Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted

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Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Importance Data on outcomes following surgical management of intrahepatic cholangiocarcinoma (ICC) are limited. The incidence of ICC is increasing and it has a poor prognosis. No consensus has been reached regarding the optimal treatment modalities. Objective To systematically review and synthesize the available evidence regarding treatment and prognosis in patients with ICC. Data Sources The PubMed database was searched for relevant articles published between January 1, 2000, and April 1, 2013. Study Selection Only studies assessing predictors of survival or recurrence in patients undergoing curative-intent surgical treatment of ICC were included. Small series, studies reporting on mixed types of cholangiocarcinoma, or exclusively on hepatolithiasis-associated cholangiocarcinoma, and those published in a language other than English, French, German, Italian, or Greek, were excluded. Fifty-seven of 960 articles were therefore analyzed. Data Extraction and Synthesis Data on preoperative, intraoperative, and postoperative variables were extracted by 3 independent reviewers. Multiple studies reporting on the same population were excluded. Data were pooled using a random-effects model. Main Outcomes and Measures We hypothesized that preoperative variables and tumor characteristics affect patient survival. The outcomes of the study were overall survival and recurrence-free survival. The hypothesis was formulated before data collection. Results Fifty-seven studies (4756 patients) were included in the review. Median patient age ranged from 49 to 67 years, and 57% were male. Most patients had a solitary (69%), large (median size, 4.5-8.0 cm) tumor of the mass-forming type (86%). Approximately one-third of the patients had lymph node metastasis (34%) or vascular (38%), perineural (29%), or biliary invasion (29%). Most underwent a major hepatectomy (82%), often accompanied by lymphadenectomy (67%) and sometimes by extrahepatic bile duct resection (23%). Median and 5-year overall survival (OS) generally were approximately 28 months (range, 9-53 months) and 30% (range, 5%-56%), respectively; factors predicting shorter OS included large tumor size, multiple tumors, lymph node metastasis, and vascular invasion. Adjuvant chemotherapy or radiotherapy did not appear to be beneficial. Seven studies (2132 patients) provided data for the meta-analysis. Factors associated with shorter OS included older age (pooled hazard ratio, 1.10; 95% CI, 1.03-1.17), larger tumor size (1.09; 1.02-1.16), presence of multiple tumors (1.70; 1.43-2.02), lymph node metastasis (2.09; 1.80-2.43), vascular invasion (1.87; 1.44-2.42), and poor tumor differentiation (1.41; 1.17-1.71). Conclusions and Relevance The prognosis of ICC is dictated mainly by tumor factors. Future research could focus on the usefulness of adjuvant treatment as well as other multidisciplinary treatment modalities.

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Treatment and Prognosis for Patients With Intrahepatic Cholangiocarcinoma Systematic Review and Meta-analysis

Purpose A nomogram is a useful and convenient tool for individualized cancer prognoses. We sought to develop a clinical nomogram for predicting survival of patients with resected non–small-cell lung cancer (NSCLC). Patients and Methods On the basis of data from a multi-institutional registry of 6,111 patients with resected NSCLC in China, we identified and integrated significant prognostic factors for survival to build a nomogram. The model was subjected to bootstrap internal validation and to external validation with a separate cohort of 2,148 patients from the International Association for the Study of Lung Cancer (IASLC) database. The predictive accuracy and discriminative ability were measured by concordance index (C-index) and risk group stratification. Results A total of 5,261 patients were included for analysis. Six independent prognostic factors were identified and entered into the nomogram. The calibration curves for probability of 1-, 3-, and 5-year overall survival (OS) showed optimal agreement...

https://ascopubs.org/doi/pdf/10.1200/JCO.2014.56.6661

Development and Validation of a Nomogram for Predicting Survival in Patients With Resected Non–Small-Cell Lung Cancer

Biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review.Significance: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC. Cancer Discov; 7(9); 943-62. ©2017 AACR.

