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Hilar cholangiocarcinoma (HCCA) is a highly aggressive biliary tract tumor. microRNAs (miRs) exert dual actions in various cancers. This paper seeks to expound on the functional mechanisms of miR-25-3p/dual specificity phosphatase 5 (DUSP5) in HCCA cell proliferation and migration. HCCA-related data were downloaded from GEO database to screen out differentially-expressed genes. The potential target miR (miR-25-3p) and its expression in HCCA were analyzed on Starbase. The binding relation between miR-25-3p and DUSP5 was confirmed by dual-luciferase assay. Levels of miR-25-3p and DUSP5 in FRH-0201 cells and HIBEpics were determined by RT-qPCR and Western blot. miR-25-3p and DUSP5 levels were intervened with to explore their effects on FRH-0201 cells. The apoptosis, proliferation, migration, and invasion of FRH-0201 cells were evaluated by TUNEL, CCK8, scratch healing, and Transwell assays. Flow cytometry was conducted to assess FRH-0201 cell cycle. Levels of cell cycle-related proteins were determined by Western blot. DUSP5 was weakly-expressed and miR-25-3p was highly-expressed in HCCA samples and cells. miR-25-3p targeted DUSP5. miR-25-3p suppressed FRH-0201 cell apoptosis and increased cell proliferation, migration, and invasion. DUSP5 overexpression partially abrogated miR-25-3p overexpression-exerted effects on FRH-0201 cells. miR-25-3p stimulated G1/S phase transition of FRH-0201 cells by targeting DUSP5. miR-25-3p regulated HCCA cell cycle and facilitated cell proliferation and migration by targeting DUSP5. [ABSTRACT FROM AUTHOR] more...

The incidence of biliary tract cancer is increasing in developed countries and is generating renewed interest in the scientific community due to the evidence of a high percentage (approximately 40%) of potentially targetable molecular alterations. However, to date, patient selection and the development of therapeutic approaches remain challenging due to the need for accurate diagnosis, adequate sampling, a specialized team for molecular analysis, centralization of patients in high-volume centers capable of supporting the high cost of these methods, and the feasibility of clinical studies on diseases with aggressive onset and poor prognosis. In this article, we would like to provide a detailed overview of the necessary tools for diagnostic framing and the various therapeutic scenarios being investigated concerning the most frequently detected molecular alterations. [ABSTRACT FROM AUTHOR] more...

The Toronto Video Atlas of Liver, Pancreas, Biliary, and Transplant Surgery (TVASurg) is a free online library of three-dimensional (3D) animation-enhanced surgical videos, designed to instruct surgical fellows in hepato-pancreato-biliary (HPB) and transplant procedures. The video ‘Klatskin tumours: Extended left hepatectomy with complex portal vein reconstruction andin situcold perfusion of the liver’, which is available to watch athttp://TVASurg.ca, is a unique and valuable visual resource for surgeons in training to assist them in learning this rare procedure. This paper describes the methodologies used in producing this 3D animation-enhanced surgical video. [ABSTRACT FROM PUBLISHER] more...

Little is known about the disease of early-onset cholangiocarcinoma (EOC). The primary objective of this study was to compare EOC with later-onset cholangiocarcinoma (LOC) concerning clinical features and survival prognosis. 19325 cholangiocarcinoma patients were extracted from 1975 to 2020 in the SEER database. Cox regression analysis and Kaplan-Meier survival curves were used for the evaluation of cause-specific survival (CSS) and overall survival (OS). To reduce confounding, we compared survival differences between the EOC and LOC groups using propensity score matching (PSM). 4037 cholangiocarcinoma patients were included in the study, of which 274 were EOC and 3763 were LOC. Early-onset patients were more likely to be non-white, and intrahepatic cholangiocarcinoma. At diagnosis, patients had advanced AJCC stage, lymph node metastase and distant metastase. The EOC patients were more likely to receive surgery, radiotherapy, and chemotherapy than later-onset patients. Multifactorial COX analysis indicated that EOC patients had lower mortality risk than later-onset patients, and similar results were obtained after PSM; Kaplan-Meier survival curves corroborated that early-onset patients exhibited better OS than later-onset patients, and this survival advantage persisted after PSM. Further subgroup analysis following matching demonstrated that early-onset patients had better OS than later-onset patients in the surgical subgroup, while there were no statistically significant differences in the radiotherapy and chemotherapy subgroups. The EOC patients typically exhibit an intrahepatic presentation and generally experience a more favorable prognosis. Surgery emerged as a critical treatment modality significantly influencing the overall prognosis of EOC. [ABSTRACT FROM AUTHOR] more...

Multicystic biliary hamartoma (MCBH) is a rare cystic disease of the liver. We herein report a case of MCBH associated with extremely elevated levels of serum carbohydrate antigen (CA) 19-9. A 53-year-old man was referred to our hospital because of extremely elevated CA19-9 levels (more than 12,000 U/mL). Enhanced abdominal computed tomography and magnetic resonance imaging (MRI) revealed a multicystic tumor with a calcified wall in the left lobe of the liver, although no apparent intracystic nodule was detected. Because of the possibility of a malignant tumor, such as intraductal papillary neoplasm of the bile duct or cystadenocarcinoma, the patient underwent left hepatectomy. Based on the postoperative pathological findings, the lesion was diagnosed as MCBH. The serum CA19-9 level drastically decreased after surgery. We encountered a rare case of MCBH with extremely elevated CA19-9 levels. [ABSTRACT FROM AUTHOR] more...

Biliary tract carcinoma (BTC) is a heterogenous group of aggressive hepatic malignancies, second to hepatocellular carcinoma per prevalence. Despite clinical research advancement, the overall 5-year survival rate is just above 2%. With the identification of somatic core mutations in half of cholangiocarcinomas. In the intrahepatic subtype (iCCA), it is possible to target mutational pathways of pharmacological interest. Major attention has been drawn to fibroblast growth factor receptor (FGFR), especially the type 2 (FGFR2), found mutated in 10–15% of iCCAs. FGFR2 fusions became the target of novel tyrosine-kinase inhibitors investigated in clinical studies, showing promising results so as to gain regulatory approval by American and European committees in recent years. Such drugs demonstrated a better impact on the quality of life compared to standard chemotherapy; however, side effects including hyperphosphatemia, gastrointestinal, eye, and nail disorders are common although mostly manageable. As FGFR inhibitors may soon become the new alternative to standard chemotherapy in FGFR-mutated cholangiocarcinoma, accurate molecular testing and monitoring of acquired resistance mechanisms will be essential. The possible application of FGFR inhibitors in first-line treatment, as well as in combination with current standard treatments, remains the next step to be taken. [ABSTRACT FROM AUTHOR] more...

