated with the 3D technique (median: 15.5 vs. 8.5 months; p=0.02).
CONCLUSION: Combined modality treatment (RT+CHT±BRT) in unresectable biliary cancer was associated with acceptable toxicity and OS comparable to the actual standard treatment (CHT). The significantly improved PFS in patients undergoing 2D-RT raises doubts regarding the adequacy of target delineation in these neoplasms.

Jung W, Kim K, Min SK, et al.
Mapping of local recurrence after pancreaticoduodenectomy for distal extrahepatic cholangiocarcinoma: implications for adjuvant radiotherapy.
Br J Radiol. 2019; 92(1100):20190285 [PubMed] Related Publications
OBJECTIVE: To generate a map of local recurrences after pancreaticoduodenectomy (PD) for patients with distal extrahepatic cholangiocarcinoma (DEHC) and to evaluate the adequate target volume coverage encompassing the majority of local recurrences when the clinical target volume (CTV) for pancreatic cancer was applied.
METHODS: We retrospectively reviewed the records of DEHC patients who underwent pancreaticoduodenectomy and had postoperative CT scans acquired between 1991 and 2015 available. The sites of local recurrence were delineated on individual CT scans, and then, mapping was manually performed onto template CT images. Coverage of each site of local recurrence was evaluated by applying the CTV defined according to Radiation Therapy Oncology Group (RTOG) consensus guidelines (CTV
RESULTS: Of the 99 patients, 36 patients had a total of 62 local relapses identifiable by postoperative CT scans; the relapses were the most frequent in the choledochojejunostomy (CJ) site, 11 sites (17.7%); para-aortic area, 10 sites (16.1%), superior mesenteric artery area, 10 sites (16.1%); and portal vein area, 9 sites (14.5%). 21 sites (33.9%) were not covered by the CTV
CONCLUSION: When mapping of local relapses was evaluated according to the CTV
ADVANCES IN KNOWLEDGE: Mapping local recurrences can aid in defining appropriate target volume for postoperative radiotherapy in DEHC.

Yoon KC, Yu YD, Kang WH, et al.
Prevalence and Clinical Significance of Biliary Intraepithelial Neoplasia (BilIN) in Cholangiocarcinoma.
Am Surg. 2019; 85(5):511-517 [PubMed] Related Publications
Biliary intraepithelial neoplasia (BilIN) is the most common noninvasive precursor lesion which progresses to cholangiocarcinoma (CC) and is often found synchronously adjacent to the tumor or at the surgical resection margin. The aim of this study was to elucidate the prevalence and prognostic effect of BilIN on survival after resection for CC. We retrospectively analyzed the database of patients with CC who underwent surgery performed at our institution from 2010 to 2017. There were 142 patients who underwent surgery for CC. BilIN was detected in 42 patients (29.5%). On univariate analysis, extrahepatic CC (ExtraH CC) patients with BilIN lesions significantly showed better disease-free survival (

Tang L, Wang Y, Wang H, et al.
Long noncoding-RNA component of mitochondrial RNA processing endoribonuclease is involved in the progression of cholangiocarcinoma by regulating microRNA-217.
Cancer Sci. 2019; 110(7):2166-2179 [PubMed] Free Access to Full Article Related Publications
Cholangiocarcinoma (CCA) is a malignant tumor originating from bile duct epithelium and its incidence is increasing year by year. In recent years, long noncoding RNAs (lncRNAs) have been found to play an important role in the occurrence and progression of malignant tumors. In the present study, for the first time, abnormal expression of lnc-RNA component of mitochondrial RNA processing endoribonuclease (RMRP) and its possible role in CCA were found. We explored the effects of RMRP on various behaviors of CCA cells in vitro and in vivo. In addition, by second-generation sequencing, we explored the microRNA expression profiles that RMRP may affect in the HCCC-9810 cell line. We also validated and explored the role of microRNA-217 (miR-217) with high differential expression by in vitro experiments. Our findings indicated that RMRP can play a part in promoting cancer by regulating the expression of miR-217. RMRP is involved in the progression of CCA and can be a novel indicator of poor prognosis in patients with CCA.