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New Horizons for Precision Medicine in Biliary Tract Cancers

Cholangiocarcinoma (CCA) is the second most common primary malignancy. Although it is more common in Asia, its incidence in Europe and North America has significantly increased in recent decades. The prognosis of CCA is dismal. Surgery is the only potentially curative treatment, but the majority of patients present with advanced stage disease, and recurrence after resection is common. Over the last two decades, our understanding of the molecular biology of this malignancy has increased tremendously, diagnostic techniques have evolved, and novel therapeutic approaches have been established. This review discusses the changing epidemiologic trends and provides an overview of newly identified etiologic risk factors for CCA. Furthermore, the molecular pathogenesis is discussed as well as the influence of etiology and biliary location on the mutational landscape of CCA. This review provides an overview of the diagnostic evaluation of CCA and its staging systems. Finally, new therapeutic options are critically reviewed, and future therapeutic strategies discussed.

Cholangiocarcinoma: Current Knowledge and New Developments

Purpose This study aimed to establish an effective prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy. Patients and Methods The nomogram was based on a retrospectively study on 367 patients who underwent partial hepatectomy for ICC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2007. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve and compared with five currently used staging systems on ICC. The results were validated using bootstrap resampling and a prospective study on 82 patients operated on from 2007 to 2008 at the same institution. Results On multivariate analysis of the primary cohort, independent factors for survival were serum carcinoembryonic antigen, CA 19-9, tumor diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extrahepatic metastasis, which were all selected into the nomogram. The calibration curve for probability of ...

https://ascopubs.org/doi/pdf/10.1200/JCO.2012.41.5984

Prognostic Nomogram for Intrahepatic Cholangiocarcinoma After Partial Hepatectomy

Background The effectiveness of adjuvant transarterial chemoembolization (TACE) for intrahepatic cholangiocarcinoma (ICC) after hepatectomy remains unclear. This study was performed to identify ICC patients who would benefit from adjuvant TACE. Patients and methods The study included 553 patients who underwent hepatectomy for ICC between January 2008 and February 2011 at the Eastern Hepatobiliary Surgery Hospital and who were treated with or without TACE (122 with TACE and 431 without TACE). Survival risk stratification was performed using the established prognostic nomogram (ICC nomogram). The predictive performance was evaluated by concordance index and calibration. The tumor recurrence and overall survival (OS) rates were analyzed by the Kaplan-Meier method before and after propensity score matching (PSM). Results The predictive performance of the ICC nomogram was demonstrated by the well-fitted calibration curves and an optimal c-index of 0.71 for OS prediction. In the whole cohort, the 5-year recurrence and OS rates between the TACE and non-TACE groups were significantly different (5-year recurrence: 72.9% vs. 78.1%; OS: 38.4% vs. 29.7%). After 1:1 PSM, the TACE and non-TACE groups (122 patients each) had similar 5-year recurrence and OS rates (5-year recurrence: 72.9% vs. 74.2%; OS: 38.4% vs. 36.0%). By survival risk stratification based on ICC nomogram, only the patients in the lowest tertile (nomogram scores ≥77) benefited from adjuvant TACE (TACE vs. non-TACE groups: 90.4% vs. 95.9% for 5-year recurrence; 21.3% vs. 6.2% for 5-year OS). Conclusion Adjuvant TACE following liver resection might be suitable for ICC patients with high ICC nomogram scores (≥77). Implications for practice The accurate predictive performance of the established prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) following liver resection was reconfirmed in an independent cohort with 553 patients. Based on the survival risk stratification using the nomogram, adjuvant transarterial chemoembolization following liver resection might be suitable only for ICC patients with high scores from the nomogram.

https://theoncologist.onlinelibrary.wiley.com/doi/pdf/10.1634/theoncologist.2014-0470

Adjuvant Transarterial Chemoembolization Following Liver Resection for Intrahepatic Cholangiocarcinoma Based on Survival Risk Stratification.