The role of laparoscopy in the treatment of intrahepatic cholangiocarcinoma (ICC) remains unclear. This multicenter study examined the outcomes of laparoscopic liver resection for ICC. Patients with ICC who had undergone laparoscopic or open liver resection between 2012 and 2019 at four European expert centers were included in the study. Laparoscopic and open approaches were compared in terms of surgical and oncological outcomes. Propensity score matching was used for minimizing treatment selection bias and adjusting for confounders (age, ASA grade, tumor size, location, number of tumors and underlying liver disease). Of 136 patients, 50 (36.7%) underwent laparoscopic resection, whereas 86 (63.3%) had open surgery. Median tumor size was larger (73.6 vs 55.1 mm, p = 0.01) and the incidence of bi-lobar tumors was higher (36.6 vs 6%, p < 0.01) in patients undergoing open surgery. After propensity score matching baseline characteristics were comparable although open surgery was associated with a larger fraction of major liver resections (74 vs 38%, p < 0.01), lymphadenectomy (60 vs 20%, p < 0.01) and longer operative time (294 vs 209 min, p < 0.01). Tumor characteristics were similar. Laparoscopic resection resulted in less complications (30 vs 52%, p = 0.025), fewer reoperations (4 vs 16%, p = 0.046) and shorter hospital stay (5 vs 8 days, p < 0.01). No differences were found in terms of recurrence, recurrence-free and overall survival. Laparoscopic resection seems to be associated with improved short-term and with similar long-term outcomes compared with open surgery in patients with ICC. However, possible selection criteria for laparoscopic surgery are yet to be defined. [ABSTRACT FROM AUTHOR] more...

Cholangiocarcinoma (CCA) is an uncommon malignancy originating from epithelial cells of the biliary tract. Regardless of the site of origin within the biliary tree, CCAs are generally aggressive with a poor survival. Surgical resection remains the only chance for cure, yet a majority of patients are not surgical candidates at presentation. Unfortunately, systemic therapies are often ineffective and complicated by side effects. As such, more effective targeted therapies are required in order to improve survival. Genetic analysis of CCA has allowed for a better understanding of the genomic landscape of CCA. Isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) mutations have emerged as the most promising molecular targets for CCA. Inhibitors of IDH and FGFR have proven to have therapeutic benefit with an acceptable safety profile. However, patients often develop resistance rendering the therapy ineffective. Understanding the molecular pathways of IDH and FGFR may lead to a better understanding of the mechanisms of resistance. Thus, novel therapies may be developed to improve the efficacy of these therapies. Developing novel biomarkers may improve patient selection and further enhance effectiveness of targeted therapies. [ABSTRACT FROM AUTHOR] more...

The prognosis of Intrahepatic cholangiocarcinoma (ICC) patients who did not undergo lymphadenectomy is difficult to assess. This study aims to have a dynamic evaluation on the postoperative survival of ICC patients by calculating conditional survival. Relevant data were from patients treated in 12 large-scale hospitals from December 2011 to December 2017. The influence of relevant clinical baseline data on the prognosis of ICC patients was analyzed by Cox regression. Conditional survival (CS) is a method that may predict the prognostic probability dynamically. For a patient with x years of survival, the 1-year CS (CS1) may be calculated as CS1= OS(x + 1)/OS(x). A total of 361 patients who met the criteria were included in the study. Conditional survival (CS) means that the patients' prognosis varies with survival time, meanwhile, relevant factors affecting the prognosis have a time-varying effect. The probability of survival assessed by CS1 increased year by year and the 1,2,3-year survival improved from 68.4% to 87.8%, while the postoperative actuarial OS decreased from 69.4% at 1 years to 36.9% at 3 years. In terms of CS, the estimated survival for ICC varies with the increase of survival time after excision. Patients who live longer were likely to live longer. At the same time, with the passage of time, the role of the original adverse factors of the tumor would gradually decrease. Conditional survival allows a more accurate assessment of ICC patients who did not undergo lymphadenectomy. [ABSTRACT FROM AUTHOR] more...

Cholangiocarcinoma (CCA) is an aggressive biliary epithelial tumor with limited therapeutic options and poor prognosis. Curcumin is a promising active natural compound with several anti-cancer properties, though its clinical uses remain hindered due to its poor bioavailability. We recently synthesized curcumin analogs with multifunctional pharmacological and bioactivities with enhanced bioavailability. Among these novel curcumin analogs, WZ26 is a representative molecule. However, the anti-tumor effect of WZ26 against CCA is unclear. In this study, we evaluated the anti-tumor effect of WZ26 in both CCA cells and CCA xenograft mouse model. The underlying molecular anti-cancer mechanism of WZ26 was also studied. Our results show that WZ26 significantly inhibited cell growth and induced mitochondrial apoptosis in CCA cell lines, leading to significant inhibition of tumor growth in xenograft tumor mouse model. Treatment of WZ26 increased reactive oxygen species (ROS) generation, subsequently decreased mitochondrial membrane potential and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inducing G2/M cell cycle arrest and cell apoptosis. Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells. Our findings provide experimental evidence that curcumin analog WZ26 could be a potential candidate against CCA via enhancing ROS induction and inhibition of STAT3 activation. [ABSTRACT FROM AUTHOR] more...

Cholangiocarcinoma (CCA) accounts for approximately 3% of gastrointestinal malignancies and is associated with a high mortality rate. Recent progress in the understanding of cholangiocarcinoma tumorigenesis and molecular markers has led to the development of several targeted therapies applicable to this disease. Fibroblast growth factor receptor 2 (FGFR2) gene fusion or translocation, resulting in constitutive activation of the FGFR tyrosine kinase, has been identified as a driver of oncogenesis in 10–15% of intrahepatic CCA. Pemigatinib is an FGFR inhibitor that has demonstrated survival benefit in the second line setting for treatment of CCA with FGFR2 fusion or rearrangement refractory to chemotherapy. Pemigatinib was the first targeted therapy to be approved by the FDA for treatment of cholangiocarcinoma. This article reviews FGFR and its dysregulation in oncogenesis, FGFR inhibitors, especially pemigatinib, utilized in treatment of CCA, common adverse events associated with FGFR inhibitors, and future directions in the field of targeted drug development for CCA. FGFR inhibitors, including pemigatinib, have shown promise in the management of CCA with FGFR2 fusion or rearrangement; however, acquired resistance remains a major barrier in the field of FGFR inhibitors and requires further study. [ABSTRACT FROM AUTHOR] more...

Typical flowchart of handling BTC tumor specimen in relation to resection margins, its associated risk management for local recurrence and adjuvant therapy strategy as well as medical involvement and their related requirements (based on mentioned/discussed literature, see [[2], [5], [12], [14], [17]]); the figure was additionally created with BioRender.com. As recently comprehensive summarized [[8]] the classical resection of BTCs, especially with perihilar localization could be extended with a more aggressive approaches: here, the operative procedures include extended liver resections and portal vein resection, or even right hepatic artery reconstruction (for left sided tumors). What is the management of resected cholangiocarcinoma in terms of intra- and postoperative status of tumor margins and lymph nodes? Does Caudate resection improve outcomes of patients undergoing curative resection for perihilar cholangiocarcinoma?. [Extracted from the article] more...