Soumarová R, Gürlich R, Hajer J, et al.
The current role of radiotherapy and systemic therapy in the multidisciplinary treatment of cholangiocarcinoma.
Cas Lek Cesk. 2019; 158(2):78-82 [PubMed] Related Publications
Cholangiocarcinoma is a cancer with very poor prognosis. The only potentially curative approach is surgical resection of tumor. However, the rate of local and distant recurrence after radical surgery is still high. Benefit of adjuvant therapy is not clearly defined, nevertheless patients at high risk of recurrence are indicated to chemotherapy or chemoradiotherapy. Locally advanced, unresectable disease can also be treated with chemotherapy alone, or with her combination with radiotherapy. Required radiation doses are relatively high, therefore it is necessary to use highly conformal radiation therapy. Treatment of metastatic disease is currently based on systemic therapy, combination of gemcitabine and cisplatin as standard of care. Benefit of targeted molecular therapy is not clear at present, but ongoing research in genetic profiling of tumor may help to improve current clinical practice. Patients with cholangiocarcinoma have to be discussed during multidisciplinary team meetings.

Hajer J, Havlůj L, Whitley A, et al.
The role of single-operator cholangioscopy (SpyGlass) in the intraoperative diagnosis of intraductal borders of cholangiocarcinoma proliferation - pilot study.
Cas Lek Cesk. 2019; 158(2):68-72 [PubMed] Related Publications
Cholangiocarcinoma is a relatively rare, highly fatal neoplasm originating from the biliary epithelium. Its only potentially curative treatment option is a radical surgical resection. The aim of our work was to evaluate the feasibility and the safety of intraoperative ERCP and direct cholangioscopy (SpyGlass) to assess the intraductal border of cholangiocarcinoma proliferation. The study ran from November 2015 to January 2018. The group included patients with histologically verified cholangiocarcinoma and, based on available examinations, the resectability of the tumor was assessed by a multidisciplinary team. In cases of indicated surgical resection we peroperatively performed ERCP with cholangioscopy SpyGlass and "diaphanoscopy" in all patients. The resectability was assessed on the basis of these examinations and the peroperative surgical findings. The resection procedure itself was performed only in 2 out of the total of 14 patients, as other patients were indicated for the implantation of metallic SEMS within the ERCP procedure in the operating room instead. To validate the cholangioscopic findings, we used our own criteria based on both the Monaco and other criteria. We divided the findings according to the presence or absence of ulceration, prominent polyposis, pathological vascularization (4 types), pressure defect with a coagulum in the presence of previous stent implantation, papillomatous changes or discolorations of the mucosa. Out of the total number of 14 patients only two patients were indicated for resection and in both cases R0 resection was achieved. The remaining patients were intraoperatively indicated for palliative implantation of SEMS based on the same unresectable finding during cholangioscopy and laparotomy. We demonstrated the technical feasibility and safety of direct peroperative cholangioscopy. Our results show that direct perioperative cholangioscopy is one of the methods which can contribute to a more accurate determination of tumor spread margins.

Staněk L, Gürlich R, Hajer J, et al.
Molecular pathology of cholangiocellular carcinomas.
Cas Lek Cesk. 2019; 158(2):64-67 [PubMed] Related Publications
Cholangiocellular carcinoma is a relatively rare malignant tumor, originating from cholangiocytes, with poor prognosis and late diagnosis. It is a malignancy with a variable biological etiology, numerous genetic and epigenetic changes. Its incidence in the Czech Republic is about 1.4 per 100,000 people per year. For good prognosis and long-term survival, early diagnosis with surgical treatment is important. In these cases, a 5-year survival rate is about 20-40 %. In the early diagnosis imaging methods and histopathological verification play an essential role, whereas laboratory oncomarkers are not yet sufficiently accurate. The same applies for genetic markers. This leads to the search of new molecular targets and the high effort in the introduction of cytological and molecular-biological methods with high specificity and sensitivity into routine practice. Current early diagnosis is based on the use of efficient imaging methods. The use of genetic testing, and especially knowledge of the molecular basis of this disease, will be of a great benefit. The observation of the association between the genetic pathways, IDH1, RAS-MAPK etc., and genetic mutations of genes, such as TP53, KRAS, SMAD4, BRAF, IDH1/2, may be significant. From the molecular point of view, it is also interesting to monitor oncogenic potential in HBV/HCV infection.

