Liver metastases of intrahepatic Cholangiocarcinoma: implications for an updated staging system

[EN] BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) with liver metastases is perceived to have a poor prognosis, but the American Joint Committee on Cancer (AJCC) classifies them as early stage in the absence of lymph nodes or extrahepatic spread. APP ROA CH AND RESULT S: Patients with iCCA from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and Surveillance, Epidemiology, and End Results (SEER) registries with survival/staging (AJCC v.7) data were eligible. Modified staging was used (mAJCC v.7): group A: stages I-III (excluding T2bN0); group B: stage IVa (excluding T2bN1M0); group C: liver metastases (T2bN0/1); and group D: stage IVb (extrahepatic metastases). Survival analysis (Kaplan-Meier and Cox regression) was performed in an ENS-CCA training cohort (TC) and findings internally (ENS-CCA iVC) and externally (SEER) validated. The aim was to assess whether liver metastases (group C) had a shorter survival compared to other early stages (group A) to propose a modified version of AJCC v.8 (mAJCC v.8). A total of 574 and 4,171 patients from the ENS-CCA and SEER registries were included. Following the new classification, 19.86% and 17.31% of patients from the ENS-CCA and SEER registries were reclassified into group C, respectively. In the ENS-CCA TC, multivariable Cox regression was adjusted for obesity (p = 0.026) and performance status (P < 0.001); patients in group C (HR, 2.53; 95% CI, 1.18-5.42; P = 0.017) had a higher risk of death (vs. group A). Findings were validated in the ENS-CCA iVC (HR, 2.93; 95% CI, 2.04-4.19; P < 0.001) and in the SEER registry (HR, 1.88; 95% CI, 1.68-2.09; P < 0.001). CONCLUSIONS: iCCA with liver metastases has a worse outcome than other early stages of iCCA. Given that AJCC v.8 does not take this into consideration, a modification of AJCC v.8 (mAJCC v.8), including “liver metastases: multiple liver lesions, with or without vascular invasion” as an “M1a stage,” is suggested. (Hepatology 2021;73:2311-2325).The authors of this article are members of the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and participate in the initiative European H2020 COST Action EURO-CHOLANGIO- NET granted by the COST Association (CA18122). The ENS-CCA registry is supported by the European Association for the Study of the Liver (EASL: Registry Grant Awards 2016 and 2019), the Spanish Association of Gastroenterology (AEG: RedCap access) and Incyte® (grant 2020). This article/publication is based upon work from COST Action European Cholangiocarcinoma Network, supported by COST (European Cooperation in Science and Technology). COST (European Cooperation in Science and Technology: www.cost.eu) is a funding agency for research and innovation networks. Drs. Angela Lamarca, Juan Valle and Jesus M. Banales also received funding from The Christie Charity and the European Union’s Horizon 2020 Research and Innovation Programme [grant number 825510, ESCALON]. Some of the authors of this manuscript are members of the European Reference Network (ERN)-Liver (Liver Tumor Working Group) (European H2020 project)

Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis

Cholangiocarcinoma (CCA) comprises a group of heterogeneous biliary cancers with dismal prognosis. The etiologies of most CCAs are unknown, but primary sclerosing cholangitis (PSC) is a risk factor. Non-invasive diagnosis of CCA is challenging and accurate biomarkers are lacking. We aimed to characterize the transcriptomic profile of serum and urine extracellular vesicles (EVs) from patients with CCA, PSC, ulcerative colitis (UC), and healthy individuals. Serum and urine EVs were isolated by serial ultracentrifugations and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting. EVs transcriptome was determined by Illumina gene expression array [messenger RNAs (mRNA) and non-coding RNAs (ncRNAs)]. Differential RNA profiles were found in serum and urine EVs from patients with CCA compared to control groups (disease and healthy), showing high diagnostic capacity. The comparison of the mRNA profiles of serum or urine EVs from patients with CCA with the transcriptome of tumor tissues from two cohorts of patients, CCA cells in vitro, and CCA cellsderived EVs, identified 105 and 39 commonly-altered transcripts, respectively. Gene ontology analysis indicated that most commonly-altered mRNAs participate in carcinogenic steps. Overall, patients with CCA present specific RNA profiles in EVs mirroring the tumor, and constituting novel promising liquid biopsy biomarkers