Thailand and Laos were classified as risk areas for cholangiocarcinoma (CCA) in a 2017 assessment in the Greater Mekong Subregion. In 2019, the potential of village health volunteers (VHVs) in both risk areas was developed. The VHVs trained in 2014 (VHV-A) were mentors transferring knowledge of CCA prevention to the trainees (known as VHV-B) in a parallel manner. After that, VHV-Bs in each area educated people to change their behavior. Both parties worked in the same direction to reduce risk factors. In 2020, data were collected after the program was organized in the same populations. The people were aged 30-69 years, whose names were in the civil registration, and had lived in that area for at least five years. Afterward, no less than 172 participants from each location were randomly selected. The research tools used were intervention and questionnaires. Descriptive and inferential statistics were employed for data analysis. After the experiment, all the experimental group's risk factors were significantly different from those of the control group. This study's outcome was an effective program for proactive action in reducing risk factors in the risk areas. Therefore, it should be applied to reduce risk factors for CCA in other regions. [ABSTRACT FROM AUTHOR] more...

To examine conditional survival (CS) in patients with non‐metastatic intrahepatic cholangiocarcinoma (nmICC) after surgical treatment according to pT and pN stages. A total of 608 patients were included. Conditional three-year cancer-specific mortality estimates were obtained according to pT and pN stages. Multivariable Cox regression analysis was applied to predict factors affecting cancer-specific mortality (CSM). According to substages based on pT and pN status, 109 patients (17.9%) with pT1aN0, 96 (15.8%) with pT1bN0, 205 (33.7%) with pT2N0, 82(13.5%) with pT3-5N0, and 116 (19.1%) with pTanyN1 were identified. Conditional CSM-free estimates increased from 75% to 87%, 66% to 70%, 53% to 86%, and 36 to 54% after three years of event-free follow-up in pT1b, pT2, pT3-4N0, and pTanyN1 patients, respectively, whereas it decreased from 87% to 79% in pT1aN0 patients. Based on multivariable analysis, patients with pT2N0 (hazard ratio [HR] 2.0 p <.01), pT3-4N0 (HR 2,7 p <.01), and pTanyN1-3 (HR 4.8 p <.01) had higher CSM than patients with pT1aN0 at baseline. CS varied across stage categories in nmICC patients after surgery, and it was important in individualized clinical counseling and decision‐making for nmICC. [ABSTRACT FROM AUTHOR] more...

The 2021 has seen the publication of two practice-changing trials on second-line fluoropyrimidine-based doublet chemotherapy for advanced biliary tract cancer (BTC) patients. Herein, we conducted a meta-analysis aimed at assessing the overall survival (OS), disease control rate (DCR), and overall response rate (ORR) in ABC-06 and NIFTY trials. We retrieved all the relevant trials through PubMed/Medline, Cochrane library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Outcomes of interest included OS, DCR, and ORR. Hazard Ratios (HRs) and their 95% Confidence Intervals (CIs) for OS, and Odds Ratios (ORs) and 95% CIs for DCR and ORR, were extracted. According to our results, fluoropyrimidine-based doublet chemotherapy significantly decreased the risk of death (HR, 0.63; 95% CI, 0.49–0.8) compared with control treatment. In addition, higher DCR and ORR were observed in BTC patients receiving fluoropyrimidine-based combinations. Although ABC-06 and NIFTY have recently established fluoropyrimidine-based doublet chemotherapy as the standard of care, the role of second-line chemotherapy remains the object of debate in the BTC medical community. Further studies are required to clarify the role of second-line fluoropyrimidine-based chemotherapy in some 'neglected' populations, including BTC patients with poor ECOG-PS. [ABSTRACT FROM AUTHOR] more...

Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations, which may have an interesting clinical application in the next future. In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures, including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease. [ABSTRACT FROM AUTHOR] more...

Introduction: Cholangiocarcinoma (CCA) is a malignancy which arises from the biliary epithelium. Carcinogenesis of CCA is mainly linked to aberrant glucose metabolism and creation of an immunosuppressive environment around normal biliary epithelium. The incidence of CCA is higher in the East due to Opisthorchis viverrini, an endemic liver fluke. CCA has also be attributed to genetic, metabolic, and lifestyle risk factors. Areas covered: Differences in epidemiological risk factors are associated with varying phenotypes of CCA. Metabolic risk factors include diabetes, obesity, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), dyslipidemia, and metabolic syndrome. Inherited metabolic risk factors include Wilson's disease and hemochromatosis. Metabolic disease is associated with a higher risk of CCA, with higher risk for the intrahepatic form. In this review, the authors provide an overview of available evidence regarding metabolic conditions associated with the development of CCA. Expert opinion: Metabolic disease is associated with a higher risk of intrahepatic CCA compared to its extrahepatic or hilar counterpart. As rates of obesity and metabolic syndrome increase, particularly in the West, it is conceivable that the incidence of CCA will also rise in the next years. [ABSTRACT FROM AUTHOR] more...

Aspirin may also synergize with systemic treatments for HCC, as clinical reports of HCC patients receiving sorafenib confirmed better outcomes among subjects receiving low-dose aspirin for concurrent cardiovascular conditions [[1]]. Aspirin to prevent liver cancer The first reports about the potential chemopreventive effect of aspirin in HCC date back to the early 2010s and include retrospective studies in the general population. Keywords: Aspirin; cirrhosis; hemostasis; liver cancer; hepatocellular carcinoma; biliary tract cancer; cholangiocarcinoma; chemoprevention; outcome EN Aspirin cirrhosis hemostasis liver cancer hepatocellular carcinoma biliary tract cancer cholangiocarcinoma chemoprevention outcome 887 889 3 09/20/22 20220901 NES 220901 1. [Extracted from the article] more...

TGR5 (G protein-coupled bile acid receptor 1, GPBAR-1) is a G protein-coupled receptor with seven transmembrane domains and is widely distributed in various organs and tissues. As an important bile acid receptor, TGR5 can be activated by primary and secondary bile acids. Increased expression of TGR5 is a risk factor for polycystic liver disease and hepatobiliary cancer. However, there is evidence that the anti-inflammatory effect of the TGR5 receptor and its regulatory effect on hydrophobic bile acid confer protective effects against most liver diseases. Recent studies have shown that TGR5 receptor activation can alleviate the development of diabetic liver fibrosis, regulate the differentiation of natural killer T cells into NKT10 cells, increase the secretion of anti-inflammatory factors, inhibit the invasion of hepatitis B virus, promote white adipose tissue browning, improve arterial vascular dynamics, maintain tight junctions between bile duct cells, and protect against apoptosis. In portal hypertension, TGR5 receptor activation can inhibit the contraction of hepatic stellate cells and improve intrahepatic microcirculation. In addition, the discovery of the regulatory relationship between the TGR5 receptor and miRNA-26a provides a new direction for further studies of the molecular mechanism underlying the effects of TGR5. In this review, we describe recent findings linking TGR5 to various liver diseases, with a focus on the mechanisms underlying its effects and potential therapeutic implications. [ABSTRACT FROM AUTHOR] more...