Hrudka J, Oliverius M, Gürlich R
Pathology of cholangiocellular carcinoma.
Cas Lek Cesk. 2019; 158(2):57-63 [PubMed] Related Publications
Cholangiocellular carcinoma (CCC) is a malignant tumor harboring a poor prognosis, occurring in the liver, gallbladder and in extra- or intrahepatic biliary ducts. The article reviews the topic concerning CCC from the point of view of a surgical pathologist. The paper deals with classification of CCC into an intrahepatic/peripheral and hilar/extrahepatic subtype with different morphology, molecular features and prognosis; together with classical gross pathology, histopathology and natural history of CCC. Hilar and extrahepatic CCC share some biological characteristics with pancreatic ductal adenocarcinoma. The review comprises various types of precancerous lesions of biliary tract, summarizes updates in 8th edition of TNM classification and describes the routine issues concerning histopathological diagnostics of CCC, including immunohistochemistry and frozen section methods.

Dušek L, Mužík J, Krejčí D
Epidemiology of gallbladder and bile duct malignancies in the Czech Republic.
Cas Lek Cesk. 2019; 158(2):52-56 [PubMed] Related Publications
Overview of epidemiology focused on tumors of the bile ducts and gallbladder is based on data of the National Cancer Registry and its newly validated and published data from 2016. In most recent period 2012-2016, 1013 patients were annually (in average) diagnosed with tumors of the bile ducts and gallbladder in the Czech Republic. In the same time, average annual mortality of this disease reached value 836. Prevalence of bile ducts and gallbladder cancer reached 1723 in 2016 and in comparison, with the value measured in 2006, it increased by 28 %. More than 50 % of bile ducts and gallbladder cancers are diagnosed in advanced clinical stages (stage III+) which makes prognosis of patients worse and limits reachable results of therapy.

Aadam AA, Liu K
Endoscopic palliation of biliary obstruction.
J Surg Oncol. 2019; 120(1):57-64 [PubMed] Related Publications
Advanced pancreaticobiliary malignancy tends to be uncurable at presentation and causes significant morbidity for patients. Palliation for malignant biliary obstruction should be minimally invasive, cost-effective, and aim to improve quality of life of patients. Strategies of endoscopic palliation of malignant biliary obstruction can differ based on sites and degree of biliary obstruction with complex decisions of optimal stent type and placement that involve conscientious planning by a multidisciplinary team.

Kariya CM, Wach MM, Ruff SM, et al.
Postbiliary drainage rates of cholangitis are impacted by procedural technique for patients with supra-ampullary cholangiocarcinoma: A SEER-Medicare analysis.
J Surg Oncol. 2019; 120(2):249-255 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: The optimal approach to biliary drainage for patients with supra-ampullary cholangiocarcinoma remains undetermined. Violation of sphincter of Oddi results in bacterial colonization of bile ducts and may increase postdrainage infectious complications. We sought to determine if rates of cholangitis are affected by the type of drainage procedure.
METHODS: We examined the Surveillance, Epidemiology, and End Results-Medicare linked database from 1991 to 2013 for cholangiocarcinoma. Biliary drainage procedures were categorized as sphincter of Oddi violating (SOV) or sphincter of Oddi preserving (SOP). Patients were stratified by resection.
RESULTS: A total of 1914 patients were included in the final analysis. A total of 1264 patients did not undergo a postdrainage resection (SOP 83, SOV 1181) while 650 did undergo a postdrainage resection (SOP 26, SOV 624). For those patients not undergoing a postdrainage resection, the rate of cholangitis 90 days after an SOP procedure was 19% compared with 34% in the SOV cohort (P = 0.007). For those patients undergoing a postdrainage resection, the rate of cholangitis 90 days after an SOP procedure was less than 42.3% compared with 30% in the SOV cohort (P = 0.66).
CONCLUSION: For patients with supra-ampullary cholangiocarcinoma that did not undergo resection, biliary drainage procedures that violated the sphincter of Oddi were associated with increased rates of cholangitis.

