Liver transplantation in the management of cholangiocarcinoma:Evolution and contemporary advances

Cholangiocarcinoma(CCA)is an aggressive malignancy arising from the biliary epithelium.It may occur at any location along the biliary tree with the perihilar area being the most common.Prognosis is poor with 5-year overall survival at less than 10%,typically due to unresectable disease at presentation.Radical surgical resection with clear margins offers a chance of cure in patients with resectable tumours,but is frequently not possible due to locally advanced disease.On the other hand,orthotopic liver transplantation(LT)allows for a radical and potentially curative resection for these patients,but has been historically controversial due to the limited supply of donor grafts and previously poor outcomes.In patients with perihilar CCA,within specific criteria and following the implementation of a protocol combining neoadjuvant chemoradiation and LT,excellent results have been achieved in the last decades,resulting in its increasing acceptance as an indication for LT and the standard of care in several centres with significant experience.However,in intrahepatic CCA,the role of LT remains controversial and owing to dismal previous results it is not an accepted indication.Nevertheless,more recent studies have demonstrated favourable results with LT in early intrahepatic CCA,indicating that,under defined criteria,its role may increase in the future.This review highlights the history and contemporary advances of LT in CCA,with particular focus on the improving outcomes of LT in intrahepatic and perihilar CCA and future perspectives.

Mechanisms of autophagy activation in endothelial cell and their targeting during normothermic machine liver perfusion

Ischaemia-reperfusion injury(IRI) is the leading cause of injury seen in the liver following transplantation. IRI also causes injury following liver surgery and haemodynamic shock. The first cells within the liver to be injured by IRI are the liver sinusoidal endothelial cells(LSEC). Recent evidence suggests that LSEC coordinate and regulates the livers response to a variety of injuries. It is becoming increasingly apparent that the cyto-protective cellular process of autophagy is a key regulator of IRI. In particular LSEC autophagy may be an essential gatekeeper to the development of IRI. The recent availability of liver perfusion devices has allowed for the therapeutic targeting of autophagy to reduce IRI. In particular normothermic machine liver perfusion(NMP-L) allow the delivery of pharmacological agents to donor livers whilst maintaining physiological temperature and hepatic flow rates. In this review we summarise the current understanding of endothelial autophagy and how this may be manipulated during NMP-L to reduce liver IRI.

Impact of machine perfusion of the liver on post-transplant biliary complications: A systematic review

AIM To review the clinical impact of machine perfusion(MP) of the liver on biliary complications post-transplantation, particularly ischaemic-type biliary lesions(ITBL). METHODS This systematic review was performed in accordance with the Preferred Reporting Systematic Reviews and MetaAnalysis(PRISMA) protocol. The following databases were searched: PubMed, MEDLINE and Scopus. The keyword "liver transplantation" was used in combination with the free term "machine perfusion". Clinical studies reporting results of transplantation of donor human livers following ex situ or in situ MP were analysed. Details relating to donor characteristics, recipients, technique of MP performed and post-operative biliary complications(ITBL, bile leak and anastomotic strictures) were critically analysed.RESULTS Fifteen articles were considered to fit the criteria for this review. Ex situ normothermic MP was used in 6 studies, ex situ hypothermic MP in 5 studies and the other 4 studies investigated in situ normothermic regional perfusion(NRP) and controlled oxygenated rewarming. MP techniques which have per se the potential to alleviate ischaemia-reperfusion injury: Such as hypothermic MP and NRP, have also reported lower rates of ITBL. Other biliary complications, such as biliary leak and anastomotic biliary strictures, are reported with similar incidences with all MP techniques. There is currently less clinical evidence available to support normothermic MP as a mitigator of biliary complications following liver transplantation. On the other hand, restoration of organ to full metabolism during normothermic MP allows assessment of hepatobiliary function before transplantation, although universally accepted criteria have yet to be validated.CONCLUSION MP of the liver has the potential to have a positive impact on post-transplant biliary complications, specifically ITBL, and expand extended criteria donor livers utilisation.

Stereotactic radiotherapy for intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma(iCCA)is an aggressive malignancy with an increasing incidence worldwide and poor prognosis,despite several advances and continuous efforts to develop effective treatments.Complete surgical resection is the mainstay of treatment and offers a potentially curative option,but is only possible in less than a third of patients,owing to advanced disease.Chemotherapy is a well-established treatment in the adjuvant and palliative setting,however,confers limited benefit.Conventional radiotherapy is challenging due to local toxicity.With recent advances in stereotactic ablative radiotherapy(SABR),it is now possible to focus ablative beams of radiotherapy precisely aimed at tumours to minimise damage to surrounding viscera.This review details the history,technical background and application of SABR to iCCA,with directions for future research suggested.