Introduction: Intrahepatic cholangiocarcinomas (iCCA) are aggressive tumors, often diagnosed in advanced stages and with limited curative treatment options. Their incidence has raised in the past years, increasing their associated economic burden. This study aimed to measure hospital incidence and mortality of iCCA and to evaluate direct medical costs.Methods: Records of admissions due to iCCA between 1 January 2000 and 31 December 2018 were obtained from a Spanish National discharge database. Hospital incidence and mortality were measured within the hospitalized population and medical costs were assessed for specialized healthcare.Results: Admission files corresponded to 23,315 patients, with a median age of 73 years (IQR = 17) and 55.9% of males. Cholangiocarcinoma presented a hospital incidence of 6.9 per 10,000 persons in 2018, increasing significantly over the study period. In-hospital mortality was 31.5% in the year 2018 and remained stable over the study period. The mean annual direct medical cost of secondary care was €9417 per patient in the year 2017, and increased significantly between 2000 and 2008, stabilizing after 2009.Conclusion: The incidence of iCCA in Spain increased over the past years. The medical costs of iCCA per patient stabilized after 2008 but total costs are expected to increase if incidence continues to raise. [ABSTRACT FROM AUTHOR] more...

Introduction: Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies comprising intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer. Although recent years have witnessed the emergence of novel treatment targets, medical therapy remains a compelling challenge in these hepatobiliary malignancies. In order to provide more effective treatment options, immune checkpoint inhibitors (ICIs) are currently under investigation in advanced BTC, with controversial results reported so far. Areas covered: This review provides an overview regarding current scenario of ICIs and immune-based combinations in advanced BTC, where several novel treatments are currently being developed, some of which have suggested interesting efficacy in recent clinical trials. In addition, we provide a report of ongoing Phase I to III clinical trials assessing ICIs and new immunotherapeutic strategies for advanced BTC. Expert opinion: Although immunotherapy has revolutionized the treatment landscape of several hematological and solid tumors, the role of ICIs and immune-based combinations in advanced BTC is still unclear. Despite ICI monotherapy has reported limited efficacy in this setting, the durable responses observed in sporadic cases suggest that testing patients for MMR, MSI, TMB, and PD-L1 expression is warranted. Results of currently ongoing trials are highly awaited. [ABSTRACT FROM AUTHOR] more...

Background: Despite recent advances in the understanding of the molecular landscape of biliary tract cancer (BTC), advanced disease continues to carry a poor prognosis, and the benefit from systemic treatments remains modest. However, BTCs have emerged as malignancies harboring specific potentially druggable aberrations, and thus, several molecularly targeted treatments have been recently tested. Among these, fibroblast growth factor receptor (FGFR) inhibitors have shown interesting results in previously treated BTC patients with advanced disease Areas covered: In this review, we aimed to provide an overview of available evidence on FGFR inhibitors in elderly patients with metastatic BTC, especially focusing on subgroup analyses of recently published trials exploring this novel therapeutic approach in these aggressive malignancies. Expert opinion: The FGFR1, FGFR2, and FGFR3 inhibitor pemigatinib has been recently approved by the United States Food and Drug Administration (FDA) in metastatic BTCs harboring FGFR2 fusion or other rearrangement. However, few data are available regarding the use of FGFR inhibitors in elderly BTCs, a patient population that remains seriously under-represented in clinical trials. [ABSTRACT FROM AUTHOR] more...

Introduction: Although the safety of biliary tract cancer resection has improved over the years, the recurrence rate is still high, and the postoperative prognosis remains low after biliary tract cancer resection. Therefore, the development of effective adjuvant therapy is essential to improve treatment outcomes. Because biliary tract cancer is rare compared with other gastrointestinal cancers, there have been only a small number of clinical trials of adjuvant therapy. However, in recent years, the results of several large-scale randomized controlled trials have been published, and clinical trials investigating the efficacy of new regimens are currently ongoing. Areas covered: This review presents the results of previously published important phase II and III clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and discusses their interpretation. The future direction of new research on resectable biliary tract cancer treatment is also discussed. Expert opinion: The foundations of large-scale clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer are underway, and new trials will establish evidence of their effectiveness. Additionally, breakthroughs in treatment through genetic and molecular research are expected. [ABSTRACT FROM AUTHOR] more...

Introduction: Primary sclerosing cholangitis (PSC) is a rare, heterogenous, chronic cholestatic liver disease that causes fibro-inflammatory destruction of the intra- and/or extrahepatic bile ducts. The disease course may be variable, though in many cases it ultimately leads to biliary cirrhosis and its associated complications. PSC is also associated with malignancies, in particular cholangiocarcinoma (CCA), a dreaded neoplasm of the biliary tract with a poor prognosis. Risk stratification and surveillance for this malignancy are important components of the care of patients with PSC. Areas covered: In this review, we discuss important considerations in the clinical epidemiology, risk factors, diagnosis, and surveillance of PSC-associated CCA. Expert opinion: Despite growing awareness of PSC, high-quality evidence regarding the management of PSC and its associated risk of CCA remains limited. Early diagnosis of PSC-associated CCA remains difficult, and treatment options are limited, especially when diagnosed at later stages. The recent introduction of recommendations for CCA surveillance will likely improve outcomes, though an optimal surveillance approach has yet to be validated prospectively. Further research is needed in the development of high-accuracy (and noninvasive) surveillance and diagnostic tools that may facilitate earlier diagnosis of CCA and potential disease cure. [ABSTRACT FROM AUTHOR] more...

Introduction: Peri-hilar cholangiocarcinoma is an aggressive bile duct cancer. Long-term survival is possible with margin-negative surgery. Historically, unresectable disease was approached with non-curative treatment options. In recent decades, an innovative approach of neoadjuvant chemoradiation and liver transplantation has demonstrated long-term survival for highly selected patients. Areas covered: This is a critical analysis of studies published to date on neoadjuvant chemoradiation and liver transplantation for selected patients with peri-hilar cholangiocarcinoma. A PubMed literature search was conducted for years 1970–2020 with the following search criteria: ['hilar' OR 'peri-hilar' AND 'cholangiocarcinoma'] AND ['treatment' OR 'transplantation' OR 'survival' OR 'outcome']; 'neoadjuvant chemoradiation' AND 'unresectable cholangiocarcinoma'. All peer-reviewed original research studies were selected for review. Expert opinion: Neoadjuvant chemoradiation and liver transplantation for patients with early stage unresectable peri-hilar cholangiocarcinoma can achieve long-term survival in highly selected patients who survive to transplantation without disease progression. There are observed differences in survival for patients with PSC-associated versus de novo cholangiocarcinoma and transplanted versus resected patients; however, these differences are not contextualized by established tumor and patient factors that influence recurrence and survival. Therefore, these results must be interpreted within the limitations of the study designs upon which they are based. [ABSTRACT FROM AUTHOR] more...