Li O, Yi W, Yang P, et al.
Relationship between serum MMP-9 level and prognosis after radical resection for Hilar cholangiocarcinoma patients.
Acta Cir Bras. 2019; 34(4):e201900409 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
PURPOSE: To analyze the preoperative serum matrix metalloproteinase-9 (MMP-9) levels and prognosis of patients with hilar cholangiocarcinoma (HC) undergoing radical resection.
METHODS: Preoperative serum MMP-9 levels in patients with HC undergoing radical resection were detected by enzyme-linked immunosorbent assay (ELISA). The ROC curve assay was used to analyze the preoperative serum MMP-9 level to determine the most valuable cut-off point. The relationship between MMP-9 and clinicopathological features of HC patients was analyzed. Kaplan-Meier method was used to analyze the prognostic factors, and COX regression model was used to analyze the independent risk factors affecting prognosis.
RESULTS: Preoperative serum MMP-9 levels were significantly elevated in the death patients compared with the survival patients. The most valuable cut-off point for preoperative serum MMP-9 for prognosis was 201.93 ng/mL. Preoperative serum MMP-9 was associated with Bismuth-Corlette classification) and lymph node metastasis. Kaplan-Meier analysis showed that MMP-9, Bismuth-Corlette classification, Lymph node metastasis, Portal vein invasion, Hepatic artery invasion, Liver invasion, Incised margin, and Preoperative biliary drainage were related to prognosis. Cox regression model confirmed that hepatic artery invasion, liver invasion, incised margin, and MMP-9 have the potential to independence predicate prognosis in HC patients.
CONCLUSION: Preoperative serum MMP-9 has high predictive value for prognosis and is an independent influencing factor for the prognosis of patients with hilar cholangiocarcinoma.

Tsilimigras DI, Hyer JM, Moris D, et al.
Prognostic utility of albumin-bilirubin grade for short- and long-term outcomes following hepatic resection for intrahepatic cholangiocarcinoma: A multi-institutional analysis of 706 patients.
J Surg Oncol. 2019; 120(2):206-213 [PubMed] Related Publications
BACKGROUND: The objective of the current study was to define the impact of albumin-bilirubin (ALBI) grade on short- as well as long-term outcomes among patients with intrahepatic cholangiocarcinoma (ICC).
METHODS: Patients who underwent hepatectomy for ICC between 1990 and 2016 were identified using an international multi-institutional database. Clinicopathologic factors including ALBI score were assessed using bivariate and multivariable analyses, as well as standard survival analyses.
RESULTS: Among 706 patients, 453 (64.2%) patients had ALBI grade 1, 231 (32.7%) ALBI grade 2, and 22 (3.1%) had ALBI grade 3. After adjusting for all competing factors, patients with ALBI grade 2/3 had higher odds of a prolonged length-of-stay (>10 days, odds ratio [OR] = 2.37, 95% confidence interval [CI]:1.47-3.80), perioperative transfusion (OR = 2.15, 95% CI:1.45-3.18) and 90-day mortality (OR = 2.50, 95% CI:1.16-5.38). Median and 5-year overall survival (OS) for the entire cohort was 41.5 months (IQR:15.7-107.8) and 39.8%, respectively. Of note, median OS incrementally worsened with increased ALBI grade: grade 1, 49.6 months (IQR:18.3-NR) vs grade 2, 29.6 months (IQR:12.6-98.4) vs grade 3, 16.9 months (IQR:6.5-32.4; P < 0.001). On multivariable analysis, higher ALBI grade remained associated with higher hazards of death (grade 2/3: hazard ratio = 1.36, 95% CI:1.04-1.78).
CONCLUSION: The ALBI score was associated with both short- and long-term outcomes following resection for ICC and could prove a useful surrogate marker to identify patients at risk for adverse outcomes.