Hepatocellular carcinoma (HCC) is one of the biggest challenges that human beings faced with in 21st century. Previous researches have revealed that miRNAs can serve as regulators in various cancers. MiR-876-5p, a member of miRNA family, has been studied in lung cancer for its anti-oncogenic function. However, the exact function of it is not reported in HCC. Our study aims to find out the effects of miR-876-5p expression on HCC progression. Two HCC cells were chosen to do functional assays after miR-876-5p expression was detected in cell lines by qRT-PCR. HepG2 cell was transfected with miR-876-5p mimics, whereas LM3 cell was transfected with miR-876-5p inhibitors. Next, cell activities of these two indicated cells were analyzed by means of MTT assay, colony forming assay, transwell migration assay and western blot analysis. Consequently, we found that miR-876-5p could inhibit both cell proliferation and metastasis. Moreover, we found out a target gene (DNMT3A) of miR-876-5p by performing bioinformatics analysis, dual luciferase reporter assay and biotin-avidin pull-down assay. Finally, rescue assays were carried out in HepG2 cells. We found that DNMT3A could reverse miR-876-5p mimics-induced inhibition. Therefore, we concluded that miR-876-5p suppressed hepatocellular carcinoma progression by targeting DNMT3A.

MiR-876-5p acts as an inhibitor in hepatocellular carcinoma progression by targeting DNMT3A.

The impact of different causative factors of intrahepatic cholangiocarcinoma (ICC) on disease outcome remains largely unknown. This study aimed to evaluate the prognosis of ICC patients with different pathogenic factors after hepatectomy. Data of 731 consecutive patients undergoing R0 liver resection for ICC at The Eastern Hepatobiliary Surgery Hospital between 2004 and 2010 were analyzed. These patients were divided into the hepatitis B virus-related (HBV-ICC, n = 519), hepatolithiasis-related (stone-ICC, n = 87), HBV plus hepatolithiasis-related (HBV/stone-ICC, n = 45), and other etiologies-related (other-ICC, n = 80) ICC groups. Propensity score matching (PSM) was used to eliminate the baseline differences between these groups. In these four groups, the 5-year tumor recurrence and overall survival (OS) rates were 75.4, 90.3, 83.0 and 81.9%, and 32.7, 16.3, 17.7 and 22.6%, respectively. The significant differences in recurrence and OS were identified between the HBV- and stone-ICC groups (both p  5 cm was demonstrated as a risk factor in the HBV-ICC patients only, and surgical margin <1 cm and human epidermal growth factor receptor 2-positive were demonstrated as risk factors in the stone-ICC patients only. With PSM, 75 patients in each of the HBV- and stone-ICC cohorts were created, and the 5-year recurrence and OS rates were 69.9 versus 88.6, and 34.6 versus 19.2%, respectively (p = 0.017, 0.027). Patients with HBV-ICC achieved better outcomes than those with stone-ICC. This prognostic difference was probably associated with biological malignant invasiveness rather than tumor stage.

Prognosis of Intrahepatic Cholangiocarcinomas with HBV Infection is Better than Those with Hepatolithiasis After R0 Liver Resection: A Propensity Score Matching Analysis

Background: Hepatocellular carcinoma (HCC), the fourth leading cause of cancer-related deaths worldwide, has increased public concern. Data from previous work have validated that long noncoding RNA...

Yizhou Wang

Papers

Prognostic Nomogram for Intrahepatic Cholangiocarcinoma After Partial Hepatectomy

Adjuvant Transarterial Chemoembolization Following Liver Resection for Intrahepatic Cholangiocarcinoma Based on Survival Risk Stratification.

MiR-876-5p acts as an inhibitor in hepatocellular carcinoma progression by targeting DNMT3A.

Prognosis of Intrahepatic Cholangiocarcinomas with HBV Infection is Better than Those with Hepatolithiasis After R0 Liver Resection: A Propensity Score Matching Analysis

SNHG7 Facilitates Hepatocellular Carcinoma Occurrence by Sequestering miR-9-5p to Upregulate CNNM1 Expression.