Introduction: PSC is a rare liver disease that leads frequently to cirrhosis and need for liver transplantation. No medical treatment is of proven value. Liver transplantation is the only curative therapy available. There is a big medical need to find medical therapy that can alter the natural history of the disease. Areas covered: The authors highlight advances in PSC, based on recent literature retrieved from PubMed until September 2020 regarding both medical and endoscopic biliary therapy. Future possibilities for treatment of PSC are discussed. Expert opinion: Biliary endoscopy is the cornerstone in the treatment of dominant strictures. Single-user peroral cholangioscopy is an emerging modality. Balloon dilatation therapy is the treatment of choice of dominant strictures. The most promising medical therapies showing efficacy in phase II trials are nor-Ursodeoxycholic acid, obethicolic acid, the non-steroidal FXR agonist Cilofexor and Aldafermin, a synthetic analogue of FGF-19. Antibiotics, particularly vancomycin have shown potential benefits, particularly in children but phase III studies are lacking. In observational studies of effects of biological therapy in patients with IBD/PSC adalimumab was associated with reduction in ALP. Results of liver transplantation are favorable but recurrence can be of clinical relevance particularly in patients transplanted before the age of 40. [ABSTRACT FROM AUTHOR] more...

Background and Objective: The preferred treatment for Cholangiocarcinoma (CCA) patients is surgery. Approximately, 35% of patients can undergo surgical resection in clinic. Biomarkers for CCA need to be identified for diagnosis, treatment, or prognosis prediction of this disease. Y-box binding protein-1 (YBOX-1) is highly correlated with tumor progression and poor overall survival in many malignancies. The prognostic value of YBOX-1 overexpression in CCA remains unclear. We examined the expression of YBOX-1 in resected tissue in CCA patients and studied the effect of YBOX-1 in CCA migration and invasion in vitro and in vivo. Methods: Expression of YBOX-1 in the tissue of 91 CCA patients was investigated by immunohistochemistry. The effects of YBOX-1 on migration, invasion, and proliferation in CCA cell lines were assessed by short hairpin RNA lentivirus or overexpression plasmid transfection. Results: A total of 55 (60.4%) of CCA cancerous tissues showed strongly positive YBOX-1 cytoplasmic staining. The strongly positive expression of YBOX-1 was close to early recurrence and poor overall survival by Kaplan–Meier analyses. Knockdown of YBOX-1 reduced migration and invasion in CCA cells and proliferation of tumor in xenotransplantation nude mice. Overexpression of YBOX-1 promoted migration and invasion in CCA cells and proliferation of tumor in xenotransplantation nude mice. Conclusion: YBOX-1 is correlated with early recurrence and poor overall survival in CCA. YBOX-1 may be a factor of predicting poor prognosis and overall survival. [ABSTRACT FROM AUTHOR] more...

Purpose: Central nervous system (CNS) metastasis from cholangiocarcinoma (CCA) are extremely rare and associated prognosis is poor. The involvement of the CNS by metastatic CCA may discourage any further treatment; however, data from the literature are discordant, due to recent reports of exceptionally long follow-up after surgical resection of a brain metastasis. Material and Methods: Electronic databases, such as PubMed/MEDLINE and Google Scholar, were analyzed for studies published up to October 2018 using the search term "cholangiocarcinoma and central nervous system metastasis or brain metastasis". Results: We found a total of 18 studies cited in the literature of the 30 year span analyzed, and we added a new case we treated at our Institution, reaching a series of 32 patients. Among these, 7 patients had leptomeningeal dissemination and 25 presented solid CNS metastasis. We analyzed the treatment options and the outcomes, addressing also histopathological insights on tumoral markers possibly involved in the mechanism of metastases of cholangiocarcinomas Conclusions: According to the literature data, the outcome remains poor, particularly for those with leptomeningeal diffusion. Nevertheless, long term follow-up is reported in case of surgical resection of CNS metastasis, when there is a good control of the primary tumor. Actually, the majority of patients are often in advanced state of disease at diagnosis and not suitable for initial resective procedure; in these cases neo adjuvant and adjuvant therapies have provided a slight improvement of the outcome. [ABSTRACT FROM AUTHOR] more...

Cholangiocarcinoma (CCA) is a dismal disease with limited management options. Surgical resection remains the only established treatment however, due to its inherent predilection to invade vascular structures, only a fraction of patients with CCA meet resection criteria at diagnosis. Furthermore, R0 margins, crucial to obtain optimum survival can often prove elusive. This review discusses the evolution of liver transplant for CCA, following its introduction in the 1990 s with less than exemplary outcomes. While transplantation is not standard of care, emerging data has suggested a crucial role in prolonging survival of those with CCA. Here we analyze the current role of orthotopic liver transplantation (OLT) in cirrhotic and non-cirrhotic patients, in the setting of both intrahepatic CCA and hilar CCA in order to establish whether this is a judicious use of a precious resource. Liver transplant has a definite role in the treatment of CCA, as highlighted by ongoing clinical trials. A greater understanding of tumor biology coupled with results of current studies will help elucidate which patients will best benefit from OLT. While significant strides are being made to improve outcomes, this must be tempered with an understanding of the finite nature of liver grafts. [ABSTRACT FROM AUTHOR] more...

Background and aims: Liver transplantation (LTx) remains the only curative treatment in patients with primary sclerosing cholangitis (PSC) and liver failure. In Helsinki we have also performed pre-emptive LTx in PSC patients without liver insufficiency but considered to have a high risk for cholangiocarcinoma. The present study evaluates the possible differences in health-related quality of life (HRQoL) in these two PSC groups before and after LTx. Methods: The total study population was 48 patients, 16 were transplanted due to increased risk of cholangiocarcinoma without liver insufficiency (the premalignant group) and 32 patients with end-stage liver disease (the symptomatic group). Results: HRQoL remained good after LTx in the premalignant group, and this difference was also clinically important compared with the symptomatic group, although not statistically significant. Both groups had slightly lower mean HRQoL scores after LTx than the age- and gender-standardized general population, and this difference was not clinically important in either group and statistically significant only in the symptomatic group. Conclusions: HRQoL does not decrease markedly after LTx in the premalignant PSC group, and this group does cope better than the symptomatic PSC group. After LTx, mean HRQoL of the premalignant group stays close to that of the age- and gender-standardized general population. [ABSTRACT FROM AUTHOR] more...

Introduction: Cholangiocarcinoma (CCA) is a malignancy of the biliary tract. CCA generally has a low incidence worldwide but incidence is typically high in Southeast Asian countries, particularly in northeastern Thailand, where small liver-fluke (Opisthorchis viverrini) infection is endemic. CCA has a poor prognosis as most CCA patients present with advanced stages. Poor prognosis and worse outcomes are due to the lack of specific and early-stage CCA biomarkers. Areas covered: In this review, we discuss the use of CCA tissues, serum and bile samples as sources of diagnostic and prognostic markers by using -omics approaches, including genomics, epigenomics, transcriptomics and proteomics. The current state of the discovery of molecular candidates and their potential to be used as diagnostic and prognostic biomarkers for CCA are summarized and discussed. Expert opinion: Various potential molecules have been discovered, some of which have been verified as diagnostic biomarkers for CCA. However, most identified molecules require much further evaluation to help us find markers with high specificity, low cost and ease-of-use in routine diagnostic laboratories. [ABSTRACT FROM AUTHOR] more...

Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies comprising ampulla of Vater cancer, gallbladder cancer, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma; unfortunately, the incidence of distant and locoregional recurrence remains high in resected BTCs, with approximately 60–70% of the patients who will experience disease relapse. Until a few years ago, adjuvant treatment was mainly based on the results of a meta-analysis including heterogeneous retrospective studies and showing a survival benefit in the selected populations of resected BTC patients with node-positive disease and/or R1 resection. More recently, the results of several prospective randomized clinical trials have been presented and published. Among these, although the randomized phase III BILCAP trial comparing adjuvant capecitabine versus placebo failed to meet its primary endpoint by intention-to-treat analysis, the preplanned sensitivity analysis highlighted a survival benefit, leading to the wide adoption of capecitabine as adjuvant treatment. However, several unanswered questions remain, including the following: may standard capecitabine represent the effective, real standard of care in this setting? Herein, we discuss the results of the BILCAP study, with a particular focus on the impact the trial had in everyday clinical practice worldwide. [ABSTRACT FROM AUTHOR] more...

Objectives: The palliative treatment of cholangiocarcinoma is based on stent placement with well-known procedure-related complications. Consequently, alternative energy-based techniques were put forward with controversial long-term results. This study aims to evaluate the safety and effectiveness of biliary tree laser ablation (LA) in terms of: (i) absence of perforation, (ii) temperature increase, (iii) induced thermal damage in in vivo models. Materials and methods: The common bile duct and cystic ducts of two pigs were ablated with a diode laser (circumferential irradiation pattern) for 6 and 3 min at 7 W. Laser settings were chosen from previous ex vivo experiments. Local temperature was monitored through a fibre Bragg grating (FBG) sensor embedded into the laser delivery probe. Histopathological analysis of the ablated specimen was performed through in situ endomicroscopy, haematoxylin and eosin (H&E) and nicotinamide adenine dinucleotide (NADH) stains. Results: Temperature reached a plateau of 53 °C with consequent thermal damage on the application area, regardless of laser settings and application sites. No perforation was detected macroscopically or microscopically. At the H&E stain, wall integrity was always preserved. The NADH stain allowed to evaluate damage extension. It turned out that the ablation spreading width depended on application time and duct diameter. In situ endomicroscopy revealed a clear distinction between ablated and non-ablated areas. Conclusions: The temperature distribution obtained through LA proved to induce a safe and effective intraductal coagulative necrosis of biliary ducts. These results represent the basis for further experiments on tumour-bearing models for the treatment of obstructive cholangiocarcinoma. [ABSTRACT FROM AUTHOR] more...

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy arising from biliary tract epithelium within bile ducts proximal to the secondary biliary radicles. The majority of patients are diagnosed with locally advanced or metastatic disease at presentation. Surgical resection remains the only potentially curative option, but poses unique challenges due to the large size and aggressive behavior of these tumors. Areas covered: The goal of surgical management of iCCA is margin negative (R0) hepatic resection with preservation of adequate size liver remnant and function. Data regarding role of staging laparoscopy, margin status, portal lymphadenectomy, and vascular resection for iCCA are reviewed. Perioperative systemic therapy may have value, although prospective data have been lacking. Recurrence rates remain high even after R0 resection; among patients with recurrent disease limited to the liver, re-resection or locoregional therapies may play a role. Liver transplantation may be an option for select patients with very early-stage iCCA, although this should be done on a protocol-only basis. Expert commentary: Appropriate preoperative patient selection and surgical technique are paramount to ensure optimal oncologic outcomes for patients with resectable iCCA. Improving systemic and locoregional therapy options may help decrease recurrence rates and improve long-term survival for this aggressive malignancy. [ABSTRACT FROM AUTHOR] more...

Introduction: Since their initial description, perihilar cholangiocarcinoma (pCCA) has remained one of the more clinically challenging scenarios encountered by hepatobiliary surgeons. Surgery remains the only potentially curative therapy, but requires complex, technically demanding operations with high associated morbidity and mortality. Over the last several decades, advances in surgical technique and perioperative management have improved patient outcomes. Areas covered: Achievement of optimal outcomes requires a multidisciplinary approach from a team of providers with expertise in hepatobiliary and oncologic surgery, medical oncology, radiation oncology, and advanced gastroenterology. We herein report a comprehensive review on pCCA with an emphasis on surgical strategies and perioperative management. Expert commentary: Despite incremental improvements from advances in surgical technique and perioperative management, outcomes remain poor due to the aggressive systemic nature of this disease and the tendency for locoregional and distant recurrence. The marginal benefit observed with traditional systemic therapies continues to be a key weakness in current management. However, improved understanding of the genetic alterations and pathways that drive tumorigenesis has the potential to dramatically alter the way in which we care for these patients. [ABSTRACT FROM AUTHOR] more...

Introduction: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the hepatobiliary system characterized by chronic inflammation, progressive fibrosis, stricture formation and destruction of extrahepatic and intrahepatic bile ducts. Areas covered: The increased incidence of cholangiocarcinoma (CCA) in PSC has been well documented and can be explained by the continuous inflammation in the biliary tree leading to an enhanced dysplasia-carcinoma sequence. Although PSC patients may progress to liver cirrhosis; CCA most commonly occurs between the ages of 30 and 45 years when cirrhosis has not yet developed. Therefore, CCA in patients with PSC occurs earlier than in patients without PSC. Expert commentary: Despite improvement in diagnostic methods and devices, the dilemma of diagnosing CCA in patients with PSC has not been solved yet and needs further investigation. [ABSTRACT FROM AUTHOR] more...

Introduction: Cholangiocarcinoma (CCA) is a poorly prognostic cancer with limited treatment options. Most patients have unresectable tumors when they are diagnosed and the chemotherapies provided are of limited benefit. Prognostic markers are therefore necessary to predict the disease outcome, risk of relapse, or to suggest the best treatment option. Areas covered: This article provides an up-to-date review of biomarkers with promising characteristics to be prognostic markers for CCA reported in the past 5 years. The biomarkers are sub-classified into tissue and serum markers. Proteins, RNAs, peripheral blood cells etc., that are associated with aggressive phenotypes, signal pathways, chemo-drug resistance, and those that reflect the survival time of CCA patients are evaluated for their prognostic prediction values. Expert commentary: CCAs are heterogeneous tumors of different histo-pathological subtypes and genetic influences and, therefore, potential markers should be validated in larger collectives with varied epidemiological backgrounds. A systematic review and meta-analysis should be done to clarify the impact of the reported biomolecules for their potential prognostic values. Non- or low-invasive sample collections, as well as the simple and affordable determination methods, should be constructed to make the prognostic biomarkers available in clinical practice. [ABSTRACT FROM AUTHOR] more...