Zhang C, Ge C
A Simple Competing Endogenous RNA Network Identifies Novel mRNA, miRNA, and lncRNA Markers in Human Cholangiocarcinoma.
Biomed Res Int. 2019; 2019:3526407 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Background: Cholangiocarcinoma (CCA) is the second most common malignant primary liver tumor and has shown an alarming increase in incidence over the last two decades. However, the mechanisms behind tumorigenesis and progression remain insufficient. The present study aimed to uncover the underlying regulatory mechanism on CCA and find novel biomarkers for the disease prognosis.
Method: The RNA-sequencing (RNA-seq) datasets of lncRNAs, miRNAs, and mRNAs in CCA as well as relevant clinical information were obtained from the Cancer Genome Atlas (TCGA) database. After pretreatment, differentially expressed RNAs (DERNAs) were identified and further interrogated for their correlations with clinical information. Prognostic RNAs were selected using univariate Cox regression. Then, a ceRNA network was constructed based on these RNAs.
Results: We identified a total of five prognostic DEmiRNAs, 63 DElncRNAs, and 90 DEmRNAs between CCA and matched normal tissues. Integrating the relationship between the different types of RNAs, an lncRNA-miRNA-mRNA network was established and included 28 molecules and 47 interactions. Screened prognostic RNAs involved in the ceRNA network included 3 miRNAs (hsa-mir-1295b, hsa-mir-33b, and hsa-mir-6715a), 7 lncRNAs (ENSG00000271133, ENSG00000233834, ENSG00000276791, ENSG00000241155, COL18A1-AS1, ENSG00000274737, and ENSG00000235052), and 18 mRNAs (ANO9, FUT4, MLLT3, ABCA3, FSCN2, GRID2IP, NCK2, MACC1, SLC35E4, ST14, SH2D3A, MOB3B, ACTL10, RAB36, ATP1B3, MST1R, SEMA6A, and SEL1L3).
Conclusions: Our study identified novel prognostic makers and predicted a previously unknown ceRNA regulatory network in CCA and may provide novel insight into a further understanding of lncRNA-mediated ceRNA regulatory mechanisms in CCA.

Sahara K, Tsilimigras DI, Mehta R, et al.
A novel online prognostic tool to predict long-term survival after liver resection for intrahepatic cholangiocarcinoma: The "metro-ticket" paradigm.
J Surg Oncol. 2019; 120(2):223-230 [PubMed] Related Publications
BACKGROUND: The aim of the current study was to develop an online calculator to predict survival after liver resection for intrahepatic cholangiocarcinoma (ICC) based on the "metro-ticket" paradigm.
METHODS: Between 1990 and 2016, patients who underwent liver resection for ICC were identified in an international multi-institutional database. The final multivariable model of survival was used to develop an online prognostic calculator of survival.
RESULTS: Among 643 patients, actual 5-year overall survival (OS) after resection for ICC was 42.7%. On multivariable analysis, CA19-9 > 200 (hazard ratio (HR), 2.62; 95% CI, 2.01-3.42), sum of the number and largest tumor size >7 (HR, 1.88; 95% CI, 1.46-2.42), N1 disease (HR, 2.87; 95% CI, 1.98-4.16), R1 resection (HR, 1.72; 95% CI, 1.21-2.46), poor/undifferentiated tumor grade (HR, 1.74; 95% CI, 1.25-2.44), major vascular invasion (HR, 1.47; 95% CI, 1.03-2.10), and adjuvant chemotherapy (HR, 0.64; 95% CI, 0.45-0.89) were significantly associated with survival and were included in the online calculator. The predictive accuracy of the model was good to very good as the C-statistics to predict 5-year OS was 0.696 in the training dataset and 0.672 with bootstrapping resamples (n = 5000) in the test dataset.
CONCLUSION: A novel, online calculator was developed to estimate the 5-year survival probability for patients undergoing resection for ICC. This tool could help provide useful information to guide treatment decision-making and inform conversations about prognosis.