Primary biliary cholangitis: A tale of epigenetically-induced secretory failure?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune-related destruction of small to medium size intrahepatic bile ducts. The aetiology of PBC is unknown and its pathogenesis remains obscure. Both genetic variants and environmental factors have been linked to increased PBC susceptibility, with other alterations known to cooperate in disease pathobiology. Increasing evidence indicates the presence of epigenetic abnormalities in PBC, particularly alterations of cholangiocellular microRNAs (miRNAs or miRs). This review highlights and discusses the most relevant epigenetic alterations found in patients with PBC, focusing on the role of miR-506 in the promotion of cholestasis and immune activation

Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets

Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with results expected in the near future. Here, we summarize the key aspects of NAFLD pathogenesis and therapeutic targets in this frequent disorder, highlighting the most recent advances in the field and future research directions

Fatty Liver Disease, Metabolism and Alcohol Interplay: A Comprehensive Review

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and its incidence has been increasing in recent years because of the high prevalence of obesity and metabolic syndrome in the Western population. Alcohol-related liver disease (ArLD) is the most common cause of cirrhosis and constitutes the leading cause of cirrhosis-related deaths worldwide. Both NAFLD and ArLD constitute well-known causes of liver damage, with some similarities in their pathophysiology. For this reason, they can lead to the progression of liver disease, being responsible for a high proportion of liver-related events and liver-related deaths. Whether ArLD impacts the prognosis and progression of liver damage in patients with NAFLD is still a matter of debate. Nowadays, the synergistic deleterious effect of obesity and diabetes is clearly established in patients with ArLD and heavy alcohol consumption. However, it is still unknown whether low to moderate amounts of alcohol are good or bad for liver health. The measurement and identification of the possible synergistic deleterious effect of alcohol consumption in the assessment of patients with NAFLD is crucial for clinicians, since early intervention, advising abstinence and controlling cardiovascular risk factors would improve the prognosis of patients with both comorbidities. This article seeks to perform a comprehensive review of the pathophysiology of both disorders and measure the impact of alcohol consumption in patients with NAFLD

Liver metastases of intrahepatic cholangiocarcinoma: implications for a potential new staging system

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) with liver metastases (LM) are perceived to have a poor prognosis but the American Joint Committee on Cancer (AJCC) classifies them as early stage in the absence of lymph nodes or extrahepatic spread.METHODS: Patients with iCCA from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and Surveillance, Epidemiology, and End Results (SEER) registries with survival/staging (AJCCv.7) data were eligible. Modified staging was used (mAJCCv.7): Group-A: stages-I-III (excluding T2bN0); Group-B: stage-IVa (excluding T2bN1M0); Group-C: LM (T2bN0/1) and Group-D: stage-IVb (extra-hepatic metastases). Survival analysis (Kaplan Meier and Cox Regression) was performed in an ENS-CCA training cohort (TC) and findings internally [ENS-CCA (iVC)] and externally [SEER] validated. The aim was to assess if LM (Group-C) had a shorter survival compared to other early stages (Group-A). A modified version of AJCCv.8 (mAJCCv.8) is proposed.RESULTS: Total of 574 and 4,171 patients from the ENS-CCA and SEER registries were included. Following the new classification, 19.86% and 17.31% of patients from the ENS-CCA and SEER registries were reclassified into the Group-C, respectively. In the ENS-CCA TC, multivariable Cox Regression was adjusted for obesity (p-value 0.026) and performance status (p-value <0.001); patients in Group-C (HR 2.53 (95%CI 1.18-5.42); p-value 0.017) had a higher risk of death (vs Group-A). Findings were validated in the ENS-CCA iVC (HR 2.93 (95%CI 2.04-4.19); p-value <0.001) and in the SEER registry (HR of 1.88 (95%CI 1.68-2.09); p-value <0.001).CONCLUSIONS: iCCA LM have a worse outcome than other early stages. As AJCCv.8 does not take this into consideration, a modification of AJCC v.8 (mAJCCv.8) including "liver metastases: multiple liver lesions, with or without vascular invasion" as a novel "M1a stage" is suggested