Objective: To evaluate the outcomes of percutaneous microwave ablation (MWA) and explore the prognostic factors for the survival of patients with intrahepatic cholangiocarcinoma (ICC). Methods: A total of 107 patients (age: mean 58.0 years, range 15-85 years) with 171 ICCs (maximum size ≤5 cm, tumour number per patient ≤3) who underwent MWA for ICC during January 2009 to February 2016 were selected, and their clinical and pathological data were collected and reviewed. The MWA-associated mortality, major complication rate and survival were evaluated. The prognostic factors for survival in patients with ICC were analysed with univariate and multivariate analyses. Results: The median follow-up after MWA was 20.1 months (2.8-63.5 months). There was no procedure-associated death. The overall procedure-associated major complication rate was 2.8%. The median PFS after MWA was 8.9 months; PFS rates after 6, 12, 18 and 24 months were 67.4%, 41.5%, 18.2% and 8.7%. The median OS was 28.0 months; OS rates after 1, 3 and 5 years were 93.5%, 39.6% and 7.9%. Child-Pugh class A and less tumour number were identified as factors predictive of prolonged PFS (HR for Child-Pugh class: 2.62, p = 0.001; HR for tumour number: 2.07, p = 0.002) and OS (HR for Child-Pugh class: 4.14, p < 0.001; HR for tumour number: 1.95, p = 0.024). Conclusions: Percutaneous ultrasound-guided MWA is safe and effective for ICC. Child-Pugh class A and less tumour number predict prolonged PFS and OS in patients with ICC treated by MWA. [ABSTRACT FROM AUTHOR] more...

Introduction: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease which is associated with inflammatory bowel disease (IBD) in most cases. As there is currently no medical therapy which alters the natural history of PSC, liver transplantation may be required. Areas covered: We searched for articles in PubMed and critically reviewed current literature on the interrelationship between PSC and IBD with a specific focus on considerations for patients in the liver transplant setting. Expert commentary: PSC is an uncommon disease which limits available studies to be either retrospective or contain relatively small numbers of patients. Based on observations from these studies, the behavior and complications of PSC and IBD impact on each other both before and after a liver transplant. Both these autoimmune conditions and their associated cancer risk also influence patient selection for transplantation and may be impacted by immunosuppression use post-transplant. Hence, a complex interplay exists between PSC, IBD and liver transplantation which requires clarification with ongoing research. [ABSTRACT FROM PUBLISHER] more...

Background: Radiofrequency ablation (RFA) causes coagulative necrosis of tissue and may be beneficial prior to biliary stenting. We report our experience using RFA for malignant biliary obstruction and review the literature. Methods: Retrospective analysis of all patients undergoing RFA for malignant biliary obstruction over the last two years. Success, complications and re-intervention following RFA were assessed. Controls were age, sex and disease matched who had stenting alone. Results: 31 patients were included and 15 patients underwent biliary RFA prior to stenting (median age 78 years, 8 females). 14 patients had pancreatic cancer, 13 cholangiocarcinoma (6 hilar lesions) and 4 malignant disease invading the bile duct. Adverse events included acute pancreatitis (n = 2) and bacteremia in (n = 1). Median duration of intervention free survival was 220 days in the RFA group compared to 106.5 days in controls (hazard ratio 2.4, 95% CI 1.1 – 5.3, p = 0.025). Multivariable Cox proportional hazard analysis showed survival was associated with RFA (hazard ratio 2.55, 95% CI 1.09–5.96, p = 0.026) but not age, site or type of malignancy. Conclusion: Biliary RFA is a technically feasible with a low adverse event rate and is associated with increased survival. Multi-centre randomized controlled trials are required. [ABSTRACT FROM AUTHOR] more...

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with an increasing incidence and a high-case fatality. While surgery offers the best hope at long-term survival, only one-third of tumors are amenable to surgical resection at the time of the diagnosis. Unfortunately, conventional chemotherapy offers limited survival benefit in the management of unresectable or metastatic disease. Recent advances in understanding the molecular pathogenesis of iCCA and the use of next-generation sequencing techniques have provided a chance to identify ‘target-able’ molecular aberrations. These novel molecular therapies offer the promise to personalize therapy for patients with iCCA and, in turn, improve the outcomes of patients. Area covered: We herein review the current management options for iCCA with a focus on defining both established and emerging therapies. Expert commentary: Surgical resection remains as an only hope for cure in iCCA patients. However, frequently the diagnosis is delayed till advanced stages when surgery cannot be offered; signifying the urge for specific diagnostic tumor biomarkers and targeted therapies. New advances in genomic profiling have contributed to a better understanding of the landscape of molecular alterations in iCCA and offer hope for the development of novel diagnostic biomarkers and targeted therapies. [ABSTRACT FROM PUBLISHER] more...

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent primary tumor of the liver and a highly lethal disease. Therapeutic options for advanced iCCA are limited and ineffective due to the largely incomplete understanding of the molecular pathogenesis of this deadly tumor. Areas covered: The present review article outlines the main studies and resulting discoveries on the molecular profiling of iCCA, with a special emphasis on the different techniques used for this purpose, the diagnostic and prognostic markers identified, as well as the genes and pathways that could be potentially targeted with innovative therapies. Expert commentary: Molecular profiling has led to the identification of distinct iCCA subtypes, characterized by peculiar genetic alterations and transcriptomic features. Targeted therapies against some of the identified genes are ongoing and hold great promise to improve the prognosis of iCCA patients. [ABSTRACT FROM PUBLISHER] more...

Introduction: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm. The incidence of ICC has been increasing world-wide over the past several decades. Areas covered: The pathogenesis of ICC is a complex process involving the alteration of specific genes and epigenetic changes. This review summarizes the advances in research of gene alterations and epigenetic changes in ICC; it also aims to promote the findings of new biomarkers that can be used to diagnose ICC and to provide novel ideas for the combination of molecular targeted therapies. Expert commentary: Surgical resection is regarded as the most effective curative treatment, although in many cases, resectability and curability are unsatisfactory. Furthermore, many patients are diagnosed at advanced stages and have to resort to chemotherapy, which is rarely curative. Many of the molecular mechanisms of ICC are yet to be determined; once these determinations are made, then ICC may be able to be treated by precise targeted drugs. [ABSTRACT FROM AUTHOR] more...

Cholangiocarcinoma (CCA) caused by opisthorchiasis is a specific public health problem in the Greater Mekong subregional countries. The Northeast Thailand is considered a world's prime area of CCA. Many epidemiological studies found the association between fruit and vegetables consumption and CCA, but their results were inconclusive. Therefore, this meta-analysis aimed to investigate the relationship between fruit and vegetables consumption and CCA prevention in the Northeast Thailand. The authors conducted a comprehensive search of scholarships on MEDLINE, EMBASE, and SCOPUS published during 1990 and 2015. Selected studies about fruit and vegetables consumption and CCA were analyzed. The fixed-effect model was used to estimate pool odds ratios for the consumption vs. nonconsumption. Based on a meta-analysis, consumption of mixed fruit [odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.65–0.96], mixed vegetables (OR = 0.61; 95% CI: 0.50–0.75), and combined fruit and vegetables (OR = 0.68; 95% CI: 0.57–0.80) was associated with the reduction of CCA risk statistically. These findings support that fruit and vegetables consumption is associated with CCA risk reduction. If implemented in a larger geographical area, the study will shed light on possibilities to future reduction of CCA. Educators can replicate the study to solve CCA or other types of cancer and discover the best practice. [ABSTRACT FROM PUBLISHER] more...