Peňázová P, Andrašina T, Novotný I, et al.
IgG4 Sclerosing Cholangitis - an Inflammation Imitating Tumour of the Pancreas and Biliary Tract.
Klin Onkol. 2019; 32(2):143-151 [PubMed] Related Publications
BACKGROUND: Immunoglobulin (Ig) G4 associated sclerosing cholangitis is a rare inflammatory disease of the biliary tract. Although it is a very progressive condition, it responds to steroid therapy. IgG4 associated sclerosing cholangitis can mimic pancreatic carcinoma, cholangiocarcinoma, and primary sclerosing cholangitis; therefore, it is very important to obtain a differential diagnosis. IgG4 sclerosing cholangitis is a biliary form of IgG4 related systemic disease, in which afflictions of more organs is afflictions of more organs are common, typically biliary form together with pancreatic one. Nonspecific symptoms are obstructive icterus, fatigue, and weight loss. Atypical imaging of the biliary tree and pancreas can be used to distinguish it from other diseases. Laboratory data show elevation of bilirubin, liver enzymes, IgG4 and total IgG concentrations. Sometimes IgE is also elevated with the eosinophilia, oncomarker CA 19-9 and autoimmune antibody is sometimes detected.
CASE: This article presents a case of IgG4 sclerosing cholangitis and its related findings. The patient was intially referred for suspected pancreatic tumour, the presumed diagnosis was later changed to cholangiocarcinoma type 4 with concurrent autoimmune pancreatitis. Atypical imaging in cholangiography made us suspect IgG4 inflammation and the diagnostic process began.
CONCLUSION: The diagnosis of this disease uses so called HISORt criteria. It is a very complex process in which the success of steroid therapy as a final step can be conclusive, as it was in our case. It is essential to exclude a malign neoplastic growth. The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 5. 12. 2018 Accepted: 10. 1. 2019.

Marafi F, Usmani S, Esmail A
68Ga-Prostate-Specific Membrane Antigen PET/CT in Cholangiocarcinoma: A Potential Biomarker for Targeted Radioligand Therapy?
Clin Nucl Med. 2019; 44(7):e439-e441 [PubMed] Related Publications
Ga-PSMA is a promising tracer for both staging and detection of biochemical recurrence in prostate cancer. Prostate-specific membrane antigen is also expressed in the endothelium of neovasculature of various solid malignancies possibly due to tumor-associated angiogenic factors and endothelial cell sprouting. We report a case of 75-year-old man with metastatic cholangiocarcinoma to liver and lymph nodes progressing on chemotherapy. Ga-PSMA PET/CT was performed to assess PSMA expression and showed additional bone and hepatic lesions compared with F-FDG PET/CT. Ga-PSMA expression in the metastatic cholangiocarcinoma potentially guides radionuclide legend therapy with α/β-emitters especially after enervation of all approved therapeutic options.

Hou L, Jiang J, Liu B, et al.
Is exposure to tobacco associated with extrahepatic cholangiocarcinoma epidemics? A retrospective proportional mortality study in China.
BMC Cancer. 2019; 19(1):348 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: Extrahepatic cholangiocarcinoma (ECC) has become one of the most rapidly increasing malignancies in China during recent decades. The relationship between tobacco exposure and ECC epidemics is unclear; this study aimed to explore this relationship.
METHODS: We included 55,806 participants aged 30 years or older from the National Mortality and Smoking Survey of China. Smoking in participants and spouses was defined as 1 cigarette or more per day for up to 1 year. Spouses' smoking was taken as a measure of exposure to passive smoking. Smoking information in 1980 was ascertained and outcomes were defined as ECC mortality during 1986-1988.
RESULTS: We found that either passive or active smoking increased the risk of death from ECC by 20% (risk ratio [RR], 1.20; 95% confidence interval [CI], 0.99-1.47), compared with no exposure to any tobacco. This risk was a notable 98% (RR, 1.98; 95% CI, 1.49-2.64) for individuals exposed to passive plus active smoking. These findings were highly consistent among men and women. Pathology-based analyses showed dose-response relationships of ECC with pack-years for all types of smoking exposure (Ps for trend < 0.05); the RR reached 2.75 (95% CI, 1.20-6.30) in individuals exposed to combined smoking with the highest exposure dose. The findings were similar for non-pathology-based analysis.
CONCLUSIONS: This study indicates that tobacco exposure increases ECC risk. Given the dramatic increase of exposure to secondhand smoke and patients with ECC, an inadequate provision of smoke-free environments could be contributing to ECC epidemics and could further challenge public health and medical services, based on the current disease spectrum.

Takenami T, Maeda S, Karasawa H, et al.
Novel biomarkers distinguishing pancreatic head Cancer from distal cholangiocarcinoma based on proteomic analysis.
BMC Cancer. 2019; 19(1):318 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: The differentiation between pancreatic head cancer (PHC) and distal cholangiocarcinoma (DCC) can be challenging because of their anatomical and histopathological similarity. This is an important problem, because the distinction has important implications for the treatment of these malignancies. However, there are no biomarkers for the differential diagnosis of PHC and DCC. The present study aimed to identify novel diagnostic immunohistochemical biomarkers to distinguish PHC from DCC.
METHODS: Liquid chromatography tandem mass spectrometry (LC-MS/MS) was employed to detect candidate proteins. Ten PHC and 8 DCC specimens were analyzed by LC-MS/MS. Selected proteins were evaluated, using immunohistochemical analysis, to determine whether they would be appropriate biomarkers. Finally, we generated biomarker panels to improve diagnostic accuracy. We applied these panels to clinically difficult cases (cases in which different diagnoses were made before and after operation).
RESULTS: Consequently, 1820 proteins were detected using LC-MS/MS. Fifteen differentially expressed proteins were selected as candidates based on semi-quantitative comparison. We first performed immunohistochemical staining on samples from the small cohort group (12 PHCs and 12 DCCs) using 15 candidates. KRT17, ANXA10, TMEM109, PTMS, and ATP1B1 showed favorable performances and were tested in the next large cohort group (72 PHCs and 74 DCCs). Based on immunohistochemical analysis, KRT17 performed best for the diagnosis of PHC as a single marker; additionally, PTMS exhibited good performance for the diagnosis of DCCs. Moreover, we indicated the KRT17+/ANXA10+/PTMS- staining pattern as a biomarker panel for the correct diagnosis of PHC and KRT17-/ANXA10-/PTMS+ for the diagnosis of DCC. After immunohistochemical staining for examining samples from the clinically difficult cases, these panels showed satisfactory diagnostic performance with 85.7% (6/7) accuracy.
CONCLUSIONS: We conclude that 5 proteins and 2 biomarker panels are promising for distinguishing PHC from DCC, and patients with an equivocal diagnosis would benefit from the application of these biomarkers. Confirmatory studies are needed to generalize these findings to other populations.

Morino K, Seo S, Yoh T, et al.
The Efficacy and Limitations of Postoperative Adjuvant Chemotherapy in Patients With Extrahepatic Cholangiocarcinoma.
Anticancer Res. 2019; 39(4):2155-2161 [PubMed] Related Publications
BACKGROUND/AIM: The impact of adjuvant chemotherapy (AC) for extrahepatic cholangiocarcinoma (ECC) remains unclear. This study evaluated the efficacy and limitations of AC.
PATIENTS AND METHODS: Between 2006 and 2016, 106 patients with stage II-IV ECC who underwent curative resection with biliary tract reconstruction were retrospectively analyzed. Patients were divided into two groups: Those who received AC (n=57) and those who did not (n=49).
RESULTS: Fewer grade 3-4 complications were observed in the AC group compared to the non-AC group (38.6 vs. 61.2%, p=0.03). In the non-AC group, complications were the most frequent reason for omitting AC (n=21, including 13 with biliary fistula). In the AC group, the therapy completion rate was 56.1% and the main reason for discontinuation was adverse events (n=12, including six with cholangitis). AC was not associated with survival benefits (median survival: 50.4 vs. 37.3 months, p=0.916).
CONCLUSION: AC for ECC might be inadequate as a standard strategy due to the low implementation and completion rates because complications often hamper administration.