Cholangiocarcinoma, a malignant tumor arising in the hepatobiliary system, presents with poor prognosis because of difficulty in its early detection/diagnosis. Recent progress revealed that cellular senescence may be involved in the pathophysiology of cholangiocarcinoma. Cellular senescence is defined as permanent growth arrest caused by several cellular injuries, such as oncogenic mutations and oxidative stress. “Oncogene-induced” and/or stress-induced senescence may occur in the process of multi-step cholangiocarcinogenesis, and overexpression of a polycomb group protein EZH2 may play a role in the escape from, and/or bypassing of, senescence. Furthermore, senescent cells may play important roles in tumor development and progression via the production of senescence-associated secretory phenotypes. Cellular senescence may be a new target for the prevention, early diagnosis, and therapy of cholangiocarcinoma in the near future. [ABSTRACT FROM AUTHOR] more...

Cholangiocarcinomas (CCAs) are anatomically classified into intrahepatic, perihilar, and distal types. The gross pathological classification of intrahepatic CCAs divides them into mass-forming, periductal-infiltrating, and intraductal-growth types; and perihilar/distal CCAs into flat- and nodular-infiltrating and papillary types. Unique preinvasive lesions appear to precede individual gross types of CCA. Biliary intraepithelial neoplasia, a flat lesion, precedes periductal-, flat-, and nodular-infiltrating CCAs, whereas intraductal papillary neoplasm of the bile duct (IPNB) precedes the intraductal-growth and papillary type of CCAs. IPNBs are heterogeneous in their histological and pathological profiles along the biliary tree. Hepatobiliary cystadenomas/adenocarcinomas are reclassified as cystic IPNBs and hepatic mucinous cystic neoplasms. Peribiliary glands may participate in the development of CCAs. These latest findings present a new challenge for understanding the pathology of CCAs. [ABSTRACT FROM PUBLISHER] more...

Objective.Covered self-expandable metal stents (SEMSs) are increasingly used as alternatives to uncovered SEMSs for the palliation of inoperable malignant distal biliary obstruction to counteract tumor ingrowth. We aimed to compare the outcomes of partially covered and uncovered SEMSs with identical mesh structures and anti-migration properties, such as low axial force and flared ends.Materials and methods.One hundred and three patients who were diagnosed with inoperable malignant distal biliary obstruction between January 2006 and August 2013 were randomly assigned to either the partially covered (n= 51) or uncovered (n= 52) SEMS group.Results.There were no significant differences in the cumulative stent patency, overall patient survival, stent dysfunction-free survival and overall adverse events, including pancreatitis and cholecystitis, between the two groups. Compared to the uncovered group, stent migration (5.9% vs. 0%,p= 0.118) and tumor overgrowth (7.8% vs. 1.9%,p= 0.205) were non-significantly more frequent in the partially covered group, whereas tumor ingrowth showed a significantly higher incidence in the uncovered group (5.9% vs. 19.2%,p= 0.041). Stent migration in the partially covered group occurred only in patients with short stenosis of the utmost distal bile duct (two in ampullary cancer, one in bile duct cancer), and did not occur in any patients with pancreatic cancer.Conclusions.For the palliation of malignant distal biliary obstruction, endoscopic placement of partially covered SEMSs with anti-migration designs and identical mesh structures to uncovered SEMSs failed to prolong cumulative stent patency or reduce stent migration. [ABSTRACT FROM PUBLISHER] more...

Research related to primary sclerosing cholangitis (PSC) has since 1980 been a major activity at the Oslo University Hospital Rikshospitalet. The purpose of this publication is to describe the development of this research, the impact of this research on the clinical handling of the patients, and finally to describe what we believe are the most urgent, remaining problems to be solved. During the early years, our research dealt primarily with clinical aspects of the disease. The concomitant inflammatory bowel disease (IBD) seen in most patients with PSC was a major interest and we also started looking into genetic associations of PSC. Prognosis, malignancy development and treatment with special emphasis on transplantation have later been dealt with. These activities has had impact on several aspects of PSC management; when and how to diagnose PSC and variant forms of PSC, how to handle IBD in PSC and how to deal with the increased rate of malignancy? The problems remaining to be solved are many. What is the role of the gut and the gut microbiota in the development of PSC? Do the PSC patients have an underlying disturbance in the bile homeostasis? And how does the characteristic type of fibrosis in PSC develop? The genetic studies have supported a role for the adaptive immune system in the disease development, but how should this be dealt with? Importantly, the development of malignancy in PSC is still not understood, and we lack appropriate medical treatment for our patients. [ABSTRACT FROM AUTHOR] more...

Aims. IgG4-related sclerosing cholangitis in extrahepatic bile ducts in the absence of autoimmune pancreatitis (AIP) is rare and is poorly studied. Herein, we present the clinicopathological features of four cases of IgG4-related sclerosing cholangitis. Methods and results. The clinicopathological features of IgG4-related sclerosing cholangitis were compared with those of IgG4-related sclerosing cholangitis with AIP ( n = 7), extrahepatic cholangiocarcinoma ( n = 29), primary sclerosing cholangitis ( n = 40), and secondary sclerosing cholangitis ( n = 12). Several histomorphologic features distinguish IgG4-related sclerosing cholangitis, including a marked degree of bile duct injury, a higher percentage of lymphoid follicle formation, a higher percentage of perineuritis, and a more diffuse and dense lymphoplasmacytic infiltrate. All four cases of IgG4-related sclerosing cholangitis occurred exclusively in males. Of these cases, none had IgG4 serology checked preoperatively, and all had a preoperative diagnosis of extrahepatic cholangiocarcinoma. Clinical follow-up was available in 2 patients with a mean time of 11 months. Follow-up confirmed the benign course of the disease as the patients showed no evidence of relapse. IgG4-related conditions, including sclerosing cholecystitis and retroperitoneal fibrosis, were noted in three patients. Conclusions. IgG4-related sclerosing cholangitis in the absence of AIP presents as a distinct and under-recognized disease that mimics extrahepatic cholangiocarcinoma clinically. Awareness of this entity is essential to avoid erroneously diagnosing malignancy. The current threshold of 10 IgG4-positive plasma cells/high-power field (HPF) in the biopsy is not specific enough to exclude cholangiocarcinoma. Therefore, we suggest the diagnostic cut-off to be 50 IgG4-positive plasma cells/HPF in the biopsy. [ABSTRACT FROM AUTHOR] more...