Miyata T, Beppu T, Imamura YU, et al.
A 12-year Recurrence-free Survival After Multidisciplinary Treatment for a Patient With Combined Hepatocellular-Cholangiocarcinoma.
Anticancer Res. 2019; 39(4):2139-2144 [PubMed] Related Publications
We report a 64-year-old woman with a 9-cm liver tumor in the left lateral section. The patient had neither hepatitis B or C virus infection, nor cirrhosis. Carbohydrate antigen 19-9 (CA 19-9) level was 1,889 U/ml. We also suspected bulky hilar lymph node metastasis, and a left lateral sectionectomy without lymph node dissection (R2) was performed. The pathological findings led to diagnosis of combined hepatocellular and cholangiocarcinoma. Three weeks post-operation, the patient underwent hepatic arterial infusion chemotherapy with cisplatin, fluorouracil, and mitomycin C. In addition, a total dose of 45 Gy of irradiation for the hilar lymph node was performed; while oral tegafur-uracil (UFT) has been administered for 10 years at a dose of 400 mg/day. The CA19-9 level of the patient was normalized after hepatectomy, hepatic arterial infusion, irradiation for hilar lymph node, and oral UFT administration. Currently, the patient is alive without any relapse for 12 years post-operation.

Yamada M, Yamamoto Y, Sugiura T, et al.
Comparison of the Clinicopathological Features in Small Bile Duct and Bile Ductular Type Intrahepatic Cholangiocarcinoma.
Anticancer Res. 2019; 39(4):2121-2127 [PubMed] Related Publications
BACKGROUND: The classification of intrahepatic cholangiocarcinomas (ICCs) has been reported in several studies, however, it remains controversial.
MATERIALS AND METHODS: Between January 2003 and December 2015, 94 patients underwent hepatectomy for ICC. The ICCs of 63 of these patients were classified as predominantly small bile duct type or bile ductular type ICC and were included in this analysis.
RESULTS: Thirty-seven patients (58.7%) were classified into the small bile duct ICC group, and 26 (41.3%) into the bile ductular ICC group. A multivariate analysis identified intrahepatic metastasis [hazard ratio (HR)=2.53, p=0.011], small bile duct ICC (HR=2.05, p=0.046) and portal vein invasion (HR 2.05, p=0.047) as independent prognostic factors for poorer survival.
CONCLUSION: It is important to correctly distinguish between small bile duct and bile ductular ICC types because these two types clearly have different clinicopathological and prognostic features.

Gaignard E, Bergeat D, Stock N, et al.
Portal vein leiomyosarcoma: A rare case of hepatic hilar tumor with review of the literature.
Indian J Cancer. 2019 Jan-Mar; 56(1):83-85 [PubMed] Related Publications
Portal vein leiomyosarcoma (LMS) is a very rare entity with poor prognosis. Only few cases have been reported in the literature. We report the case of a 53-year-old man with portal vein LMS presenting as a hilar tumor and causing cholestasis. The tumor measured 10 cm and was responsible for right portal vein thrombosis and compression of the biliary convergence. A right hepatectomy with hilar en bloc resection was performed with portal vein and biliary reconstruction. Pathology confirmed the complete resection of a well-differentiated leiomyosarcoma of the portal vein. The postoperative outcome was uneventful and the patient received no adjuvant treatment. Six months after the procedure, the patient is doing well with a normal quality of life and without any sign of recurrence. Aggressive and radical surgery should be proposed in first intention for the treatment of portal vein LMS.

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